1.1
ETHICON
V Women’s Health & Urology A Prospective, Multi-centre Study to Evaluate the Clinical Performance of the GYNECARE PROLIFT +M* Pelvic Floor Repair System as a Device for Pelvic Organ Prolapse PROTOCOL 300-07-006 Final Version 2 29 October 2007
Document
Changes
Effective Date
Original
10 August 2007
Amendment #1
29 October 2007
Sponsor ETHICON Clinical Development & Medicat Affairs, wlth addresses at: ETHICON AJohnson & Johnson Company P.O. Box 151, Route 22 West Som ervlile, NJ 08876-0151
Johnson & Johnson Medical Ltd. Simpson Parkw’ Kirkton Campus Livingston EH54 OAB
CON FIDENTIALITY STATEMENT The information in this document contains trade secrets and commercial Information that are privileged or confideritial and may not be dlsciosed unless sucti disclosure Is ,-equlred by applicable law or regulations. In any event, persons to wtiom the Information is disciosed must be Infornied that the information Is privileged or confidentia! and may not be fuither disciosed ly them. These restrictions on disciosure Will apply equally to all future information suppiled to you, whlch Is indicated asprivlleged orcorifidential. *
Trademark
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A Prospective, Multi-centre Study to Evaluate the Clinical Performance of the GYNECARE PROLIFT +M* PeMc Floor Repair System as a Device for Pelvic Organ Prolapse
PROTOCOL 300.07-006 Amendment #1 Final Verslon 2 29 October 2007
1 O.2.e
ETHICON
1O.2.e
Name of Meaicai uirector i ypea or Printed)
Compliance Statement This study wDi be conducted In accordance with EN ISO 14155 and the Dedaratlon of Helsinki.
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A Prospective, Multi-centre Study to Evaluate the Clinical Performance of the GYNECARE PROLJFT +M* Pelvic Floor Repair System as a Device for Pelvic Organ Prolapse PROTOCOL 300-07-006 Amendment # 1 FinalVersion2
29 October 2007
c
INVESTIGATOR AGREEMENT
1 have read this protocot and agree to conduct the study as outlined herein. 1 will provide copies of the protocol and all pertinent information to all individuals responsible to me who assist in the conduct of this study. 1 will discuss this material with them to ensure they are fully informed regarding the device and the conduct of the study.
Principal Investigator’s Signature
C
Date
Name of Principal Investigator (Typed or Printed)
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TABLE OF CONTENTS
INVESTIGATOR AGREEMENT
3
SYNOPSIS
7
1.
INTRODUCTION
13
2.
OBJECTIVES
16
3.
OVERVIEW OF STUDY DESIGN
16
4.
STUDY POPULATION
4.1. 4.2. 4.3.
GENERAL CONSIDERATIONS INCLUS)ON CRITERIA ExcLusioN CRITERIA
17 17 17 17
5.
RANDOMISATION AND BLINDING
18 18 18
6.
STUDYDEVICES
6.1.
THE GYNECARE PROLIFT
7. 7.1
STUDY EVALUATIONS
7.2. 7.3.
+
M* PELVIC FLOORREPAIR SYSTE
STUDYPROCEDURESBYVISIT 7.1.1. Overview 7.1.2. Visit 1 Pre-Surgery Evaluation (Screening) 7.1.3. Visit 2 Surgical Procedure 7.1.4. Visit 3 Post-Surgery Evaluation 7.1.5. Visit4 Post-Surgery Evaluatiori (1 month post-procedure) 7.1.6. Visit 5 Post-Surgery Evaluation (3 Months Post Procedure) 7.1.7 Visit 6 Post-Surgery Evaluation (12- Months Post Procedure) 7.1.8 Visit 7 Post-Surgery Evaluation (24- Months Post Procedure) 7.1.9 Visit 8 Post-Surgery Evaluation (36- Months Post Procedure) EARLY WTHDRAWAL EVALUATIONS 7.3.1. Sample Collection and Handling 7.3.2. Analytical Procedures 7.3.3. Subject questionnaires
8.
SUBJECT COMPLETIONIEARLY TEINATION
8.1. 8.2.
COMPLETION EARLY TERMINATION OF SUBJECT INVOLVEMENT
9.
STATISTICAL METHODS
9.1. 9.2.
SAMPLE SIzE DETERMINATION PLANNEDANALYSIS 9.2.1. Analysis Sets 9.2.2. Effectiveness 9.2.2.1 Primary Effectiveness Vanables/Critena 9.2.2.2 Secondary Effectiveness Variables/Criteria 9.2.3 SAFETY 9.2.3.1 SAFETY VARIABLESICRITERIA 9.2.3.2 METHODSOFANALYSIS
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18 18 18 18 19 20 20 21 21 22 22 22 23 23 23 23
24 24 24 25 25 25 25 25 25 26 27 27 27
9.2.4
Interim and Follow-up Analyses
9.2.5
HANDLING OF MISSING DATA
.27 27
10.
ADVERSEEVENTS
10.1. 10.2.
10.6 10.7 10.8
ADVERSEEVENT SERIOUSADVERSEEVENT(SAE) SERIOUS AD VERSE DEVICE EVENT (SADE) ADVERSEEVENT SEVERITYCATEGORIES ANTICIPATED ADVERSE EVENTS RELATED TO THE PROCEDURE ANTICIPATED ?DVERSE DEVICE EFFECTS AD VERSE EVENT COLLECTION ADVERSEEVENTREPORTING
28 28 29 29 29 30 30 30
11.
COMPLAINT REPORTING
31
12.
CONTACTING SPONSOR
31
13. 13.1.1 13.1.2 13.1.3 13.1.4 13.1.5 13.1.6 13.1.7
CLINICAL StJPPLIES INFORMATION PHYSICAL DESCRIPTION OF STUDY DEVICE GYNECAREGYNEMESHM Total Mesh Implant Anterior Mesh Implant Posterior Mesh Implant GYNECAREPROLIFT*Guide GYNECARE PROLIFT* Cannula GYNECARE PROLIFT* Retrieval Device
13.2
PACKAGING AND LABELLING
13.2.1 Packaging 13.2.2 Labels And Labelling Instructions 13.3 DEVICE ADCOUNTABILITY
31 31 31 31 32 32 32 32 32 32 33 33 33
14.
TRIAL-SPECIFIC SUPPLIES
33
15.
ETHICS
10.3. 10.4
10.5
13.1.
15.1. 15.2. 15.3.
28
33 INVESTIGATORRESPONSIBILITIES 33 MEDICAL ETHICS COMMITTEE OR INSTiTUTIONAL REvIEw BaARD (MEC/IRB)....33 INFORMED CONSENT
34
16.
ADMINISTRATIVE REQUIREMENTS
16.1.
35
16.2.
PROTOCOL MODIFICATIONS REQUIRED DOCUMENTATION
16.3
Confidentiality of Subject Records
35 35 36 36 36 36 37 37 37 37 38 38
16.4 RECORD RETENTION 16.4.1 Case Report Form Completion 16.4.2 Study Completion/Termination 16.4.2.1 Study Completion 16.4.2.2 StudyTermination 16.4.3 Monitoring 16.4.4 Data Quality Assurance 16.4.5 On-Site Audits 16.4.6 Use Of Information And Publication Protocol: 30OO7-006 Firial Verslon 2; 29 October 2007
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53
16.5
REFERENCES
.39
Appendix 1
40
Appendix2
41
Appendix 3
42
Appendix4
43
Appendix 5
45
Appendix 6
50
Appendix7
51
0
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A Prospective, Multi-centre Study to Evaluate the Cflnical Performance of the GYNECARE PROLIFT +M* Pelvic Floor Repair System as a Device for Pelvic Organ Prolapse PROTOCOL 300-07-006 SYNOPSIS OBJECTIVES: The pnmary objective of this study is to evaluate the anatomical success of the GYNECARE PROLIFT + M* system in women with symptomatic ICS POP-Q Stage III or IV, requiring surgical correction of pelvic organ prolapse (POP). Secondary objectives include the evaluation of patient reported outcomes (PFDI-20, PFIQ-7, PISQ-12, Euro-QOL), Iength of procedure, length of hospital stay, post-operative pain, return to normal activities, and pen- and post-operative complications. OVERVIEW OF STUDY DESIGN: This study is a prospective, multi-centre, single-arm design. Subjects will be assessed prior to surgery, during and after the procedure, and at 1, 3, 12, 24 and 36 months post-procedure. STUDY SITES: The study will include approximately 10 study sites in Europe (e.g. France, Germany, Belgium, the Netherlands) and the US. Each investigator will have extensive experience with the use of the GYNECARE PROLIFT* Pelvic Floor Repair System. REGULATORY STATUS: 510k Clearance (Class II, US); pre-CE Mark in Europe (Class III).
C.
STUDY Atotal of 125 subjects will be enrolled to allow for approximately 118 evaluable subjects at 12 months. Evaluable subjects will be defined as those providing baseline data and having POP-Q evaluation completed at the 12-month visit. To be eNgible, female subjects must meet the following inclusion critena: 1. Candidates with symptomatic pelvic organ prolapse of ICS POP-Q Stage III or IV, suitable for surgical repair. Perineal repair, vaginal hysterectomy and/or mid urethral sling procedures for incontinence may be performed concurrently. 2. Agel8years.
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3. Agrees to participate in the study, including completion of all studyrelated procedures, evaluations and questionnaires, and documents this agreement by signing the Ethics Committee / IRB approved informed consent. Subjects who meet any of the following criteria will be excluded from participating in the study: 1. Additional surgical intervention for POP repair concurrent to the Gynecare Prolift +M procedure (e.g. paravaginal repair, sacrocolpopexy, colporraphy in a non-Gynecare Prolift+M treated compartment). 2. Previous repair of pelvic organ prolapse involving insertion of mesh. 3. Previous hysterectomy within 6 months of scheduled surgery. 4. Experimental drug or experimental medical devico within 3 months prior to the planned procedure. 5. Active genital, urinary or systemic infection at the time of the surgical procedure. Surgery may be delayed in such subjects until the infection is cleared. 6. Coagulation disorder or on therapeutic anticoagulant therapy at the time of surgery. 7. History of any pelvic radiation therapy. 8. History of chemotherapy within 6 months of the planned procedure. 9. Systemic disease known to affect bladder or bowel function (e.g. Parkinson’s disease, multiple sclerosis, spina bifida, spinal cord injury ortrauma). 10. Current evaluation or treatment for chronic pelvic pain (e.g. interstitial cystitis, endometriosis, coccydynia, vulvadynia). 11. Nursing or pregnant or intends future pregnancy. 12. In the investigator’s opinion, any medical condition or psychiatric illness that could potentially be life threatening or affect their ability to complete the study visits according to this protocol. STUDY DEVICE: The GYNECARE PROLIFT +M* Pelvic Floor Repair System will be used for all study subjects. Depending on the site of the prolapse, the repair can be anteror, posterior or total. The prolapse repair is achieved by the placement of mesh implant(s) via a vaginal approach. The pre-shaped mesh implants are made of GYNECARE GYNEMESH M, which is a composite mesh, comprising two components of approximately equal parts of absorbable Polyglecaprone 25 monofilament fiber and non-absorbable polypropylene monofilament flber. Following resorption of the absorbable component, the weight of the remaining polypropylene will be approximately 28g1m , compared to 45g/m 2 2 for Gynemesh PS.
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Hysterectomy or uterine conservation can be combined with this procedure. Tension-free support procedures using mid-urethral polypropylene sling for the treatment of stress urinary incontinence may be Ferformed concurrent to placement of the GYNECARE PROLIFT +M* system. PRIMARY ENDPO1NT: There will be one primary effectiveness end-point: •
POP-Q score at 12 months post-procedure. Success will be determined by achievement of a POP-Q score of ICS Stage =1, in the treated compartment, without further surgical re intervention for POP in that compartment.
SECONDARY ENDPOINTS: • • •
c
Summary of ICS Stages al 3, 24 and 36 month visits. Summary of treated compartment ICS POP-Q stage at 3, 12, 24 and 36 months. Proportion of subjects with the leading edge within the hymen (i.e. all POP-Q values to be less than 0) and without further re-intervention for POP at 12, 24 and 36 months. • Incidence of de novo prolapse as defined as occurrence of a post-operative prolapse (ICS Stage II or greater) only in the untreated compartment, provided there was no pre-operative defect in that compartment (Le. ICS Stage 0 or 1). • Maan scores and change from baseline in PFDI-20 scores at 3, 12, 24 and 36-month visits inciuding sub scores (POPDI, CRADI and UDI). • Proportion of subjects with a change from baseline 45 points in the PFDI-20 summary score al 12, 24 and 36 months. • Mean scores and change from baseline In PFIQ-7 at 3, 12, 24 and 36 month visits including sub-scores (POPIQ, CRAIQ and UIQ). • Proportion of subjects with a change from baseline 36 points in the PFIQ -7 summary score at 12, 24 and 36 months. • Days to return to normal activities (walking, driving, work, household activities and sexual intercourse). • EuroQol (EQ-5D health State) mean change from baseline al 3 and 12 months visit (overall using the EQ-5D index score, and also for each individual item). • In subjec sexually active at baseline, assessment of sexual function using PISQ-12 assessed at 12, 24 and 36 month visits (mean scores and change from baseline). • Incidence of new onset dyspareunia, resolution or continuance of pre-existing dyspareunia • Incidence of mesh contraction, as detem,ined by pain on palpation of mesh during pelvic examination at3, 12, 24 and 36 months. • Incidence of vaginal wall stiffness, as determined by the investigator on physical examination at 3, 12, 24 and 36 months. • Total time in the operating room. Protocol: 300.07-006 Fin al Version 2; 29 October 2007
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• • • • •
Length of procedure (from time of first incision to time of last suture). Nights in hospital (from date of admission to date of discharge; based on actual data and “readiness for discharge”). Pain score 24 hours post surgery and at the 1 month visit, measurecl using Visual Analog Scale (VAS). Subject global impression assessed on a 5 point Likert scale at 3, 12, 24 and 36-morith visits. Surgical satisfaction question assessed at 3 and 12 month visits.
SAFETY: • Adverse events. •
Determination of any exposures/erosions including location (exposure is any visible mesh or mesh that can be determineci to be exposed by palpation but is not visible).
•
Haemoglobin and haematocrit
STATISTICAL METHODS: The full analysis will be performed once data are available for all subjects at 12 months, and fo!low-up analysis will be performed once data are available for all subjects at 24 and 36 months. An interim analysis will be performed on the 3-nionth data, comprised of a minimum of 60 subjects.. The 3-month POP-Q data will be summarised, however, the success criterton will not be applied. All other parameters will be summarised as applicable. As the primary ertdpoint is only relevant at 12 months there are no stopping rules, although alpha will be arbitrarily assigned 0.002 (two tailed).
(
As this is not a comparative study, one-sided 97.6% (adjusting for an interim analysis) confidence intervals (Cl) will be estimated for recurrence of POP-Q (defined as Stage II or surgical re-intervention) at 12 months. Whilst this is not a hypothesis testing study, should the upper 97.6% one-tailed Cl not exceed 20%, this will be considered a good result. The following primary endpoint will be analysed using the Per Protocol Set: POP-Q score at 12 months post-procedure. Success (overall) will be determined by achievement of a POP-Q score of ICS Stage =1, without further re-intervention for POP. With 118 evaluable subjects there needs to be 15 or less recurrences for the 97.6% upper Cl to fail at or below 20.0% using exact binomial confidence limits. TIME AND EVENTS SCHEDULE: The time and events schedule for this study is shown on the following page.
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A Prospective, Multi-centre Study to Evaluate the Clinical Performance of the GYNECARE PROLIFT +M* Pelvic Floor Repair System as a Device for PeMc Organ Prolapse LIST OF ABBREVIATIONS AE ATFP Cl CRF DCF EuroQol FAS GCP Hb Hot HRT ICS IFU IRB LOCF MEC MedDRA PFDI —20 PFIQ —7 PISO —12 POP POP-Q PPS SAE VAS__—
Adverse event Arcus teridineus fascia pelvis Confidence Interval Case Report Form Data clarification form Standardized instrument to measure health outcome Full Analysis Set Good Clinical Practice Hemoglobin Haematocrit Horrnone Replacement Therapy International Continence Society lnstnictions For Use Institutional Roview Board Last observation carried forward Medical Ethics Committee Medical Dictionary for Regulatory Activities Pelvic Floor Distress Inventory Short form of Pelvic Floor Impact Questionnaire Short form of PeMc Organ ProlapselUrinary Incontinence Sexual Function Questionnaire Pelvic Organ Prolapse Pelvic Organ Prolapse Quantification system Per Protocol Set Serlous adverse event Visual Analogue Scale
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1. INTRODUCTION Pelvic organ prolapse or vaginal wall prolapse are general terms used to describe varlous clinical conditions that are associated with pelvic floor relaxation in female subjects. The clinical manifestations inciude:
• • •
Anterior vaginal prolapse (medial, lateral, andlor apical cystocele) Posterior vaginal wall prolapse (rectocele andlor enterocele) Vault prolapse (enterocele, uterine prolapse, and vaginal vault prolapse)
Pelvic organ prolapse is thought to result from a stretching, weakening or teaning of the soft tissue structures that support the pelvic organs. These tissues become compromised as a result of a weakened or damaged levator ani muscie group. This muscle group is the platform at the base of the pelvis responsible for supporting the pelvic organs. It works with the connective tissues to support these organs. As the levator ani is damaged and drops, the opening between the levator ani is widened. lntra-abdominal forces are then relatively unopposed by the weakened muscle. This increases forces applied to the connective tissue support structures, which resuits in their teaning or stretching. Risk factors for pelvic organ prolapse inciude vaginal panty, neuropathy, obesity, chronic Valsalva, connective tissue disorders, prior surgery, estrogen status and advancing age . Of the factors identitled, 4 3 2 ’ 1 vaginal panty and its associated neuropathy appear to play the biggest role in pelvic floor disorders Damage to the nerves supplying the levatorani during childbirth result in weakening . 2 of muscle and subsequent prolapse of the organs. Surgical correction of these problems is a major health care issue for women. An analysis of members of a lange health maintenance organization estimated the lifetime risk of 11.1% of at least one operation for pelvic organ prolapse and urinary incontinence with a re-operation rate of 29.2%. These numbers have been confirmed in other studies . 6 Management Options Non-surgical interventions for prolapse management include pelvic tloor exercises and pessany support. Surgical options are many, made more challenging as multiple weakened regions often occur in a subject and incomplete correction of any may lead to worsening of the others. The surgical procedures may involve tightening and reinforcing of weakened tissue, suspension of unsupported structures or a combination of both. The tighteninglreinforcing and suspension procedure may utilize several matenials including: •
suture alone
•
autologous tissue
•
cadavenic material
•
allograft matenial
•
synthetic absorbable mesh
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•
synthetic permanent mesh
Synthetic meshes, first used for abdominal wall hernia repairs, are often produced from matenals originally used for sutures. They are able to provide support where autologous tissues are not adequate, but they do add the risks of erosion and rejection . Synthetic meshes have 7 been used with increasing frequency in gynecologic surgery over the past 30 years . 9 Reinforcement of tissue is sought because of the weakened state of the subject’s own tissue. These grafts may be placed using an abdominal or vaginat approach. Potypropylene mesh has been the most widely used mesh in gynecologic surgery incuding many types of pelvic floor repair procedures .
ETHICON developed a modifled PROLENE Mesh identifled as GYNECARE GYNEMESH PROLENE Soft (Polypropylene) Mesh (PS), a reduced density construction PROLENE Polypropylene Mesh. The product is fabricated of knitted monofllaments of natural and blue pigmented polypropylene produced to be more flexible than earlier versions of polypropylene mesh. The more flexible material is intended to offer improved intraoperative handling for pelvic organ prolapse repair procedures. Less total polypropylene is present per unit area when compared to traditional PROLENE mesh. One of the major issues with the use of mesh for POP repair has been the lack of standardization in surgical technique. Between 1999 and 2003, a group of French uro gynecologists worked together to develop a standardized mesh shape that could be placed consistently through the vagirial route. The result of the group’s work was the creation of the Trans-Vaginal Mesh technique (TVM). TVM was the precursor to the GYNECARE Prolift system for pelvic floor repair, and was the first standardized kit for POP repair. The GYNECARE PROLIFT system has been available for use since 2005, and by end of 2006, approximately 63,000 devices have been used. Overall the complication rates appear to be low based on those reported through ori Medical Device Vigilance Reporting (MDVR) system within ETHICON, and are detailed in the table below:
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MDVR DATA to end of 2006 Complication # of Complaints Injury Bladder Bowel Rectum Vascular/haematoma Nerve Fistula Vesicovaginal Rectovaginal Exposure Pain Dyspareunia Retention / Voiding difficulty
US 2 1 4 8 0 1 1 11 4 1 4
Ex-US 2 0 1 2 1 0 0 4 0 0 0
Total Complalnts 4 1 5 10 1 1 1 15 4 1 4
The longest-term follow-up data available is with the precursor to the Prolift system, known as TVM (Trans-Vaginal Mesh), with anatomical fallure rates of approximately 15% at 12 months. There are numerous ongoing research studies to evaluate the long-term effecti veness of Prolift compared with other types of repair, hcluding non-mesh repairs and mesh repairs such as sacrocolpopexy. Although Prolift signiflcantly reduces recurrences compared to traditional POP repairs, it can lead to other complications such as mesh exposure and mesh retraction. Mesh exposure is a common complication, which can be managed by excision and closure. Mesh retraction (“shrinkage”) is Iess common but it is considered more serious. It can cause vaginal anatomic distortion, which may eventually have a negative impact on sexual function. ts treatment is difficult. Additionally, the scar plate that forms with in-growth of tissue into the mesh can cause stiffness of the vagina that further impacts sexual function in a negative manne r. In an effort to minimize these complications, a Iighter-weight alternative mesh for Prolift* has been introduced. This mesh replaces the Gynecare Gynemesh PS used within the Gynecare Prolift* Pelvic Floor Repair system. The ULTRAPRO” Mesh is a composite mesh, comprising two components of approximately equal parts of absorbable Polyglecaprone-25 monofilament fiber and non-absorbable polypropylene monofilament fiber. Following resorption of the absorbable component, the weight of the remaining polypropylene would be approximately 28g/m , compared to 45g1m 2 2f Gynernesh PS. Pre-clinical evaluation in a porcine ventral hernia model demonstrated that ULTRAPR maintains a comparable mean burst strength to Gynemesh PS, whilst was loss stuff after tissue incorporatiori (Cobb et al).
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ULTRAPRO is currently indicated for tissue reinforcement and long lasting stabilization of fascial structures of the abdominal wall. However, some gynecologists have used it for POP repair though the information gathered from these cases is limited due to: the small number of cases, the mesh was placed from an abdominal rather than vaginal approach, the size of mesh used was small relative to the current irttended use. In order to differentiate between the use of ULTRAPRO in hernia repair, it will be known as GYNECARE GYNEMESH M for use in POP repair. Rationale for Clinical Evaluation The development of the GYNECARE PROLIFT + M* system provides a composite lighter weight mesh compared to the original PROLIFT system which uses Gynemesh PS. Following resorption of the absorbable component, the weight of the remaining polypropylene will be approximately 28g/m , compared to 45g/m 2 2 for Gynemesh PS. The purpose of this clinical study is to evaluate the clinical performance of the PROLIFT system with the new (ighter-weigh t mesh.
2. OBJECT IVES The primary objective of this study is to evaluate the anatomical success of the GYNECARE PROLIFT + M* system in women with symptomatic ICS POP-Q Stage III or IV, requiring surgical correction of pelvic organ prolapse (POP). There will be one primary effectiveness endpoint: •
(
POP-Q score at 12 months post-procedure. Success will be determined by achievement of a POP-Q score of ICS Stage 1, in the treated compartment, without further surgical re-intervention for POP in that compartment.
Secondary objectives inciude the evaluation of subject reported outcomes (PFDI-20, PFIQ-7, PISQ-12, Euro-QOL), length of procedure, length of hospital stay, post-operative pain, return to normal activities, and pen- and post-operative complications. 3. OVERVIEW OF STUDY DESIGN This study is a prospective, multi-centre, single-arm design. Subjects will be assessed prior to surgery, during and after the procedure, and at 1, 3, 12, 24 and 36 months post-procedure. Analyses will be carried out at 3 rnonths (interim on a minimum of 60 subjects) and 12 months (primary), with a follow-up analysis at 24 and 36 months. A total of 125 subjects will be enrolled to allow for approximately 118 evaluable subjects at 12 months. Evaluable subjects will be defined as those providing baseline data and having POP-Q evaluation corn pleted at the 1 2-month visit.
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4. 4.1.
STUDY POPULATION GENERAL CONSIDERATIONS
The study population will include women with POP who are considered suitable for mesh repair. The specific inciusion and exclusion criteria for enrolling subjects in this study are described in the following sections. The investigator is expected to offer the opportunity to participate In the study to all subjects meeting the study entry criteria. 4.2. INciusloN CRITERIA To be eligible, female subjects must be diagriosed with POP and meet the following criteria: 1. Candidates with symptomatic pelvic organ prolapse of (CS POP-Q Stage III or IV, suitable for surgical repair. Perineal repair, vaginal hysterectomy and/or mid urethral sling procedures for incontinence may be performed concurrently. 2. Agel8years.
3. Agrees to participate in the study, inciuding completion of all studyrelated procedures, evaluations and questionnaires, and documents this agreement by signing the Ethics Committee / IRB approved informed consent. 4.3. ExcLusioN CRITERIA Potential subjects who meet any of the following criteria will be excluded from participating in the study: 1.
Additional surgical intervention for POP repair concurrent to the Gynecare Prolift 4-M procedure (e.g. paravaginal repair, sacrocolpopexy, colporraphy in a non-Gynecare Prolift+M treated compartment)
2. Previous repair of pelvic organ prolapse involving insertion of mesh. (
3. Previous hysterectomy within 6 months of scheduled surgery. 4. Experimental drug or experimental medical device within 3 months prior to the planned procedure. 5. Active genital, urinary or systemic infection at the time of the surgical procedure. Surgery may be delayed in such subjects until the infection is cleared. 6. Coagulation disorder or on therapeutic anticoagulant therapy at the time of surgery. 7.
History of any pelvic radiation therapy.
8.
History of chemotherapy within 6 months of the planned procedure.
9.
Systemic disease known to affect bladder or bowel function (e.g. Parkinson’s disease, multiple sclerosis, spina bifida, spinal cord injury or trauma).
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10. Current evaluation or treatment for chronic pelvic pain (e.g. interstitial cystitis, endometriosis, coccydynia, vulvadynia). 11. Nursing or pregnant or intends future pregnancy. 12. In the investigator’s opinion, any medical condition or psychiatric illness that could potentially be life threatoning or affect their ability to complete the study visits according to this protocol. 5. RANDOMISATION AND BUNDING As this is a single-arm study, randomisation is not applicable. All subjects will receive GYNECARE PROLIFT + M*. The surgeon and subjects will not be blinded to the treatment. 6. STUDY DEVICES 6.1. T GYNECARE PROLIFT + M 4 PELVIC FLOOR REPAIR SYSTEM GYNECARE PROLIFT + M* Pelvic Floor Repair System is indicated for surgical repair of POP. It comprises mesh imptants constructed of GYNECARE GYNEMESH M, comprising two components of absorbable polyglecaprone-25 monotilament fiber and non-absorbable polypropylene monofilament fiber. The Instructions for Use (IFU) should be followed for all study procedures. STUDY EVALUATIONS
7. 7.1
Study Procedures By Visit
7.1.1. OVERVIEW The Time and Events Schedule inciuded in the Synopsis summarizes the frequency and timing of the various effectiveness and safety measurements.
All consented subjects who are eligible for the study and successfully complete screening (Visit 1) will be scheduled for the surgical procedure (Visit 2). The post-operative visit (Visit 3) will be on the day of discharge, which is dependent on normal clinical practice atthe site. The follow-up visits will include Visit4 (1 month post surgery), Visit5 (3 months post surgery), Visit 6 (12 months post surgery). Visit 7 (24 months post surgery) and Visit 8 (36 months post surgery). 7.1.2.
VIsIT 1 PRE-SURGERY EVALUATION (SCREENING)
Prospective subjects will be screened within 90 days prior to surgery. Prior to any study related procedures, subjects will be fully iriformed of all aspects of the study, including the beriefits, risks and constraints of the study, and will be asked to sign a Consent Form. The following information will be performed and recorded at the screening visit: •
Iriformed corisent process.
•
Review of lnclusion / Exclusion criteria to confirm subject eligibility. In the event that a subject is not eligible, the reason will be documented on the worksheet and scieening log.
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•
Allocation of a 5-digit ID number to each subject, which will be recorded on all study-specific documents. As a subject is screened, her initials and date of birth will be added to the Subject Identification Log.
•
Documentation of demography (date of birth, ethnic origin) and subject height and weight. Documentation of relevant medical and surgical history. This will include connective tissue disorders, constipation, chronic bronchitis, previous POP repair, previous incontinence treatment, number of pregnancies and mode of delivery i.e. vaginal or C-section, details of hysterectomy (if applicable), menopausal status and details of current HRT treatments. Physical exam.
•
• • •
•
Pelvic exam inciuding baseline assessment of pain on palpation and vaginal wall stiffness. POP-Q assessment by an independent, appropnately qualified assessor, as determined by the Principal Investigator. In instances where this is not possible, the Principal Investigator may perform POP-Q assessment. The site must use the CD —Rom provided by the sponsor to calculate the overall prolapse stage. Completion of PFIQ-7, PISQ-12, PFDI-20 and Euro-QOL questionnaire responses by the subject.
7.1.3.
Visrr 2 SURGICAL PROCEDURE
(Visit 2 should occur wlthin 90 days after screenlng)
•
Date and time of hospital admission
•
Pre-procedure pregnancy test within 24 hours pilor to the procedure. • The surgeon should follow the Instructions for Use (IFU) for the GYNECARE PROLIFT system. The following activities will be performed prior to or during the procedure: (,j
+
M*
•
Confirm inclusion/exclusion criteria.
•
Confirm medical/surgical history.
•
Pre-procedure blood count: haemoglobin (Hb) and haematocrit [HCT] can be within 21 days pnor to procedure.
•
Type of anaesthesia used (i.e. general or regional).
•
Details cf procedure type (i.e. anterior, posterior or total GYNECARE PROLIFT system).
•
Total time in the operating room. Start and finish time of procedure, defined as first incision to last suture, respectively. Details of concurrent procedures (e.g. mid-urethral sling procedure for incontinence, vaginal hysterectomy).
• • •
Perform cystoscopy for anterior GYNECARE PROLIFT+M* and detail resuits.
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+
M*
• •
Details of prophylactic oral and vaginal oestrogen and antibiotics. Intra operative adverse events.
7.1.4.
VIsIT 3 POST-SURGERYEVAL.UATION
(Subject Visit
—
Dlscharge date)
From the end of the procedure until the time of hospital discharge, the following data will be recorcied: •
Pain VAS, 24 hours post op, or at time of discharge, whichever occurs first, noting time of assessment.
•
Haemoglobin (Hb) and haematocrit (HCT) on post-operative day 1. Details of post-procedure analgesia, prophylactic antibiotic regimen, and prophylactic use of oestrogen.
• • • •
Date of removal of catheter placed at time of surgery. Date and time of hospital dischaie.
•
Date when subject is ready for discharge, if different from actual date of discharge. Prior to discharge, the subject will be provided with a diary card to complete dates when they stopped taking analgesia for post-operative pain, retumed to normal activities ie. walking, drivirig, working, household activities, and sexual intercourse. These will be provided to the investigator at subsequent follow up visits. Subjects will be instructed to avoid strenuous activity for a period of 3 to 4 weeks, and avoid sexual intercourse for at leest four weeks following surgery. Pelvic floor exercises may be recommenced based on the surgeon’s guidance. Complete Gynaecologic Intervention form if necessary
•
Adverse Events.
•
•
7.1.5. Visir 4 POST-SURGERY EVALUATION
(Visit window +1- 14 days)
(1 MONTH POST-PROCEDUR
The following assessments will be recorded at the clinical follow-up visit approximately 1 month following surgery: •
PainVAS.
•
Date of removal of
• • •
catheter placed at surgery (if not previously recorded). Documentation of any intermittent catheterisations. Evaluation of subject voidirig function. Return to usual activities questionnaire the diary card will be checked for completeness and dates transcribed into the CRF. 1f the subject has not retumed to all activities, they will be asked to continue to carry the card until all applicable dates have been completed.
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•
Pelvic Exam
•
Complete Gynaecologic Intervention form 1f necessary
•
Adverse Events.
7.1.6. VISIT 5 POST-SURGERY EVALUATION (3 MONTHS POST PROCEDURE) (Visit window +1- 14 days)
The following assessments will be recorded at the clinical follow-up visit approximately 3 months following surgery: •
•
Investigator to perfomi a pelvic examination for incidence of mesh contraction and vaginal wall stiffness determiried by pain on ntle palpation of mesh and its attachment points during pelvic and or rectal examination. Evaluation of subjeot voiding function. Return to usual activities questionnaire should be collected if any activity did not resume by the 1-month visit. Subject to record EuroQol, PFIQ-7, PISQ-12, and PFDI-20, surgical satisfaction questionriaire responses, and the global patient impression question. POP-Q assessment by an independent, appropriately qualified assessor, as determined by the Principal Investigator. In instances where this is not possible, the Principal Investigator may perform POP-Q assessment. The site must use the CD —Rom provided by the sponsor to calculate the overall prolapse stage. Complete Gynaecologic Intervention form 1f necessary.
•
Adverse Ents.
• • • •
7.1.7
VISIT 6 POST-SURGERY EVALUATION
(12- MONTHS POST PROCEDURE)
(VIsIt window +1-28 days)
(
The following assessments will be recorded at the clinical follow-up vislt approximately 12 months following surgery: •
• • •
•
Investigator to perform a pelvic examination for incidence of mesh contraction and vaginal wall stiffness determined by pain on gentle palpation of mesh and its attachment points during pelvic and or rectal examination. Return to usual activities questionnaire should be collected 1f any activity did not resume by the 3-month visit. Subject to record EuroQol, PFIQ-7, PISQ-12, and PFDF2O and surgical satisfaction questionnaire responses and the global patient impression question. POP-Q assessment by an independent, appropriately qualified assessor, as determined by the Principal lnvestigator. In instances where this is not possible, the Principal Investigator may perform POP-Q assessment. The site must use the CD —Rom provided by the sponsor to calculate the overall prolapse stage. Complete Gynaecoiogic Inter-vention form 1f necessary
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•
Adverse Events.
7.1.8
VIsIT 7 POST-SURGERY EVALUATION (24.. MONTHS POST PROCEDURE)
(Visit window +1.. 56 days)
The following assessments wiN be recorded at the clinical follow-up visit approximately 24 months following surgery: •
•
•
() • •
Investigator to perform a pelvic examination for incidence of mesh contraction and vaginal wall stiffness determined by pain on gentle palpation of mesh during pelvic and or rectal examination. Subject to record PFIQ-7, PISQ-12, and PFD2O, surgical satisfaction questionnaire responses and the global patient impression question.
POP-Q assessment by an Independent, appropnately qualified assessor, as determined by the Principal Investigator. In instances where this is not possible, the Principal Investigator may perform POP-Q assessment. The site must use the CD —Rom provided by the sponsor to calculate the overall prolapse stage. Complete Gynaecologic Intervention form if necessary Adverse Events.
7.1.9 VISIT 8 POST-SURGERY EVALUATION (36- MONTHS POST PROCEDURE) (VIsIt wlndow +1- 90 days) The following assessments will be recorded at the clinical follow-up visit approximately 36 months following surgery: •
• •
• • 7.2.
