number NL Short title Ideal DVT study

Protocol ID/number NL 32073.068.10

Short title

The Ideal DVT study Acronym: Individualized duration elastic compression therapy against long-term duration of therapy.

Individually tailored elastic compression therapy after deep venous thrombosis in relation to the incidence of post thrombotic syndrome, a randomized multicenter trial

Version 1.2 date 14 June 2010

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PROTOCOL TITLE „

Individually tailored elastic compression therapy after deep venous thrombosis in relation to the incidence of post thrombotic syndrome, a randomized multicenter trial Protocol ID Short title

The Ideal DVT study

Version

1.2

Date

14 June 2010

Coordinating investigator/project leader

Dr. A.J. ten Cate- Hoek, laboratory of Haematology, Internal medicine , P. Debyelaan 25, P.O. Box 5800, 6202 AZ Maastricht ,Tel: 043-3871243, pager *4523

Project team Prof. dr. H. ten Cate, Internal Medicine, MUMC+/CARIM Prof. dr. M H Prins, Epidemiology MUMC+/CAPHRI Dr. M.A. Joore, Epidemiology MUMC+/KEMTA Dr. K. Hamulyák, Internal Medicine , Head laboratory of Hematology , MUMC+

Sponsor (in Dutch: verrichter/opdrachtgever)

Prof. dr. H. ten Cate, Internal Medicine, MUMC+/CARIM, P. Debyelaan 25, P. O. Box 5800, 6202 AZ Maastricht, Tel: 043-384262

Independent physician(s)

Drs. R. Rennenberg, Internal Medicine, MUMC+, Debyelaan 25, P. O. Box 5800, 6202 AZ Maastricht, Tel: 3843387


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PROTOCOL SIGNATURE SHEET Name For non-commercial research, Head of Department: Prof. dr. C.D.A. Steehouwer Internal Medicine, Maastricht Universi y Medical Center

Coordinating Investigator/Project leader/Principal Investigator: Dr. A. J. ten Cate- Hoek Internal Medicine, Maastricht University Medical Center, [email protected] [email protected]


Signature

Date

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TABLE OF CONTENTS 1. 2. 3.

INTRODUCTION AND RATIONALE .............................................................................. 8 OBJECTIVES ................................................................................................................11 STUDY DESIGN ...........................................................................................................11 3.1 Population (base) ..................................................................................................12 3.2 Inclusion criteria .....................................................................................................12 3.3 Exclusion criteria ....................................................................................................12 3.4 Sample size calculation ..