Investigator to perform a pelvic examination for incidence of mesh contraction and vaginal wall stiffness determined by pain on gentle palpation of mesh during pelvic and or rectal examination. Subject to record PFIQ-7, PISQ-12, and PFD2O, surgical satisfaction questionnaire responses and the global patient impression question. POP-Q assessment by ari independent, appropnately qualified assessor, as deterrnined by the Principal Investigator. In instances where this is not possible, the Principal Investigator may perform POP-Q assessment. The site must use the CD —Ram provided by the sponsor to calculate the overall prolapse stage. Complete Gynaecologic Interverition form if necessary Adverse Events. EARLY WITHDRAWAL
1f a subject wants to withdraw early from the study, the study completion page should be completed. 1f the withdrawal occurs after the 1-month visit every attempt should be made to encourage the patient to return for an unscheduled visit to complete all assessments required for the 12- month visit.
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7.3. 7.3.1.
EVALUATIONS SAMPLE COLLECTION AND HANDLING Pre and post-operative blood samples for Hb and Hct will be collected and analysed at the
investigational site’s local laboratory. Handling of samples and assessment assays will be canied out using local laboratory procedures. Lab normal ranges and accreditation of the hospital lab will be obtained for all sites. 7.3.2. ANALYTICAL PROCEDURES Pelvic Organ Prolapse Quantification system (POP-Q) The standardised POP-Q will be used for measuring the required anatomie landmarks and distances required for calculation of the stages of POP-Q (Aa, Ba, C, Ap, Bp, TVL, gh, pb). The POP-Q assessment will be performed by an independent, appropriately qualified assessor, as determined by the Principal Investigator. In instances where this is not possible, the PrincipaT Investigator may perform POP-Q assessment. The site must use the CD —Rom provided by the sponsor to calculate the overall prolapse stage. During the POP-Q examination, the POP-Q assessors should ensure that the POP-Q measurements are recorded whilst ensuring:
7.3.3.
•
subject in semi-lithotomy position
•
standard examination table
•
vaginal speculum
•
type of intensity Valsalva manoeuvre, cough -
SUBJECT QUESTIONNAIRES
Subject questionnaires will be translated into the local language of the subject and will be completed by the subject. The investigator/study nurse, for completeness, will check completed questionnaires before the monitor for the site collects them. Collected questionnaires will be sent to Ethicon’s Clinical Data Management Department for entry into the clinical database.
Pelvic Floor Distress Inventory (PFDI-20); The short form of the PFDI will be used to measure the degree of bother and distress caused by pelvic floor symptoms . 12 Pelvic Floor Impact Questionnaire (PFIQ-7): The short form of the PFIQ will be used to assess the degree to which bladder, bowel, or vaginal symptoms affect the daily activities, relationships, and emotions of women with pelvic floor disorders . 12 Pelvic Organ ProlapselUrinary Incontinence Sexual Function (PISQ-12): The short fomi of the PISQ will be used to evaluate sexual function in wornen with pelvic floor symptoms . 13 EuroQol: The EuroQol will be used to assess health outcome following surgery, on a common scale for purposes of evaluation, allocation and monitonng 14
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Return to Usual Activities Questionnaire: Subjects will be asked 1f they have retumed to their usual activities: walking, driving, working, household activities and sexual intercourse. 1f they have returned to usual activities, they will be asked how long after their operation they were able to resume these activities. Global patient impression : Subjects will be asked the global impression question: ‘Compared 15 with how you were doing before your recent pelvic floor operation, would you say that you are: much better / a 11111e better / about the same / a 11111e worse / much worse?” Brief Pain Inventory (VAS) : Subjects will be asked to rate their level of postoperative pain. 16 Surgical Satisfaction Questionnaire: Subjects will be asked to rate their satisfaction with their surgical procedure. (Appendix 3)
( 8.
SUBJECT COMPLETIONIEARLY TERMINATION
8.1.
COMPLETON
A subject will be considered as having completed the study when she has completed all visits through Visit 8 (36 months post surgery) and has been in the study for >337 days. All other subjects will not be considered to have completed the study. 8.2. EARLY TERMINATION OF S UBJECT INVOLVEMENT Subject participation may be considered terminated prior to completing the study (i.e. the 36 month follow up Visit) for any of the following reasons: • •
Subject voluntarily withdrew consent Subject Lost to follow-up
A certified, retum-receipt letter must be sent to the subject after attempts to reach the subject by telephone have failed. The subject will be considered lost to follow-up 1f this communication is unsuccessful. •
Other
Any other reason for early termination should be recorded. When a subject’s participation is terminated prior to completing the study, the reason for withdrawal is to be documented on the CRF and in the source documentation. 1f participation is terminated prior to the 12-month visit every attempt should be made to complete the procedures scheduled for this time point.
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9. STATISTICAL METHODS Ethicon’s Clinical Development department will be responsible for the analysis of data from this protocol. The detailed Statistical Analysis Plan (SAP) will be based on and will suppiement the statistical design and analysis described in this section. 9.1. SAMPLE SIzE DETERMINATION This is not a hypothesis generating study. A total of 125 subjects will be enrolled. Assuming a 40% drop out rate over 3 years (estimated from study CT-TVT-001-97 based on 2- year data and extrapolated) this shoufd lead to 75 subjects providing 3- year data and at least 100 (118 subjects assuming a 5% drop outto 1 year) providing 12-month data. It is expected that this will lead to approximately 118 evaluable subjects at 12 months. Evaluable subjects will be defined as those providing baseline data and having POP-Q evaluation at the 1 2-month visit. 9.2. PLANNEDANALYSIS 9.2.1. ANALYSIS SETS Three main analysis sets are defined: •
The Safety Set will contain all subjects who receive treatment.
•
The Full Analysis Set (FAS) will contain all treated subjects This set is sub-divided (based on the treated compartment) into: ?
Anterior only analysis set
?
Posterior only analysis set Anterior and Posterior analysis set In addition a ‘sexually active analysis set’ is defined as subjects in the FAS who are sexually active at baseline and complete the PISQ-12 questionnaire
?
? •
The Per-protocol Set (PPS) inciudes all subjects without major protocol violations (to be agreed at the pre-database lock meeting) who either:
? ?
complete the 12-month POP-Q evaluation or are failures at any time up to withdrawal
?
This set may be sub-divided as above, based on the treated compartment.
9.2.2. EFFECTPJENESS 9.2.2.1 Primary Effectiveness Variables!Criteria
The following primary endpoint will be analysed using the PPS and FAS Set: POP-Q score at 12 months post-procedure. Success (overall) will be determined by achievement of a POP-Q score of ICS Stage =1, in the treated compartment, without further re-intervention for POP in that compartment. Since subjects may only have one compartment treated, ICS stage scores will be calculated on the affected side(s) only for each of the ‘Anterior only’, ‘Posterior only’ and ‘Anterior and Protocol: 300.07-006 Aniendment #1 FiraI Version 2; 29 October 2007
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posterior’ analysis sets and the FAS (Affected side success) ICS stage will be calculated’° and success will be achieved 1f the stage is =1 For the calculation of POP-Q ICS stage on subjects with only one affected side, the mies ° will 1 be applied to the anterlor or posterior side only and success will be achieved 1f the stage is =1. 9.2.2.2 Secondary Effectiveness Variables/Criteria The following secondary endpoints will be analysed using the FAS unless otherwise stated: •
Summary of ICS Stages at 3, 24 and 36-month visit.
•
Summary of treated compartment ICS POP-Q stage at 3, 12, 24 and 36 months. Proportion of subjects with the leading edge within the hymen (Le. all POP-Q values to be less than 0), and without further re-intervention for POP. lncidence of de novo prolapse as defined as occurrence of a post-operative prolapse ICS Stage II or greater) only in the untreated compartment, provided there was no pre-operative defect in that compariment (ie. ICS Stage 0 or 1). (FAS set excluding combined treatment patients).
• •
•
Mean scores and change from baseline in PFDI-20 scores at 3,12, 24 and 36 month visits including sub scores (POPDI, CRADI and UDI).
•
Days to return to normal activities (walking, driving, work, household activities and sexual intercourse). Proportion of subjects with a change from baseline 45 points in the PFDI-20 summary score at 12, 24 and 36 months.
• •
EuroQol (EQ-5D health state) change from baseline at 3 and 12 months visit (overall using the EQ-5D index score, and also for each individual item.
•
Mean scores and change from baseline in PFIQ-7 at 3, 12, 24 and 36 months visit including sub scores (POPIQ, CRAIQ and UIQ). Proportion of subjects with a change from baseline 36 points in the PFIQ-7 summary score
•
at 12, 24 and 36 months. •
In subjects sexually active at baseline, assessment of sexual function using PISQ-12 assessed at 12, 24 and 36 month visits (mean scores and change from baseline).
• •
•
Incidence of new onset dyspareunia, resolut ion or continuance of pre-existing dyspareunia. Incidence of mesh contraction, as determined by pain on palpation of mesh during pelvic examination at 3, 12, 24 and 36 months. Incidence of vaginal wall stiffness, as determined by the investigator on physical examination at 3, 12, 24 and 36 months. Total time in the operating room.
•
Length of procedure (from time of first incision to time of last suture).
•
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•
Nights in hospital (from date of admission to date of discharge; based ori actual data and ‘readiness for discharge”).
•
Pain score 24 hours post surgery and at the 1 month visit, measured using VAS. • Subject global impression assessed on a 5 point Likert scale at 3, 12, 24 and 36-month visit. 9.2.2.3 METHODS OF ANALYSIS Since this is a single arm study, output will be limited to summary data (mean, standard deviation, minimum, median, maximum and 95% CI for continuous data and number, percent for discrete data). The Cl for the primary endpoint will bo expressed as a 97.6% one-tailed Cl. Time to events will be analysed using Kaplan-Meier methods, with centre in the model. 9.2.3 SAFETY 9.2.3.1 SAFErY VARIABLESICRITERIA The following will be summarised using the Safety Set: •
Adverse events,
•
Determination of any exposures/erosions including location (exposure is any visible mesh or
any mesh that can be appreciated to be exposed by palpation but is not visible). •
Haemoglobin and haematocrit expressed as actual values and change from baseline.
9.2.3.2 METHODS OF ANALYSIS
All safety variables will be summarised using the safety set (all subjects treated). All safety variables will be summarised only, no statistical analysis will be carried out. The Medical Dictionary for Regulatory Activities (MedDRA) will be used to code Adverse Events. 9.2.4
0
INTERIM AND FOLLOW-LJP ANALYSES
An interim analysis will be performed on the 3-month data, comprised of a minimum of 60 subjects. The 3month POP-Q data will be summarised, however, the success criterion will not be applied. All other parameters will be summarised as applicable. As the primary endpoint is only relevant at 12 months there are no stopping rules, although alpha will be arbitrarily assigned 0.001 (one tailed). Follow-up analyses will be carried out at 24 and 36 months. 9.2.5
HANDLING OF MISSING DATA
The pilmary analysis will be based on the PPS. Contirmatory analyses will be conducted using the FAS, with the following methods used to impute missing data values for the primary endpoint: a) FAS with latest post operative result used in the absence of a 12 month result (last observation carned forward (LOCF). b) FAS with missing data imputed to success. c) FAS with missing data imputed to failure. Protocol: 300.07-006 Amendment #1 Final Version 2; 29October2007
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For secondary endpoints missing data will not be estimated. 1f a POP-Q score on the affected side is missing then the overall and affected side POP-Q ICS stage will be missing. 1f the missing value is on the unaffected side then only the overall POP-Q stage is missing. However in most cases It will be possible to determine if the result is a success based on available scores. In these cases success/failure will be determined manualty and documented. 1f success/failure is not available at 12 months, then the 3-month result will be carried forward (LOCF). PFDI-20 and PFIQ-7: Missing values will be assigned the mean score of the non-missing value within the scale (each has three scales plus summary score). PISQ-12: Missing values will be assigned the mean score of the non-missing value providing there are no more than 2 missing values. EuroQoL Missing data will not be estimated. 10.
ADVERSEEVENTS
10.1. ADVERSEEVENT For purpose of this protocol, an adverse event (AE) is any undesirable clinical occurrence in a subject irrespective if attributed to the device or study-related procedure. Those AEs considered to be related or possibly related to the device will be defined as Adverse Device Effects (ADEs). Any worsening of a pre-existing condition or illness is considered an adverse event. 10.2. SERIOUS ADVERSE EVENT (SAE) An adverse event that resulted in one of the following: • Death • Life-threatening illness or injury • A permanent impairment of a body structure or a body function • Required in-patient hospitalization or prolongation of existing hospitalization • Medical or surgical intervention to prevent permanent impairment to body structure or a body function • Foetal distress, foetal death or a congenital abnormality or birth defect
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10.3.
SERIOUS ADVERSE DEVICE EVENT (SADE) Those SAEs considered to be related er possibly retated to the device will be defined as Serlous Adverse Device Effects (SADEs).
10.4
ADVERSE EVENT S EVERITY CATEGORIES
The following categories of adverse event severity are to be used: Mild:
Moderate:
Awareness of a sign or symptom that does not interfere with the subject’s usual activity er is transient Interferes with the subject’s usual activity
Severe:
Incapacitating with inability to work or perform usual activity
10.5
ANTICIPATED ADVERSE EVENTS RELATEDTO THE PROCEDURE
The following adverse events are defined as anticipated adverse events associated with gynecological procedures: • Cramping/pelvic pain • Vaginal discharge • Vaginal bleeding/spotting • Site-specific laceration with bloeding • Edema of vagina • Headache • Nausea and vomiting • Febrile morbidity (temperature of 38.0°CI1 00.4°F or greater on any 2 post-procedure days at least 6 hours apart, excluding the first 24 hours after the procedure) • Fatigue • Bladder irritation (Le. dysuria with urinary frequency or urgency) • Bloating sensation • Difficulty voiding or urinary retention • Bladder infection!cystitis/lower urinary tract infection confirmed by a positive culture • Upper urinary tract infection • Worsened bulk effects • Increased pain with menses • Vaginal and cervical lacerations • Vaginal infection • Endometritis • Utenne perforation • Cervical tear • Hematoma • Vaginal lesions • Vaginitis • Edema of extern al gen italia • Edema of lower extremities • Life-threatening cardiac or respiratory arrest or other Iife-threatening event • Additional anesthesia risks
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• 10.6
Uterine infection or injury leading to hysterectomy and pulmonary embolism leading to death
ANTICIPATED ADVERSE DEvIcE EFFECTS
The following adverse events are defined as anticipated adverse events that may be associated with the GYNECARE PROLIFT+M Mesh device: • Mesh exposure is a common complication, which can be managed by excision and closure. •
Mesh retraction (‘shrinkage”) is less common but is considered more serious than mesh exposure. It can cause vaginal anatomic distortion, which may eventually have a negative impact on sexual function. Shrinkage of the mesh is expected under normal circumstances; however, excessive shrinkage resulting in pain is not a common finding.
•
The scar plate that forms with in-growth of tissue into the mesh can cause stiffness in the vagina that further impacts sexual function in a negative manner.
•
Punctures or lacerations of vessels, nerves, bladder, urethra or bowel may occur during GYNECARE PROLIFT Guide passage and may require surgical repair.
10.7
ADVERSE EVENT COLLECTION Subjects should be encouraged to report AEs spontaneously or in response to general, non directed questioning (e.g., ‘How has your health been since the last visit?”). All adverse events must be followed untfl resolution or until a stable clinical endpoint is reached. Details of all AEs and SAEs occurring during the study must be recorded on the Adverse Event Form in the CRF, as follows:
Q
• • •
Description of the event Dates of onset and resolution Severity
• •
Action taken Outcome
•
Relationship to device or study-procedure (related, possibly related, not related)
10.8
ADVERSE EVENT REPORTING
It is a requirement that the Principal Investigator promptly reports the following events to the Sponsor within 24 hours of becoming aware of the event occurring:
• •
SAEs irrespective of their relationship to the device SADEs and non-serlous ADEs, whether expected or not
Contact information will be provided in a separate document. Reporting
to Ethics:
It is the kwestigator’s responsibility to report all senous adverse events occuriing at their site, based on their applicable ethics committee requirements. Protocol: 300.07-006 Amendment #1 Final Verslon 2; 29 October 2007
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Informing Investigators: It is the responsibility of the Sponsor to report all serlous adverse device effects (SADEs) to all participating lnvestigators. Reporting to Competent Authorities: The Sponsor will notify each Competent Authority of reportable events, based on national regulations. It Is the responsibility of the principal investigator at each site to inform their local ethics committee of relevant SAE’s occurring at their site, according to IRB / local ethics committee requirements. It is the responsibility of the monitor to ensure that the Principal Investigator has reported all relevant SAEs to their IRBI local ethics committee. The Sponsor will notify Investigators of the occurrence of unanticipated and associated serlous adverse events. The investigator must report these events to the appropriate Medical Ethies Committeellnstitutional Review Board (MEC/IRB) that approved the protocol unless otherwise required and documented by the MEC/IRB. 11. COMPLAINT REPORTING Product complaints indicating dissatisfaction with the identity, labelling, quality, durability, reliability, safety, effectiveness or performance of the study device, whether or not the complaint resulted in a subject AE, must be reported within 48 hours to the study sponsor. 12. CONTACTING SPONSOR The names of the individuals (and corresponding phone numbers) who are to be contacted regarding adverse events, safety issues, and complaints are provided in the Investigator Study File. 13. CLINICAL SUPPLIES INFORMATION The GYNECARE PROLIFT + M* System must be kept in a secure locatlon with restricted access under appropriate environmental conditions. The device is only intended for use in this study protocol and only by the investigator identified for this study. 13.1.
PHYSICAL DESCRIPTION OF STUDY D EVICE
13.1.1
GYNECAREGYNEMESH M
13.1.2 TorAl. MESH IMPLANT The Total mesh implant is constructed from GYNECARE GYNEMESH M and is shaped for perforrning a total vaginal repair. The implant has 6 straps: 4 for securing the anterior portion of Protocol: 300.07-006 Amendment#1 FIriaI Verslon 2; 29 October 2007
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the implant via a transobturator approach and 2 for securing the posterior portion of the implant in the sacrospinous ligament via a transgiuteal approach. Altematively, the 2 posterior straps may be cut to reduce their length and secured in the sacrospinous ligament via a vaginal approach. The proximal and distal anterior straps have squared and triangular ends, respectively, while the posterior straps have rounded ends. 13.1.3 ANTERIOR MESH MPLANT The Anterior mesh implant is constructed from GYNECARE GYNEMESH M and is shaped for repair of anterior vaginal defects. The implant has 4 straps that are secured via a transobturator approach. The proximal and distal anterior straps have squared and triangular ends, respectively. 13.1.4 POSTERIOR MESH IMPLANT The Postenor mesh implant is constructed from GYNECARE GYNEMESH M and is shaped for repair of posterior and/or apical vaginal vault defects. The implant has 2 straps that are secured in the sacrospinous ligarnent via a transgiuteal approach. Alternatively, the 2 posterior straps may be cut to reduce their length and secureci in the sacrospinous ligament via a vaginal approach. The posterior straps have rounded ends. 13.1.5 GYNECARE PROLIFGUIDE The GYNECARE PROLIFT * guide is a single-patient use instrument designed to create tissue paths to allow placement of the Total, Anterior and Postenor mesh implants and to facilitate placement of the GYNECARE PRQLIFT* Cannula. Its length and curvature are specifically designed to create proper placement paths for all mesh implant straps. The GYNECARE PROLIFT+M Guide is suitable for use en both sides of the patient.
(j)
13.1.6 GYNECARE PROLIFT* CANNULA The GYNECARE PROLIF Cannula is a single-patient use instrument used in conjunction with the GYNECARE PROLIFT Guide to facilitate passage of the implant straps while protecting the surrounding tissue. Each GYNECARE PROLIFT* Cannula is placed over the GYNECARE PROLIFT* prior to passage and remains in place after the GYNECARE PROLIFT+M* guide is withdrawn. 13.1.7 GYNECARE PROLIFT* RETRIEVAL DEVICE The GYNECARE PROLIFT * Retrieval Device is a single-patient use instrument designed to facilitate placement of the mesh implant straps. The GYNECARE PROLIFT* Retrieval Device is passed through the previously positioned GYNECARE PROLIFT* Cannula until its distal end is retrieved through the vaginal dissection. The distal end of the GYNECARE PROLIFT* Retrieval Device has a loop to securely capture the mesh implant strap is drawn out through the GYNECARE PROLIFT* Cannula. 13.2 PACKAGING AND LABELLING
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13.2.1 PACKAGING The GYNECARE PROLIFT + M* System is provided sterile (ethylene oxide) for single use. Do not re-sterilize. Do not use 1f package is opened or damaged. Discard opened, unused devices. 13.2.2 LABELS AND LABELUNG INSTRUCTIONS There will be a label bearing information that will meet all appilcable clinical requirements. 13.3 DEVICE ACCOUNTABILITY It is the responsibility of the clinical investigator to ensure that all study devices received at the site will be inventoried and accounted for throughout the study and the result recorded in the device accountability form maintained in the Study Binder. The sponsor’s site monitor will verify the device accountability during on-site monitoring visits. Unless otherwise instructed by the sponsor, the investigator agrees at the end of the study to return all unuseci study devices, to the sponsor as instructed by the sponsor’s site monitor. The investigator agrees neither to dispense the study devices from, nor store it at, any site other than the study sites agreed upon with the sponsor. On a country-specific basis, permission may be granted for local disposition, with supporting documentation. 14.
TRIAL-SPECIFIC SUPPLIES The investigator will be provided with the following supplies:
• • •
GYNECARE PROLIFT + M* Petvic Floor Repair System Case Report Forms (CRF) Investigator Study Binders
15. ETHICS 15.1. INVESTIGATOR REsP0NsIBILITIEs The investigator is responsible for ensuring that the clinical study is performed in accordance with the protocol, the Declaration of Helsinki, principles of Good Clinical Practice (GCP), and applicable regulatory requirements. These documents set forth that the informed consent of the subjects is an essential precondition for participation in the clinical study. 15.2.
MEDICAL ETHICS COMMITTEE OR INSTITUTIONAL REvIEw B0ARD(MECIIRB)
The investigator may begin enrolment in the study after full approval of the protocol and adjunctive materials (eg., informed consent form, advertising) has been obtained from a local MEC/IRS and the sponsor has received a copy of this approval. lnvestigator responsibilities relevant to the MEC/IRB include the following: 1. During the conduct of the study, submit progress reports to the IRB or MEC as required, and request re-review and approval of the study at least once a year; Protocol: 300-07-006 Amendment #1 Final Version 2; 29 October 2007
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2. Report immediately to the IRB or MEC any unexpected adverse device effects that occur during the study, and provide the ETHICON designated monitor with a copy of the site correspondence; 3. 1f ETHICON notifies the investigator about any unexpected adverse device effects reported in other studies using this subject device, report that information to the IRB or MEC; 4. As required, obtain approval from the IRB or MEC for protocol amendments and for revisions to the consent form or subject recruitment advertisements; 5. Reports on, and reviews of, the trial and its progress will be submitted to the IRB/MEC by the investigator at intervals stipulated in their guidelines and in accordance with pertinent regulations and guidelines. 6. Maintain a file of study-related information (see study files) that includes all correspondence wlth the IRB or MEC; 7. Notify IRB or MEC when study is completed (i.e. after the last study visit of the final study subject); 8. After study completion (within 3 months is recommended) provide the IRB or MEC with a final report on the study. The recommended components of a final report are as follows; dates of study start and completion, number of subjects enrolled/treated, number of subjects who discontinued participation early and reason why, itemization and discussion of any serlous adverse event. 15.3. INFORMED CONSENT Each subject (or a legally authorized representative) must give written consent (and sign other locally required documents) according to local requirements after the nature of the study has been fully explained, The consent form must be signed prior to pformance of any study related activity. The consent forrn that is used must be approved both by the sponsor and by the reviewirig IRB/MEC. The informed consent will be in accordance with the Declaration of Helsinki, current principles of Good Clinical Practice, applicable regulatory requirements, privacy requirements, and ETHICON policy.
The investigator must explain to potential subjects or their legal representatives the aims, methods, reasonably anticipated benefits and potential hazards of the tilal and any discomfort It may entail. The other elements of the infomed consent will be explained and subjects will be given the opportunity to ask questions. After this explanation and before entry into the trial, consent should be appropriately recorded by means of the subject’s or his/her legal representative’s dated signature. 1f a subject and his/her legal representative are unable to read, an impartial witness must be present during the entire informed consent discussion. The signature of the impartial witness will certify the subject’s consent. The subject or his/her legal representative will be given a signed and dated copy of the informed consent form.
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16.
ADMINISTRATIVE REQUIREMENTS
16.1. PROTOCOL M0DIFIcATI0Ns Neither the investigator nor sponsor will modify this protocol without obtaining the concurrence of the other. All protocol amendments must be issued by the sponsor, signed and dated by the investigator, and should not be implemented without prior IRB/MEC approval, except where necessary to eliminate immediate hazards to the subjects or when the change(s) involves only logistical or administrative aspects of the trial (e.g., change in monitor(s), change of telephone number(s)). It is the sponsor’s responsibility for reporting protocol amendments to any Regulatory Authority (as applicable). The principal investigator reports the protocol amendments to the EC/IRB as per their local requirements.
0
In situations requiring a departure from the protocol, the investigator or other physician in attendance will contact the appropriate sponsor representative by fax or telephone (see Contact Information page). This contact must be made before implementing any departure from protocol. In all cases, contact with the sponsor must be made as soon as possible in order to discuss the situation and agree on an appropriate course of action. The CRF and source document will desoribe any departure from the protocol and the circumstances requiring it. 16.2. REQUIRED DOCUMENTATION Documents that must be provided to the sponsor prior to study start are as follows:
0
•
A copy of the formal written notification to the investigator regarding approval of the protocol by an EC/IRB that is in compliance with regulatory guidelines. The written notification is to be signed by the chairman or authorized designee and must identify the specific protocol. In cases where an EC/IRB member has a known conflict of interest, abstention of that individual from voting should be documented; an investigator (or sub-investigator) may be a member of the EC/IRB, but may not participate in the deliberation or vote on any research in which he or she is involved;
.
A copy of the EC/IRS approved informed consent form and other adjunctive materials (e.g., advertising) to be used in the study, including written docurnentation of EC/IRB approval of these items;
•
Name and address of the EC/IRB with a statemerit that It is organized and operates according to GCP and the appilcable laws and regulations, and a current list of the EC/IRB members. 1f accompanied by a lefter of explanation from the EC/IRB, a general statement may be substituted for this list, or a general assurance number.
•
Regulatory authority approval or notification, if applicable; Applicable local regulatory documentation (e.g. Statement of Investigator);
• • •
Financial disclosure statement(s) for each investigator and sub-investigator, if appilcable; Signed and dated Investigator Agreemerit page
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• • •
Signed and dated clinical study agreement, incluciing financial agreement Up-to-date signed and dated curriculum vitae for each investigator and sub-investigator; Name and address of any local laboratory conducting tests for the study, a dated copy of the laboratory reference values for tests to be performed during the study and a copy of the certification or other documentation establishing adequacy of the facility, 1f applicable.
Other documents may also be required prior to the study, and during the course of the study. 16.3
CONFIDENTIALITY OF SUBJECT RECORDS
The Investigator will ensure that the subjects’ anonymity will be maintained. On CRF’s or other study documents submitted to ETHICON CDMA, subjects will not be identified by their names, but an identification code. Documents not for submission to ETHICON i.e. Investigator Log and original subjects’ consent forms will be maintained in the Investigator Site File. 16.4
C)
RECORD RETENTI0N
The investigator/institution will maintain all CRF’s and all source documents that support the data collected from each subject, and all trial documents as specif’ied by applicable regulatory requirement(s). The investigator/institution will take measures to prevent accidental or premature destruction of these documents. Essential documents must be retained until at least 2 years after the last approval of a marketing application or until at least 2years have elapsed since the formal discontinuation of clinical development of the investigational product. These documents will be retained for a longer period 1f required by the applicable regulatory requirements or by an agreement with the sponsor. It is the responsibility of the sponsor to inform the investigator/institution as to when these documents no longer need to be retained. 1f the responsible investigator retires, relocates, or for other reasons withdraws from the responsibility of keeping the study records, custody must be transferred to a person who will accept the responsibility. The sponsor must be notified in writing of the name and address of the new custodian. 16.4.1 CASE REPORT FORM COMPLETION Designated study site personnel will enter study data into the CRF’s. Such data will be supported by source documents. The investigator shali maintain the records of study article clisposition, firial CRF’s, worksheets, and any other study-specific source documentation, until notifled by the Sponsor that study-specific records may be destroyed. The sponsor should be notified 1f the investigator plans to leave the institution so that arrangements can be made for transfer of study obligations and records. 16.4.2 STLJDY COMPLETION’TERMINATION
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16.42.1
STUDY COMPLETION
The final data from the centre will be sent to ETHICON (or designee) following completion of the final subject visit at that centre. 16.4.2.2
STUDY TERMINATION
An initiative for centre closure or trial termination can be taken at any time either by the sponsor or by the investigator, provided there is reasonable cause and sufficient notice is given in advance of the intended termination. Reasons for such action taken by the sponsor inciude, but are not limited to the following: • • • • • •
Successful corn pletion of the trial at the centre; The required number of subjects for the trial has been recruited; Failure of the investigator to comply with the protocol, the sponsor’s procedures or GCP guidelines; Safety concerns; Sufficient data suggesting lack of effectiveness; Inadequate recruitment of subjects by the investigator.
16.4.3 MONITORING
The sponsor will perform on-site monitoring visits as frequently as necessary. Visits are usually made at regular intervals. The frequency of monitoring visits will be docurnented in the monitoring guidehries for this study. The monitor will record the dates of the visits in a trial centre visit log to be kept at the site. The first post-initiation visit will usually be made as soon as possible after enrolment has begun. At these visits, the monitor will compare the data entered onto the CRF’s with the hospital or clinic records (source documents). At a minimum, source documentation must be available to substantiate subject identification, eligibility and participation, proper informed consent procedures, dates of visits, adherence to protocol procedures, record of safety and efficacy parameters, adequate reporting and follow-up of AE’s, device receiptlusefreturn records, and date of completion and reason. Specific items required as source documents will be reviewed with the investigator prior to the study. Findings from this review of CRF’s and source documents will be discussed with the investigational staff. The sponsor expects that, during monitoring visits, the relevant investigational staff will be available, the source documentation will be available, and a suitable environment will be provided for review of study-related documents. The monitor will meet with the investigator on a regular basis during the trial to provide feedback on the tnal conduct. 16.4.4 DATA QUALI1V SSURANCE
Steps to be taken to assure the accuracy and reliability of data inciude the selectiori of qualifled investigators and appropriate study centres, revlew of protocol procedures with the investigator and assocated personnel prior to the study, periodic monitoring visits by the sponsor. The sponsor will review CRF’s for accuracy and completertess during on-site monitoring visits and Protocol: 300.07-006 Amendment #1 Final Version 2; 29October2007
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after their return to ETHICON; any discrepancies will be resolved with the Investigator or designees, as appropriate. The data will be entered into the cIinica tnal database and verified for accuracy. 16.4.5 ON-SITE ALJDFTS Representatives of the sponsor’s Clinical Development and Medical Affairs Department or Quality Assurarice Department may visit the site to carry out an audit of the study in compliance with regulatory guidelines and company policy. Such audits will require access to all study records, includirig source documents, for inspection and comparison with the CRF’s. Subject privacy must, however, be respected. Sufficient prior notice will be provided to allow the investigator to prepare properly for the audit. Similar auditing procedures may also be conducted by agents of any regulatory body reviewing the results of this study in support of a Licensing Application. The investigator should immediately notify the sponsor if they have been contacted by a regulatory agency concerning an upcoming inspection.
16.4.6 IJSE OF INFORMATION AND PUBLICATION All information concerning the GYNECARE PROLIFT + M* System, ETHICON operations, patent application, formulas, manufacturing processes, basic scientific data, and formulation information, supplled by the sponsor to the investigator and not prevlously published, is considered confidential and remains the sole property of ETHICON. The investigator agrees to use this information ortiy to accomplish this study and will not use it for other purposes without the sponsor’s written consent.
C)
The investigator understands that the information developed in the clinical study will be used by ETHICON in connection with the continued development of the GYNECARE PROLIFT + M* System, and thus may be disciosed as required to other clinical investigators or government regulatory agencies. To permit the information denved from the clinical studies to be used, the investigator is obligated to provide the sponsor with all data obtained in the study. Any publication or other public presentation of resuits from this study requires prior review by ETHICON. Draft abstracts, manuscripts, and materials for presentation at scientific meetings must be sent to the sponsor at least 30 working days prior to abstract or other relevant submission deadlines. Authorship of publications resulting from this study will be based on generally accepted criteria for major medical journals. The investigator understands not to use the name of ETHICON or the GYNECARE PROLIFT + M* System, or any of its employees, in any publicity, news release or other public announcement, written or oral, whether to the public, press or otherwise, relating to this protocol, to any amendment hereto, or to the performance hereunder, without the prior consent of ETHICON.
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16.5
1 2
3 4 5
(
6
7 8 9 10 11
12 13
14 15 16
REFERENCES
Smith ARB, Hosker GL, Warreli DW. The Role of partial denervation of the Felvic floor the in aetiology of genitourinary prolapse and stress incontinence of urine. A neurophysiologic study. BrJ Obstet Gynaecol 1989; 96:24-28. Gilpin SA, Gosling JA, Smith ARB, et al. The pathogenesis of genitourinary prolapse and stress incontinence of urine. A histological and histochemical study. Br J Obstet Gynecol 1989; 96:1523. Norton PA, Baker JE, Sharp HC, et al. Genitourinary prolapse and joint hypermobility in women. Obstet Gynecol 1995; 85(2):225-228. Smith P, Heimer G, Norgen A, et al. Steroid Horrnone Receptors in Pelvic Muscies and Ligament in Women. Gyrieco) Obstet lnvest 1990; 30:27-30. Olsen A, Srnith V, et. al. Epidemiology of Surgically Managed Pelvic Organ Prolapse and Urinary Incontinence. Obstet Gynecol 1997; 89:501 -506. Benson JT, Lucente V, McCle)lan E. Vagina) versus abdominal reconstructive surgery for the treatment of pelvic support defects: A prospective randomized study with long-term outcome evaluation. Am J Obstet Gynecol 1996; 175:1418-1422. Fenner, D. New Surgical Mesh. Clin Obstet Gynecol. 2000:43:650-8. Cobb, William S, MD, Kercher, Kent W, MD, and Heniford, Todd B., MD. The Argument for Lightweight Polypropylene Mesh in Hernia Repair. Surgical Innovation 2005: 63-69. Iglesia C, Fenner D, Brubaker L. The Use of Mesh in Gynecotogic Surgery. Int. Urogynecol J. 1997:105-115. Carey M, Slack M, Higgs P, Wynn-WiIIiams M and Comish A. Vaginal surgery for pelvic organ prolapse using mesh and a vaginal support device. Submitted to Br J Ob Gyn; 2006 Bump RC, Mattiasson A, Bo K, Brubaker LP, DeLancey JOL, Klarskov P, Shuil BL, Smith ARB. “The standardisation of terminology of female pelvic organ prolapse and pelvic floor dysfunction”. Am J Obstet Gynecol 1996; 175:10-7 Barber MD, Walters MD and Bump RC. Short forms of two condition-specific quality of life questionnaires for women with pelvic floordisorders. Am J Ob Gyn 2005; 193:103-13 Rogers RG, Coates, KW, Kammerer-Doak D, Khalsa, S, QuaIls C. A short form of the Pelvic Organ Prolapse/Urinanry Incontinence Sexual Questionnaire (PISQ-12). IUGJ 2003; 14:164-8. Knd P. The EuroQol lnstrutment: An Index of Health-Related QuaIity of Life. Quality of Life 1d 2 and Pharmacoeconomics in Clinical Trials ( Edition) Spilker B. 1996; Pg 191-210 Wren PA, Janz NK, Brubaker L, Fitzgerald MP, Weber AM, LaPorte FB, Wei JT. uReliability of health-related quality of life measures 1 year after surgical procedures for pelvic floor disorders. Am J Ob Gyn 2005; 192:780-8. Keller et al. “Validity of the brief pain inventory for use in docu-nenting the outcomes of subjects with non-cancer pain.” Clin J Pain 2004; 20 (5): 309-18
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APPENOIX
1
ETHICON CONTACT DETAILS
10.2.e
ETHICON Clinical Development & Medical Affairs
MEDICAL DIRECTOR F.A.C.OG.
Medical Director ETHICON Women’s Health and Urology P.O. Box 151, Route 22 West Somerville, NJ 08876-0151, US
(
CLINICAL RESEARCH MANAGER
GLOBAL CLINICAL PROJECT MANAGER
CLINICAL PROJECT MANAGER
Clinical Development & Medical Affairs ETHICONI P0 Box 1988 Simpson Parkway Kirkton Campus Livingston EH54 OABI UK Clinical Development & Medical Affairs ETHICON P.0. Box 151, Route 22 West Somerville, NJ 08876-0151, US Clinical Development & Medical Affairs ETHICON, P0 Box 1988 Kirkton Campus Livingston
Tel: +1-.._ Fax: +1-908-
Tel: +44 Fax: +44
10.2.e
‘1
10.2.e
Tel: +1Fax: ÷1-
10.2.e
Tel: +44 Fax: ÷44
10.2. e
EH54OABIUK
Contract Research Organisation (EU sites)
D-TARGET SA En Chamard 55C 1442 Montagny-priis-Yverdon Switzerland
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1O.2.e
APPENDIX 2 GLOBAL PATIENT IMPRESSON
Compared with how you were dong before your recent pelvic floor operation, would you say that now you are: • • • • •
Much botter A little better About the same Alittieworse Much worse
Please circie the term that most applies to you.
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APPENDX 3
Surgical Satisfaction Questionnaire Instructions: Following are a list of questions about your satisfaction with your surgery. All infornntion is strictly confidential. Your confidential answers will be used only to help doctors understand and improve what is important to patients before, during and after surgery. Please check the box that best answers the question for you. Thank you for your help.
(
1. How satisfied are you with how your pain was controlled in the hospital after surgery? Very Satisfied El Satisfied []Neutral EI Unsatisfied [1 Very unsatisfied 2. How satisfied are you with how your pain was controlled when you returned home after surgeiy? EE] Very Satisfied LE] Satisfled [1 Neutral EE] Unsatisfied []Very unsatisfied 3. How satisfied are you with the arnount of time it took for you to return to your daily activities, for example housework or social activities outside the home? []Very Satisfied Neutral EE] Unsatisfied EI Very EI Satisfled unsatisfied 4. How satisfied are you with the amount of time it took for you to return to work? Very Satisfied Neutral [1 Unsatisfied EI Very El Satisfied unsatisfied 5. How satisfied are you with the amount of time it took for you to return to your normal exercise routine? Satisfled Ej Neutral EI Unsatisfled El Veiy J Very Satisfied unsatisfled 6. How satisfied are you with the resuits for your surgery? LiVery Satisfied Satisfied Neutral unsatisfled
[}
Unsatisfied
EI
Very
7. Looking back, if you “had to do it all over again” would you have the surgery again? EE] Yes El Maybe [1 No 8. Would you recommend this surgery to someone else? [jYes []Maybe [1 No
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APPENDIX4 PELVIC ORGAN PROLAPSEIURINARY INCONTINENCE SEXUAL FUNCTION QUESTIONN AIRE (PISQ-1 2)
Instructions: Following are a list af questions about you and your partner’s sex life. All information is strictly confidential. Your confidential answers will be used only to help doctors understand what is important to subjects about their sex lives. Please check the box that best answers the question for you. Wbile answering the questions, consider your sexuality over the past six months. Thank you for your help. 1. How frequently do you feel sexual desire? This feeling may inciude wanting to have sex, planning to have sex, feeling frustrated due to lack of sex, etc. Daily?
Weekly?
Monthly?
Less than once a month? Never? 2. Do you climax (have an orgasm) when having sexual intercourse with your partner? Always? Usually? Sometimes? Seldom? Never? 3. Do you feel sexually excited (turned on) when having sexual activity with your partner? Always? Usually? Sometimes? Seldom? Never? 4. How satisfied are you with the variety of sexual activities in you current sex life? Always?
Usually?
Sometimes?
Seldom?
Never?
Seldom?
Never?
5. Do you feel pain during sexual intercourse?
0
Always?
Usually?
Sometimes?
6. Are you incontinent of urine (leak urine) with sexual activity? Always? Usually? Sometimes? Seldom?
Never? 7. Does fear of incontinence (either stool or urine) restrict your sexual activity? Always? Usually? Sometimes? Seldom? Never? 8. Do you avoid sexual intercourse because of bulging in the vagina (either the bladder, rectum or vagina falling out?). Always?
Usually?
Sometimes?
Seldom? Never? 9. When you have sex with your partner, do you have negative emotional reactions such as fear, disgust, shame or guilt?
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Always?
Usually?
Sometimes?
Usually?
Sometimes?
Seldom? Never? 10. Does your partner have a probm with erections that affects your sexual activity? Always? Usually? Sometimes? Seldom? Never? 11. Does your partner have a problem with premature ejaculation that affects your sexual activity?
Always?
Seldom?
Never? 12. Compared to orgasms you have had in the past, how intense are the orgasms you have had in the past six months? Much less intense?? Less intense??
CD
More Intense??
Same intensit)/? 7
Much more intense?
Scoring: Scores are calculated by totaling the scores for each question with 0=always, 4never . Reverse scoring is used for items 1,2,3 and 4. The short form questionnaire can be used with up to two missing responses. To handle missing values the sum is calculated by multiplying the number of items by the mean of the answered items.
1f there are more than two missing
responses, the short form no longer accurately predicts long form scores. comparable to long form scores multiply the total by 2.58 (31/12).
0
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To make scores
APPENDIX5
PELVIC FLOOR DISTRESS INVENTORY
-
SHORT FORM 20
1NSTRUCTIONS
Please answer all of the questions in the following survey. These questions will ask you if you have certain bowel, bladder or pelvic symptoms and if you do how much they bother you. Answer these questions by putting a X in the appropriate box or boxes. 1f you are unsure about how to answer a question, give the best answer you can. While answering these questions, please consider your symptoms over the last 3 months. EXAMPLE
For the following question: 1f you do not usually have headaches just put an X in the ‘No’ box Do you usually experience headaches?
)cNo; ? Yes
1f yes, how much does this bother you? 71 Not at All
72 -
73
Somewhat
Moderately
-
74 -
Quite a bit
1fyou usually have headaches, put an X in the ‘Yes’ box indicate how much the headaches bother you. (In this example, the headaches were moderately bothersome) Do you usually experience headaches? 7 No; ‘es
1f yes, how much does this bother you? 71 Not at All
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X3
72 -
Somewhat
-
Moderately
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74 -
Quite a bit
Name:
Date:
/
/
Do you usually experiencepressure in the lower abdomen?
?
No;? Yes
0 jf.yç, how much does this bother you? ?i ?2 ?3 Not at All Somewhat Moderately -
c
2.
-
-
?4 Quite a bit
Do you usually experience heaviness or dullness in the pelvic area?
?
No;? Yes
0 ILs, how much does this bother you? ?i ?2 ?3 Not at All Somewhat Moderately -
3.
-
-
Quite a bit
Do you usually have a bulge or something falling out that you can see or feel in the vaginal area?
?
No;? Yes
0
ILyi how much does this botber you? ?i Not at All
4.
(2)
?2 Somewhat
-
Moderately
-
Quite a bit
Do you usually have to push on the vagina or around the rectum to have or complete a bowel movement?
?
No;? Yes
0 jf.y. how much does this bother you? ?i NotatAli
5.
-
?2 Somewhat
-
?3 Moderately
-
Quiteabit
Do you usually experience a feeling of incomplete bladder emptying?
?
No;? Yes
0
ILy how much does this bother you? Not at All
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-
?2 Somewhat
-
?3 Moderately
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-
Quite a bit
6.
Do you ever have to push U on a bulge in the vaginal area with your fingers to start or complete urination?
7
No;? Yes
0
If.y, how much does this bother you? ?i Not at All
7.
-
?2 Somewhat
?3 Moderately
-
-
?4 Quite a hit
Do you feel you need to strain too hard to have a bowel movement?
7
No;? Yes
0
ILy, how much does this bother you?
(
Not at All 8.
-
72 Somewhat
?3 Moderately
-
-
?4 Quite a bit
Do you feel you have not completely emptied your bowels at the end of a bowel movement?
?
No;? Yes
0 1Ly, how much does this bother you? 71 Not at All
9.
-
?2 Somewhat
? Moderately
-
-
Quite a bit
Do you usually lose stool beyond your control if your stool is well forrned?
?
No;? Yes
0
IL.s, how much does this bother you? ?i Not at All
-
?2 Somewhat
?3 Moderately
-
-
?4 Quite a bit
10. Do you usually lose stool beyond your control if your stool is loose orliquid?
?
No;? Yes
0
iLy, how Not at All
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much does this bother you?
-
72 Somewhat
-
?3 Moderately
47 of 53
-
?4 Quite a bit
11. Do you usually lose gas from the rectum beyond your control?
?
No;? Yes
0
ILy, how much does this bother you? ?i Not at All
-
?2 Somewhat
?3 Moderately
-
-
Quite a bit
12. Do you usually have pain when you pass your stool?
?
No;? Yes
0
iLx how much does this bother you?
(.
Not at All
-
?2 Somewhat
-
?3 Moderately
-
Quite a bil
13. Do you experience a strong sense of urgency and have to rush to the bathroom to have a bowel movement? ? No;? Yes 0 iLy, how much does this bother you? ?i Not at All
?2 Somewhat
-
?3 Moderately
-
Quite a bit
14. Does a part ofyour bowel ever pass through the rectum and bulge outside during or after a bowel movement?
?
No;? Yes
0
iLyi, how much does this bother you?
? Not at All
0
-
?2 Sornewhat
-
?3 Moderately
-
Quite a bit
-
Quhe a bil
15. Do you usually experience frequent urination?
?
No;? Yes
0
JLyg, how much does this bother you? ?i Not at All
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-
?2 Somewhat
-
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?3 Moderately
16. Do you usually experience urine leakage associated with a feeling of urgency; that is, a strong sensation of needing to go to the bathroom?
?
No;? Yes
0 how much does this bother you? ?i Not at All
-
?2 Somewhat
?3 Moderately
-
?4 Quite a bil
17. Do you usually experience urine leakage related to coughing, sneezing, or laughing?
?
No;?
Yes
0 JLy.&, how much does this bother you? Not at All
-
?2 Somewhat
?3 Moderately
-
-
?4 Quite a bit
18. Do you usually experience small amounts of urine leakage (that is, drops)?
?
No;? Yes
0 jLy, how much does this bother you? Not at All
-
?2 Somewhat
?3 Moderately
-
-
?4 Quite a bit
19. Do you usually experience difficulty emptying your bladder?
?
No;?
Yes
0
ILy, how much does this bother you? ?i Not at All
-
?2 Soiuewhat
-
?3 Moderately
-
Quite a bit
20. Do you usually experiencepain ordiscomfort in the lower abdomen or genital region?
?
No;? Yes
0
IL& how much does this bother you? ?i Not al All
Thank you for taking the
time
-
?2 Somewbat
-
?3 Moderately
to complete this questionnaire
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-
Quite a bil
APPENDIX 6 Protocol Number: 3o07-oo6
Pelvic Floor Impact Questionnalre Short Form 7
—
Subject Initials:
Subject Number: 1 lnstructlons: Sorne woméri find that bladder, bowel, or vaginal symploms attect tileir activmes, reblionshps, and feelings. For each question placo an X the
in response that best descrlbes how much your actMties, relationships, or feelings have been affected by your bladder, bowel, er vaginal symptoms er coriditions over the last 3 months. Please make sure you make en answer in all 3 for How do symptoms or conditionsrelatetothefotowlng» Bowel or Vagina or Bladder or urine usually affect your rectum pelvis ‘‘
“
.
1. Abillty to do household chores (cooking, housecleaning, laundry)?
LI LI El El
Not at all Sorriewhat Moderately Quite a bil
LI Not at all [1 Somewhat El Moderately El Qulte a bit
LI Not aL all [1 Somewhat El Moderately El Quito a blt
2. Ability to do physical activities such as walking, swimming. er other exercise?
LI Not at all El Somewhat El Moderately El Quite a bit
El Not at all El Somewhat El Moderatoly El Quite a bit
El Not at all LI Somewhat El Moderately El Quito a bil
3. Enlertainmont activities such as going to a movie or concert?
El El El El
Moderalely Quite a bil
El Not aL all El Somewhat El Moderately El Quito a bil
El Not al all El Sornewhat El Moderately El Qulte a bit
4. Ability to travel by car er bus for a distance greater than 30 minutes away from home?
El Not at all El Somewhat Ei Moderately El Quite a bit
El Not at all El Somewhat El Moderately El Quite a bil
El Not at all El Somewhat El Moderately El Quito a bit
5. Participating in social activities outside your home?
El El El El
El Not at all El Somowhat El Moderately El Quito a bit
El Not al all El Somewhat El Moderately El Quite a bit El Not at all El Somewhat El Moderately El Quite a bil
El Not at all El Somewhat El Moderately El Qulte a bil
0 6. Emotlonal health (nervousness, depression, etc)?
7. Feeling frustrated?
Protocol; 300-07-006 Amendment #1 Final Version 2; 29October2007
Not at all Somewhat
Not at all Somewhat Moderately Quite a bit
El El El El
Quito a bit
El Not at all El Somewhat El Moderately El Quito a bil
El El El El
Not al all Somewhat Moderately Quito a bil
El Not at all El Somewhat El Moderately El Quito a bil
50 of 53
Not at all Somewhat Moderately
APPENDIX 7
5D
HEALTH QUESTIONNAIRE
(ENGLISH VERSION FOR THE UK) (validated for use in Eire)
Protocol: 300-07-006 Amendment #1 Final Version 2; 29 October 2007
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By placing a tick in one box in each group below, please indicate which statements best describe your own health state today. Mobility 1 have no problems in walking about
Li IJ
1 have some problems in walking about lam confined to bed
ED
Self-Care 1 have no problems with self-care 1 have some problems washing or dressing myself 1 am unable to wash or dress myself
LJ
Usual Activities (e.g. work, study, housowork, family or leisure activities) t have no problems with performing my usua 1 activities t have some problems with performing my usual activities t am unable to perform my usual activities PainlDiscomfort 1 have no pain or discomfort 1 have moderate pain or discomfort 1 have extreme pain or discomfort AnxietylDepression t am not anxious or depressed 1 am moderately anxious or ciepressed t am extremety anxious or depressed
Protocol: 300.07-006 Arnendment #1 Final Verson 2; 29 October 2007
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Best imaginable health state 100
To help people say how good or bad a health state is, we have drawn a scale (rather like a thermometer) on which the best state you can imagine is marked 100 and the worst state you can imagine is marked 0. We would like you to mdicate on this scale how good or bad your own health is today, in your opinion. Please do this by drawing a line from the box below to whichever point on the scale indicates how good or bad your health state is today.
9 0
80
70
60
Votir
OWfl
heakh state
50
tO(Iav 40
30
(-
20
10
0 Protocol: 30007-006 Amendment #1 Final Version 2; 29 October 2007
53 of 53
Worst imaginable health state
1.2
Een prospectief, multicenter onderzoek waarin de klinische prestaties van het GYNECARE PROLI FT +M*bekkenbodemreparatjesysteem geëvalueerd wordt als hulpmiddel voor een b ken demverzakking PROTOCOL 300-07-006 versie 1, 29
ober 200
SAMENVATTING DOELSTELLINGEN: Het primaire doel van dit onderzoek is de evaluatie van het anatomische succes van het GYNECARE PROLIFT + M*systeem bij vrouwen met symptomatische ICS POP-Q stadium III of IV, waarvoor operatieve correctie van een bekkenbodemverzakking (POP) nodig is. De secundaire doelen zijn de evaluatie van de door de patiënt gerapporteerd uitkomsten e (PFDI-20, PFIQ-7, PISQ-12, Euro-QOL), lengte van de procedure, lengte van het verblijf in het ziekenhuis, postoperatieve pijn, hervatting van normale activiteiten en pen- en postop eratieve complicaties. OVERZICHT VAN DE ONDERZOEKSOPZET: Dit onderzoek is opgezet als een prospectief, multicenter onderzoek met één groep. Patiënten worden vôôr, tijdens en na de procedure en 1, 3, 12, 24 en 36 maanden na de procedure geëvalueerd. ONDERZOEKSLOCATIES: Het onderzoek vindt aan ongeveer 10 onderzoekscentra in Europa (bijv. Frankrijk, Duitsland, België, Nederland) en de VS plaats. Iedere onderzoeker heeft uitgebreide ervaring met het gebruik van het GYNECARE PROLlFT*bekkenbodemreparatiesysteem. REGULATORISCHE STATUS: 510k toestemming (klasse II, VS); voorlopige CE-markering in Europa (klasse III). ONDERZOEKSPOPULATIE: In totaal worden 125 patiënten ingeschreven zodat er na 12 maand en ongeveer 118 evalueerbare patiënten zijn. Evalueerbare patiënten zijn gedefinieerd als patiënten die zowel basisljngegevens hebben en bij het bezoek na 12 maanden de POP-Q-evalua tie voltooid hebben. Om in aanmerking te komen voor deelname moeten vrouwelijke patiënten voldoen aan de volgende inciusiecniteria: 1. Kandidaten met symptomatische bekkenbodemverzakking van ICS POP-Q-stadiu m III of IV, die operatief gerepareerd kan worden, Een perineumreparatie, vaginale hysterectomie en/of milde urethrale slingprocedures voor incontinentie mogen gelijktijdig uitgevoerd worden. Protoco): 300-07-006 Versie 1, 29.10.2007
1 van 6
2. 18 jaar. 3. De patiënt gaat akkoord met deelname aan het onderzoek, inclusief voltoo iing van alle procedures, evaluaties en vragenlijsten, die in het kader van het onderz oek uitgevoerd moeten worden; deze instemming wordt gedocumenteerd door het informatie- en toestemmingsformulier dat door de ethische commissie /IRB goedgekeurd is, te tekenen. Patiënten die aan een van de volgende criteria voldoen, worden van deelna me aan het onderzoek uitgesloten: 1. Andere chirurgische ingrepen voor POP-reparatie die gelijktijdig worden uitgevoerd met de Gynecare Prolift +M-procedure (bijv. paravaginale reparatie, sacrocolpope xie, colporafie in een compartiment dat niet met de Gynecare Prolift+M behandeld wordt). 2. Eerdere reparatie van een bekkenbodemverzakking waarbij mesh geplaa tst is. 3. Hysterectomie die binnen 6 maanden vôôr de geplande ingreep heeft plaatsg evonden. 4. Gebruik van een experimenteel geneesmiddel of experimenteel medisc h hulpmiddel binnen 3 maanden vÖôr de geplande procedure. 5. Actieve genitale, urinaire of systemische infectie ten tijde van de chirurg ische procedure. De operatie mag bij deze patiënten uitgesteld worden tot de infectie verdwenen is. 6. Stollingsstoornis of gebruik van anticoagulantia ten tijde van de ingreep . 7. Geschiedenis van bestraling van het bekken. 8. Geschiedenis van chemotherapie binnen 6 maanden vôôr de geplande procedure. 9. Systemische ziekten die de blaas- of darmfunctie aantasten (bijv. ziekte van Parkirison, multiple sclerosis, spina bifida, letsel of trauma van het ruggenmerg). 10. Huidige evaluatie of behandeling van chronische bekkenpijn (bijv, interstitiële cystitis, endometriosis, coccydynie, vulvadynie).
()
11. De patiënt geeft borstvoedirig of is zwanger of is van plan zwanger te worden . 12. Medische aandoeningen of psychiatrische stoornissen die volgen s de onderzoeker levensbedreigend kunnen zijn of het onmogelijk maken de onderzoeksbe zoeken volgens dit protocol te voltooien. ONDERZOEKSMIDDEL: Het +M*bekkenbodemreparatiesysteem GYNECARE PROLIFT wordt bij alle onderzoekspatiënten gebruikt. Afhankelijk van waar de verzakking geloka liseerd is, kan de reparatie anterieur, posterieur of totaal zijn. De verzakking wordt gerepareerd door (een) mesh implanta(a)t(en) via de vagina te plaatsen. De voorgevormde meshimplantat en zijn vervaardigd van GYNECARE GYNEMESH M; dit is een samengesteld mesh, die uit twee compo nenten van ongeveer gelijke delen resorbeerbare poliglecapron-25 monofilamen t vezel en niet resorbeerbare polypropyleen monofilament vezel bestaan. Na resorptie van de resorbeerbare Protocol: 300-07-006 Versie 1, 29.10.2007
2 van 6
component is het gewicht van de resterende polypropyleen ongeveer 28 g/m , vergeleken met 2 45 g/m voor Gynemesh PS. 2 In combinatie met deze procedure kan een hysterectomie uitgevoerd worden of kan de baarmoeder behouden worden. Spanningsvrije steunprocedures die gebruik maken van een midurethrale polypropyleen sling voor de behandeling van stressincontinentie kunnen tegelijk met de plaatsing van het GYNECARE PROLIFT +M*systeem verricht worden . PRIMAIR EINDPUNT: Er is één primair werkzaamheidseindpunt: •
POP-Q-score 12 maanden na de procedure. Succes wordt bepaald aan de hand van het bereiken van een POP-Q-score van ICS stadium 1 in het behandelde compa rtiment zonder verdere chirurgische interventie voor POP in dat compartiment.
SECUNDAIRE EINDPUNTEN: • • •
•
• •
( • • • •
•
Samenvatting van ICS-stadia bij het bezoek na 3, 24 en 36 maanden. Samenvatting van het ICS POP-Q-stadium van het behandelde compa rtiment na 3, 12, 24 en 36 maanden. Percentage patiënten bij wie de voorste rand in het hymen ligt (ciw.z. alle POP-Q-waarden zijn kleiner dan 0) en die verder geen interventie voor POP nodig hebben na 12, 24 en 36 maanden. Frequentie van de novo prolaps, gedefinieerd als het optreden van een postoperatieve prolaps (ICS-stadium II of hoger) alleen in het onbehandelde compartimen t, mits er geen preoperatief defect was in dat compartiment (d.w.z. ICS-stadium 0 of 1). Gemiddelde scores en verandering in PFDI-20-scores ten opzichte van basislijn bij de bezoeken ria 3, 12, 24 en 36 maanden, inclusief de subscores (POPDI, CRAD I en UDI). Percentage patiënten dat na 12, 24 en 36 maanden een verandering in de samenvattende PFDI-20-score 45 punten ten opzicht van de basislijn heeft. Gemiddelde scores en verandering in PFIQ-7-scores ten opzichte van basislijn bij de bezoeken na 3, 12, 24 en 36 maanden, inclusief de subscores (POPIQI CRAIO and UIQ). Percentage patiënten dat na 12, 24 en 36 maanden een verandering in de samenvattende PFIQ-7-score 36 punten ten opzicht van de basislijn heeft. Aantal dagen tot de patiënt normale activiteiten kan hervatten (lopen , autorijden, werken, huishoudelijk werk en seksuele gemeenschap). Gemiddelde verandering ten opzicht van basislijn in EuroQol (EQ-5D gezondheidsstatus) bij bezoek na 3 en 12 maanden (totaalscore met behulp van de EQ-5D -indexscore en een score voor elk afzonderlijk item). Bij patiënten die bij basislijn seksueel actief zijn, een evaluatie van de seksue le functie met behulp van de PISQ-12 bij het bezoek na 12, 24 en 36 maanden (gemiddelde scores en verandering ten opzichte van basislijn).
Protocol: 300-07-006 Vorse 1, 2910.2007
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• • • • • •
• • •
Frequentie van nieuw ontstane dyspareunie, oplossing of voortzetting van reeds bestaande dyspareuriie Frequentie van meshcompressie, zoals bepaald door pijn bij het palperen van de mesh tijdens bekkenonderzoek na 3, 12, 24 en 36 maanden. Frequentie van stugheid van de vaginale wand, zoals bepaald door de onderzoeker bij lichamelijk onderzoek na 3, 12, 24 en 36 maanden. Totale tijd in de operatiekamer. Lengte van de procedure (vanaf het moment van de eerste incisie tot de laatste hechting). Aantal nachten in het ziekenhuis (vanaf de datum van opname in het ziekenhuis tot de datum van ontslag uit het ziekenhuis, op basis van feitelijke gegevens en ‘ontslaggereedheid). Pijnscore 24 uur na de ingreep en bij het bezoek na 1 maand, gemeten met behulp van een visuele analoogschaal (VAS). De algemene impressie van de patiënt geëvalueerd op een 5-punts Likert-schaal bij de bezoeken na 3, 12, 24 en 36 maanden. Vraag over de tevredenheid met de ingreep bij de bezoeken na 3 en 12 maanden.
VEILIGHEID: • Bijwerkingen.
Ç
•
Bepaling van blootligging/erosie inclusief locatie (blootligging is ieder zichtbaar mesh of mesh dat volgens palpatie blootligt, maar niet zichtbaar is).
•
Hemoglobine en hematocriet
STATISTISCHE METHODEN: De volledige analyse wordt uitgevoerd nadat de gegevens van alle patiënten beschikbaar zijn na 12 maanden; de follow-up-analyse wordt verricht nadat de gegevens van alle patiënten beschikbaar zijn na 24 en 36 maanden. Een interimanalyse wordt na 3 maanden op de gegevens van ten minste 60 patiënten uitgevoerd. De POP-Q-gegevens na 3 maanden worden samengevat; het succescriterium wordt echter niet toegepast. Alle andere parameters worden iriden van toepassing samengevat. Aangezien het primaire eindpunt pas na 12 maanden relevant is, zijn er geen stopregels, hoewel aan alfa willekeurig een waarde van 0,002 (tweezijdig) wordt toegekend. Aangezien dit geen vergelijkend onderzoek is, worden eenzijdige betrouwbaarheidsintervallen van 97,6% (gecorrigeerd voor interimanalyse) geschat voor recidief van POP-Q (gedefinieerd als stadium II of chirurgische herinterventie) na 12 maanden. Hoewel in dit onderzoek geen hypothese getoetst wordt, wordt een bovenste eenzijdig BI van 97,6% dat niet groter is dan 20% beschouwd een goed resultaat te zijn.
Protocol: 300-07-006 Verste 1, 29.10.2007
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De volgende primaire eindpunten worden geanalyseerd met behulp van de per protocol-set. POP-Q-score 12 maanden na de procedure. Succes (totaal) wordt bepaald aan de hand van het bereiken van een POP-Q-score van ICS stadium 1, zonder verdere interventie voor POP. Met 118 evalueerbare patiënten moeten er 15 of minder recidieven zijn om het bovenste 976%BI op of onder 20% te laten vallen met behulp van exacte binomiale betrouwbaarheidsintervallen.
TIJD- EN PROCEDURESCHEMA: Het tijd- en procedureschema voor dit onderzoek wordt op de volgende pagina weergegeven.
Ç.)
(
Protocol: 300-07-006 Versie 1, 29.10.2007
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Pro-
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Bezoek 2
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Bezoek 3
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Bezoek 4
(+1-14 dagen)
ingreep
chirurgische evaluatie, 1 maand na do
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Bezoek 5
chirurgischo evaluatie, 3 maanden na de Ingreep (+1- 14 dagen)
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Bezoek 6
de ingreep (+1-28 dagen)
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chirurgische evaluatie,
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Protocol: 300-07-006 Versie 1, 29.10.2007
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Atleen bij patiënten die bij basisljn seksueel actief zijn. 5 4 Dagboeklçaart 5 uitgereikt. . Evaluatie van pijn bij palperen en stugheid van de vaginale wand
—
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Bezoek 8
(+1-90 dagen)
na do ingreep
24maandon (+1-56 dagen)
Post chirurgische evaluatie, 36 maanden na do Ingreep
chirurglsche evaluatie,
Post-
geövalueerd wordt als
WOlK van etoe net eerst optr000t. Zwangetshepstest vô?fdi proceaure çpauenien in ae vrucntoare leeruja). i-n en ii tot maximaal 21 dagen vôôr de ingreep, en 24 uur na de ingreep of ten tijde van het ontslag welk van beide het eerst optreedt Lopen, autoniden. huishoudelijk werk, werken en seksuele gemeenschap bij volgende bezoeken opnieuw gevraagd als activiteit nog niet hervat is.
X X X X
X
X X
X X
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Bezoek 1
procedure
Chirurgisc ho procedure
TIJD- EN PROCEDURESCHEMA
PROTOCOL 300-07-006
:linlscho prestaties van het GYNECARE PROLIFT +M-be’ hulpmiddel voor een bekkenbodemverzakklng
Binnen 90 dagen vöôr de chlrurglsche
(screening)
chirurgische evaluatie
ingreep Gynaecologische Interventie (indien nodig> werkingen a uur na ae Ingreep, or ten tijoe van net ontslag
Vragenlijst over tevredenheid met de
Zwangersctiapstest, I-IbIHCT 2 Hervatten van activiteiten Globale impressie patiënt
Documentatie van intermitterende katheterisatie Datum ontslag: gereed en feitelijk
katheier
Analgesie na de procedure Profylactische vaginale of orale oestrogenen en profylactische antibiotica Verwijdering van de chirurgische
PFIQ-7-vragenlijst PISQ-12-vragenlijst PFDI-20-vragenljst Euro-QOL Intraoperatieve gegevens Pijn VAS
Ledigingsfunctie POP-Q-evaluatie
Bekkenonderzoek
lndusie/exciusie Geïnformeerde toestemming Opnemen van demografische gegevens Medische/cliirurgische geschiedenis Lichamelijk onderzoek
Procedures
Een prospoctlef, multicentar onderzoek waarin
1.3
Patiëntinformatieformulier
Volledige titel: Een prospectief, multicenter onderzoek waarin de klinische effecten van het GYNECARE PROLIFT +M* bekkenbodem reparatiesysteem geëval ueerd wordt als hulpmiddel voor een verzakkingsoperatie 1.
Inleiding
U wordt gevraagd om deel te nemen aan een wetenschappelijk onderzoek. Voor u
besluit deel te nemen, is het van belang dat u begrijpt waarom dit onderzoek gedaan wordt en wat het inhoudt voor u. Neem de tijd om de onderstaande informatie zorgvuldig te lezen en deze, indien u wilt, met anderen te bespreken. Als iets niet duidelijk is of u wilt graag meer informatie hebben, dan kunt u dat aan uw onderzoeksarts vragen. Als u besluit om aan het onderzoek deel te nemen, wordt u gevraagd het toestemmingsformulier dat aan dit informatieblad voor patiënten bevestigd is, te tekenen. 2. Wat is het doel van dit onderzoek? Ongeveer 10% van de vrouwen krijgt tijdens hun leven last van een vaginale verzakking (het gevoel dat u een bobbel hebt in of buiten uw vagina). Een verzakking kan enkele verontrustende symptomen veroorzaken, zoals controleveriles over uw blaas of darmen en kan bovendien uw seksleven negatief beïnvloeden. Er is een aantal chirurgische procedures bekend om een verzakking operatief te herstellen. Soms wordt er mesh (stukje gaas) geplaatst in uw bekken om het verzwakte weefsel te ondersteunen. Er is momenteel een aantal onderzoeken gaande om het type mesh te vinden dat het meest geschikt is om een vaginale verzakking te herstellen. Het GYNECARE PROLIFT + M* bekkenbodemreparatiesysteem lijkt op een mesh die al voor deze procedure gebruikt wordt, maar in het huidige onderzoek is deze lichter van gewicht.
Q
Afhankelijk van waar de verzakking gelokaliseerd is, kan de mesh aan de voorkant en/of achterkant van de vaginawand geplaatst worden. De mesh is vervaardigd uit oplosbaar poliglecapron-25 monofilament vezel en niet-oplosbaar polipropyleen monofilament vezel, dat een zacht flexibel materiaal is. Deze mesh heet ULTRAPRO*. ULTRAPRO* is momenteel alleen goedgekeurd voor gebruik bij hernia (iesbreuk) operaties en is (nog) niet goedgekeurd voor gynaecologische operaties. Dit onderzoek is het eerste onderzoek naar het gebruik van deze mesh bij vaginale verzakkirigoperaties. Het doel van dit onderzoek is te zien hoe de nieuwe, lichtere mesh functioneert bij vrouwen na een vaginale verzakkingoperatie. In totaal nemen 125 vrouwen in ongeveer 10 ziekenhuizen in Europa en de VS aan het onderzoek deel. 3. Waarom ben ik gevraagd? U bent gevraagd om deel te nemen aan het onderzoek omdat u een vaginale verzakking hebt waardoor u bepaalde symptomen kunt hebben, zoals: het gevoel dat er een bobbel in of buiten uw vagina zit, problemen met de ontlasting en/of plassen, pijn in het bekken of pijn tijdens de seksuele gemeenschap. Uw onderzoeksarts heeft uw medische geschiedenis gecontroleerd en is van mening dat u een geschikte proefpersoon bent voor deze procedure. 1 van 10
Reinier de Graaf Groep, versie december 2007
4. Moet ik deelnemen? Het is aan u om te beslissen of u wel of niet wilt deelnemen. Als u besluit om aan het onderzoek deel te nemen, krijgt u dit informatieblad dat u kunt houden en wordt u gevraagd een toestemmingsformulier te tekenen. U kunt zich ook tijdens het onderzoek te allen tijde en zonder opgaaf van redenen terugtrekken. Als u besluit zich op een gegeven moment terug te trekken of besluit niet aan dit onderzoek deel te nemen, heeft dit geen invloed op de zorg die u krijgt.
5. Wat gebeurt er met me als ik deelneem? Als u besluit om deel te nemen, wordt u gevraagd het toestemmingsformulier dat bij dit informatieblad is gevoegd, te ondertekenen. U wordt verzocht 7 keer naar het ziekenhuis te komen: screeningsbezoek, de dag van uw operatie, follow-up bezoeken die 6 weken, 3, 12 en 24 maanden na de ingreep plaatsvinden. Het laatste bezoek vindt 3 jaar na de procedure plaats. Bezoek 1 Screeningsbezoek Bij het eerste bezoek wordt u door uw onderzoeksarts lichamelijk en inwendig onderzocht. Hijlzij neemt bovendien enkele metingen om te bepalen wat de afmeting en de locatie van uw verzakking is. De arts stelt u vragen over eventuele medische problemen die u hebt en over eerdere operaties. U wordt gevraagd drie vragenljsten in te vullen over de symptomen van uw verzakking en over uw kwaliteit van leven. Als u seksueel actief bent of daartoe een wens hebt, wordt u gevraagd nog een vragenlijst in te vullen over hoe de verzakking uw seksleven beïnvloedt. IJ kunt deze vragenljsten in afzondering invullen en het duurt ongeveer 10 minuten om de vragenlijsten in te vullen. -
Als uw arts besluit dat tegelijk met het operatieve herstel van uw verzakking ook een andere procedure uitgevoerd moet worden, zal hij/zij dit met u bespreken. Bezoek 2 Dag van de procedure V65r de procedure wordt u gevraagd bloed te geven voor een routine bloedtest; er wordt ongeveer 10 ml (1-2 theelepels) bloed uit uw arm afgenomen en in een buisje verzameld. Als u in de vruchtbare leeftijd bent, wordt een bloed- of urinezwangerschapstest uitgevoerd om te bevestigen dat u niet zwanger bent. —
De procedure wordt in de operatiekamer onder algemene of regionale ariesthesie (ruggenprik) uitgevoerd. De anesthesist zal met u beslissen welk type anesthesie u krijgt; uw anesthesist zal de anesthesie en de daaraan verbonden risico’s met u bespreken. Een katheter (een kleine flexibele slang) wordt in uw blaas geplaatst om uw urine tijdens de procedure en korte tijd na de procedure af te voeren. Dit betekent dat uw urine afgevoerd wordt, zodat u niet naar het toilet hoeft te gaan. Het operatieve herstel van uw verzakking wordt tot stand gebracht door afhankelijk van de locatie en de afmeting van uw verzakking, een of twee mesh implantaten in uw vagina te plaatsen. Uw onderzoeksarts kan ervoor kiezen een andere procedure te combineren met het operatieve herstel van uw verzakking, zoals de verwijdering van uw baarmoeder en/of plaatsing van een sling om urine incontinentie te behandelen (“bandje onder Reinier de Graaf Groep, versie december 2007
2van 10
de plasbuis’). Uw onderzoeksarts zal deze opties vôôr de operatie met u bespreken. Na de operatie wordt u naar de afdeling gebracht en door het verplegend personeel gecontroleerd en verzorgd. Als u pijn of ongemak hebt, kunt u om extra pijnmedicatie vragen. U blijft minstens twee nachten in het ziekenhuis; dit kan ook langer zijn afhankelijk van het oordeel van uw arts en hoe u zicht voelt. Bezoek 3— De dag waarop u ontslagen wordt U wordt gevraagd bloed te geven voor een routine bloedtest; er wordt ongeveer 10 ml (1-2 theelepels) bloed uit uw arm afgenomen en in een buis verzameld. Na 25 uur of op de dag dat u uit het ziekenhuis wordt ontslagen, krijgt u ook een vraag over de hoeveelheid pijn die u hebt. Uw urine katheter kan verwijderd worden of u krijgt te horen wanneer en hoe de katheter in de komende paar dagen verwijderd moet worden. Voordat u het ziekenhuis verlaat, krijgt u een dagboekkaart waarop u kunt noteren wanneer u uw normale activiteiten weer hervat hebt. U kunt ons helpen door deze dagboekkaart precies in te vullen en mee te brengen naar het volgende bezoek. Het verdient aanbeveling inspannende activiteiten 3-4 weken te vermijden en seksuele gemeenschap tot tenminste zes weken na de operatie te vermijden. Bezoek 4— Opvolgbezoek Zes weken na uw operatie komt u naar het ziekenhuis voor een inwendig onderzoek. U krijgt vragen over eventuele pijn na de operatie en andere symptomen waar u last van hebt. De dagboekkaart met de datum waarop u normale activiteiten hervat hebt, wordt gecontroleerd. Als u sommige activiteiten ten tijde van dit bezoek nog niet hervat hebt, wordt u gevraagd de dagboekkaart te houden en in te vullen wanneer u deze activiteiten wel hervat hebt. Bezoek 5 en 6— Opvoigbezoeken na 3 en 12 maanden U bezoekt het ziekenhuis voor een inwendig onderzoek. U wordt gevraagd de vragerilijsten over uw symptomen en kwaliteit van leven in te vullen; u hebt deze vragenlijsten ook aan het begin van het onderzoek ingevuld. U wordt altijd gevraagd hoe het met u gegaan is sinds het laatste bezoek en of u sindsdien andere medische of chirurgische behandelingen hebt ondergaan. U wordt ook gevraagd of u normale activiteiten hervat hebt en of u tevreden bent met uw operatie. Bezoek 7 en 8— Opvolgbezoeken na 2 en 3 jaar U bezoekt het ziekenhuis voor een inwendig onderzoek. U wordt gevraagd de vragenljsten over uw symptomen en kwaliteit van leven in te vullen; u hebt deze vragenljsten ook aan het begin van het onderzoek ingevuld. U wordt altijd gevraagd hoe het met u gegaan is sinds het laatste bezoek en of u sindsdien andere medische of chirurgische behandelingen hebt ondergaan. Als u de kliniek vaker moet bezoeken dan normaal is na een dergelijke procedure, worden uw reiskosten vergoed. Uw onderzoeksarts zal dit met u bespreken. 6. Wat moet ik doen? Het is belangrijk dat u naar alle opvoigbezoeken komt. U wordt verzocht de datum te noteren waarop u normale activiteiten hervat hebt na uw operatie. De symptoomvragenhijst moet door u persoonlijk worden ingevuld. Neem de tijd om de vragenlijst in te vullen. Sommige vragen zijn persoonlijk van aard, maar u wordt verzocht ze zo goed mogelijk alle te beantwoorden. U kunt erop vertrouwen dat uw antwoorden op deze vragen strikt vertrouwelijk behandeld worden. Reinier de Graaf Groep, versie december 2007
3 ‘san 10
Als u in de vruchtbare leeftijd bent, mag u niet zwanger zijn aan het begin van het onderzoek en u mag niet van plan zijn (meer) kinderen te krijgen. Deze procedure kan uw vermogen om een kind te baren belemmeren. Als u zwanger wordt, is het belangrijk dat u uw onderzoeksarts onmiddellijk raadpleegt. 7. Welk hulpmiddel of procedure wordt in dit onderzoek getest? Het GYNECARE PROLIFT + M*bekkenbodemreparatiesysteem is een nieuwe, lichtere mesh die nog niet eerder bij gynaecologische procedures toegepast is. Deze mesh wordt gebruikt bij hemia(liesbreuk)operaties en bestaat uit ongeveer gelijke delen van een oplosbare vezel (poliglecapron-25 monofilament) en een niet oplosbare vezel (polypropyleen monofilament). De GYNECARE PROLIFT + M*mesh is goedgekeurd voor gebruik in de \renigde Staten, maar heeft in Europa voor deze operatie nog geen goedkeuring (geen CEmarkering).
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8. Welke alternatieven zijn er voor de behandeling? Er zijn andere behandelingen mogelijk met een gelijksoortige mesh, die via uw vagina of uw buik wordt ingebracht. U kunt weigeren deel te nemen en wordt dan toch normaal door uw onderzoeksarts behandeld. U kunt er ook voor kiezen geen enkele verdere behandeling te ondergaan. Uw onderzoeksarts kan u informatie geven over uw toestand en de voordelen en risico’s van de verschillende behandelingsopties. We moedigen u aan deze keuzes met uw onderzoeksarts te bespreken. 9. Risico’s van de procedure: De risico’s voor deze procedure verschillen naar verwachting niet van de bekende risico’s van andere chirurgische operaties van een verzakking. • Een gat of scheur in de bloedvaten, zenuwen, blaas, urinebuis of darmen kan tijdens het doorvoeren van de GYNECARE PROLIFT-geleider voorkomen; dit moet dan misschien operatief hersteld worden. • Het kan gebeuren dat u problemen met plassen of incontinentie krijgt. • Andere problemen die gewoonlijk verband houden met een reparatie van een verzakking zijn onder andere pijn tijdens de seksuele gemeenschap en bekkenpijn. • Infecties na de operatie zijn gewoonlijk mild van aard en kunnen met antibiotica behandeld worden. • Littekenweefsel dat tot samendrukking van het implantaat leidt. • Zeer zelden doet zich bij een operatie van dit type een reactie op de anesthesie, een hartaanval of de dood voor. Hieronder worden de bekende risico’s van chirurgisch herstel van een verzakking met behulp van mesh beschreven: •
•
In zeldzame gevallen kan er een reactie op het meshmatenaal optreden, zoals blootligging van de mesh waarvoor het nodig kan zijn een deel of alle mesh te verwijderen. Een klein stukje mesh kan verwijderd worden met een eenvoudige procedure, maar verwijdering van het hele stuk mesh betekent dat u een nieuwe operatie moet ondergaan. Fistelvorming (ontstaan van een verbinding tussen uw darmen en de vagina) is een zeldzaam probleem dat chirurgisch hersteld moet worden.
Bijwerkingen die na een gynaecologische procedure met anesthesie gemeld worden, zijn onder andere: 4 van 10 Reinier de Graaf Groep, versie december 2007
• • • • • •
pijn en ongemak kramp/bekkenpijn vaginale afscheiding vaginaal bloedverlies / minimaal bloedverlies vermoeidheid misselijkheid en braken
Risico’s van het verzamelen van bloedmonsters
•
flauwvallen
• • • • • •
ontsteking van de ader duizeligheid pijn blauwe plekken bloeding bij de wond zelden kan een infece op de plaats van de punctie ontstaan
10. Wat zijn de andere mogelijke nadelen en risico’s van deelname? Er kunnen nsico’s zijn van het gebruik van GYNECARE PROLIFT + M* die nog niet
bekend zijn. Uw onderzoeksarts zal u inlichten over eventuele nieuwe veiligheidsinformatie over dit hulpmiddel dat tijdens dit onderzoek beschikbaar komt.
11. Wat zIjn de mogelijke voordelen van deelname? Mogelijke voordelen kunnen zijn dat uw vaginale verzakking hersteld wordt en uw symptomen afnemen. De informatie die door dit onderzoek verkregen wordt kan bovendien nuttig zijn bij het ontwikkelen van nieuwe hulpmiddelen en behandelingen tijdens gynaecologische procedures. Deze kennis kan de medische wetenschap verder helpen en andere patiënten met een vaginale verzakking kunnen hiervan profiteren. Het is mogelijk dat u geen direct voordeel hebt van uw deelname aan dit onderzoek.
C)
12. Wat gebeurt er als relevante, nieuwe Informatie beschikbaar komt? Soms komt in de loop van een wetenschappelijk onderzoek nieuwe informatie beschikbaar over de behandeling die onderzocht wordt. Als dit gebeurt, zal de onderzoeksarts u hierover informeren en met u bespreken of u met het onderzoek wilt of moet doorgaan. Als u besluit niet verder te gaan, zal uw onderzoeksarts ervoor zorgen dat uw medische zorg gecontinueerd wordt. Als u besluit om verder te gaan met het onderzoek, wordt u gevraagd een nieuwe versie van het toestemmingsformulier te tekenen. Het is ook mogelijk dat uw onderzoeksarts op basis van de nieuwe informatie besluit dat het beter voor u is om u uit het onderzoek terug te trekken. Hij of zij zal u in dat geval de redenen hiervoor uitleggen en ervoor zorgen dat uw medische zorg gecontinueerd wordt. Als het onderzoek om enige andere reden gestopt wordt, krijgt u te horen waarom
en wordt gezorgd dat u verder behandeld wordt.
5
Reinier de Graaf Groep, versie december 2007
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_____
13. Wat gebeurt er als ik niet verder aan het onderzoek wil meedoen? U kunt zich op ieder gewenst moment zonder opgaaf van redenen uit het onderzoek terugtrekken. Als u besluit zich terug te trekken of besluit niet aan dit onderzoek deel te nemen, heeft dit geen invloed op de zorg die u knjgt. 14. Wat gebeurt er als er Iets fout gaat? Informatie proefpersonenverzekering (zie bijlage). 15. Wat moet ik doen als ik nog vragen heb? Als u een klacht wilt indienen over enig aspect van de manier waarop u benaderd of behandeld bent in de loop van dit onderzoek, staan de normale klachtenprocedures in dit ziekenhuis tot uw beschikking.
U krijgt een kopie van het patiëntinformatieblad en een getekende en gedateerde kopie van het toestemmingsformulier die u kunt behouden.
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Met wie kan ik contact opnemen voor meer informatie of als ik vragen of problemen heb tijdens het onderzoek? U kunt contact opnemen met: gynaecoloog. 10.2.e Telefoonnr: 015 Mochten nog vragen overblijven dan kunt u contact opnemen met de projectleider van het onderzoek in het ziekenhuis. De projectleider in het ziekenhuis is
10.2.e
gynaecoloog (tel. nr.: 015—
Voor klachten omtrent het onderzoek lunt u contact opnemen met de klachtenfunctionaris van ons ziekenhuis, coördinator klachtenopvang, tel. nr. 015 10.2. e —
Als u twijfelt over deelname kunt u een onafhankelijke arts raadplegen, die zelf niet bij
Ç
)
het onderzoek betrokken is, maar die wel deskundig is op het gebied van dit onderzoek. Ook als u voor of tijdens de studie vragen heeft die u liever niet aan de onderzoekers stelt, kunt u contact opnemen met de onafhankelijke arts: gynaecoloog, tel. nr.: 024
‘
16. Zal mijn deelname aan dit onderzoek vertrouwelijk blijven? Als u instemt met deelname aan dit onderzoek, krijgt u een uniek onderzoeksnummer dat samen met uw initialen en geboortedatum gebwikt wordt om u in de database van het onderzoek te identificeren. Uw identiteit blijft vertrouwelijk. De informatie wordt doorgegeven aan Ethicon Clinical Development & Medical Affaires (CDMA) en Johnson & Johnson Medical Limited in het VK. De resultaten van de monsters die tijdens het onderzoek verzameld worden, worden vernietigd nadat de resultaten gedocumenteerd zijn. De informatie die rechtstreeks tot u herleid kan worden, wordt naar verwachting in 2025 gewist, maar het kan nodig zijn deze informatie langer te moeten bewaren als dit vereist wordt door regelgevende instanties.
Reinier de Graaf Groep, versie december 2007
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Door toestemming te geven voor deelname aan dit onderzoek, gaat u ermee akkoord dat uw onderzoeksarts, geautoriseerd personeel van Ethicon of bedrijven die voor Ethicon werken en mogelijk de van toepassing zijnde regelgevende gezondheidsinstanties van de overheid inzage hebben in uw medische dossier. Het doel van deze inzage van uw medische dossier is ervoor te zorgen dat uw informatie correct in de database ingevoerd is. Alle betrokkenen zijn ten overstaan van u, als deelnemer aan het onderzoek, verplicht uw gegevens vertrouwelijk te behandelen en niets dat uw identiteit zou kunnen onthullen, wordt buiten het onderzoekscentrum vrijgegeven. Uw gegevens worden in overeenstemming met de Europese wetgeving met betrekking tot de Bescherming van Persoonsgegevens opgeslagen. Door toestemming te verlenen voor deelname aan dit onderzoek, gaat u ermee akkoord dat uw gegevens in overeenstemming met deze wet worden opgeslagen.
(j)
Uw gegevens worden in dit onderzoek op papieren formulieren verzameld en veilig door Ethicon opgeslagen. De gegevens die tijdens het onderzoek worden verzameld, kunnen voor verwerkingsdoeleinden of analyse, enz. worden doorgestuurd naar samenwerkende onderzoekers buiten de Europese Economische Ruimte. Sommige landen buiten Europa hebben misschien geen wetten die uw privacy in dezelfde mate beschermen als de Europese wetten. Ethicon zal er al het redelijke aan doen om uw gegevens te beschermen en uw identiteit zal vertrouwelijk blijven. Uw gegevens worden voor onbepaalde tijd veilig opgeslagen; alleen gemachtigd personeel van Ethicon of bedrijven die voor Ethicon werken en mogelijk van toepassing zijnde regeïgevende gezondheidsinstanties van de overheid hebben toegang tot deze gegevens. U kunt uw toestemming op ieder gewenst moment intrekken. Als u uw toestemming intrekt, kunt u niet blijven deelnemen aan het onderzoek en worden er na deze datum geen verdere gegevens over u verzameld. Alle gegevens die eerder geregistreerd zijn kunnen gebruikt worden zoals hierboven beschreven is. Als u toestemming geeft voor deelname aan dit onderzoek wordt uw huisarts van uw deelname op de hoogte gebracht.
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17. Wat gebeurt er met de monsters die ik geef? Twee keer wordt een klein bloedmonster uit uw arm genomen een keer voorafgaande aan uw procedure en een keer de dag na uw procedure. Het monster wordt naar het laboratorium van het ziekenhuis gestuurd waar het geanalyseerd wordt. De resultaten worden op de gebruikelijke wijze naar uw onderzoeksarts gestuurd. Het lab vernietigt de bloedmonsters een paar dagen nadat het rapport verzonden is. —
Afhankelijk van de normale ziekenhuispraktijk kunt u voorafgaande aan uw procedure gevraagd worden een urine- of bloedmonster te geven voor een zwangerschapstest. Het urinemonster wordt vernietigd zodra het resultaat bekend is; het bloedmonster wordt een paar dagen nadat het resultaat gerapporteerd is, vernietigd. 18. Wat gebeurt er met de resultaten van het onderzoek? Wanneer het onderzoek voltooid is, worden alle resultaten geanalyseerd en kunnen in een medisch tijdschrift gepubliceerd worden (terwijl uw identiteit vertrouwelijk blijft). Dit vindt waarschijnlijk ergens in 2011 plaats. Als u een kopie van de resultaten wilt ontvangen, kunt u dit aan de onderzoeksarts laten weten. Reinier de Graaf Groep, versie december 2007
7 van 10
U dient te weten dat alle gegevens van deelname aan het onderzoek gehanteerd, opgeslagen en vernietigd worden in overeenstemming met de plaatselijke regelgeving op het gebied van de bescherming van persoonsgegevens. De resultaten van dit onderzoek kunnen in de toekomst gebruikt worden voor verdere analyses die op dit moment niet voorzien kunnen worden. Het gaat dan bijvoorbeeld om een meta-analyse, waarbij de resultaten van verschillende gelijksoortige onderzoeken gecombineerd worden. 19. Wie organiseert en financiert het onderzoek? Ethicon Clinical Development & Medical Affairs (CDMA), Johnson & Johnson Medical Ltd, VK financieren dit onderzoek.
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20. Wordt mijn onderzoeksarts betaald voor mijn deelname? Het ziekenhuis wordt betaald voor het aantal patiënten dat aan het onderzoek deelneemt. Deze betaling dekt de aanvullende kosten van uw behandeling in het kader van het onderzoek. Deze betaling dekt dus ook de kosten van het extra administratieve werk, zoals het invullen van de formulieren die we gebruiken om de informatie te verzamelen die we nodig hebben. Artsen ontvangen geen persoonlijke gelden voor hun betrokkenheid bij het onderzoek. 21. Door wie is het onderzoek beoordeeld? Dit onderzoek is beoordeeld door de Medisch Ethische Toetsingscommissie Zuidwest Holland. 22. Contactgegevens Met wie kan ik contact opnemen voor meer informatie of als ik vragen of problemen heb tijdens het onderzoek? U kunt contact opnemen met: Telefoonnr: 015
,
gynaecoloog.
1O.2.e
U wordt bedankt voor de tijd die u hebt genomen om deze informatie te lezen
Reinier de Graaf Groep, versie december 2007
8 van 10
______ ______
TOESTEMMINGSFORMULIER VOOR PATIÈNTEN
Een prospectief, multicenter onderzoek waarin de klinische prestaties van het GYNECARE PROLIFT +M* bekkenbodemreparatiesysteem geëvalueerd wordt als hulpmiddel voor een bekkenbodemverzakking. 1
Plaats uw initialen in het vakje Ik heb het patiëntinformatieblad, versie 29 oktober 2007, voor bovengenoemd onderzoek gelezen en begrepen en een kopie ervan gehouden.
2
Ik heb het onderzoek met de onderzoeksarts besproken en al mijn vragen zijn naar tevredenheid beantwoord.
3
Ik heb het doel van het onderzoek begrepen en weet op welke manier ik bij het onderzoek betrokken zal zijn.
4
Ik heb op dit moment geen behoefte aan verdere informatie, maar begrijp dat ik op ieder gewenst moment om nadere informatie kan verzoeken.
5
Ik kan weigeren om aan dit onderzoek deel te nemen of me op ieder gewenst moment zonder opgaaf van redenen tewgtrekken zonder dat dit invloed heeft op mijn medische zorg of wettelijk rechten.
6
Ik begrijp dat gedeelten van mijn medisch dossier kunnen worden bekeken door verantwoordelijke medewerkers van Ethicon Johnson & Johnson Medical Ltd of door hen aangewezen personen, of door regelgevende instanties wanneer dit relevant is voor mijn deelname aan dit onderzoek.
(
L
Ik ga ermee akkoord dat deze personen mijn gegevens mogen inzien. 7
Ik begrijp dat mijn medische dossier gehanteerd, opgeslagen en vernietigd zal worden in overeenstemming met de plaatselijke regelgeving op het gebied van de bescherming van gegevens.
8
Ik begrijp dat sommige van de landen waarnaar mijn anoniem gemaakte gegevens gestuurd kunnen worden, misschien niet eenzelfde mate van bescherming van mijn persoonlijke gegevens bieden als Nederland, maar Ethicon zal alle redelijke stappen doen om mijn recht op privacy te beschermen.
9
Ik stem erin toe om deel te nemen aan het hierboven beschreven onderzoek.
Reinier de Graaf Groep, versie december 2007
9 van 10
Naam van de patiënt
——
Naam van de persoon die toestemming verkrijgt (als dit iemand anders is dan de onderzoeker)
Datum
Handtekening
Datum
Handtekening
Hierbij verklaar ik dat de bovengenoemde proefpersoon schriftelijk en mondeling is ingelicht over de aard en het doel, de procedures en mogelijke risico’s van deelname aan de studie.
i:. Onderzoeker
Datum
Handtekening
De patiënt MOET dit formulier PERSOONLIJK tekenen EN dateren, Li wordt verzocht de patiënt een kopie van dit Ingevulde en getekende formulier en een kopie van het patiëntinformatieblad te geven dat zij kan houden. Berg het originele, getekende en gedateerde formulier op in de onderzoeksmap van de onderzoeker.
10 van 10 Reinier de Graaf Groep, versie december 2007
Informatie over verzekeringstechnische aspecten voor patiënten die deelnemen aan het onderzoek. Als U deelneemt aan het onderzoek bent U verzekerd tegen eventuele schade die deelname aan het onderzoek met zich mee zou kunnen brengen. Overeenkomstig de Wet medisch-wetenschappelijk onderzoek met mensen heeft de Reinier de Graaf Groep voor medisch-wetenschappelijk onderzoek een verzekering afgesloten die door het onderzoek veroorzaakte schade door dood of letsel van de proefpersoon dekt. • •
Dit betreft schade die zich tijdens of binnen vier jaar na de deelname aan het onderzoek openbaart en gemeld is binnen vier jaar na beëindiging van de deelname aan het onderzoek. Het bedrag waarvoor de verzekering is afgesloten bedraagt € 450.000 per proefpersoon, met een maximum van € 3.500.000 voor het hele onderzoek en € 5.000.000 voor schade tengevolge van medisch-wetenschappelijk onderzoek die per verzekeringsjaar wordt gemeld.
De verzekering biedt dekking • Voor schade tengevolge van de verwezenlijking van de aan deelname aan het wetenschappelijk onderzoek verbonden risico’s waarover men niet schriftelijk is ingelicht; • Voor schade tengevolge van de verwezenlijking van de risico’s waarover de deelnemer wel is ingelicht, maar die zich in ernstiger mate voordoet dan is voorzien; • Voor schade tengevolge van de verwezenlijking van de risico’s waarover de deelnemer wel is ingelicht, maar die zeer onwaarschijnlijk werd geacht. De verzekering biedt geen dekking • Voor schade die het gevolg is van het uitblijven van een vermindering van de gezondheidsproblemen van de proefpersoon, dan wel het gevolg is van de verdere verslechtering van de gezondheidsproblemen, indien de deelname aan het wetenschappelijk onderzoek plaatsvindt in het kader van de behandeling van deze gezondheidsproblemen; • Voor schade door aantasting van de gezondheid van de proefpersoon waarvan aannemelijk is dat deze zich ook zou hebben geopenbaard wanneer de proefpersoon niet aan het onderzoek had deelgenomen; • Voor schade tengevolge van deelname aan medisch-wetenschappelijk onderzoek waarbij in de kring van beroepsgenoten gebruikelijke handelingen op het gebied van de geneeskunst met elkaar worden vergeleken en aannemelijk is dat de schade het gevolg is van de toegepaste handelingen; • Voor schade die zich bij een nakomeling van de proefpersoon openbaart als gevolg van een nadelige inwerking van het onderzoek op de proefpersoon of de nakomeling; • Voor schade die het gevolg is van het niet of niet volledig opvolgen van aanwijzingen en instructies door de proefpersoon, indien de proefpersoon daartoe althans in staat is. De verzekering dekt uitsluitend de schade van natuurlijke personen. De dekking van specifieke schades en kosten is tot bepaalde bedragen beperkt. Om aanspraak te kunnen maken op schadevergoeding dient de proefpersoon in geval van vermeende schade als gevolg van het onderzoek dit te melden aan: Naam verzekeraar Adres verzekeraar Polisnummer
: ACE Insurance N.V. : Marten Meesweg 8-10, 3068 AV Rotterdam : 2910 225 V0003
Voorts wordt de proefpersoon verzocht dienaangaande contact op te nemen met gynaecoloog Reinier de Graaf Groep (tel. 0151O.2.e ).
cj
1.4
Overzicht bekkenbodemkiachten
—
beknopt formulier 20
INSTRUCTIES Beantwoord alstublieft alle vragen van het volgende onderzoek. Er zal u worden gevraagd of u last hebt van bepaalde darm-, blaas- of bekkenbodernklachten en als dat het geval is, hoeveel last u daarvan hebt. Beantwoord deze vragen door een X in het juiste vakje of de juiste vakjes te zetten. Als u niet zeker weet welk antwoord u moet kiezen, kies dan het antwoord dat het best met uw klachten overeenkomt. Gaat u bij het beantwoorden van de vragen uit van uw klachten in de af2elopen drie maanden. ( VOORBEELD Voor de volgende vraag: Als u niet vaak hoofdpijn hebt, zet dan een X in het vakje ‘Nee’. Hebt u vaak hoofdpijn?
XNee
Ja
Als het antwoord ja is, hoeveel last hebt u hier dan van? 1 Helemaal niet
(
-
2
3
Enigszins
Matig
4 -
Vrij veel
Hebt u vaak hoofdpijn, plaats dan een X in het vakje ‘Ja’ geef aan hoeveel last u daarvan hebt. (In dit voorbeeld was de hoofdpijn matig hinderlijk). Hebt u vaak hoofdpijn?
Nee XJa
Als het antwoord ja is, hoeveel last hebt u hier dan van? 1 Helemaal niet
Dutch (Netherlands) version
X3
2 -
Enigszins
-
Matig
4 -
Vrij veel
Pagina
van 5
PRELIMINARY VERSION
Naam:
1.
Datum:
/_____
Voelt u vaak een drukkend gevoel in uw onderbuik? Nee
Ja
0 Als het antwoord ja is, hoeveel last hebt u hier dan van? 1 Helemaal niet
2.
2 Enigszins
-
3 Matig
-
-
4 Vrij veel
Hebt u vaak een zwaar ofdafgevoel in uw bekken?
(
Nee
Ja
0 Als het antwoord ja is, hoeveel last hebt u hier dan van?
1 Helemaal niet
3.
-
2 Enigszins
-
3 Matig
4 -
Vrij veel
Voelt of ziet u vaak dat er iets uit het gebied rond de vagina stuipt of valt? Nee
Ja
0 Als het antwoord ja is, hoeveel last hebt u hier dan van? 1 Helemaal niet 4.
-
2 Enigszins
-
3 Matig
-
4 Vrij veel
Moet u vaak op de vagina of rond het rectum drukken om uw ontlasting eruit te helpen?
0
Nee
Ja
0 Als het antwoord la is, hoeveel last hebt u hier dan van? 1 Helemaal niet 5.
-
2 Enigszins
-
3 Matig
-
4 Vrij veel
Hebt u vaak het gevoel dat uw blaas na het plassen niet helemaal leeg is? Nee
Ja
0 Als het antwoord In is, hoeveel last hebt u hier dan van?
1 Helemaal niet
Dutch (Netherlands) vemsion
-
2 Enigszins
-
3 Matig
-
4 Vrij veel
Pagina 2 van 5
PRELIMINARY VERSION
6.
Moet u wel eens met uw vingers op een uitstulping in het gebied rond de vagina drukken om ervoor te zorgen dat u kunt beginnen met plassen of uit kunt plassen? Nee
Ja
0 Als het antwoord ja is, hoeveel last hebt u hier dan van? 1 2 3 4 Helemaal niet Enigszins Matig Vrij veel -
7.
-
Hebt u het gevoel dat u te hard moet persen om uw ontlasting kwijt te raken? Nee
Ja
0 Als het antwoord ja is, hoeveel last hebt u hier dan van? 1 2 3 4 Helemaal niet Enigszins Matig Vrij veel -
8.
-
-
Hebt u het gevoel dat uw daen na de stoelgang niet helemaal leeg zijn? Nee
Ja
0 Als het antwoord ja is, hoeveel last hebt u hier dan van?
1 Helemaal niet 9.
-
2 Enigszins
-
3 Matig
4 -
Vrij veel
Verliest ii vaak vaste ontlasting zonder dat u daar controle over hebt? Nee
Ja
0 Als het antwoord ja is, hoeveel last hebt u hier dan van?
1 Helemaal niet
-
2 Enigszins
-
3 Matig
4 -
Vrij veel
10. Verliest u vaak dunne of vloeibare ontlasting zonder dat u daar controle over hebt? Nee
Ja
0 Als het antwoord ja is, hoeveel last hebt u hier dan van? 1 2 3 4 Helemaal niet Enigszins Matig Vrij veel -
-
-
11. Laat u vaak windjes zonder dat u daar controle over hebt? Nee
Ja
0 Als het antwoord ja is, hoeveel last hebt u hier dan van?
1 Helemaal niet Dutch (Netherlands) version
-
2 Enigszins
-
3 Matig
4 -
Vrij veel Pagina 3 van 5
PRF1IMINARV ‘ERS1ON
12, Hebt u tijdens de stoelgang vaak pijn? Nee
Ja
0 Als het antwoord ja is, hoeveel last hebt ii hier dan van? 1 2 3 4 Helemaal niet Enigszins Matig Vrij veel -
-
-
13. Voelt u vlak voor de stoelgang sterke aandrang en moet u dan zo snel mogelijk een we opzoeken? Nee
Ja
0 Als het antwoord ja is, hoeveel last hebt u hier dan van?
1 Helemaal niet
(Z
2 -
3
Enigszins
-
Matig
-
4 Vrij veel
14. Komt het tijdens of vlak na de stoelgang wel eens voor dat een stukje darm uit het rectum naar buiten stilipt? Nee
Ja
0 Als het antwoord ja is, hoeveel last hebt u hier dan van?
1 Helemaal niet
-
2 Enigszins
-
3 Matig
-
4 Vrij veel
15. Moet u vaak plassen?
Nee
Ja
0 Als het antwoord ja is, hoeveel last hebt u hier dan van?
1 Helemaal niet
-
2 Enigszins
-
3 Matig
4 -
Vrij veel
16. Hebt u vaak ongewenst urineverlies als u aandrang voelt om te plassen? Nee
Ja
0 Als het antwoord la is, hoeveel last hebt
1 Helemaal niet
-
2 Enigszins
-
ii
3 Matig
hier dan van? 4 -
Vrij veel
17. Verliest u vaak urine als u moet hoesten, niezen of lachen?
Nee
Ja
0 Als het antwoord ja is, hoeveel last hebt u hier dan van? 1
Flelemaal niet Dutch (Netherlands) version
2 -
Enigszins
-
3 Matig
4 -
Vrij veel Pagina 4 van 5
PRELIMINARY VERSION
18. Verliest u vaak kleine hoeveelheden urine (dat wil zeggen druppeltjes)? Nee
Ja
0 Als het antwoord la is, hoeveel last hebt u hier dan van?
1 Helemaal niet
-
2 Enigszins
-
3 Matig
-
4 Vrij veel
19, Hebt u vaak moeite om uw blaas te legen? Nee
Ja
0 Als het antwoord ja is, hoeveel last hebt u hier dan van?
1 Helemaal niet
()
-
2 Enigszins
-
3 Matig
-
4 Vrij veel
20. Ervaart u vaak pijn of ongemak in de onderbuik of de schaanistreek?
Nee
Ja
0 Als het antwoord ja is, hoeveel last hebt u hier dan van? 1 2 3 4 Helemaal niet Enigszins Matig Vrij veel -
-
-
Hartelijk dank voor het invullen van deze vragenlijst.
0
Dutch (Ncthcrlands) version
Pagina 5 van 5
PRELIMINARY VERSION
Protocolnummer:300-05-003
Vragenlijst invloed van bekkenbodemproblemen beknopt formulier 7
—
Initialen patiënt: Nummer patiënt:
1 1 Ï1
Instructies: sommige vrouwen ervaren dat blaas- of darmklachten of vaginale klachten invloed hebben op hun activiteiten, relaties en gevoelens. Plaats bij iedere vraag een X bij het antwoord dat het beste aangeeft in hoeverre uw activiteiten, relaties of gevoelens In de afgelopen drie maanden zijn beïnvloed door uw klachten/ aandoeningen in verband met de blaas, darmen of vagina. Geef per vraag steeds voor alle 3 de kolommen uw antwoord aan. In hoeverre zijn klachten of aandoeningen met betrekking tot»
Darmen of rectum
Vagina of bekken
El Matig El Vrij veel
El Helemaal niet LI Enigszins El Matig LI Vrij veel
El Helemaal niet El Enigszins EI Matig El Vrij veel
2. Uw vermogen lichamelijke activiteiten te ondernemen zoals wandelen, zwemmen of andere oefeningen?
LI Helemaal niet Ei Enigszins El Matig Ei Vrij veel
El Helemaal niet El Enigszins El Matig El Vrij veel
El Helemaal niet El Enigszins Ei Matig El Vrij veel
3. Het bezoeken van een uitvoering zoals een film of een concert?
El Helemaal niet El Enigszins El Matig El Vrij veel
El Helemaal niet El Enigszins El Matig El Vrij veel
El Helemaal niet El Enigszins El Matig El Vrij veel
4. Uw vermogen met de auto of de bus te reizen, verder dan 30 minuten van huis?
El Helemaal niet El Enigszins El Matig El Vrij veel
El Heiemaal niet El Enigszins El Matig El Vrij veel
El Helemaal niet El Enigszins El Matig El vrij veel
5. Uw deelname aan sociale activiteiten buitenshuis?
El Helemaal niet El Enigszins El Matig El Vrij veel
El Helemaal niet El Enigszins [1 Matig El Vrij veel
El Helemaal niet El Enigszins [1 Matig El Vrij veel
6. Uw emotionele gezondheid (nervositeit, depressie enz.)?
El Helemaal niet El Enigszins El Matig El Vrij veel
El Helemaal niet El Enigszins EI Matig El Vrij veel
El Helemaal niet Ei Enigszins El Matig El Vrij veel
7. Gevoelens van frustratie?
El Helemaal niet EI Enigszins El Matig El Vrij veel
El Helemaal nIet El Enigszins El Matig El Vrij veel
El Helemaal niet El Enigszins El Matig El Vrij veel
van invloed
1. Uw vermogen om huishoudelijk werk te doen (koken, schoonmaken, wassen)?
0
Blaas of urine
El
Helemaal niet
n Enigszins
Dutch (Netherlands) verion
PRELIMINARY VERSION
BIJLAGE B Vragenlijst verzakkin! (Pelvic Oran Prolapse /urine-incontinentie in relatie tot seksueel functioneren (PISQ- 12)
Instructies: hieronder vindt u een lijst met vragen over het seksieven van u en uw partner. Alle informatie is strikt vertrouwelijk. Uw vertrouwelijke antwoorden worden uitsluitend gebruikt om artsen een indicatie te geven van wat patiënten belangrijk vinden in hun seksieven. Kruis het vakje aan dat in uw ogen de vraag het beste beantwoordt. Gaat 1] bij het beantwoorden van de vragen uit van uw seksuele beleving van de afgelopen zes maanden. Wij danken u hartelijk voor uw medewerking. 1. Hoe vaak ervaart u seksuele verlangens? Het kan hierbij gaan om de behoefte aan seks, het voornemen om seks te hebben, frustraties als gevolg van gebrek aan seks,
enz. Dagelijks
Wekelijks
Minder dan één keer per maand
Maandelijks Nooit
2. Bereikt u een orgasme als u geslachtsgemeenschap hebt met uw partner? Altijd
Meestal
Soms
Zelden
Nooit
3. Voelt u zich seksueel geprikkeld (opgewonden) als u met uw partner vrijt? Altijd Meestal Soms Zelden Nooit 4. Hoe tevreden bent u met de variatie in uw huidige seksleven? Altijd Meestal Soms Zelden Nooit 5. Voelt u pijn tijdens de geslachtsgemeenschap? Altijd
Meestal
Soms
Zelden
Nooit
Soms
Zelden
Nooit
6. Verliest u urine tijdens het vrijen? Altijd
Meestal
7. Belemmert angst voor incontinentie (verlies van ontlasting of urine) u als u aan het vrijen bent? Altijd
Meestal
Soms
Zelden
Nooit
8. Vermijdt u geslachtsgemeenschap vanwege uitstulpingen uit de vagina (waarbij de blaas, het rectum of de vagina naar buiten zakt)? Altijd
Dutch (Nelherlands) version
Meestal
Soms
Zelden
Nooit
PRELIMINARY VERSION
9. Ervaart u tijdens het vrijen met uw partner negatieve emotionele reacties zoals angst, afkeer, schaamte of schuidgevoelens? Altijd
Meestal
Soms
Zelden
Nooit
10. Heeft uw partner erectieproblemen die van invloed zijn op uw seksuele activiteiten? Altijd Meestal Soms Zelden Nooit 11. Heeft uw partner vroegtijdige zaadlozingen waardoor uw seksuele activiteiten beïnvloed worden? Altijd
Q
Meestal
Soms
Zelden
Nooit
12. Hoe intens zijn de orgasmes die u de afgelopen zes maanden hebt gehad in vergelijking tot orgasmes die u in de periode daarvoor had? Veel minder intens Intenser
Minder intens
Even intens
Veel intenser
Score: De score wordt berekend door de scores voor elke vraag bij elkaar op te tellen waarbij 0
=
altijd, 4 = nooit. Voor vraag 1, 2, 3 en 4 geldt een omgekeerde score. De
1
beknopte vragenlijst kan worden gebruikt als er maximaal twee antwoorden ontbreken. Als er antwoorden ontbreken, dan wordt de uiteindelijke score berekend door het totale aantal vragen te vermenigvuldigen met het gemiddelde van de vragen waarop wel antwoord is gegeven. Als er meer dan twee antwoorden ontbreken, dan kan met de beknopte vragenlijst geen nauwkeurige voorspelling van de score van de uitgebreide vragenlijst worden gegeven. Om de score te vergelijken met de score voor de uitgebreide vragenlijst moet het totaal worden vermenigvuldigd met 2,58 (31/12).
Dutch (Netherlands)versjon
PRELIMINARY VERSION
Gezond heidsvragenlijst (Nedeilandse versie)
(Dutch version)
(
© EuroQoL Group 1990
Zet bij iedere groep in de lijst hieronder een kruisje in het hokje achter de zin die het best past bij uw eigen gezondheidstoestand vandaag. Mobiliteit Ik heb geen problemen met lopen Ik heb enige problemen met lopen Ik ben bediegerig Zelfzorg Ik heb geen problemen om mijzelf te wassen of aan te kleden Ik heb enige problemen om mijzelf te wassen of aan te kleden Ik ben niet in staat mijzelf te wassen of aan te kleden
0 Dagelijkse activiteiten (bfjv. werk, studie, huishouden, gezins- en vnjetijdsactiviteiten) Ik heb geen problemen met mijn dagelijkse activiteiten Ik heb enige problemen met mijn dagelijkse activiteiten Ik ben niet in staat mijn dagelijkse activiteiten uit te voeren Pijnlklachten Ik heb geen pijn of andere klachten Ik heb matige pijn of andere klachten Ik heb zeer ernstige pijn of andere klachten Stemming Ik ben niet angstig of somber Ik ben matig angstig of somber Ik ben erg angstig of somber
© EuroQoL Group 1990
2
Best
voorstelbare gezondheidstoestand
Om mensen te helpen bij het aangeven hoe goed of hoe slecht een gezondheidstoestand is, hebben we een meetschaal (te vergelijken met een thermometer) gemaakt. Op de meetschaal hiernaast betekent “100” de beste gezondheidstoestand die u zich kunt voorstellen, en “0” de slechtste gezondheidstoestand die u zich kunt voorstellen. We willen u vragen op deze meetschaal aan te geven hoe goed of hoe slecht volgens u uw eigen gezondheidstoestand vandaag is. Trek een lijn van het hokje hieronder naar het punt op de meetschaal dat volgens u aangeeft hoe goed of hoe slecht uw gezondheidstoestand vandaag is.
100
90
80
70
60
tJw gezo 11(1 I1ei(IStOCSt1 Iid
50
a n(Iaag
40
30
20
10
0 Slechtst voorstelbare gezondheidstoestand
© EuroQoL Group 1990
3
GLOBALE IMPRESSIE PATIËNT
1
Hoe vindt u dat het met u gaat vergeleken met vÖÖr uw recente bekken bodemoperatie? • • • • •
Veel beter Enigszins beter Ongeveer hetzelfde Enigszins slechter Veel slechter
Omcirkel de woorden die het meest op u van toepassing zijn.
0
Vragenlijst over tevredenheid met de ingreep Aanwijzingen: Hieronder staan een aantal vragen over uw tevredenheid met de ingreep. Alle informatie wordt strikt vertrouwelijk behandeld. Uw vertrouwelijke antwoorden worden uitsluitend gebruikt om artsen te helpen begrijpen en te verbeteren wat patiënten belangrijk vinden véér, tijdens en na de ingreep. Kruis het vakje aan dat de vraag op de beste manier voor u beantwoordt. Dank u voor uw hulp. 1. Hoe tevreden bent u met de mate waarin uw pijn na de operatie onder controle gehouden werd in het ziekenhuis? fl Zeer tevreden LI Tevreden fl Neutraal EJ Ontevreden EJ Zeer ontevreden 2. Hoe tevreden bent u met de mate waarin uw pijn na de operatie onder controle gehouden werd nadat 11 weer thuis was? EJ Zeer tevreden LI Tevreden EJ Neutraal EJ Ontevreden EJ Zeer ontevreden 3. Hoe tevreden bent u met de tijd die het duurde voordat u uw dagelijkse activiteiten, zoals huishoudelijk werk of sociale bezigheden buitenshuis, weer kon opvatten? EJ Zeer tevreden EJ Tevreden EJ Neutraal Lj Ontevreden EJ Zeer ontevreden 4. Hoe tevreden bent u met de tijd die het duurde voordat u uw werk weer kon opvatten? EJ Zeer tevreden EJ Tevreden EJ Neutraal EJ Ontevreden EJ Zeer ontevreden 5. Hoe tevreden bent u met de tijd die het duurde voordat u uw normale fitnessroutine weer kon opvatten? EJ Zeer tevreden EJ Tevreden El Neutraal EJ Ontevreden EJ Zeer ontevreden
6. Hoe tevreden bent u met de resultaten van de ingreep? Ei Zeer tevreden Ei Tevreden Neutraal EJ Zeer ontevreden
EJ Ontevreden
7. Als u op het geheel terugkijkt en ‘alles weer opnieuw zou moeten doen’, zou u de ingreep dan opnieuw ondergaan? El Ja Ei Misschien Ei Nee 8. Zou u deze ingreep aan anderen aanbevelen? EJ Ja El Misschien Ei Nee
Versie: 20 sep. 07
Als u vragen hebt over het onderzoek, kunt u contact opnemen met:
n
Versie: 20 sep. 07
PROLIFT +M* afspraak- en dagboekkaart
Women’s Health & Urology
ETHICON
36 maanden
12 maanden
3 maanden
1 maand
Procedure
Bezoek
Datum Tijd
Afspraken Locatie
Seksuele gemeenschap
Werk
Autorijden
Huishouding
Lopen
Activiteit
Datum van hervatting
N.v.t.
werkte v66r uw procedure, zet u in de tabel een kruisje in de kolom N.V.T.)
Schrijf de datum op waarop u normale activiteiten hervat in onderstaande tabel. Als de activiteit geen betrekking heeft op u, schrijft u een kruisje in de kolom N.v.t. (Bijvoorbeeld: als u niet
Hervatting van normale activiteiten
1.5
MARSH Marsh BV. Postbus 8900 3009 AX Rotterdam Telefoon 010 40 60 922 Telefax 0104060 806 www.marsh.nl
Certificaat van Verzekering OPMERKING:
Dit Certificaat van Verzekering is in geen geval van invloed op de dekking zoals die is wcergcgcven in de polis, welke in alle gevallen bindend zal zijn.
Wij, ondergetekenden, verklaren hierbij, dat wij een proefp ersonenverzekering hebben gesloten ten behoeve van:
Jaussen-Cilag B.V. Johnson & Johnson Medical BV. Cordis E.H.Q. Johnson & Johnson PRD Biosense Webster Cordis Amersfoort Cordis Roden Janssen Cilag Emea DePuy AcroMed Centocor B.V. Centocor mc. Vistakon Benelux J&J Gaba BV. Jansen Pharmaceutica N.V. EMEA Meclical Affairs TEBOTEC-VIRCO Ethicon mc., Ethicon, Jonhson & Johnson Medical Ltd. DePu International Ltd ALlA Corporation Janssen-Cilag International N.V. McNeil Consumer & Specialty Pharmaceuticals overige niet genoemde gelieerde bedrijven en dochteronder nemingen die de schade dekt in verband met haar onderzoeken met proefpersonen welke zijn gestart op of na 1 maart 2004. Verzekerden: Proefpersonen die zich ondenverpen aan een wetenschappe lijk onderzoek. 1O.2.e
fA Beeadrs Mrten Meesweg 50,3099 AV RotierOam Barile Forils BAN NL1 t FTSB 0259 990999 BIC FTSBNL2R Postbank 6622 Handelsregister Rotterdam iv. 24120005
Ec
Marsh & Mclennari Campal
MARSH
Poils nummer: 2910225 V0003 Gedekt risico: Doorlopende proefpersonenverzekeririg.
(
Verzekerd bedrag: EUR 450.000,00 als maximum per verzekerde, met een maximum van: EUR 3.500.000,00 per wetenschappelijk onderzoek en EUR 5.000.000,00 als maximum per verzekeringsjaar indien meer dan één onderzoek per jaar wordt verricht. Indien de verzekeringsovereenkomst is beëindigd geldt een verzekerd bedrag EUR 5.000.000,00 als maximum voor schade welke zich binnen vier jaar na deelname aan een wetenschappelijk onderzoek openbaart. Verzekeraar: ACE Insurance N.V. Marten Meesweg 8-10 3068 AV Rotterdam Nederland Voorwaarden: Algemene voorwaarden Marsh 2006, welke voldoen aan de eisen zoals gesteld in de Wet Medisch Wetenschappelijk Onderzoek met mensen (W.M.O.) en het Besluit verplichte verzekering bij medisch-wetenschappelijk onderzoek met mensen van 23juni 2003. n geval van discrepantie tussen dc polistekst en de wetteksi, zal de wettekst te allen tijde prevaleren. Dekkingsgebied: Nederland Verzekeringsperiode:
Gehele periode zolang de onderzoeken met proefjersonen welke zijn gestart op of na 1 maart 2004 lopen.
Rc
iO2.e
1.6
CLINICAL INVESTIGATOR’S BROCHURE
ETHICON
Women’s Health & Urology
Date: Product:
10 September 2007 GYNECARE PROLIFT+M* Pelvic Floor Repair System
Sponsor ETHICON Clinical Development & Medical Affairs, wlth addresses at: ETHICON A Johnson & Johnson Company P.O. Box 151, Route 22 West Somerville, NJ 08876-0151
0
Johnson & Johnson Medical Ltd. Simpson Parkway Kirkton Campus Livingston EH54 OAB
Sponsor Contact:
1O.2.e
Medi Director, WW, EWH&U Tel: 4-1 Fax: +1
*Tradema CONFIDENTIALITY STATEMENT
The intormatlon in this document contalns trade secrets and commercial information that are pnvileged or confidential and may not be disciosed unless such dsclosure is required by appilcable law or regulations. In any event, persons to whom the information is disclosed must be lnforrned that the information Is pnvifeged er con fidential and may not be further disclosed by them. These restrictions on disciosure will apply equally to all future information supplied to you, whlch Is indicated as privileged er confidentiai.
Final Version 1; 10 September 2007
Page 1 of 20
TABLE OF CONTENTS 1.OSUMMARY 3 2.0 INTRODUCTION 3 3.0 PRODUCT DESCRIPTION 7 3.1 MECHANISM OF ACTION: PROLIFT+M PELVIC FLOOR DEVICE SYSTEM 7 3.2 MATERIALS USED IN THE DEVICE 7 4.0 PRECLINICAL TESTING 8 4.1 Cytotoxicity 8 4.2 Sensitization 8 4.2.1 Materials were evaluated using the Murine Local Lymph Node Assay (LLNA) to assess the dernal sensitization potential of the materials 8 4.3 Irritation 8 4.4 Assessment of Burst Strength and Stiffness 8 5.0 CLINICAL INVESTIGATIONS 10 5.1 Clinical Study CT-TVM-001-03 “Prospective clinical assessment of the Total TransV aginal Mesh (TVM) technique for treatment of Pelvic Organ Prolapse 6 and 12 month resuits .” 10 5.2 Clinical Study 2003-016 “Prospective Clinical Assessment of the Total Vaginal Mesh (TVM) Technique for Treatment of Pelvic Organ Prolapse— 6 and 12 months” 12 5.3 Differences between Studies CT-TVM-001-03 and 2003-016 13 6.0 CLINICAL USE 13 7.OSTANDARDS 14 8.0 RISK ANALYSIS 14 9.0 REFERENCES 16 APPENDIXA 17 Instructions for Use (IFU) GYNECARE PROLIFT+M * Pelvic Floor Repair System 17 APPENDIXB 18 Declaration of Helsinki 18 -
Final Version 1; 10 September 2007
Page 2 of 20
1.0 SUMMARY This Clinical Investigator Brochure summarises the technical, pre-clinical and clinical information available to support the clinical investigation of GYNECARE PROLIFT+M* Pelvic Floor System. Many women with Pelvic Organ Prolapse POP seek an alternative to non-su rgical interventions of pelvic floor exercises and pessary support. Synthetic meshes have been used with increasing frequency in gynecologic surgery over the past 30 years. These synthetic meshe s have been demonstrated to be an effective alternative treatment for POP.
C)
Currently the GYNECARE PROLIFT Pelvic Floor System is licensed and market ed in treatment of POP. Whilst successful anatomical resuits are being reported follow ing of the device, there is a need to reduce the incidence of mesh-related compl ications retraction and stiffness leading to pain, inciucling dyspareunia. Replacing the existing
Europe for the the placement such as rnesh
polypropylene mesh (GYNECARE GYNEMESH PS) with a lighter weight composite mesh (GYNECARE GYNEMESH M), it is ariticipated that there will be reduction in these sympto ms. Therefore, the purpose of this study is to evaluate the clinical performance of the PROLIFT+M system in wornen with symptomatic ICS POP-Q Stage III or IV, requiring surgical correction of POP. The planned study is a prospective multi-centre (approximately 10 sites in the US and Europe) single-arm design enrolling a total of 125 women. Follow up will continue for up to 3 years following the procedure.
2.0 INTRODUCTION Pelvic organ prolapse or vaginal wall prolapse are general terms used to describ e various clinical conditions that are associated with pelvic floor relaxatiori in female subjec ts. The clinical manifestations include: •
Anterior vaginal prolapse (medial, lateral, and/or apical cystocele)
•
Posterior vaginal wall prolapse (rectocele and/or enterocele)
•
Vault prolapse (enterocele, uterine prolapse, and vaginal vault prolapse)
Pelvic organ prolapse is thought to result from a stretching, weakening or tearing of the soft tissue structures that support the pelvic organs. These tissues become compromised as a result of a weakened or damaged levator ani muscie group. This muscle group is the platfor m at the base of the pelvis responsible for supporting the pelvic organs. It works with the connec tive tissues to support these organs. As the levator ani is damaged and drops, the openin g between the levator af! is widened. Intra-abdominal forces are then relatively unopposed by the weake ned muscle.
Final Version 1; 10 September 2007
Page 3 of 20
This increases forces applied to the connective tissue support structures, which resuits in their tearing or stretching. Risk factors for pelvic organ prolapse inciude vaginal panty, neuropathy, obesity, chronic Valsalva, connective tissue disorders, prior surgery, estroge n status and advancing . Of the factors identified, vaginal panty and its associated neuropathy 4 3 2 ’ 1 age appear to play the biggest role in pelvic floor . 2 disord ers Damage to the nerves supplying the levator ani during childbirth result in weakening of muscie and subsequent prolapse of the organs. Surgical correction of these problems is a major health care issue for woman. An analysis of members of a large health maintenance organization estimated the lifetime risk of 11.1% of at east one operation for pelvic organ prolapse and urinary incontinence with a re-operation rate of 29.2%. These numbers have been confirmed in other studies . 6 Non-surgical interventions for prolapse management include pelvic floor exercis es and pessary support. Surgical options are many, made more challenging as multiple weakened regions often occur in a subject and incomplete correction of any may lead to worsen ing of the others. The surgical procedures may involve tightening and reinforcing of weake ned tissue, suspension of unsupported structures or a combination of both. The tighteninglreinforcing and suspension procedure may utilize several materi als inciuding:
Ç)
•
suture alone
•
autologous tissue
•
cadaveric material
•
allograft material
•
synthetic absorbable mesh
•
synthetic permanent mesh
Synthetic meshes, first used for abdomirial wall hernia repairs, are often produc ed from materials oniginally used for sutures. They are able to provide support where autolo gous tissues are not adequate, but they do add the risks of erosion and 7 rejection Synthetic meshes have been used . with increasing frequency in gynecologic surgery over the past 30 years 8 as material science has made advances allowing for decreased rates of erosion and rejection. Reinfo rcement of tissue is sought because of the weakened state of the subject’s own tissue. These grafts may be placed using an abdominal or vaginal approach. Polypropylene mesh has been the most widely used mesh in gynecologic surgery inciuding many types of pelvic floor repair 3 procedures . ETHICON developed a modified PROLENE Mesh identified as GYNE CARE GYNEMESH PROLENE Soft (Polypropylene) Mesh (PS), a reduced density constru ction PROLENE Polypropylene Mesh. The product is fabricated of knitteci monofilamen ts of natural and blue Final Version 1; 10 September 2007
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pigmented polypropylene produced to be more flexible than earlier versions of polypropylen e mesh. The more flexible material is intended to offer improved intraoperative handling for pelvic organ prolapse repair procedures and fewer postoperative complications. Less total polypropylen e is present per unit area when compared to traditional PROLENE mesh. One of the major issues with the use of mesh for POP repair has been the lack of standardizati on in surgical technique. Between 1999 and 2003, a group of French uro-gynecologists worked together to develop a standardized mesh shape that could be placed consistently through the vaginal route. The result of the group’s work was the creation of the Trans-Vaginal Mesh technique (TVM). TVM was the precursor to the GYNECARE PROLIFT* system for pelvic floor repair, and was the first standardized kit for POP repair. The GYNECARE PROLIFT system has been available for use since 2005, and by end of 2006, approximately 63,000 devices have been used. Overall the complicatiori rates appear to be low based on those reported through on Medical Device Vigilance Reporting (MDVR) system within ETHICON, and are detailed in the table below: INCIDENCE OF COMPLAINTS REPORTED TO ETHICON (to end 2006, based on approximately 63,000 kits used) Complication Injury
Fistula
# of Complaints Bladder Bowel Rectum Vascular/ haematoma Nerve Vesicovaginal Rectovaginal
Exposure Pain Dyspareunia Retention Voiding difficulty
1
US 2 1 4 8 0 1 1 11 4 1 4
Ex-US 2 0 1 2 1 0 0 4 0 0 0
Total Complalnts 4 1 5 10 1 1 1 15 4 1 4
The longest-term follow-up data available is with the precursor to the PROLIFT system, known as TVM (Trans-Vaginal Mesh), with anatomicalfailure rates of approximately 15% at 12 rnonths. There are numerous origoing research studies to evaluate the long-term effectiveness of PROLIFT compared with other types of repair, inciuding non-mesh repairs and mesh repairs such as sacrocolpopexy.
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Although PROLIFT significantly reduces recurrences compared to traditional POP repairs, It can lead to other complications such as mesh exposure and mesh retraction. Mesh exposure is a common complication, which can be managed by excision and closure. Mesh contraction (“shrinkage”) is less common but It is considered more serlous. It can cause vaginal anatomic distortion, which may eventually have a negative impact on sexual function. Its treatment is difficult. Additionally, the scar plate that forms with in-growth of tissue into the mesh can cause stiffness of the vagina that further impacts sexual function in a negative manner. In an effort minimize to these complications, a Iighter-weight altemative mesh for PROLIFT has been introduced. This mesh replaces the GYNECARE GYNEMESH PS used within the GYNECARE PROLIFT Pelvic Floor Repair system. The TM LILTRAPRO Mesh has been identified as a suitable candidate to replace GYNEMESH PS. It is a composite mesh, comprising two components of approximately equal parts of absorbable Polyglecaprone-25 monofUament fiber and non-absorbable polypropylene monofilamen t fiber. Following resorption of the absorbable component, the weight of the remaining polypropylen e would be approximately 28g1m , compared to 45g1m 2 2 for GYNEMESH PS. Pre-clinical evaluation in a porcine ventral hernia model demonstrated that ULTRAPROTM maintains a comparable mean burst strength to GYNEMESH PS, whilst was less stuff after tissue 10 ULTRAPROT i5 incorporation TM . currently indicated for Lissue reinforcement and long lasting stabilization of fascial structures of the abdominal wall.
However, some gynecologists have used It for POP repair though the information gathered from these cases is limited due to: the small number of cases, the mesh was placed from an abdominal rather than vaginal approach, and the size of mesh used was small relative to the current intended use. To differentiate betweeri the use of ULTRAPRO* in hernia repair and POP procedures, It will be referred to as GYNECARE GYNEMESH M. The development of the GYNECARE PROLIFT + M* system provides a composite lighter-weight mesh (GYNEMESH M) compared to the original PROLIFT system which uses GYNEMESH PS. Following resorption of the absorbable component, the weight of the remaining polypropylene will be approximately 28g1m , compared to 45g/m 2 2 for GYNEMESH PS. WhiIst successful anatomical resuits are being reported following the placement of the Prolift device, there is a need to reduce the incidence of mesh-related complications such as mesh retraction and stiffness leading to pain and dyspareunia. Replacing the existing polypropylene mesh (GYNECAR E GYNEMESH PS) with a Iighter weight composite mesh (GYNECARE GYNEMESH M), It is ariticipated that there will be reduction in these symptoms.
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3.0 PRODUCT DESCRIPTION The GYNECARE PROLIFT+M* Pelvic Floor Repair System Device The GYNECARE PROLIFT+M Total, Anterior, and Posterior Pelvic Floor Repair Systems are indicated for tissue reinforcement and long -lasting stabilization of fascial structures of the pelvic floor in vaginal wall prolapse where surgical treatment is intended, either as mechanical support or bridging material for the fascial defect. The device is supplled sterile for single use. Please refer to the Instructions for lise (IFU) presented in Appendix A.
0
3.1 MECHANISM OF ACTION: PROLIFT+M PELVIC FLOOR DEVIC E SYSTEM The GYNECARE PROLIFT+M systems are indicated for tissue reinforcement and long lasting stabilization of fascial structures of the pelvic floor in vaginal wall prolap se where surgical treatment is intended, either as a mechanical support or bridgirig material for the fascial defect. Clinical studies have shown the Prolift system provides improvement in stabilization of vaginal prolapse. 3.2 MATERIALS USED IN THE DEVICE The GYNECARE PROLIFT+M Pelvic Floor Device is single-use and must not be resterilized or reused. The device should be disposed of according to the facility ’s policies and procedures concerning biohazardous materials and waste. It is recommended that the devices are stored at a controlled room temperature and relative humidity (approximately 25°C, 60% RH), away from moisture and direct heat. The table below lists the materials used in each component of the device :
c
Component Description Mesh (mplants
GYNECARE PROLIFT GUIDE GYNECARE PROLIFT CANNULA GYNECARE PROLIFT RETRIEVAL DEVICE
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Materlal A composite mesh comprising two components of approximately equal parts of absorbable Poliglecaprone-25 monofilament fiber and non-absorbable polypropylene monofilament fiber. The handle is composed of polycarbonate and the guide is composed of 316 stainless steel needies. The Pebax (polyether block amide) tubing contains 2% Titanium Dioxide for color, 1% zinc stearate. Pebax hub contains 2% Titanium Dioxide for color. The Cannula has 304 stainless steel wire-reinforcement. The Retneval Device is composed of Prolene (polypropylene) monofilament; silicone elastomer adhesiver and polyolefin heat shrink tubing.
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4.0 PRECLINICAL TESTING In accordance to ISO 10993-1:2003 requirements for mucosal memb rane contact devces with limited contact duration (24 hours); the GYNECARE GYNEMESH M Mesh instruments for mesh application have been tested for cytotoxicity, sensitization, and irritation. AppTec Laboratory Services conducted all biocompatibility testing according to AppTe c protocols and Good Laboratory Practices (GLP). The test resuits are summarized below: 4.1 4.1.1
Cytotoxicity Test materials were evaluated for the ability to elicit a cytotoxic respon se in cultured mouse fibroblast ceils when conducted in accordance with test methods specified in ANSI/MMI/ISO 10993-5:1999.
4.1.2
1.1.2 All materials scored “0” at 24, 48 and 72 hours. “0” meanin g there was no reactivity in the test cells.
4.2 4.2.1
Sensitization Materials were evaluated using the Murine Local Lymph Node Assay (LLNA) to assess the dermal sensitization potential of the materials. Normal Salirie and Polyethylene glycol (PEG) were used as test article extracts. The stimulation index (SI) for the normal saline test article was 0.36. The Sl for the test article in PEG extract was 0.58. Note: materials are considered sensitizers at SI of 3.0.
4.2.2 4.2.3 4.2.4
4.3 4.3.1
Irritation Materials were tested to determine if any chemicals that may leach or be extracted from the test article were capable of causing local irritation to the dermal tissues of the rabbit. Testing was conducted in accordance to ISO 10993-10:2002.
4.3.2
Normal Saline and Cottonseed OiI were used as the test article extract s.
4.3.3
All materials scored a “0” for edema and erythema (no irritation) at the dermal sites for both extracts at the 24, 48 and 72 hour observation periods.
In conclusion, the test materials are considered to be non-toxic, non-se nsitizing and non-irritants. The test materials meet biocompatibility requirements per ISO 109931:2003 standards for mucosal membrane contact devices with limited contact duration (24 hours) .
4.4 Assessment of Burst Strength and Stiffness Textile Analysis of Heavywelght, Mldwelght, and Lightweight Polypr
opylene Mesh in a
Porcine Ventral Hernia Model ° 1 4.4.1 Objectives The purpose of this study was to assess the burst strength and stiffness of heavy weight (HW, Marlex), mid-weight (MW, Prolene Soft Mesh) and light weight (LW, Ultrapro) polypropylerie meshes Final Version 1; 10 September 2007
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after repair of abdominal wall defects in a porcine model. The primar y endpoint was to determine differences in mesh strength and abdominal wall compliance. A second alm was to evaluate the percent of mesh shrinkage of the different weight polypropylen e meshes after 5 months of implantation. 4.4.2
Methods
Three polypropylene meshes of differing weights were chosen for the experiment. Marlex (HW), (Bard mc, Murray Hfl1, NJ) contains 95 gIm of polypropylene and has relatively small pore measuring 0.6 mm. Prolene Soft Mesh (MW), (Ethicon, Somerville, NJ) contains 45 g/m with pores 2 measuring up to 2.4 mm. Ultrapro (LW), (Ethicon, Somerville, NJ) is a partially absorbable mesh comprisirig a weave of polypropylene and poliglecaprone, which is found in monocryl sutures. The monocryl gives the mesh added stiffness for handling, and dissolv es at approximately 90 days. The remaining polypropylene mesh contains 28 gIm 2 with pores up to 5.0 mm in size. Eighteen mini-pigs were used for the experiment. Esch pig underw ent four full-thickness defects (one per quadrant of the abdomen). Each incision was 4 cm, made through fascia and all muscle layers; the peritoneum was left intact. The fascia and muscle were left divided, and the skin and subcutaneous tissue were re-approximated with an absorbable suture and dermal adhesive. The pigs were allowed to convalesce for 3 weeks, during which time a hernia reliably formeci at the operative sites. After the 3 week recovery period, the pigs had surgery for repair of their defects. Each pig was randomly assigned to receive one type of mesh for all 4 repairs. The skin and subcutaneous tissue overlying each hernia was reopened, and a Stoppa retromuscular, sublay repair was performed. All meshes measured 8 cm x 10 cm at implan tation. A standard placement and fixation protocol was used to place all meshes.
(
The animals were survived for 5 months to allow complete healing and ensure dissolution of the absorbable poliglecaprone in the LW mesh. Euthanasia was perform ed. All animals underwent necropsy for tissue explantation. Full thickness abdominal wall at each site of mesh implantation was widely excised en bloc for immediate study. A stamp strain machine was used to determine burst bad. The stamp strain test generated a plot of bad versus displacement. Stiffness was calculated by measuring the slope of the line over the range of 250-500 N. Shrinkage was calculated as a shrink percentage of the surface area. 4.4.3
Resuits
The table below presents the resuits of the burst strength and stiffne ss.
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Marlex (HW)
Burst
Prolene Soft (MW)
Ultrapro (LW)
pre
post
pre
post
pre
Post
1165
1218
558
590
812
576*
57.2
59.1
52.9
49.1
68.6
43.2*
Strength (N) Stiffness (N/cm) denotes p>0.0001. Significance demonstrated when comparing LW post with LW pre and HW post. For reference, the burst strength of the abdominal wall fascia aione averag ed 232 N. Thus, all meshes exhibited supraphysiologic strength. The LW mesh was the least stuff (or most compliant) foilowing implantation for 5 months, but when compared to MW, It was not signifi cantiy Iess. The percent of contraction of the 3 meshes was no different. The reducti on from initial surface area was 33% for MW, 28% for HW and 29% for LW. 4.4.4
Conclusion
A reduction in the mean burst strength and stiffness occurs after 5 months implan tation of LW mesh with an absorbable monofilament. All meshes exhibited burst strengths that were much greater than the burst strength of the abdominal wall fascia aione. After tissue incorp oration, the LW mesh maintains mean burst strength comparabie to MW mesh, while becoming less stuff than HW mesh. Long-term, this may contribute to more physiologicai abdominal wall compl iance after LW mesh implantation.
L)
5.0 CLINICAL INVESTIGATIONS The foilowing discussion describes ciinicai experience in human subjects with the GYNECARE GYNEMESH PS Mesh. Two post-marketing clinical studies have been conduc ted in the US. and France under institutional/Ethics Review Board approval. Review Board requirements have been foliowed. Informed consent was received from all erirolled subjects. 5.1
Clinical Study CT-TVM-OO1-03 “Prospective clinical assessment of the Total TransVaginat Mesh (TVM) technique for treatment of Pelvlc Orgari Prolap se 6 and 12 month results.” Jacquetin B , Cosson M 1 , Berrocal J 2 , Clavé H 3 , Debodinance P 4 , Garbin 06, Rosenthal C 5 , Salet T Lizée D , Villet R 8 8 Maternité Hotei-Dieu, CHU, 2 1 Hôpital Jeanne de Fiandre, CHRU de Liiie, 3 Clinique de i’Europe, Rouen, 4 Ciinique Saint George, Nice, 5 Maternité Les Bazennes, CH de Dunkerque, 6 S1HCUSCMCO, Schiltigheim, 7 Clinique Saint Germain, Bnve-La Gaillarde, 8 Groupe Hospitalier Des Diaconesses, Paris -
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5.1.1
Objectives
The TVM technique involves a polypropylene mesh of specific size and shape that is secured tension free by extension arms that pass through the arcus tendineous via a transobturator approach anteriorly and through the sacrospinous ligament via a transgiuteal approach posteriorly. The aim of this evaluation is to report on effectiveness and complications at 6 and 12 months post TVM. 5.1.2
(
Methods
Women from 8 French centres with symptomatic POP (POP-Q Stage 11-1V) were invited to participate in this prospective study. It was a requirement of the protocol that patients ware to have either prior or concurrent hysterectomy. Follow-up visits were planned at 6 weeks, months, 6 and 1, 3 and 5 years post-TVM. Assessments inciuded: POP-Q, Quality of Life (QOL) and Prolapse Symptorn Inventory (PSI). The primary endpoint was prolapse recurrence rate at 12 months post TVM. Procedural success was defined as POP-Q Stage < II, without further re-intervention. 5.1.3
Resuits
90 women participated in the study. Mean age was 65.3 years; 18 had prior hysterectomy and 72 underwent concurrent hysterectomy. Total mesh repair was performed in 89 women; 1 woman had anterior repair only. At 12 months, overall mean recurrence rate was 18.4% (90% Cl 11.9 to 26.6). Of the 16 women with Stage
II at 12 months, the leading edge was inside the introitus in 10 of the anatomical failures (most of them were asymptomatic). In 5 patients, the leading edge was at the introitus and beyond the hymen in only 1 patient. lmprovements in QOL and PSI ware observed from baseline to 12 months (3.4 to 0.4 and 13.9 to 1.9, respectively). Vaginal pain was reported in 28.9% at baseline, and reduced to 13.8% by 12 months. Moderate or severe vagina) retraction was reported in 12.6%. The rate of patients with suppressed or impaired sexual activity due to prolapse was reduced from 32.2% to 6.9% by 12 months. Of the 61 patients sexually active at baseline, 4.9% reported new onset dyspareunia. Of the 40 sexually active at 12 months, 3 (7.5%) complained of dyspareunia.There were 9 cases of mesh exposure, 5 of them requiring surgical intervention. There was 1 case of vesico-vaginal fistula, which resolved with surgery. 5.1.4
Conciusion
This study demonstrates reasonable 12-month success rates with low mesh exposure and complication rates. Substantial improvements to QOL were observed. Longer term follow-up is required to determine if the failure rate remains stable over time.
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5.2
Clinical Study 2003-016 “Prospective Clinical Assessment of the Total Vaginal Mesh (TVM) Technique for Treatment of Pelvic Organ Prolapse —6 and 12 months’ Miller D , Lucente V 1 , D 3 2 Robinson Babin E , 3 ‘Advanced Health Care; 2 lnstitute for Female Pelvic Medicine and Reproductive Surger y; 3 Lincoln Center OB/GYN
5.2.1
Objective
To assess one year effectiveness and peri-operative complication s for the French Total Vaginal Mesh procedure in a multi-center, prospective clinical trial. 5.2.2
(j
85 women from 3 US centers with symptomatic POP (POPQ Stage 11-1V) were prospectively enrolled under IRS guidelines. Assessments were done pre-op and at 6 & 12 months. Included were POP-Q, Quality of Life (QOL) VAS and Prolapse Symptom Irivent ory (PSI). Changes in functional status (urinary & prolapse symptoms) sexual & vaginal pain, mesh erosions and all adverse events ware recorded at each visit. The primary endpoint was prolap se recurrence rate at 12 months. Procedural success was defined as POP-Q Stage 0/1 asymp tomatic, without further intervention. Study success was defîned by protocol as an upper 90% Confid ence Interval (Cl) for recurrence rate < 20% at 12 months. Polypropylene mesh of specific size and shape is secured tension -free by extension arms that pass through the arcus tendineous via a transobturator approach anteriorly and passed through or fixed to the sacrospirlous ligament posteriorly. 5.2.3
()
Methods
Resuits
Maan age was 61.6; 26% had previous prolapse repair. Transo bturator anterior mesh placed in 26 women, posterior in 8 and combined in 51. Concurrent Hysterectomy was performed in 20.0% Maan duration of procedure was 101.2 minutes with a return to full activity in 18.3 days (SD7.4). Mesh exposure occurred in 9.6% at 6months and 6.0% at 12 month s. 6/85 patients required brief outpatient intervention for mesh exposure. Vaginal pain was reporte d by 1/85 at 6 months and new onset dysparunia by 3/83. 2/85 patients required fistula repair and 2/85 have undergone recurrence repair POPQ resuits are summarized in the table below. At 12 month s, overall mean recurrence rate was 12.0% (90% CI 6.7 to 19.6). Improvements in QOL and PSI were observed from baseline to 12 months (5.0 to 0.7 and 18.0 to 6.2, respectively).
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POP-Q Stages at Baseline, 6 and 12 Months Stage 0 Stage 1 Stage II Baseilne 23 -
6 moriths l2months
5.2.4
Stage III
Stage IV
Not known
34
23
5 (St II)
(28.8%)
(42.5%)
(28.8%)
7 (8.3%)
-
-
-
36
41
(42.9%)
(48.8%)
35
38
10
(42.2%)
(45.8%)
(12.0%)
-
1
-
2
Conciusion
12 month results for TVM are favorable with a mean recurrence rate of 12.0%, confirming the true rate is <20%. Mesh erosion and dysparunia rates are low, Further follow up continues at 3 and 5 years post-procedure.
5.3
Differences between Studies CT-TVM-001-03 and 2003-016
These studies were conducted concurrently and a number of differences between the two studies, which may account for the differing success rates, are explained below. Either previous or concurrent hysterectomy was required in the French study (20% previous hysterectomy, 80% concurrent) but this was not a f’ixed require ment in the US study (67.1% previous, 20% concurrent and 12.9% with uterine preservation. Total TVM was placed in all but one of the subjects in the French study (98.9%) while in the US study, investigators had the options of placing anterior (30.6% ), posterior (9.4%) or total TVM (60%). In the French study, only 51(56.7%) had a transgluteal approa ch compared to the US study where all of the total TVM repairs were performed using the transgl uteal approach. The remaining 39 (43.3%) subjects in the French study had mesh placed by the vaginal route only, with direct fixation of the implant on the sacrospirious ligament. There were 8 French sites compared with 3 US sites, and this may have led to the increased variability in the resuits observed between French sites. The POP-Q scoring system (measuring stage of prolapse) is not routinely used in France whereas it is more commonly used in the US.
6.0 CLINICAL USE The PROLIFT Pelvic Floor System device is currently licensed for use in the US and Europe. 510k clearance is being sought in the US for the PROLIFT+M system, and the US investigational sites will
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not start enrolment until 510k clearance is obtained. The PROLIFT+M system does not yet have a CE-mark, although this is expected to be obtained by April 2008.
7.0 STANDARDS All pre-clinical testing was completed in accordance with ISO 10993-1; 2003, Biological evaluation of medical devices, part 1: evaluation and testing GLP? The previous clinical studies have been conducted according to with local regulat ions, and requirements of the Institutional Review Board (IRB) in the USA and the lndepe ndent Ethics Committee in France. lnformed consent was obtained from all enrolled subjec ts. The planned clinical study will be conducted in accordance with ISO 14155, parts 1 and 2.
The GYNECARE GYMEMESH M Mesh complies with the essential requirements stated in Annex 1 of the Council Directive 93/42/EEG (Medical Device Directive), apart from those aspects constit uting the object of the investigations and that, with regards to these aspects, every precaution has been taken to protect the health and safety of the patient. 8.0 RISK ANALYSIS Risk & Benefit Assessment The GYNECARE PROLIFT+M systems are indicated for tissue reinforcemen t and long lasting stabilization of fascial structures of the pelvic floor in vaginal wall prolapse where surgica l treatment is intended, either as a mechanical support or bridging material for the fascial defect. Clinical studies have shown the system provides improvement in stabilization of vaginal prolapse. Report ed adverse events for this device urinary tract infection, urinary incontinence, voiding dysfun ction, vaginal atrophy, mesh exposure, anterior prolapse, pain, and dyspareunia.
Potentiat Benefits of GYNECARE PROLIFT+M Systems The device is intended for surgical repair of pelvic floor prolapse. Through a transva ginal approach, gynecologists can offer a treatment option with the following possible benefits and advant ages. 1. Reinforcement of weakened tissue, suspension of unsupported structu res or a combination of both. 2. Offers a minimally invasive treatment. 3. Presents a minimal number and degree of observed adverse events from prior clinical expenence. 4. Provides
an
alternative
treatment
option
for
physicians
and
their
patients. Urogynecologists are the primary physicians in the medical care of women with pelvic floor prolapse.
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Gynecological procedures for the treatment of pelvic floor prolapse are associa ted with certain risks. These risks are outline in section 10 of the protocol. Additionally, there are potential risks that may be directly associated with the device. These risks are as follows:
Potential Risks of GYNECARE PROLIFT+M Systems Mesh exposure is a common complication, which can be managed by excisio n and closure. Mesh retraction (‘shrinkage’) is less common but is considered more serious than mesh exposure. It can cause vaginal anatomic distortion with pain, which may also have negativ a e impact on sexual function. The scar plate that forms with in-growth of tissue into the mesh can cause stiffness in the vagina that can further impact sexual function in a negative manner. In an effort to minimize mesh retraction and reduce mesh stiffness, the GYNE CARE GYNEMESH M Mesh is being studied.
Conciuslon Clinical experience with the Prolift system has demonstrated promising anatomical resuits with improvements in POP-related symptoms. Overall, complications are low, but generally related to the mesh. In order to improve the device, a Iighter-weight mesh has been introduced into the system and this will be evaluated in the proposed clinical study.
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9.0 REFERENCES
1
(
Smith ARB, Hosker GL, Warreli DW. The Role of partial denervation of the pelvic floor in the aetiology of genitourinary prolapse and stress incontinence of unne. A neurophysiolo gic study. Br J Obstet Gynaecol 1989; 96:24-28. 2 Gilpin SA, Gosling JA, Smith ARBI et al. The pathogenesis of genitourinary prolap se and stress incontinence of urine. A histological and histochemical study. Br J Obstet Gynecol 1989; 96:1523. 3 Norton PA, Baker JE, Sharp HC, et al. Genitourinary prolapse and joint hyperm obility in women. Obstet Gynecol 1995; 85(2):225-228. 4 Smith P, Heimer G, Norgen A, et al. Steroid Hormone Receptors in Pelvic Muscl es and Ligament in Women. Gynecol Obstet Invest 1990; 30:27-30. 5 Olsen A, Smith V, et. al. Epidemiology of Surgically Managed Pelvic Organ Prolap se and Urinary ncontinence. Obstet Gynecol 1997; 89:501-506. 6 Benson JT, Lucente V, McClellan E. Vaginal versus abdominal reconstructiv surgery e for the treatment of pelvic support defects: A prospective randomized study with long-te rm outcome evaluation. Am J Obstet Gynecol 1996; 175:1418-1422. 7 Fenner, D. New Surgical Mesh. Clin Obstet Gynecol. 2000:43:650-8. 8 Cobb, William S, MD, Kercher, Kent, W, MD and Heniford, Todd 6., MD. The Argument for Lightweight Polypropylene Mesh in Hernia Repair. Surgical Innovation 2005: 63-69. 9 Iglesia C, Fenner D, Brubaker L. The Use of Mesh in Gynecologic Surger y. Int. Urogynecol J. 1997:105-115. 10 Cobb, William S, MD, Bums, Justin, M, MD, Peindl, Richard D., MD, Carboneil, Alfredo, M., MD, Matthews, Brent D., MD, Kercher, Kent, MD and Heniford, 8. Todd, MD. Textile Analys is of Heavy Weight, Mid-Weight, and Light Weight Polypropylene Mesh in a Porcine Ventral Hernia Model. JoumalofSurgical Research 2006; 136:1-7.
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APPENDIX A: Instructioris for Use (IFU) GYNECARE PROLIFT+M
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*
Pelvic Floor Repair System
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APPENDIX B: Declaration of Helsinki WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI Ethical Principles for Medical Research Involving Human Patlents Adopted by the lBth WMA General Assembly, Helsinki, Finland, June 1964, and amended by the 29th WMA General Assembly, Tokyo, Japan, October 1975 35th WMA General Assem bly, Venice, Italy, October 1983 4lst WMA General Assembly, Hang Kong, September 1989 48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 and the 52nd WMA General Assembly, Edlnburgh, Scotland, October 2000 Nota of Clarificatlon on Paragraph 29 added by the WMA General Assembly, Washington 2002 Note of Clarification on Paragraph 30 added by the WMA General Assembly Tokyo 2004 A. INTRODUCTION 1. The World Medical Association has developed the Declaration of Helsinki as a statement of ethical principles to provide guidance to physicians and other participants in medical research involving human subjects. Medical research involving human subjects indudes researc h on identifiable human material or identifiable data. 2. It is the duty of the physician to promote and safeguard the health of the people . The physician’s knowledge and conscience are dedicated to the fulfihiment of this duty. 3. The Declaration of Geneva of the World Medical Association binds the physician with the words, ‘The health of my patient will be my first consideration,’ and the International Code of Medical Ethics declares that, ‘A physician shall act only in the patient’s interest when providing medical care which might have the effect of weakening the physical and mental condition of the patient.” 4. Medical progress is based on research which ultimately must rest in part on experimentation involving human subjects. 5. In medical research on human subjects, considerations related to the weil-beirig of the human subject should take precedence over the interests of science and society. 6. The primary purpose of medical research involving human subjects is to irnprove prophylactic, diagnostic and therapeutic procedures and the understanding of the aetiolo and pathogenesis of disease. Even the best proven prophylactic, diagnostic, and therapegy utic methods must continuously be challenged through research for their effectiveness efficiency, , accessibility and qualily. 7. In current medical practice and in medical research, most prophylactic, diagno stic and therapeutic procedures involve risks and burdens. 8. Medical research is subject to ethical standards that promote respect for all human beings and protect their health and rights. Some research populations are vulnerable and need special protection. The particular needs of the economically and medically disadv antaged must be recognized. Special attention is also required for those who cannot give or refuse consent for themselves, for those who may be subjectto giving consent under duress , for those who will not benefit personally from the research and for those for whom the research is combined with care. 9. Research Investigators should be aware of the ethical, legal and regulatory roquire ments for research on human subjects in their own countries as well as applicable international requirements. No national ethical, legal or regulatory requirement should be allowed to reduce or eliminate any of the protections for human subjects set forth in this Declaration. B. BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 10. It is the duty of the physician in medical research to protect the life, health, privacy, and dignity of the human subject. 11. Medical research involving human subjects must conform to generally accept ed scientific principles, be based on a thorough knowledge of the scientific literature, other relevant sources of information, and on adequate laboratory and, where appropriate, animal experimentation. 12. Appropriate caution must be exercised in the conduct of research, which may affect the environment, and the welfare of animals used for research must be respected.
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13. The design and performance of each experimental procedure involv ing human subjects should be clearly formulated in an experimental protocol. This protoc should ol be submitted for consideration, comment, guidance, and where appropriate, approval to a specially appointed ethical review committee, which must be independent of the investigator, the sponsor or any other kind of undue influence. This independent comm ittee should be in conformity with the laws and regulations of the country in which the researc h experiment is perforrned. The committee has the right to monitor ongoing trials. The researc her has the obligation to provide nionitoring information to the committee, especia lly any serious adverse events. The researcher should also submit to the committee, for review , information regarding funding, sponsors, iristitutional affiliations, other potential conflicts of interes t and incentives for subjects. 14. The research protocol should always contain a statement of the ethical considerations involved and should indicate that there is compliance with the princip les enunciated in this Declaration. 15. Medical research involving human subjects should be conducted only by scientifically qualified persons and under the supervision of a clinically competent medica l person. The responsibility for the human subject must always rest with a medically qualifi ed never rest on the subject of the research, even though the subject has given person and consent. 16. Every medical research project involving human subjects should be preced ed by careful assessment of predictable risks and burdens in comparison with foresee able benefits to the subject or to others. This does not preclude the participation of healthy volunteers in medical research. The design of all studies should be publicly available. 17. Physicians should abstain from engaging in research projects involv ing human subjects unless they are confident that the risks involved have been adequately assesse d and can be satisfactorily managed. Physicians should cease any investigation if the risks are found to outweigh the potential benefits or 1f there is conclusive proof of positiv e and beneficial results. 18. Medical research involving human subjects should only be conducted if the importance of the objective oulweighs the inherent risks and burdens to the subjec t. This is especially important when the human subjects are healthy volunteers. 19. Medical research is only justified if there is a reasonable likelihood that the populations in which the research is carried out stand to benefit from the resuits of the research. 20. The subjects must be volunteers and inforrned participants in the researc h project. 21. The right of research subjects to safeguard their integrity must always be respected. Every precaution should be taken to respect the privacy of the subject, the confid entiality of the patient’s information and to minimize the impact of the study on the subjec t’s physical and mental integrity and on the personality of the subject. 22. In any research on human beings, each potential subject must be adequa tely informed of the aims, methods, sources of funding, any possible confiicts of interes t, institutional aftitiations of the researcher, the anticipated benefits and potential risks of the study and the discomfort it may entail. The subject should be informed of the iight to abstain from participation in the study or to withdraw consent to participate at any time without reprisal. After ensuring that the subject has understood the information, the physic ian should then obtain the subject’s freely-given inforrned consent, preferably in writing . 1f the consent cannot be obtained in writing, the non-written consent must be formally documented and witnessed. 23. When obtaining informed consent for the research project the physic ian should be particularly cautlous if the subject is in a dependent relationship with the physician or may consent under duress. In that case the informed consent should be obtain ed by a well informed physician who is not engaged in the investigation and who is completely independent of this relationship. 24. For a research subject who is legally incompetent, physically or mental ly incapable of giving consent or is a legally incompetent minor, the investigator must obtain informed consent from the legally authorized representative in accordance with applicable law. These groups should not be included in research unless the research is necess ary to promote the health of the population represented and this research cannot instead be performed en legally competent persons. 25. When a subject deemed legally incompetent, such as a minor child, is able to give assent to decisions about participation in research, the investigator must obtain that assent in addition to the consent of the legally authorized representative. 26. Research on individuals from whom It is not possible to obtain consen t, including proxy or advance consent, should be done only 1f the physical/mental condition that prevents obtaining informed consent is a necessary characteristic of the research population. The specific
Final Version 1; 10 September 2007
Page 19 of 20
reasons for involving research subjects with a condition that renders them unable to give informed consent should be stated in the experimental protocol for consideration and approval of the review committee. The protocol should state that consent to remain in the research should be obtained as soon as possible from the individual or a legaUy authorized surrogate. 27. Both authors and publishers have ethical obligations. In publication of the results of research, the investigators are obliged to preserve the accuracy of the results. Negative as well as positive results should be published or otherwise publicly available. Sourcos of funding, institutional affiliations and any possible conflicts of interest should be declared in the publication. Reports of experimentation not in accordance with the principles laid down in this Declaration should not be accepted for publication. C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH MEDICAL CARE 28, The physician may combine medical research with medical care, only to the extent that the research is justified by its potential prophylactic, diagnostic or therapeutic value. When medical research is combined with medical care, additional standards apply protect to the patients who are research subjects. 29. The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of placebo, or no treatment, in studies where rio proven prophylactic, diagnostic or therapeutic method exists. See footnote 1 30. At the conclusion of the study, every patient entered into the study should be assured of access to the best proven prophylactic, diagnostic and therapeutic methods identified by the study. See footnote 2 31. The physician should fully inform the patient which aspects of the care are related to the research. The refusal of a patient to participate in a study must never interfere with the patient-physician relationship. 32. In the treatment of a patient, where proven prophylactic, diagnostic and therapeutic methods do not exist or have been ineffective, the physician, with informed consent from the patient, must be free to use unproven or new prophylactic, diagnostic and thorapeutic measures, if in the physician’s judgement it offers hope of saving life, re-establishing health or alleviating sufferirig. Where possible, these measures should be made the object of research, designed to evaluate their safety and efficacy. In all cases, new information should be recorded and, where appropriate, published. The other relevant guidelines of this Declaration should be followed. FOOTNOTE: Note of clarification on paragraph 29 of the WMA Declaratlon of Helsinki The WMA hereby reaffirms its position that extreme care must be taken in making use of a placebo-controlled trial and that in general this methodology should only be used in the abserice of existirig proven therapy. However, a placebo-controlled trial may be ethically acceptable, even if proven therapy is available, under the following circumstances: Where for compelling and scientifically sound methodological reasons ts use is necess ary to determirie the efficacy or safety of a prophylactic, diagnostic or therapeutic method; or Where a prophylactic, diagnostic or therapeutic method is being investigated for a minor condition and the patients who receive placebo will not be subject to any additional risk of serious or irreversible harm. All other provisions of the Declaration of Helsinki must be adhered to, especially the nood for appropriate ethical and scientific review -
-
2
Note of clarification on paragraph 30 of the WMA Declaration of Helsinki The WMA hereby reaffim,s its position that it is necessary during the study planning process to identify post trial access by study participants to prophylactic, diagnostic and therapeutic procedures identified as benoficial in the study or access to other appropriate care. Post-trial access arrangements or other care must be described in the study protocol so the ethical review committee may consider such arrangements during its review.
Final Version 1; 10 September 2007
Page 20 of 20
1.7
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ETHICON
Women’s Health & Urology
A Prospective, Multi-centre Study to Evaluate the Clinical Performance of the GYNECARE PROLIFT +M* Pelvic Floor Repair System as a Device for Pelvic Organ Prolapse
PROTOCOL 300-07-006
C)
Final Verslon 3 01 February 2008 Document
Changes
Effectve Date
Originaf
10 August 2007
Amendment #1
1
29 October 2007
Administrative Change #1
2-5
04 February 2008
Sponsor ETHICON Clinical Development & Medlcal Affairs, wlth addresses at: ETHICON A Johnson & Johnson Company P.O. Box 151, Route 22 West Somerville, NJ 08876-0151
Johnson & Johnson Medical Ltd. Simpson Parkway Kirkton Campus Livingston EH54 OAB CON FIDENTIALITY STATEMENT
The Information in this document contains trade secrets and commercial information that are privileged be diaclosed unless such disciosure is required by appilcable law or regulatlons. In any event, persons or conhldential and may not to whom the informaUon Is disciosed must be Infomied that the information is privilagad or confidential and may not be furiher disclosed by them. These restrictions on disciosure will apply equally to all future information supplied to you, which is indicated as privileged om confidential. *
Trademark
Protocol: 300-07-006 Administrative Change #1 Final Version 3: 04 February 2008
1 of 54
A Prospective, Multi-centre Study to Evaluate the CHnical Performance of the GYNECARE PROIIFT +MR PeMc Floor Repair System as a Device for Pelvic Organ Prolapee
PROTOCOL 0O.O7-OO6 Mmlnlstmtive Chang1 Final Version 04 February 2008
1 O.2.e Date
ETHICON
Name of Medical Director (Typed or Printed)
-
1O.2.e
Compliance Statement This study will be conducted in accordance with EN ISO 14155 and the Declaration of Helsinki.
Protocol: 300-07-006 Admnistrative Charige #1 Fina) Verslori 3: 04 Febrijary 2008
2 of 54
A Prospective, Multi-centre Study to Evaluate the Clinical Performance of the GYNECARE PROLIFT +M* Pelvic Floor Repair System as a Device for Pelvic Organ Prolapse PROTOCOL 300-07-006 Administrative Change # 1 Final Verslon 3 04 February 2008
INVESTIGATOR AGREEMENT
1 have read this protocol and agree to conduct the study as outlined herein. 1 will provide copies of the protocol and all pertinent information to all individuals respon sible to me who assist in the conduct of this study. 1 will discuss this material with them to ensure they are fully informed regarding the device and the conduct of the study.
Principal Investigator’s Signature
Date
L) Name of Principal Investigator (Typed or Printed)
Protocol: 300-07-006 Admiriistrative Chartge #1 Final Version 3: 04 February 2008
3 of 54
TABLE OF CONTENTS
INVESTIGATOR AGREEMENT
3
SYNOPSIS
7
1.
INTRODUCTION
2.
OBJECTIVES
3.
OVERVIEW OF STUDY DESIGN
4.
STUDY POPULATION
4.1.
GENERALCONSIOERATIONS
4.2. 4.3.
INcLusIoN CRITERIA EXCLUSION CRITERIA
0
14
17 17
18 18 18 18
RANDOMISATION AND BLINDING
19
6. 6.1.
STUDYDEVICES THE GYNECARE PROLIFT
19 19
7. 7.1
STUDYEVALUATIONS Study Procedures By Visit 7.1.1. Overview 7.1.2. Visit 1 Pre-Surgery Evaluation (Screening) 7.1.3. Visit 2 Surgical Procedure 7.1.4. Visit3 Post-Surgery Evaluation 7.1.5. Visit4 Post-Surgery Evaluation (1 month post-procedure) 7.1.6. Visit 5 Post-Surgery Evaluation (3 Months Post Procedure) 7.1.7 Visit 6 Post-Surgery Evaluation (12- Months Post Procedure) 7.1.8 Visit 7 Post-Surgery Evaluation (24- Months Post Procedure) 7.1.9 Visit 8 Post-Surgery Evaluation (36- Months Post Procedure) 7.2. Early withdrawal EVALUATIONS 7.3.1. Sample Collection and Handling 7.3.2. Analytical Procedures 7.3.3. Subject questionnaires
7.3.
+ M* PELVIC FLOOR REPAIR SYSTEM
8. 8.1.
COMPLETION
8.2.
EARLY TERMINATION OF SUBJECT INVOLVEMENT
9.
STATISTICAL METHODS
SUBJECT COMPLETIONIEARLY TERMINATION
9.1. 9.2.
SAMPLE SIZE DETERMINATION PLANNED ANALYSIS 9.2.1. Analysis Sets 9.2.2. Effectiveness 9.2.2.1 Primary Effectiveness VariableslCriteria 9.2.2.2 Secondary Effectiveness Variables/Crlteria 9.2.3 Safety 9.2.3.1 SAFETY VARIABLES/CRITERIA Protoccl: 300-07-006 Adminlstratlve Change #1 Final Version 3: 04 February 2008
4 of 54
19 19 19 19 20 21 21 22
22 23
23 23 24 24 24 24 25 25 25 26 26 26 26 26 26 27 28 28
9.2.3.2 METHODS OF ANALYSIS 9.2.4 9.2.5
10. 10.1.
INTERIM AND FOLLOW-UP ANALYSES HANDLING OF MISSING DATA
.28 28 28
ADVERSEEVENTS
29
10.6 10.7 10.8
ADVERSEEVENT SERIQUS ADVERSE EVENT (SAE) SERIOUS ADVERSE DEVICE EVENT (SADE) ADVERSE EVENT SEVERITY CATEGORIES ANTICIPATED ADVERSE EVENTS RELATED TO THE PROCEDURE ANTICIPATED ADVERSE DEVICE EFFECTS ADVERSE EVENT COLLECTION ADVERSE EVENT REPORTING
11.
COMPLAINT REPORTING
32
12.
CONTACTING SPONSOR
32
13.
CUNICAL SUPPLIES INFORMATION
13.1.
PHYSICAL DESCRIPTION OF STUDY DEVICE
10.2. 10.3. 10.4 10,5
29 29 30 30 30
31 31 31
32 32
13.1.1 GYNECAREGYNEMESHM
32 32 33 33
13.1.2
TOTALMESHIMPLANT
13.1.3 13.1.4 13.1.5 13.1.6 13.1.7 13.2 13.2.1 13.2.2 13.3
ANTERIOR MESH IMPLANT POSTERIOR MESH IMPLANT GYNECARE PROLIFT* GUIDE GYNECARE PROLIFT* CANNULA GYNECARE PROLIFT* RETRIEVAL DEVICE PACKAGING AND LABELLING PACKAGING LABELS AND LABELLING INSTRLJCTIONS DEVICE ACCOUNTABILITY
33 33 34 34 34 34
14.
TRIAL-SPECIFIC SIJPPLIES
34
ETHICS
34 34 34 35
15. 15.1. 15.2. 15.3.
INVESTIGATOR RESPONSIBILITIES MEDICAL ETHICS COMMI’TTEE DR INSTITUTIONAL REVIEW BOARD (MECRRB) INFORMEDCONSENT
16.
ADMINISTRATIVE REQUIREMENTS
16.1. 16.2. 16.3
PROTOCOL MODIFCATIONS REQUIRED DOCUMENTATION CONFIDENTIALITY OF SUBJECT RECORDS 16.4 RECORD RETENTION 16.4.1 CAsE REPORT FORM COMPLETION 16.4.2 STUDY COMPLETION/TERMIMATION 16.4.2.1 Study Completion 16.4.2.2 Study Termination 16.4.3 MONITORING 16.4.4 DATAQUALITYASSURANCE 16.4.5 ON-SITEAUDITS 16.4.6 UsE OF INFORMATION AND PUBLICATION
16.5
36 36 36
37 37 37 38 38 38
38 38 39 39
REFERENCES
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40 5 of 54
Appendix 1.41 Appendlx2
.42
Appendix3
43
Appendix 4
44
Appendix 5
46
Appendix 6
51
Appendix 7
52
t
(N
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A Prospective, Multi-centre Study to Evaluate the Clinical Performance of the GYNECARE PROLIFT +M* Pelvic Floor Repair System as a Device for Pelvic Organ Prolapse PROTOCOL 300-07-006
SYNOPSIS OBJECTIVES: The primary objective of this study is to evaluate the anatomical success of the GYNECARE PROLIFT + M* system in women with symptomatic ICS POP-Q Stage III or IV, requiring surgical correction of pelvic organ prolapse (POP). Secondary objectives include the evaluation of patient reported outcomes (PFDI-20, PFIQ-7, PISQ-12, Euro-QOL), length of procedure, length of hospital stay, post-operative pain, return to normal activities, and pen- and post-operative complications. OVERVIEW OF STUDY DESIGN: This study is a prospective, multi-centre, single-arm design. Subjects will be assessed prior to surgery, during and after the procedure, and at 1,3, 12,24 and 36 months post-procedure. STUDY SITES: The study will include approximately 10 study sites in Europe (e.g. France, Germany, Belgium, the Netherlands). Each investigator will have extensive experience with the usa of the GYNECARE PROLIFT* Pelvic Floor Repair System. REGULATORY STATUS: Pre-CE Mark in Europe (Class III). STUDY POPULATION: A total of 125 subjects will be enrolled to allow for approximately 118 evaluable subjects at 12 months. Evaluable subjects will be defined as those providing baseline data and having POP-Q evaluation completed at the 1 2-month visit. To be eligible, female subjects must meet the following inciusion criteria: 1. Candidates with symptomatic pelvic organ prolapse of ICS POP-Q Stage III or IV, suitable for surgical repair. Penineal repair, vaginal hysterectomy and/or mid urethral sling procedures for incontinence may be performed concurrently. 2. Agel8years. Protocol: 300-07-006 Administrative Change #1 Final Version 3: 04 February 2008
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3. Agrees to participate in the study, including completion of all study-related procedures, evaluations and questionnaires, and documents this agreement by signing the Ethics Corn mittee / IRB approved informed consent. Subjects who meet any of the foflowing criteria will be excluded from participating in the study: 1
Additional surgical intervention for POP repair concurrent to the Gynecare Prolift +M procedure (e.g. paravaginal repair, sacrocolpopexy, colporraphy in a non-Gynecare Prolift+M treated compartment).
2. Prevlous repair of pelvic organ prolapse involving insertion of mesh. 3. Previous hysterectorny within 6 months of scheduled surgery. 4. Experimental drug or experimental medical device within 3 months prior to the planned procedure. 5. Active genital, urinary or systemic infection at the time of the surgical procedure. Surgery may be delayed in such subjects until the infection is cleared. 6. Coagulation disorder or on therapeutic anticoagulant therapy at the time of surgery. 7. History of any pelvic radiation therapy. 8. History of chemotherapy within 6 months of the planned procedure. 9. Systemic disease known to affect bladder or bowel function (e.g. Parkinson’s disease, multiple scierosis, spina bifida, spinal cord injury or trauma). 10. Current evaluation or treatment for chronic pelvic pain (e.g. endometriosis, coccydynia, vulvadynia).
interstitial cystitis,
11. Nursing or pregnant or intends future pregnancy.
()
12. In the irivestigator’s opinion, any medical condition or psychiatric illness that could potentially be life threatening or affect their ability to complete the study visits according to this protocol. STUDY DEVICE: The GYNECARE PROLIFT +M* Pelvic Floor Repair System will be used for all study subjects. Depending on the site of the prolapse, the repair can be anterior, posterior or total. The prolapse repair is achieved by the placement of mesh implant(s) via a vaginal approach. The pre-shaped mesh implants are made of GYNECARE GYNEMESH M, which is a composite mesh, comprising two components of approximately equal parts of absorbable Polyglecaprone 25 monofilament fiber and non-absorbable polypropylene monofilament fiber. Following resorption of the absorbable component, the weight of the remaining polypropylene will be approximately 28g/m , compared to 45g/m 2 2 for Gynemesh PS.
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Hysterectomy or uterine conservation can be combined with this procedure. Tension-free support procedures using mid-urethral polypropylene sling for the treatment of stress urinary incontinence may be performed concurrent to placement of the GYNECARE PROLIFT +M* system. PRIMARY ENDPOINT: There will be one primary effectiveness end-point: •
POP-Q score at 12 months post-procedure. Success will be determined by achievement of a POP-Q score of ICS Stage 1, in the treated compartment, without further surgical re intervention for POP in that compartment.
SECONDARY ENDPOINTS:
C)
(3
Summary of ICS Stages at 3, 24 and 36 month visits. • Summary of treated compartment ICS POP-Q stage at 3, 12, 24 and 36 months. The success criteria of a POP-Q score of ICS Stage 1, in the treated compartment, without further surgical re-intervention for POP in that compartment, will also be applied at 36 months. • Proportion of subjects with the leading edge within the hymen (i.e. all POP-Q values to be less than 0) and without further re-intervention for POP at 12, 24 and 36 months. • Incidence of de novo prolapse as defined as occurrence of a post-operative prolapse (ICS Stage II or greater) only in the untreated compartment, provided there was no pre-operative defect in that compartment (Le. ICS Stage 0 or 1). • Mean scores and change from baseline in PFDI-20 scores at 3, 12, 24 and 36-month visits including sub scores (POPDI, CRADI and UDI). • Proportion of subjects with a change from baseline 45 points in the PFDI-20 summary score at 12, 24 and 36 months. • Mean scores and change from baseline in PFIQ-7 at 3, 12, 24 and 36 month visits inciuding sub-scores (POPIQ, CRAIQ and UIQ). • Proportion of subjects with a change from baseline 36 points in the PFIQ-7 summary score at 12, 24 and 36 months. • Days to return to normal activities (walking, driving, work, household activities and sexual intercourse). • EuroQol (EQ-5D health State) mean change from baseline at 3 and 12 months visit (overall using the EQ-5D index score, and also for each individual item). • In subjects sexually active at baseline, assessment of sexual function using PISQ-12 assessed at 12, 24 and 36 month visits (mean scores and change from baseline). • Incidence of new onset dyspareunia, resolution or continuance of pre-existing dyspareunia •
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• • • • • • • •
Incidence of mesh contraction, as determined by pain on palpation of mesh during pelvic examination at 3, 12, 24 and 36 months. Incidence of vaginal wall stiffness, as determined by the investigator on physical examination at 3, 12, 24 and 36 months. Total time in the operating room. Length of procedure (from time of first incision to time of last suture). Nights in hospital (from date of admission to date of discharge; based on actual data and “readiness for discharge”). Pain score 24 hours post surgery and at the 1 month visit, measured using Visual Analog Scale (VAS). Subject global impression assessed on a 5 point Likert scale at 3, 12, 24 and 36-month visits. Surgical satisfaction question assessed at 3 and 12 month visits.
SAFETY: • Adverse events. •
Determination of any exposures/erosions including location (exposure is ariy visible mesh or mesh that can be determined to be exposed by palpation but is not visible).
•
Haemoglobin and haematocrit
STATISTICAL METHODS: The full analysis will be performed once data are available for all subjects at 12 months, and follow-up analysis will be performed once data are available for all subjects at 24 and 36 months. An interim analysis will be performed on the 3-month data, comprised of a minimum of 60 subjects. The 3-month POP-Q data will be summarised, however, the success criterion will not be applied. All other parameters will be summarised as applicable. As the primary endpoint is only relevant at 12 months there are no stopping rules, although alpha will be arbitrarily assigned 0.002 (two tailed). As this is not a comparative study, one-sided 97.6% (adjusting for an interim analysis) confidence intervals (Cl) will be estimated for recurrence of POP-Q (defined as Stage II or surgical re-intervention) at 12 months. Whilst this is not a hypothesis testing study, should the upper 97.6% one-tailed Cl not exceed 20%, this will be considered a good result. The following primary endpoint will be analysed using the Per Protocol Set: POP-Q score at 12 months post-procedure. Success (overall) will be determined by achievement of a POP-Q score of ICS Stage 1, without further re-intervention for POP.
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With 118 evaluable subjects there needs to be 15 or (ess recurrences for the 97.6% upper Cl to fail at or below 20.0% using exact binomial confidence limits. TIME AND EVENTS SCHEDULE: The time and events schedule for this study is shown on the following page.
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—
Pre-Surgery Evaluatlon (Screening) WIthIn 90 days prlor to surgical procedure Visit 1
Post surgery evaiuatton, 3 months post surgery (+1. 14 days) Post surgery evaluatlon, 12 months post surgery (11- 28 days)
-
Post surgery evaluation, 24 months post surgery (+1- 56 days)
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—
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-
--
-
X X
X
X X X
x
8
Post surgery evaluation, 36 months post surgery (+1- 90 days)
Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Visit 7 Visit Inclusion/exclusion X X informed consent X Demographlcs X Medical/Surgical history X X Physlcalexam X Pelvic exam X X X X X Voidirig Function X X POP-Q assessment X X X x PFIQ-7 guestionnalre X X X X PISQ-12 guestiannaire X X X X PFDI-20 gueslionnaire X X X X Euro-QOL X X X Intra-operative data X PSIrIVAS X Post-procedure analgesla X Prophyfactic vaginal or oral estrogen X X and prophylactic antibiotics Removal of Surgical Catheter X X Documentatioi, of fntermittent X Cathensations Discharge date: ready & actual X Pregnancy test. Hb/HCT X X Return to ectivities X X 3 X Subject Global Impression X X X Surgical Satistaction Questiorinaire x x Gynecologic Intervention (It any) X x x x X Adverseevents X X X X X 24 hours post surgery, or time of cllscflarge whlctrever occurs tirst Pregnancy test pre-procedure (subjects of chuIcI-beanflg potential). HCT & 1-Ib up to 21 doys pre-surgery, and at 24 hours post-surgery or time of discharge whichever occurs first Walking, driving, househofd activities, working and soxual intercourse asked at subsequent visits it activity not restarted. 1n subjects sexually active at baselirie only. 5 4 Diary card issued. ,Assessmerit of pain on palpatlon and vaglnal wall stlffness 8
Procedures
PROTOCOL 300-07-006 TIME AND EVENTS SCHEDULE Surgical Post surgery Post surgery Procedure evaluatlon, evaluatlon, 1 dlscharge date month past surgery (+1- 14 days)
A Prospective, Muiti-centre Study te Evatuate the CtInIcaI Performance of the GYNECARE PROLIFT +M* PeMc Floor Repair Systern as a Devlce for Peivic Organ Prolapse
A Prospective, MultI-centre Study to Evaluate the Clinical Performance of the GYNECARE PROLIFT +M* Pelvic Floor Repair System as a Devlce for Pelvic Organ Prolapse LIST OF ABBREVIATIONS AE ATFP Cl CRF DCF EuroQol FAS GCP Hb Hot HRT ICS IFU IRB LOCF MEC MedDRA PFDI —20 PFIQ —7 PISQ —12 POP POP-Q PPS SAE VAS
Adverse event Arcus tendineus fascia pelvis Confidence Interval Case Report Form Data clarification form Standardized instrument to measure health outcome Full Analysis Set Good Clinica) Practice Hemoglobin Haematocrit Hormone Replacement Therapy International Continence Society Instructions For Use Institutional Review Board Last observation carried forward Medical Ethics Committee Medical Dictionary for Regulatory Activities Pelvic Floor Distress Inveritory Short form of Pelvic Floor Impact Questionnaire Short form of Pelvic Organ Prolapse/Urinary Incontinence Sexual Function Questionnaire Pelvic Organ Prolapse Pelvic Organ Prolapse Quantifîcation system Per Protocol Set Serious adverse event Visual Arialogue Scale
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1. INTRODUCTION Pelvic organ prolapse or vaginal wall prolapse are general terms used to describe various clinical conditions that are associated with pelvic floor relaxation in female subjects. The clinical manifestations include: •
(
•
Anterior vaginal prolapse (medial, lateral, and/or apical cystocele) Posterior vaginal wall prolapse (rectocele and/or enterocele)
•
Vault prolapse (eriterocele, uterine prolapse, and vaginal vault prolapse)
Pelvic organ prolapse is thought to result from a stretching, weakening or tearing of the soft tissue structures that support the pelvic organs. These tissues become compromised as a result of a weakened or damaged levator ani muscle group. This muscle group is the platform at the base of the pelvis responsible for supporting the pelvic organs. It works with the connective tissues to support these organs. As the levator arii is damaged and drops, the opening between the levator ani is widened. Intra-abdominal forces are then relatively unopposed by the weakened muscle. This increases forces applied to the connective tissue support structures, which results in their tearing or stretching. Risk factors for pelvic organ prolapse include vaginal panty, neuropathy, obesity, chronic Valsalva, connective tissue disorders, prior surgery, estrogen status and advancing age . Of the factors identifled, 4 ’ 123 vaginal panty and its associated neuropathy appear to play the biggest role in pelvic floor . Damage to the nerves supplying the levator en! during childbirth result in weakening 2 disorders of muscle and subsequent prolapse of the organs. Surgical correction of these problems is a major health care issue for women. An analysis of members of a large health mainteniance organization estimated the lifetime risk of 11.1% of at least one operation for pelvic organ prolapse and urinary incontinence with a re-operation rate of 29.2%, These numbers have been confïrmed in other studies . 6 Management Options Non-surgical interventions for prolapse management inciude pelvic floor exercises and pessary support. Surgical options are many, made more challenging as multiple weakened regions often occur in a subject and incomplete correction of any may lead to worsening of the others. The surgical procedures may involve tightening and reinforcing of weakened tissue, suspension of unsupported structures or a combination of both. The tightening/reinforcing and suspension procedure may utilize several materials including: •
suture alone
•
autologous tissue
•
cadaveric material
•
allograft material
•
synthetic absorbable mesh
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•
synthetic permanent mesh
Synthetic meshes, first used for abdominal wall hernia repairs, are often produced from materials originally used for sutures. They are able to provide support where autologous tissues are not adequate, but they do add the risks of erosion and rejection . Synthetic meshes have 7 been used with increasing frequency in gynecologic surgery over the past 30 years°. Reinforcement of tissue is sought because of the weakened state of the subject’s own tissue. These grafts may be placed using an abdominal or vaginal approach. Polypropylene mesh has been the rnost widely used mesh in gynecologic surgery inciuding many types of pelvic floor repair procedures . 7 ETHICON developed a modified PROLENE Mesh identified as GYNECARE GYNEMESH PROLENE Soft (Polypropylene) Mesh (PS), a reduced density construction PROLENE Polypropylene Mesh. The product is fabricated of knitted monofllaments of natura! and blue pigmented polypropylene produced to be more flexible than earlier versions of polypropylene mesh. The more flexible material is intended to offer improved intraoperative handling for pelvic organ prolapse repair procedures. Less total polypropylene is present per unit area when compared to traditional PROLENE mesh. One of the major issues with the use of mesh for POP repair has been the lack of standardization in surgical technique. Between 1999 and 2003, a group of French uro gynecologists worked together to develop a standardized mesh shape that could be placed consistently through the vaginal route. The result of the group’s work was the creation of the Trans-Vaginal Mesh technique (TVM). TVM was the precursor to the GYNECARE Prolift system for pelvic floor repair, and was the first standardized kit for POP repair. The GYNECARE PROLIFT system has been available for use since 2005, and by end of 2006, approximately 63,000 devices have been used. Overall the complication rates appear to be low based on those reported through on Medical Device Vigilance Reporting (MDVR) system within ETHICON, and are detailed in the table below:
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MDVR DATA to end of 2006 Complicatlon # of Complalnts Injury Blacider Bowel Rectum Vascular/haematoma Nerve Fistula Vesicovaginal Rectovaginal Exposure Pain Dyspareunia Retention / Voiding difficulty
US 2 1 4 8 0 1 1 11 4 1 4
j
Ex-US 2 0 1 2 1 0 0 4 0 0 0
Total Complalnts 4 1 5 10 1 1 1 15 4 1 4
The longest-term follow-up data available is with the precursor to the Prolift system, known as TVM (Trans-Vaginal Mesh), with anatomical failure rates of approximately 15% at 12 months. There are numerous ongoing research studies to evaluate the long-term effectiveness of Prolift compared with other types of repair, inciuding non-mesh repairs and mesh repairs such as sacrocolpopexy. Although Prolift signiticantly reduces recurrences compared to traditional POP repairs, It can laad to other complications such as mesh exposure and mesh retraction. Mesh exposure is a common complication, which can be managed by excision and closure. Mesh retraction (“shrinkage) is less common but It is considered more serious. (t can cause vaginal anatomic distortion, which may eventually have a negative impact on sexual function. Its treatment is difficult. Additionally, the scar plate that forms with in-growth of tissue into the mesh can cause stiffness of the vagina that further impacts sexual function in a negative manner. In an effort to minimize these complications, a lighter-weight alternative mesh for Prolift* has been introduced. This mesh replaces the Gynecare Gynemesh PS used within the Gynecare Prolift* Pelvic Floor Repair system. The ULTRAPRO Mesh is a composite mesh, comprising two components of approximately equal parts of absorbable Polyglecaprone-25 monofilament fiber and non-absorbable polypropylene monofilament fiber. Following resorption of the absorbable component, the weight of the remaining polypropylene would be approximately 28g1m , compared to 45g1m 2 2 for Gynemesh PS. Pre-clinical evaluation in a porcine ventral hernia model demonstrated that ULTRAPRO” maintains a comparable mean burst strength to Gynemesh PS, whilst was less stuff after tissue incorporation (Cobb et al). 8
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ULTRAPRO’’is currently indicated for tissue reinforcement and long lasting stabilization of fascial structures of the abdominal wall. However, some gynecologists have used It for POP repair though the information gathered from these cases is limited due to: the small number of cases, the mesh was placed from an abdominal rather than vaginal approach, the size of mesh used was small relative to the current intended use. In order to differentiate between the use of ULTRAPRO in hernia repair, it will be known as GYNECARE GYNEMESH M for use in POP repair. Ratlonale for Clinical Evaluatlon The development of the GYNECARE PROLIFT + M* system provides a composite lighter weight mesh compared to the original PROLIFT system which uses Gynemesh PS. Following resorption of the absorbable component, the weight of the remaining polypropylene will be approximately 28g1m , compared to 45g/m 2 2 for Gynemesh PS. The purpose of this dilnical study is to evaluate the clinical performance of the PROLIFT system with the new lighter-weigh t mesh.
2. OBJECTIVES The primary objective of this study is to evaluate the anatomical success of the GYNECARE PROLIFT + M* system in women with symptomatic ICS POP-Q Stage III or IV, requiring surgical correction of pelvic organ prolapse (POP). There will be one primary effectiveness endpoint: •
C)
POP-Q score at 12 months post-procedure. Success will be determined by achievement of a POP-Q score of ICS Stage 1, in the treated compartment, without further surgical re-intervention for POP in that compartment.
Secondary objectives inciude the evaluation of subject reported outcomes (PFDI-20, PFIQ-7, PISQ-12, Euro-QOL), Iength of procedure, Iength of hospital stay, post-operative pain, return to normal activities, and pen- and post-operative complications. 3. OVERVIEW OF STUDY DESIGN This study is a prospective, multi-centre, single-arm design. Subjects will be assessed prior to surgery, during and after the procedure, and at 1, 3, 12, 24 and 36 months post-procedure. Analyses will be carried out at 3 months (interim on a minimum of 60 subjects) and 12 months (primary), with a follow-up analysis at 24 and 36 months. A total of 125 subjects will be enrolled to allow for approximately 118 evaluable subjects at 12 months. Evaluable subjects will be defined as those providing baseline data and having POP-Q evaluation completed atthe 12-month visit. Protocol: 300-07-006 Administrative Change #1 Final Verslon 3: 04 February 2008
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4. 4.1.
STUDY POPULATION GENERAL CONSIDERATIONS
The study population will include woman with POP who are considered suitable for mesh repair. The specific inciusion and exclusion criteria for enrolling subjects in this study are described in the following sections. The investigator is expected to offer the opportunity to participate in the study to all subjects meeting the study entry criteria.
4.2.
INCLUSION CRITERIA
To be eligible, female subjects must be diagnosed with POP and meet the following criteria: 1. Candidates with symptomatic pelvic organ prolapse of ICS POP-Q Stage III or IV, suitable for surgical repair. Perineal repair, vaginal hysterectomy and)or mid urethral sling procedures for incontinence may be performed concurrently. 2. Agel8years. 3. Agrees to participate in the study, including completion of all study-related procedures, evaluations and questionnaires, and documents this agreement by signing the Ethics Committee) IRB approved informed consent. 4.3.
EXCLUSION CRITERIA
Potential subjects who meet any of the followirig criteria will be excluded from participating in the study: 1.
Additional surgical intervention for POP repair concurrent to the Gynecare Prolift +M procedure (e.g. paravaginal repair, sacrocolpopexy, colporraphy in a non-Gynecar e Prolift+M treated compartment)
2. Previous repair of pelvic organ prolapse involving insertion of mesh. 3. Previous hysterectomy within 6 months of scheduled surgery. 4.
Experimental drug or experimental medical device within 3 months prior to the planned procedure.
5. Active genital, urinary or systemic infection at the time of the surgical procedure. Surgery may be de)ayed in such subjects unti) the infection is cleared. 6. Coagulation disorder or on therapeutic anticoagulant therapy at the time of surgery. 7.
History of any pelvic radiation therapy.
8.
History of chemotherapy within 6 months of the planned procedure.
9.
Systemic disease known to affect bladder or bowel function (e.g. Parkinsons disease, multiple sclerosis, spina bifida, spinal cord injury or trauma).
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10. Current evaluation or treatment for chronic pelvic pain (e.g. interstitial cystitis, endometriosis, coccydynia, vulvadynia). 11. Nursing or pregnant or intends future pregnancy. 12. In the investigator’s opinion, any medical condition or psychiatric illness that could potentially be life threatening or affect their ability to complete the study visits according to this protocol. 5. RANDOMISATION AND BLINDING As this is a single-arm study, randomisation is not applicable. All subjects will receive GYNECARE PROLIFT + M*. The surgeon and subjects will not be blinded to the treatment. 6. STUDY DEVICES 6.1. THE GYNECARE PROLIFT + M* PELVIC FLOOR REPAIR SYSTEM GYNECARE PROLIFT + M* Pelvic Floor Repair System is indicated for surgical repair of POP. It comprises mesh implants constructed of GYNECARE GYNEMESH M, comprising two components of absorbable polyglecaprone-25 monofilament fiber and non-absorbable polypropylene monofUament fiber. The Instructions for Use (IFU) should be followed for all study procedures.
7.
STUDY EVALUATIONS Study Procedures By Visit
7.1
7.1.1. OVERVEW The Time and Events Schedule inciuded in the Synopsis summarizes the frequency and timing of the various effectiveness and safety measurements. All consented subjects who are eligible for the study and successfully complete screening (Visit 1) will be scheduled for the surgical procedure (Visit 2). The post-operative visit (Visit 3) will be on the day of discharge, which is dependent on normal clinical practice at the site. The follow-up visits will include Visit 4 (1 month post surgery), Visit 5 (3 months post surgery), Visit 6 (12 months post surgery). Visit 7 (24 months post surgery) and Visit 8 (36 months post surgery). 7.1.2.
VISIT 1 PRE-SURGERY EVAL.UATION (SCREENING)
Prospective subjects will be screened within 90 days prior to surgery. Prior to any study related procedures, subjects will be fully informed of all aspects of the study, including the benefits, risks and constraints of the study, and will be asked to sign a Consent Form. The following information will be performed and recorded at the screening visit: •
Informed consent process.
•
Review of lnclusion 1 Exclusion criteria to confirm subject eligibility. In the event that a subject is not eligible, the reason will be documented on the worksheet and screening log. Protocol: 300-07-a06 19 of 54
Administrative Change #1 Final Version 3: 04 February 2008
•
Allocation of a 5-digit ID number to each subject, which will be recorded on all study-specific documents. As a subject is screened, her initials and date of birth will be added to the Subject ldentification Log.
•
Documentation of demography (date of birth, ethnic origin) and subject height and weight. Documentation of relevant medical and surgical history. This will include connective tissue disorders, constipation, chronic bronchitis, previous POP repair, previous incontinence treatment, number of pregnancies and mode of delivery Le. vaginal or C-section, details of hysterectomy (if applicable), menopausal status and details of current HRT treatments. Physical exam.
•
• • •
•
Pelvic exam including baseline assessment of pain on palpation and vaginal wall stiffness. POP-Q assessment by an independent, appropriately qualified assessor, as determined by the Principal Investigator. In instances where this is not possible, the Principal Investigator may perform POP-Q assessment. The site must use the CD —Ram provided by the sponsor to calculate the overall prolapse stage. Completion of PFIQ-7, PISQ-12, PFDI-20 and Euro-QOL questionnaire responses by the subject.
7.1.3.
VISIT 2 SURGICAL PROCEDURE (Visit 2 should occur within 90 days after screening)
•
Date and time of hospital admission
•
Pre-procedure pregnancy test within 24 hours prior to the procedure. • The surgeon should follow the lnstructions for Use (IFU) for the GYNECARE PROLIFT system. The following activities will be performed prior to or during the procedure:
+
M*
•
Confirm inclusion/exolusion criteria.
•
Confirm medical/surgical history.
•
Pre-procedure blood count: haemoglobin (Hb) and haematocrit [HCTJcan be within 21 days prior to procedure.
• •
Type of anaesthesia used (Le. general or regional). Details of procedure type (i.e. anterior, posterior or total GYNECARE PROLIFT system).
•
Total time in the operating room.
•
Start and finish time of procedure, defined as first incision to last suture, respectively.
•
Details of concurrent procedures (e.g. mid-urethral sling procedure for incontinence, vaginal hysterectomy).
•
Perform cystoscopy for anterior GYNECARE PROLIFT+M* and detail resuits.
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+
M*
•
Details of prophylactic oral and vaginal oestrogen and antibiotics.
•
Intra operative adverse events.
7.1.4. VISIT 3 POST-SURGERY EVALUATION (Subjecf Visit Discharge date) —
From the end of the procedure until the time of hospital discharge, the following data will be recorded: •
Pain VAS, 24 hours post op, or at time of discharge, whichever occurs first, noting time of assessment.
• •
Haemoglobin (Hb) and haematocrit (HCT) on post-operative day 1. Details of post-procedure analgesia, prophylactic antibiotic regimen, and prophylactic use of oestrogen.
•
Date of ramoval of catheter placed at time of surgery.
•
Date and time of hospital discharge.
•
Date when subject is ready for discharge, if different from actual date of discharge. Prior to discharge, the subject will be provided with a diary card to complete dates when they stopped taking analgesia for post-operative pain, returned to normal activities i.e. walking, driving, working, household activities, and sexual intercourse. These will be provided to the investigator at subsequent follow up visits.
•
•
Subjects will be instructed to avoid strenuous activity for a period of 3 to 4 weeks, and avoid sexual intercourse for at least four weeks following surgery. Pelvic floor exercises may be recommenced based on the surgeon’s guidance.
•
Complete Gynaecologic lntervention form It necessary
•
Adverse Events.
7.1.5. Vlsrr 4 POST-SURGERY EVALUATION (1 MONTH POST-PROCEDURE) (Visit window +1- 14 days)
The following assessments will be recorcied at the clinical follow-up visit approximately 1 month following surgery: •
Pain VAS.
• • • •
Date of removal of catheter placed at surgery (1f not previously recorded). Documentation of any intermittent catheterisations. Evaluation of subject void Ing function. Return to usual activities questionnaire the diary card will be checked for completeness and dates transcribed into the CRF. 1f the subject has not retumed to all activities, they will be asked to continue to carry the card until all applicable dates have been completed.
•
Pelvic Exam
—
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•
Complete Gynaecologic Intervention form 1f necessary
•
Adverse Events.
7.1.6.
VISIT 5 POST-SURGERY EVALUATION (3 MONTHs POSTPROCEDURE)
(Visit window +1- 14 days)
The following assessments will be recorded at the clinical follow-up visit approximatel y 3 months following surgery: •
• • • •
Investigator to perform a pelvic examination for incidence of mesh contraction and vaginal wall stiffness determined by pain on gentie palpation of mesh and its attachment points during pelvic and or rectal examination. Evaluation of subject voiding function. Return to usual activities questionnaire should be collecteci if any activity did not resume by the 1 -month visit. Subject to record EuroQol, PFIQ-7, PISQ-12, and PFDI-20, surgical satisfaction questionnaire responses, and the global patient impression question. POP-Q assessment by an independent, appropriately qualified assessor, as determined by the Principal Investigator. In instances where this is not possible, the Principal Investigator may perform POP-Q assessment. The site must use the CD —Rom provided by the sponsor to calculate the overall prolapse stage.
•
Complete Gynaecologic Intervention form if necessary.
•
Adverse Events.
7.1.7 Visir 6 POST-SURGERY EVALUATION (12- MONTHS POST PROCEDURE) (Visit window +1-28 days)
The following assessments will be recorded at the clinical follow-up visit approximatel y 12 months following surgery: •
• • •
• •
Investigator to perform a pelvic examination for incidence of mesh contraction and vaginal wall stiffness determined by pain on gentie palpation of mesh and its attachment points during pelvic and or rectal examination. Return to usual activities questionnaire should be coflected if any activity did not resume by the 3-month visit. Subject to record EuroQol, PFIQ-7, PISQ-12, and PFDI-20 and surgical satisfaction questiorinaire responses and the global patient impression question. POP-Q assessmerit by en independent, appropriately qualified assessor, as determined by the Principal Investigator. In instances where this is not possible, the Principal Investigator may perform POP-Q assessment. The site must use the CD —Rom provided by the sponsor to calculate the overall prolapse stage. Complete Gynaecologic lntervention form if necessary Adverse Events.
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7.1.8 VISIT 7 POST-SURGERY EVALUATION (24- MONTHS POSTPROCED URE) (Visit window +1-56 days)
The following assessments will be recorded at the clinical follow-up visit approx irriately 24 months following surgery: •
• •
• •
Investigator to perform a pelvic examination for incidence of mesh contraction and vaginal wall stiffness determined by pain on gentle palpation of mesh during pelvic and or rectal examination. Subject to record PFIQ-7, PISQ-12, and PFDI-20, surgical satisfaction questionnaire responses and the global patient impression question. POP-Q assessment by an independent, appropriately qualifled assessor, as determ ined by the Principal Investigator. In instances where this is not possible, the Principal Investi gator may perform POP-Q assessment. The site must use the CD —Rom provided by the sponsor to calculate the overall prolapse stage. Complete Gynaecologic Intervention form if necessary Adverse Events.
7.1.9 VISIT 8 POST-SURGERY EVALUATION (36- MONTHS POST PROCEDURE) (Visit window +1- 90 days) The following assessments will be recorded at the clinical foilow-up visit approx imately 36 months following surgery:
•
• •
• •
Investigator to perform a pelvic examination for incidence of mesh contrac tion and vaginal wall stiffness determined by pain on gentle palpation of mesh during pelvic and or rectal examination. Subject to record PFIQ-7, PISQ-12, and PFDI-20, surgical satisfaction questio nnaire responses and the global patient impression question. POP-Q assessment by an independent, appropriately qualified assessor, as determ ined by the Principal Investigator. In instances where this is not possible, the Principal Investi gator may perform POP-Q assessment. The site must use the CD —Rom provided by the sponsor to calculate the overaU prolapse stage.
Complete Gynaecologic Intervention form 1f necessary Adverse Events.
7.2.
EARLY WITHDRAWAL 1f a subject wants to withdraw early from the study, the study completion page should be completed. 1f the withdrawal occurs after the 1-month visit every attempt should be made to encourage the patient to return for an unscheduled visit to complete all assessm ents required for the 12- month visit.
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7.3. EVALUATIONS 7.3.1. SAMPLE COLLECTION AND HANDLJNG Pre and post-operative blood samples for Hb and Hct will be collected and analysed at the investigational sites local laboratory. Handling of samples and assessm ent assays will be carried out using local laboratory procedures. Lab normal ranges and accreditation of the hospital lab will be obtained for all sites. 7.3.2. ANALYTICAL PROCEDURES Pelvic Oman ProlaDse Quantlflcption system (POP-Q The standardised POP-Q will be used for measuring the required anatomic landmarks and distances required for calculation of the stages of POP-Q (Aa, Ba, C, Ap, Bp, TVL, gh, pb). The POP-Q assessment will be performed by an independent, appropriately qualifled assesso r, as determined by the Principal Investigator. In instances where this is not possible, the Principal Investigator may perform POP-Q assessment. The site must use the CD —Rom provided by the sponsor to calculate the overall prolapse stage. During the POP-Q examination, the POP-Q assessors should ensure that the POP-Q measurements are recorded whilst ensuring:
•
subject in semi-lithotomy position
•
standard examination table
•
vaginal speculum
•
type of intensity Valsalva manoeuvre, cough -
7.3.3. SUBJECT QUESTIONNAIRES Subject questionnaires will be translated into the local language of the subject and will be completed by the subject. The investigator/study nurse, for completeness, will check completed questionnaires before the monitor for the site collects them. Collected questionnaires will be sent to Ethicons Clinical Data Management Department for entry into the clinical databa se. Pelvic Floor Distress Inventory (PFDI-20): The short form of the PFDI will be used to measure the degree of bother and distress caused by pelvic floor 12 symptoms . Pelvic Floor lmpact Questionnaire (PFIQ-7): The short form of the PFIQ will be used to assess the degree to which bladder, bowel, or vaginal symptorns affect the daily activities, relationships, and emotions of women with pelvic floor 12 disorders . Pelvic Oman ProlaDselUrinarv Incontinence Sexual Function (PISQ-12): The short form of the PISQ will be used to evaluate sexual function in women with pelvic floor 13 symptoms . EuroQol: The EuroQol will be used to assess health outcome following surgery, on a common scale for purposes of evaluation, allocation and 4 monitoring’ . Protoco: 300-07-006 Administrative Change #1 Final Vers ion 3: 04 February 2008
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Return to Usual Activities Questionnaire: Subjects will be asked 1f they have returned to their usual activities: walking, driving, working, household activities and sexual intercourse. 1f they have returned to usual activities, they will be asked how long after their operation they were able to resume these activities. Global patient impression 15 Subjects will be asked the global impression question: “Compared with how you were doing before your recent pelvic floor operation, would you say that you are: much better / a littie better / about the same / a little worse / much worseT’ Brief Pain lnventory (VAS) 1 Subjects will be asked to rate their level of postoperative pain.
c
Surnical Satisfaction Questionnaire: Subjects will be asked to rate their satisfaction with their surgical procedure. (Appendix 3)
8. SUBJECT COMPLETIONIEARLY TERMINATION 8.1. COMPLETION A subject will be considered as having completed the study when she has completed all visits through Visit 8 (36 months post surgery) and has been in the study for >337 days. All other subjects will not be considered to have completed the study. 8.2. EARLY TERMINATION OF SUSJECT INVOLVEMENT Subject participation may be considered terminated prior to completing the study (ie. the 36
month follow up Visit) for any of the following reasons: • •
Subject voluntarily withdrew consent Subject Lost to follow-up
A certified, retum-receipt letter must be sent to the subject after attempts to reach the subject by telephone have failed. The subject will be considered lost to follow-up if this communication is unsuccessful. •
Other
Any other reason for early termination should be recorded. When a subjects participation is terminated prior to completing the study, the reason for withdrawal is to be documented on the CRF and in the source documentation. 1f participation is terminated prior to the 1 2-month visit every attempt should be made to complete the procedures scheduled for this time point.
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9. STATISTICAL METHODS Ethicon’s Clinical Development department will be responsible for the analysis of data from this protocol. The detailed Statistical Analysis Plan (SAP) will be based on and will suppiement the statistical design and analysis descnbed in this section.
9.1. SAMPLE SIzE DETERMINATION This is not a hypothesis generating study. A total of 125 subjects will be enrolled. Assuming a 40% drop out rate over 3 years (estimated from study CT-T’JT-001-97 based on 2- year data and extrapolated) this should lead to 75 subjects providing 3- year data and at least 100 (118 subjects assuming a 5% drop out to 1 year) providing 12-month data. It is expected that this will lead to approximately 118 evaluable subjects at 12 months. Evaluable subjects will be defined as those providing baseline data and having POP-Q evaluation at the 12-month visit. (N
9.2. 9.2.1.
PLANNED ANixsIs ANALYSIS SETS
Three main analysis sets are defined: • •
The Safety Set will contain all subjects who receive treatment. The Full Analysis Set (FAS) will contain all treated subjects This set is sub-divided (based on the treated compartment) into: o
Anterior only analysis set
o
Posterior only analysis set
o
Anterior and Posterior analysis set
In addition a ‘sexually active analysis set’ is defined as subjects in the FAS who are sexually active at baseline and complete the PISQ-12 questionnaire The Per-protocol Set (PPS) inciudes all subjects without major protocol violations (to be agreed at the pre-database lock meeting) who either: o complete the 12-month POP-Q evaluation or o
•
o
are failures at any time up to withdrawal
o
This set may be sub-divided as above, based on the treated compartment.
9.2.2. EFFECTIVENESS 9.2.2.1 Prlmary Effectlveness VariableslCriteria The following primary endpoint will be analysed using the PPS and FAS Set: POP-Q score at 12 months post-procedure. Success (overall) will be determined by achievement of a POP-Q score of ICS Stage 1, in the treated compartment, without further re-intervention for POP in that compartment. Since subjects may only have one compartment treated, ICS stage scores will be calculated on the affected side(s) only for each of the ‘Anterior only’, ‘Posterior only’ and ‘Anterior and
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posterior’ analysis sets and the FAS (Affected side success) ICS stage will be calculated ° and 1 success will be achieved 1f the stage is 1. For the calculation of POP-Q ICS stage on subjects with only one affected side, the wles ° will 1 be applied to the anterior or posterior side only and success will be achieved if the stage is 1. 9.2.2.2 Secondary Effectiveness Varlables!Crlterla
The following secondary endpoints will be analysed using the FAS unless otherwise stated: • •
t—’
Summary of ICS Stages at 3, 24 and 36-month visit. Summary of treated compartment ICS POP-Q stage at 3, 12, 24 and 36 moriths. The success criteria of a POP-Q score of ICS Stage l, in the treated compartment, without further surgical re-intervention for POP in that compartment, will also be applied at 36 months.
•
Proportion of subjects with the leading edge within the hymen (i.e. all POP-Q values to be less than 0), and without further re-intervention for POP.
•
Incidence of de navo prolapse as defined as occurrence of a post-operative prolapse ICS Stage II or greater) only in the untreated compartment, provided there was no pre-operative defect in that compartment (ie. ICS Stage 0 or 1). (FAS set exciuding combined treatment patients).
•
Mean scores and change from baseline in PFDI-20 scores at 3,12, 24 and 36 month visits including sub scores (POPDI, CRADI and UDI).
•
Days to return to normal activities (walking, driving, work, household activities and sexual intercourse). Proportion of subjects with a change from baseline 45 points in the PFDI-20 summary score at 12, 24 and 36 months.
• •
EuroQol (EQ-5D health state) change from baseline at 3 and 12 months visit (overall using the EQ-5D index score, and also for each individual item.
•
Mean scores and change from baseline in PFIQ-7 at 3, 12, 24 and 36 months visit inciuding sub scores (POPIQ, CRAIQ and UIQ). Proportion of subjects with a change from baseline 36 points in the PFIQ-7 summary score at 12, 24 and 36 months.
• •
In subjects sexually active at baseline, assessment of sexual function using PISQ-12 assessed at 12, 24 and 36 month visits (mean scores and change from baseline).
• •
Incidence of new onset dyspareunia, resolution or continuance of pre-existing dyspareunia. Incidence of mesh contraction, as determined by pain on palpation of mesh during pelvic examination at 3, 12, 24 and 36 months. Incidence of vaginal wall stiffness, as determined by the investigator on physical examination at 3, 12, 24 and 36 months.
•
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•
Total time in the operating room.
•
Lerigth of procedure (from time of first incision to time of last suture). Nights in hospital (from date of admission to date of discharge; based on actual data and “readiness for discharge”).
• • •
Pain score 24 hours post surgery and at the 1 month visit, measured using VAS. Subject global impression assessed on a 5 point Likert scale at 3, 12, 24 and 36-month
visit.
9.2.2.3 METHODS op ANALYSIS Since this is a single arm study, output will be limited to summary data (mean, standard deviation, minimum, median, maximum and 95% Cl for continuous data and number, percent for discrete data). The Cl for the primary endpoint will be expressed as a 97.6% one-tailed Cl. Time to events will be analysed using Kaplan-Meier methods, with centre in the model. 9.2.3
SAFETY
9.2.3.1 SAFETY VARIABLESICRITERIA The following will be summarised using the Safety Set: •
Adverse events.
•
Determination of any exposures/erosions inciuding location (exposure is any visible mesh or any mesh that can be appreciated to be exposed by palpation but is not visible).
•
Haemoglobin and haematocrit expressed as actual values and change from baseline.
9.2.3.2 METHODS OF ANALYSIS All safety variables will be summarised using the safety set (all subjects treated). All safety variables will be summarised only, no statistical analysis will be carried out. The Medical Dictionary for Regulatory Activities (MedDRA) will be used to code Adverse Events. 9.2.4 INTERIM AND FoLlow-up ANALYSES An interim analysis will be performed on the 3-month data, comprised of a minimum of 60 subjects. The 3-month POP-Q data will be summarised, however, the success criterion will not be applied. All other parameters will be summarised as applicable. As the primary endpoint is only relevant at 12 months there are no stopping rules, although alpha will be arbitrarily assigned 0.001 (one tailed). Follow-up analyses will be carried Out at 24 and 36 months. 9.2.5 HANDLING OF MISSING DATA The primary analysis will be based on the PPS. Confirmatory analyses will be conducted using the FAS, with the following methods used to impute missing data values for the primary endpoint:
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a) FAS with latest post operative result used in the absence of a 12 month result (last observation carried forward (LOCF). b) FAS with missing data imputed to success. c) FAS with missing data imputed to failure. For secondary endpoints missing data will not be estimated. 1f a POP-Q score on the affected side is missing then the overall and affecte d side POP-Q ICS stage will be missing. 1f the missing value is on the unaffected side then only the overall POP-Q stage is missing. However in most cases it will be possible to determ ine if the result is a success based on available scores. In these cases success/failure will be determined manually and documented. 1f success/failure is not available at 12 months, than the 3-month result will be carried forward (LOC F). PFDI-20 and PFIQ-7: Missing values will be assigned the mean score of the non-missing value within the scale (each has three scales plus summary score). PISQ-12: Missing values will be assigned the mean score of the non-m issing value providing there are no more than 2 missing values. EuroQoL Missing data will not be estimated. 10.
ADVERSE EVENTS
10.1.
ADVERSE EVENT
For purpose of this protocol, an adverse event (AE) is any undesirable clinical occurrence in a subject irrespective 1f attributecl to the device or study-related procedure. Those AEs considered to be related or possibly related to the device will be defined as Adverse Device Effects (ADEs). Any worseriing of a pre-existing condition or illness is considered an adverse event. 10.2. SERlous ADVERSE EVENT (SAE) An adverse event that resulted in one of the following: • Death • Life-threatening illness or injury • A permanent impairment of a body structure or a body function • Required in-patient hospitalization or prolongation of existing hospita •
lization Medical or surgical intervention to prevent permanent impairment to body structure or a body function
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•
Foetal distress, foetal death or a congenital abnormality or birth defect
10.3.
SERIOUS ADVERSE DEVICE EVENT (SADE) Those SAEs considered to be related or possibly related to the device will be defined as Serious Adverse Device Effects (SADEs).
10.4
ADVERSE EVENT SEVERITY CATEGORIES
The following categories of adverse event severity are to be used: MUd:
Awareness of a sign or symptom that does not interfere with the subjec t’s usual activity or is transient
Moderate:
Interferes with the subject’s usual activity Incapacitating with inability to work or perform usual activity
Severe: 10.5
ANTICIPATED ADVERSE EVENTS RELATED TO THE PROCEDURE The following adverse events are defined as anticipated adverse events associa ted with gynecological procedures: • Cramping/pelvic pain • Vaginal discharge • Vaginal bleeding/spotting • Site-specific laceration with bleeding • Edema of vagina • Headache • Nausea and vomiting • Febrile morbidity (temperature of 38.O°C/100.4°F or greater on any 2 post-p rocedure days at least 6 hours apart, excluding the first 24 hours after the procedure) • Fatigue • Bladder irritation (Le. dysuria with urinary frequency or urgency) • Bloating sensation • Difficulty voiding or urinary retention • Bladder infection/cystitis/lower urinary tract infection confirmed by a positive culture • Upper urinary tract infection • Vaginal and cervical lacerations • Vaginal infection • Hematoma • Vagirial lesions • Vaginitis • Edema of extemal genitalia • Edema of lower extremities • Life-threateriing cardiac or respiratory arrest or other life-threatening event • Additional anesthesia risks • Uterine infection or injury leading to hysterectomy and pulmonary embolism leading to death
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10.6
ANTICIPATEDADVERSE DEVICE EFFECTS
The following adverse events are defined as anticlpated adverse events that may be assoclated wlth the GYNECARE PROLIFT+M Mesh device: • Mesh exposure is a common complication, which can be managed by excision and closure.
(
•
Mesh retraction (shrinkage”) is less common but is considered more serious than mesh exposure. It can cause vaginal anatomic distortion, which may eventually have a negative impact on sexual function. Shrinkage of the mesh is expected under normal circumstances; however, excessive shrinkage resulting in pain is not a common finding.
.
The scar plate that forms with in-growth of tissue into the mesh can cause stiffness in the vagina that further impacts sexual function in a negative manner.
•
Punctures or lacerations of vessels, nerves, bladder, urethra or bowel may occur during GYNECARE PROLIFT Guide passage and may require surgical repair.
10.7 AD VERSE EVENT COLLEC11ON Subjects should be encouraged to report AEs spontaneously or in response to general, non directed questioriing (e.g., ‘How has your health been since the last visit?”). All adverse events must be followed until resolution or until a stable clinical endpoint is reached. Details of all AEs and SAEs occurring during the study must be recorded on the Adverse Event Form in the CRF, as follows: • • • • •
(
•
10.8
Description of the everit Dates of onset and resolution Severity Action taken Outcome Relationship to device or study-procedure (related, possibly related, not related)
AD VERSE EVENT REPORTING
It is a requirement that the Principal Investigator promptly reports the following events to the Sponsor within 24 hours of becoming aware of the event occurring: • SAEs irrespective of their relationship to the device • SADEs and non-serlous ADEs whether expected or not Contact information will be provided in a separate document. Reporting to Ethlcs: It is the Investigator’s responsibility to report all serious adverse events occurring at their site, based en their applicable ethics committee requirements. Protocol: 300-07-006 Administrativo Change #1 I9naI Version 3: 04 February 2008
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Informlrig Investigators:
It is the responsibility of the Sponsor to report all serlous adverse device effects (SADEs) to all participating Investigators. Reporting to Competent Authoritles: The Sponsor will notify each Competent Authority of reportable events, based on national regulations. It is the responsibility of the principal investigator at each site to inform their local ethics committee of relevant SAE’s occurring at their site, according to IRB / local ethics committee requirements. It is the responsibility of the monitor to ensure that the Principal Investigator has reported all relevant SAE’s to their IRB! local ethics committee. The Sponsor will notify Investigators of the occurrerice of unanticipated and associated serious adverse events. The investigator must report these events to the appropriate Medical Ethics Committee/Institutional Review Board (MEC/IRB) that approved the protocol unless otherwise required and documented by the MEC/IRB. II. COMPLAINT REPORTING Product complaints indicating dissatisfaction with the identity, labelling, quality, durability, reliability, safety, effectiveness or performance of the study device, whether or not the complaint resulted in a subject AE, must bo reported within 48 hours to the study sponsor. 12. CONTACTING SPONSOR The names of the individuals (and corresponding phone numbers) who are to be contacted regarding adverse events, safety issues, and complaints are provided in the lnvestigator Study File. 13.
CLINICAL SUPPLIES INFORMATION The GYNECARE PROLIFT + M* System must be kept in a secure location with restricted access under appropriate erivironmental conditions. The device is only intended for use in this study protocol and only by the investigator identifled for this study. 13.1.
PI-IYSICAL DESCRIPTION OF STUDY DEVICE
13.1.1
GYNECARE GYNEMESH M
131.2
TOTAL MESH IMPLANT
The Total mesh implant is constructed from GYNECARE GYNEMESH M and is shapeci for performing a total vaginal repair. The implant has 6 straps: 4 for securing the anterior portion of
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the implant via a transobturator approach and 2 for securing the posterior portion of the implant in the sacrospinous ligament via a transgiuteal approach. Alternatively, the 2 posterior straps may be cut to reduce their length and secured in the sacrospinous ligament via a vaginal approach. The proximal and distal anterior straps have squared and triangular ends, respectively, while the posterior straps have rounded ends. 13.1.3 ANTERIOR MESH IMPLANT The Anterior mesh implant is constructed from GYNECARE GYNEMESH M and is shaped for repair of anterior vaginal defects. The implant has 4 straps that are secured via a transobturato r approach. The proximal and distal anterior straps have squared and triangular ends, respectively. 13.1.4 POSTERIOR MESH IMPLANT The Posterior mesh implant Is constructed from GYNECARE GYNEMESH M and is shaped for repair of posterior and/or apical vaginal vault defects. The implant has 2 straps that are secured in the sacrospinous ligament via a transgluteal approach. Alternatively, the 2 posterior straps may be cut to reduce their length and secured in the sacrospinous ligament via a vaginal approach. The posterior straps have rounded ends. 13.1.5 GYNECARE PROLIF GUIDE The GYNECARE PROLIFT * guide is a single-patient use instrument designed to create tissue paths to allow placement of the Total, Anterior and Posterior mesh implants and to facilitate placement of the GYNECARE PROLIFT* Cannula. Its length and curvature are specifîcally designed to create proper placement paths for all mesh implant straps. The GYNECARE PROLIFT+M Guide is suitable for use on both sides of the patient. 13.1.6 GYNECARE PROLIFT* CANNULA The GYNECARE PROLIFT* Cannula is a single-patient use instrument used in conjunction with the GYNECARE PROLIFT Guide to facilitate passage of the implant straps while protecting the surrounding tissue. Each GYNECARE PROLIFT* Cannula is placed over the GYNECARE PROLIFT* prior to passage and remains in place after the GYNECARE PROLIFT+M* guide is withdrawn. 13.1.7 GYNECARE PROLIFT* RETRIEVAL DEVICE The GYNECARE PROLIFT * Retrieval Device is a single-patient use instrument designed to facilitate placement of the mesh implant straps. The GYNECARE PROLIFT* Retrieval Device is passed through the prevlously positioned GYNECARE PROLIFT* Canriula until its distal end is retrieved through the vaginal dissection. The distal end of the GYNECARE PROLIFT* Retrieval Device has a loop to securely capture the mesh implant strap is drawn out through the GYNECARE PROLIFT* Cannula.
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13.2 PACKAGING AND LABELLING 13.2.1 PACKAGING The GYNECARE PROLIFT + M System is provided sterile (ethylene oxide) for single uso. Do not re-sterilize. Do not use 1f package is opened or daniaged. Discard opened, unused devices. 13.2.2 LABELS AND LABELLING INSTRUCTIONS There will be a label bearing information that will meet all applicable chnical require ments. 13.3 DEVICE ACCOUNTABILITY It is the responsibility of the clinical investigator to ensure that all study device s received at the site will be inventoried and accounted for throughout the study and the result recorded in the device accountability form maintained in the Study Binder. The sponsors site monitor will verify the device accountability during on-site monitoring visits.
Unless otherwise instructed by the sponsor, the investigator agrees at the end of the study to return all unused study devices, to the sponsor as instructed by the sponso r’s site monitor. The investigator agrees neither to dispense the study devices from, nor store It at, any site other than the study sites agreed upon with the sponsor. On a country-speciflc basis, permission may be granted for local disposition, with supporting documentation. 14. TRIAL-SPECIFIC SUPPLIES The investigator will be provided with the following supplies:
• • •
GYNECARE PROLIFT + M* Pelvic Floor Repair System Case Report Forms (CRF) Investigator Study Binders
15.
ETHICS
15.1.
INVESTIGATOR REsPONSIBIUTIES
The investigator is responsible for ensuring that the clinical study is perform ed in accordance with the protocol, the Declaration of Helsinki, principles of Good Clinical Practic e (GCP), and applicable regulatory requirements. These documents set forth that the informed consent of the subjects is an essential precondition for participation in the clinical study. 15.2.
MEDIc ETHICS COMMITIEE OR INSTITUTIONAL REvIEw BOARD (MECIIRB)
The investigator may begin enrolment in the study after full approval of the protocol and adjunctive materials (e.g., informed consent form, advertising) has been obtaine d from a local MEC/IRB and the sponsor has received a copy of this approval. Investigator responsibilities relevant to the MECIIRB include the following: Protocol: 300-07-006 AdmirIstratve Charige #1 Final Version 3: 04 February 2008
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1. During the conduct of the study, submit progress reports to the IRB or MEC as required, and request re-review and approval of the study at least once a year; 2. Report immediately to the IRB or MEC any unexpected adverse device effects that occur during the study, and provide the ETHICON designated monitor with a copy of the site correspondence;
(.
3. 1f ETHICON notifies the investigator about any unexpected advers e device effects reported in other studies using this subject device, report that information to the IRB or MEC; 4. As required, obtain approval from the IRB or MEC for protoc ol amendments and for revisions to the consent form or subject recwitment advertisements; 5. Reports on, and reviews of, the trial and its progress will be submit ted to the IRB/MEC by the investigator at intervals stipulated in their guidelines and in accordance with pertinent regulations and guidelines. 6. Mairitain a file of study-related information (see study files) that inciud es all correspondence with the IRB or MEC; 7. Notify IRB or MEC when study is completed (i.e. after the last study visit of the final study subject); 8. After study completion (within 3 months is recornmended) provid e the IRB or MEC with a final report on the study. The recommended components of a final report are as follows; dates of study start and completion, number of subjects enrolledltreat ed, number of subjects who discontinued participation early and reason why, itemization and discussion of any serious adverse event. 15.3. INFORMED CON SENT Each subject (Dr a legally authorized representative) must give written consent (and sign other locally required documents) according to local requirements after the nature of the study has been fully explained. The consent form must be signed prior to performance of any study related activity. The consent form that is used must be approved both by the sponsor and by the reviewing IRBIMEC. The informed consent will be in accordance with the Declaration of Helsinki, current principles of Good Clinical Practice, applicable regulat ory requirements, privacy requirements, and ETHICON policy. The investigator must explain to potential subjects or their legal representatives the aims, methods, reasonably anticipated benefits and potential hazards of the trial and any discomfort It may entail. The other elements of the informed consent will be explained and subjects will be
given the opportunity to ask questions. After this explanation and before entry into the trial, consent should be appropriately recorded by means of the subject’s or his/her legal representative’s dated signature. 1f a subject and his/her legal represe ntative are unable to read, an impartial witness must be present during the entire informed consent discussion. The signature of the impartial witness will certify the subject’s consent. The subject or his/her legal representative will be given a signed and dated copy of the informed consent form. Protocol: 300-07-006 Administrative Change #1 Final Version 3: 04 February 2008
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16.
ADMINISTRATIVE REQUIREMENTS
16.1.
PROTOCOL MODIFICATIONS
Neither the investigator nor sponsor will modify this protocol without obtain ing the concurrence of the other. All protocol amendments must be issued by the sponsor, signed and dated by the investigator, and should not be implemented without prior IRB/MEC approv al, except where necessary to eliminate immediate hazards to the subjects or when the change (s) involves only logistical or administrative aspects of the trial (eg., change in monitor(s), change of telephone number(s)). It is the sponsor’s responsibility for reporting protocol amend ments to any Regulatory Authority (as applicable). The principal investigator reports the protocol amendnients to the EC/IRB as per their local requirements. In situations requiring a departure from the protocol, the investigator or other physician in attendance will contact the appropriate sponsor representative by fax or telepho ne (see Contact Information page). This contact must be made before implementing any departure from protocol. In all cases, contact with the sponsor must be made as soon as possible in order to discuss the situation and agree on an appropriate course of action. The CRF and source document will describe any departure from the protocol and the circumstances requiring it. 16.2.
REQUIRED DOCLJMENTATION
Documents that must be provided to the sponsor prior to study start are as follows: • A copy of the formal written notification to the investigator regarding approv al of the protocol by an EC/IRB that is in compliance with regulatory guidelines. The written notific ation is to be signed by the chairman or authorized designee and must identify the specifî c protocol. In cases where an ECIIRB member has a known conflict of interest, abstention of that individual from voting should be documented; an investigator (or sub-investiga tor) may be a member of the EC/IRB, but may not participate in the deliberation or vote on any research in which he or she is irivolved; •
A copy of the ECRRB approved informed consent form and other adjunctive materials (e.g., advertising) to be used in the study, including written documentation of EC/IRB approval of these items;
•
Name and address of the EC/IRB with a statement that it is organi zed and operates according to GCP and the applicable laws and regulations, and a curren t list of the ECIIRB members. It accompanied by a letter of explanation from the EC/lRB, a general statement may be substituted for this list, or a general assurance number.
•
Regulatory authority approval or notification, if appilcable; Applicable local regulatory documentation (e.g. Statement of Investigator); Financial disciosure statement(s) for each investigator and sub-investigat or, if applicable;
• •
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•
Signed and dated Investigator Agreement page
•
Signed and dated clinical study agreement, including nancial agreement Up-to-date signed and dated curriculum vitae for each investigator and sub-investigator;
• •
Name and address of any local laboratory conducting tests for the study, a dated copy of the laboratory reference values for tests to be performed during the study and a copy of the certification or other documentation establishing adequacy of the facility, if applicable.
Other documents may also be required prior to the study, and during the course of the study. 16.3
CONFIDENTIALITY OF SUBJECT RECORDS
The Investigator will ensure that the subjects’ anonymity will be maintained. On CRF’s or other study documents submitted to ETHICON CDMA, subjects will not be identified by their narnes, but an identification code. Documents not for submission to ETHICON ie. Investigator Log and orig Ina! subjects’ consent forms will be maintained in the Investigator Site File. 16.4 RECORD RETENTION The investigator/institution will maintain all CRF’s and all source documents that support the data collected from each subject, and all trial documents as specified by appllcable regulatory requirement(s). The investigator/institution will take measures to prevent accidental or premature destruction of these documents. Essential documents must be retained until at least 2 years after the last approval of a marketing application or until at least 2 years have elapsed since the forma! discontinuation of clinical development of the investigational product. These documents will be retained for a longer period 1f required by the applicable regulatory requirements or by an agreement with the sponsor. It is the responsibility of the sponsor to inform the investigator/institution as to when these documents no longer need to be retained. 1f the responsible investigator retires, relocates, or for other reasons withdraws from the responsibility of keeping the study records, custody must be transferred to a person who will accept the responsibility. The sponsor must be notified in writing of the name and address of the new custodian.
16.4.1 CASE REPORT FORM COMPLETION Designated study site personnel will enter study data into the CRF’s. Such data will be supported by source documents. The investigator shali maintain the records of study article disposition, final CRF’s, worksheets, and any other study-specific source documentation, until notified by the Sponsor that study-specific records may be destroyed. The sponsor should be notified if the investigator plans to leave the institution so that arrangements can be made for transfer of study obligations and records.
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16.4.2 STUDY COMPLETIONITERMINATION 16.4.2.1
STUDY COMPLETION
The final data from the centre will be sent to ETHICON (or designee) following complotion of the final subject visit at that centre. 16.4.2.2 STUDY TERMINATION An initiative for centre closure or trial termination can be taken at any time either by the sponsor or by the investigator, provided there is reasonable causo and sufficient notice is given in advance of the intended termination. Reasons for such action taken by the sponsor include, but are not limited to the following: •
(
•
• • • •
Successful completion of the trial at the centre; The required number of subjects for the trial has been recruited; Failure of the investigator to comply with the protocol, the sponsor’s procedures or GCP guidelines; Safety concerns; Sufficient data suggesting lack of effectiveness; Inadequate recruitment of subjects by the investigator.
16.4.3 MONITORING The sponsor will perform on-site monitoring visits as frequently as necessary. Visits are usually made at regular intervals. The frequency of monitoring visits will be documented in the monitoring guidelines for this study. The monitor will record the dates of the visits in a trial centre visit log to be kept at the site. The first post-initiation visit will usually be made as soon as possible after enrolment has begun. At these visits, the monitor will compare the data entered onto the CRFs with the hospital or clinic records (source documents). At a minimum, source documentation must be available to substantiate subject identification, eligibility and participation, proper informed consent procedures, dates of visits, adherence to protocol procedures, record of safety and efficacy parameters, adequate reporting and follow-up of AE’s, device receipt/use/return records, and date of completion and reason. Specific items required as source documents will be reviewed with the investigator prior to the study. Findings from this review of CRF’s and source documents will be discussed with the investigational staff. The sponsor expects that, during monitoring visits, the relevant investigational staff will be available, the source documentation will be available, and a suitable environment will be provided for review of study-related documents. The monitor will meet with the investigator on a regular basis during the trial to provide feedback on the trial conduct. 16.4.4 DATA OUALITY ASSURANCE Steps to be taken to assure the accuracy and reliability of data include the selection of qualified investigators and appropriate study centres, review of protocol procedures with the investigator Protocol: 300-07-006 Admirlstrative Change #1 Final Version 3: 04 February 2008
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and associated personnel prior to the study, periodic monitoring visits by the sponsor. The sponsor will review CRF’s for accuracy and completeness during on-site monitoring visits and after their return to ETHICON; any discrepancies will be resolved with the investigator or designees, as appropriate. The data will be entered into the clinical trial databa se and verified for accuracy. 16.4.5 ON-SITE AUDITS Representatives of the sponsor’s Clinical Development and Medical Affairs Department or Quality Assurance Departrnent may visit the site to carry out an audit of the study in compliance with regulatory guidelines and company policy. Such audits will require access to all study records, including source documents, for inspection and comparison with the CRF’s. Subject privacy must, however, be respected. Sufficient prior notice will be provided to allow the investigator to prepare properly for the audit. Similar auditing procedures may also be conducted by agents of any regulatory body reviewing the results of this study in support of a Licensing Application. The investigator should immediately notify the sponsor 1f they have been contacted by a regulatory agency concerning an upcoming inspection. 16.4.6 USE OF INFORMATION AND PUBLICATION
All information concerning the GYNECARE PROLIFT + M* System, ETHICON operations, patent application, forrnulas, manufacturing processes, basic scientific data, and formulation information, supplied by the sponsor to the investigator and not previously published, is considered confidential and remairis the sole property of ETHICON. The investigator agrees to use this information only to accomplish this study and will not use It for other purposes without the sponsor’s written consent. The investigator understands that the information developed in the clinical study will be used by ETHICON in connection with the continued development of the GYNECARE PROLIFT + M* System, and thus may be disclosed as required to other clinical investigators or government regulatory agericies. To permit the information derived from the clinical studies to be used, the investigator is obligated to provide the sponsor with all data obtained in the study. Ariy publication or other public presentation of results from this study requires prior review by ETHICON. Draft abstracts, manuscripts, and materials for presentation at scientific meetings must be sent to the sponsor at least 30 working days prior to abstract or other relevant submission deadlines. Authorship of publications resulting from this study will be based on generally accepted criteria for major medical journals. The investigator understands not to use the name of ETHICON or the GYNECARE PROLIFT + M* System, or any of its employees, in any publicity, news release or other public announcement, written or oral, whether to the public, press or otherwise, relating to this protocol, to any amendment hereto, or to the performance hereunder, without the prior consent of ETHICON. Protocol: 300-07-006 Administrativo Change #1 Firial Version 3: 04 February 2008
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16.5 1
2
3 4 5 6
7 8 9 10 11
12 13 14 15
16
REFERENCES
Smith ARB, Hosker GL, Warrell DW. The Role of partial denervation of the pelvic floor in the aetiology of genitourinary prolapse and stress incontinence of urine. A neurophysiologic study. Br J Obstet Gynaecol 1989; 96:24-28. Gilpin SA, Gosling JA, Smith ARB, et al. The pathogenesis of genitourinary prolapse and stress incontinence of uilne. A histological and histochemical study. Br J Obstet Gynecol 1989; 96:1523. Norton PA, Baker JE, Sharp HC, et al. Genitourinary prolapse and joint hypermobilit y in women. Obstet Gynecol 1995; 85(2):225-228. Smith P, Heimer G, Norgen A, et al. Steroid Hormone Receptors in Pelvic Muscies and Ligament in Women. Gynecol Obstet Invest 1990: 30:27-30. Olsen A, Smith V, et. al. Epiderrilology of Surgically Mariaged Pelvic Organ Prolapse and Unnary Incontinence. Obstet Gynecol 1997; 89:501-506. Benson JT, Lucente V, McClellan E. Vaginal versus abdominal reconstructive surgery for the treatment of pelvic support defects: A prospective randomized study with long-term outcome evaluation. Am J Obstet Gynecol 1996; 175:1418-1422. Fenner, D. New Surgical Mesh. Clin Obstet Gynecol. 2000:43:650-8. Cobb, William S, MD, Kercher, Kent W, MD, and Heniford, Todd B., MD. The Argument for Lightweight Polypropylene Mesh in Hernia Repair. Surgical Innovation 2005: 63-69. Iglesia C, Fenner D, Brubaker L. The Usa of Mesh in Gynecologic Surgery. Int. Urogynecol J. 1997:105-115. Carey M, Slack M, Higgs P, Wynn-Williams M and Comish A. Vaginal surgery for pelvic organ prolapse using mesh and a vaginal support device. Submitted to Br J Ob Gyn; 2006 Bump RC, Mattiasson A, Bo K, Brubaker LP, DeLancey JOL, Klarskov P, Shuil BL, Smith ARB. “The standardisation of terminology of female pelvic organ prolapse and pelvic floor dysfunction. Am J Obstet Gynecol 1996; 175:10-7 Barber MD, Walters MD and Bump RC. Short forms of two condition-specific quality of life questionnaires for women with pelvic floor disorders. Am J Ob Gyn 2005; 193:103-13 Rogers RG, Coates, KW, Kammerer-Doak D, Khalsa, S, Qualls C. A short form of the Pelvic Organ Prolapse/Urinanry Incontinence Sexual Questionnaire (PISQ-12). IUGJ 2003; 14:164-8. Kind P. The EuroQol lnstrutment: An Index of Health-Related Quality of Life. Quality of Life n1d 2 and Pharmacoeconornics in Clinical Trials ( Edition) Spilker B. 1996; Pg 191 -210 Wren PA, Janz NK, Brubaker L, Fitzgerald MP, Weber AM, LaPorte F8, Wei JT. ReIiability of health-related quality of life measures 1 year after surgical procedures for pelvic floor disorders. Am J Ob Gyn 2005:192:780-8. Keller et al. “Validity of the brief pain inventory for use in documenting the outcomes of subjects with non-cancer pain.” Clin J Pain 2004; 20 (5): 309-18
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APPENDIX 1 ETHICON CONTACT DETAILS ETHICON ClinIcal Development & Medical Affairs MEDICAL DIRECTOR
CLINICAL RESEARCH MANAGER
CLINICAL PROJECT MANAGER
Contract Research Organisation (EU sites)
F.A.C.O.G. Medical Director ETHICON Women’s Health and Urology P.O. Box 151, Route 22 West Somerville, NJ 08876-0151, US Clinical Development & Medical Affairs ETHICON, P0 Box 1988 Simpson Parkway Kirkton Campus Livingston EH54 OAB, UK Clinical Development & Medical Affairs ETHICON, P0 Box 1988 Kirkton Campus Livingston EH54 OAB, UK D-TARGET SA En Chamard 55C 1442 Montagny-prûs-Vverdon Switzerland
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Tel: +1 Fax: +1-
iO.2.e
Tel: +44 Fax: +44
102e
Tel: +44 Fax: +44
10.2.e
+41
10 2 e
APPENDIX 2 GLOBAL PATIENT IMPRESSION
Compared with how you were doing before your recent pelvic floor operation, would you say that now you are: • • • • •
Much better A littie better About the same A littie worse Much worse
Please circie the term that most applies to you.
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APPENDIX 3
Surgical Satisfaction Questionnaire Instructions: Following are a list of questions about your satisfaction with your surgery. All information is strictly confidential. Your conlidential answers will be used only to help doctors understand and improve what is important to patients before, during and after surgery. Please check the box that best answers the question for you. Thank you for your help. 1. How satisfied are you with how your pain was controlled in the hospital after surgery? LJ Vety Satisfied fl Satisfied E Neutral Unsatisfied fl Very unsatisfïed 2. How satisfied are you with how your pain was controlled when you returned home after surgery? Satisfied El Neutral El Very Satisfied Unsatisfied Very unsatisfied 3. How satisfied are you with the amount of time it took for you to return to your daily activities, for example housework or social activities outside the home? fl Very Satisfied fl Satisfled Neutral [1 Unsatisfied El Vety unsatisfied 4. How satisfied are you with the amount of time it took for you to return to work? ElVeiy Satisfied Satisfied Neutral fl Unsatisfled ElVery unsatisfied 5. How satisfied are you with the amount of time it took for you to return to your normal exercise routine? Satisfied [1 Neutral El Very Satisfied Unsatisfled El Very unsatisfied 6. How satisfied are you with the resuits for your surgery? EZVery Satisfled El Satisfled El Neutral unsatisfied
Unsatisfied
Very
7. Looking back, if you “had to do it all over again” would you have the surgery again? Yes El Maybe El No 8. Would you recommend this surgery to someone else? El Yes [1 Maybe El No
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APPENDIX4 PELVIC ORGAN PROLAPSEIURINARY INCONTINENCE SEXUAL FIJNCTION QUESTIONNAIRE (PISQ-12)
O
Instructions: Following are a list of questions about you and your partner’s sex life. All information is strictly conlidential. Your confidential answers will be used only to help doctors understand what is important to subjects about their sex lives. Please check the box that best answers the question for you. While answering the questions, consider your sexuality over the past six months. Thank you for your help. 1. How frequently do you feel sexual desire? This feeling may inciude wanting to have sex, planning to have sex, feeling frustrated due to lack of sex, etc. Daily Ei
Weekly
MonthlyJ
Less than once a month
Never
2. Do you climax (have an orgasm) when having sexual intercourse with your partner? Always [1 Usually Sometimes Seldom Never Ei 3. Do you feel sexually excited (tumed on) when having sexual activity with your partner? Always Ei
Usually
Sometimes
Seldom Never Ei 4. How satisfied are you with the variety of sexual activities in you current sex life? Always Ei Usually Sometimes Seldom 3 Never Ei 5. Do you feel pain during sexual intercourse?
()
A!ways Ei
Usually[]
Sometimes
Seldom
6. Are you incontinent of urine (leak urine) with sexual activity? Always UsualIyE Sometimes Seldomti
Never
Never Ei
7. Does fear of incontinence (either stool or urine) restrict your sexual activity? Always UsuaIIyEi Sometimes SeIdom Never Ii 8. Do you avoid sexual intercourse because of bulging in the vagina (either the bladder, recturn or vagina falling Out?). Always Ei
Usually
Sometimes
Seldom
Never Ei 9. When you have sex with your partner, do you have negative emotional reactions such as fear, disgust, shame or guilt? Protocol: 300-07-006 Administrative Change #1 Final Verson 3: 04 February 2008
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Always j1
Usually
SometimesEl
Usually
Sometimes
Seldomri Never 0 10. Does your partner have a problem with erections that affects your sexual activity? Always 1 Usually Sometimes Seldom Never 0 11. Does your partner have a problem with premature eaculation that affeets your sexual activity? Always
Seldomfl Never 0 12. Compared to orgasms you have had in the past, how intense are the orgasms you have had in the past six months? Much less intense, More Intense
Less intense
Same intensity
Much more intense
Scoring: Scores are calculated by totaling the scores for each question with O=always, 4=never. Reverse scoring is used for items 1,2,3 and 4. The short form questionnaire eau be used with up to two missing responses. To handle missing values the sum is calculated by multiplying the number of items by the mean of the answered items.
1f there are more than two missing
responses, the short form no longer accurately predicts long form scores. comparable to long form scores multiply the total by 2.58 (3 1/12).
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To make scores
APPENDIX 5
PELVIC FLOOR DTSTRESS 1NVENTORY
-
SHORT FORM 20
INSTRUCTIONS Please answer all of the questions in the following survey. These questions will ask you if you have certain bowel, bladder or pelvic symptoms and if you do how much they bother you. Answer these questions by putting a X in the appropriate box or boxes. 1f you are unsure about how to answer a question, give the best answer you can. While answering these questions, please consider your symptoms over the last 3 months. EXAMPLE
For the following question: 1f you do not usually have headaches just put an X in the ‘No’ box Do you
XNo;
usually experience headaches? Yes
1f yes, how much does this bother you? Pl Not at All
P2 -
Somewhat
-
03 Moderately
04 -
Quite a bit
1f you ç usually have headaches, put an X in the ‘Yes’ box indicate how much the headaches bother you. (In this example, the headaches were moderately bothersome) Do you usually experience headaches? No; XYes
1f ves, how much does this bother you? 1 Not at All
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-
02 Somewhat
X3 -
460f 54
Moderately
-
04 Quite a bit
_____/
Name: 1.
Date:
/______
Do you usually experience pressure in the lower abdomen?
Ei
No;
Ei
Yes
0 how much does this bother you?
Ei Not at All
2.
(•.
-
fl2 Somewhat
03
Ei
Moderately
-
-
Quite a bit
Do you usually experience heaviness or dullness in the pelvic area?
Ei
No;
Ei
Yes
0 jf.y, how much does this bother you?
Ei
.
Not at All
3.
-
Do you usually have a bulge or something falling
Ei
No;
Ei
Eist
03
fl2 Somewhat
Moderately
Out
-
Quite a bit
that you can see or feel in the vaginal area?
Yes
0
iLï, how much does this bother you? Ei E fl..i Not at All
C)
4.
-
Somewhat
-
Moderately
fli -
Quite a bit
Do you usually have to push on the vagina or around the rectum to have or complete a bowel movement?
Ei
No;
Ei
Yes
0 how much does this bother you 9
Ei Not at All 5.
-
fl2 Somewhat
-
fl Moderately
Eist -
Quite a bit
Do you usually experience a feeling of incomplete bladder emptying?
Ei
No;
Ei
Yes
0
iLy, how much does this bother you? Ei fl2 fl3 Not at All Protocol: 300-07-006 Administrative Change #1 Final Version 3: 04 February 2008
-
Somewhat
-
Moderately
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-
fl4 Quite a bit
6.
Do you ever have to push up on a bulge in the vaginal area with your fingers to start or complete urination?
Li
No;
Li
Yes
0 lli, how much does this bother you?
Lii
[z
Not at All 7.
-
L]3
Somewhat
-
[14
Moderately
-
Quite a bit
Do you feel you need to strain too hard to have a bowel movement?
Li No;
[1
Yes
0 how much does this bother you?
Lii
[2
Not aL All 8.
-
[3
Soniewhat
-
[4
Moderately
-
Quite a bit
Do you feel you have not completely emptied your bowels at the end of a bowel movement?
[1
No;
LI
Yes
0 how much does this bother you?
Lii Not at All 9.
L] -
Somewhat
-
[3 Moderately
L1 -
Quite a bit
Do you usually lose stooi beyond your control if your stool is well formed?
El
No;
[1
Yes
0 how much does this bother you?
Lii Not at All
0
-
[2 Somewhat
Li.i
[3 -
Moderately
-
Quite a bit
10. Do you usually lose stool beyond your control if your stool is loose or liquid?
El
No;
[1
Yes
0
!Ly, how much does this bother you?
Lii Not at All
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[2 -
Li
[3
Somewhat
-
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Moderately
-
Quite a bit
11. Do you usually lose gas from the rectum beyond your control?
El
No;
Ei
Yes
0 jjy, how much does this bother you?
Eli Not at All
-
[13
[12 Somewhat
-
[14
Moderately
-
Quite a hit
12. Do you usually have pain when you pass your stool?
[1
No;
[1
Yes
0 how much does this bother you?
Ei Not at All
-
[12 Somewhat
[13 -
Moderately
-
Quite a bit
13. Do you experience a strong sense of urgency and have to rush to the bathroom to have a bowel movement? Ei No; [1 Yes 0 how much does this bother you?
Ei Not at All
Elz -
Somewbat
-
[13 Moderately
Ei -
Quite a bit
14. Does a part of your bowel ever pass through the rectum and bulge outside during or after a bowel movement?
Ei
No;
Ei
Yes
0 !fi how much does this bother you?
[Ii Not at All
c
-
[12 Somewhat
-
[13 Moderately
[Li -
Quite a bit
15. Do you usually experience frequent urination?
Ei
No;
Ei
Yes
0
jfj, how much does this bother you?
Ei Not at All
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-
[12 Somewhat
E -
490f54
Moderately
-
Quite a bit
16. Do you usually experience urine leakage associated with a feeling of urgency; that is, a strong sensation of needing to go to the bathroom?
LI
No;
El
Yes
0 how much does this bother you?
Lii Not at All
-
L14
[13
[12 Somewhat
-
Moderately
-
Quite a bil
17. Do you usually experience urine leakage related to coughing, sneezing, or laughing?
LINo;[lyes 0 how much does this bother you?
(.
Lii Not at All
-
E14
03
02 Somewhat
-
Moderately
-
Quite a bit
18. Do you usually experience small amounts of uririe leakage (that is, drops)?
[1
No;
[1
Yes
0
il.y, how much does this bother you?
Lii Not at All
[13
02 -
Somewhat
-
Moderately
[14 -
Quite a bit
19. Do you usually experience difficulty emptying your bladder?
0
No;
El
Yes
0 how much does this bother you?
Lii Not at All
-
02 Somewhat
03 -
Moderately
04 -
Quite a bit
20. Do you usually experi ence puin or discomfort in the lower abdornen or genital region?
El
No;
[1
Yes
0 jfj, how much does this bother you?
Lii Not at All
-
[12 Somewhat
Moderately
Thank you for taking the time to complete this questiounaire Protocol: 300-07-006 Administrative Change #1 Final Version 3: 04 February 2008
[14
03 -
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-
Quite a bit
APPENDIX 6 Protocol Number: 300-07-006
PeMc Floor Impact Questionnaire Short Form 7
—
Subject Initials:
Subject Number: 1 Instructions: Soms women find that bladder, bowel, or vaginal symploms affect their activities, relatlonshlps, and feelings. For each question place an X In the response that best describes how much your activities, relationshlps, or feelings have been affected by your bladder, bowol, or vaginal symptoms or conditlons over the last 3 months. Please make sure you make an answer in all 3 columns for each Questlon. How do symptoms or conditions relate to the following» Bowel or Vaglna or usually effect your.. Bladder or urine rectum pelvis
c
1. Ability to do household chores (cooking, housecleaning, laundry)?
EI Not at all Ei Somewhat Ei Moderately Ei Quito a bit
El Not at all El Somewhat Ei Moderately El Quito a bit
Ei Not at all Ei Somewhat Ei Moderately Ei Quito a bit
2. Ablilty to do physlcal activitles such as walklng, swimmlng, or other exorcise?
Ei Not at all [1 Somewhat Ei Moderately Ei Quito a bit
Ei Not at all Ei Somewhat Ei Modorately El Quito a bit
Ei Not at all Ei Somewhat Ei Moderately Ei Quito a bit
3. Entertainment activities such as going to a movie or concert?
Ei Not at all Ei Somewhat Ei Moderately El Quito e bit
Ei Not at all Ei Somewhat Ei Moderately [1 Quito a bit
Ei Not at all Ei Somewhat Ei Moderately Ei Quito a bit
4. Ability to traval by car or bus for a distance greatar than 30 minutes away from home?
Ei Not at all Ei Somowhat Ei Moderately Ei Quito a bit
Ei Not at all Ei Somewhat Ei Moderately Ei Quito a bit
Ei Not at all Ei Somewhat Ei Moderately Ei Qulte a bit
5. Participating In social activities outsido your home?
Ei Not at all Ei Somewhat Ei Moderately Ei Quito a bit
Ei Not at all Ei Somewhat Ei Moderately Ei Quito a bit
El Not at all Ei Somewhat El Moderately [1 Quito a bit
6. Emotional health (nervousness, depression, etc)?
El Not at all Ei Somewhat Ei Moderately Ei Quito a bit
Ei Not at all Ei Somewhat Ei Moderately Ei Qulte a bit
Ei Not aL all Ei Somewhat Ei Moderately Ei Quito a bit
7. Feeling frustratod?
Ei Ei Ei Ei
Ei Not at all Ei Somewhat Ei Moderately Ei Qulte a bit
Ei Not at all Ei Somewhat Ei Moderately Ei Quito a blt
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Not at all Somewhat Moderately Quito a bit
APPEN DIX 7
EQ-5D C Health Questionnaire (English version for the UK) (validated for use in Eire)
n
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By placing a tick in one box in each group below, please indicate which statements best describe your own health State today. Mobility 1 have no problems in walking about 1 have some problems in walking about 1 am confined to bed Self-Care 1 have no problems with self-care 1 have some problems washing or dressing myself t am unable to wash or dress myself Usual Activities (e.g. work, study, housework, family or leisure activities) 1 have no problems with performing my usual activities 1 have some problems with performing my usual activities 1 am unable to perform my usual activities PainlDiscomfort
t have no pain or discomfort 1 have moderate pain or discomfort t have extreme pain or discomfort AnxietylDepression 1 am not anxious or depressed t am moderately anxious or depressed t am extremely anxious or depressed Protocol: 300-07-006 Administrative Change #1 Final Versbn 3: 04 February 2008
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Best
To help people say how good or bad a health state is, we have drawn a scale (rather like a thermometer) on which the best state you can imagine is marked 100 and the worst state you can imagine is marked 0. We would like you to indicate on this scale how good or bad your own health is today, in your opinion. Please do this by drawing a line from the box below to whichever point on the scale indicates how good or bad your health state is today.
imaginable health state 100
9: 0
80
70
60
Your own Iwalth state iodav
50
40
c
30
20
10
0 Protoco!: 300-07-006 Administrative Change #1 Final Version 3: 04 February 2008
54 of 54
Worst
imaginable health state
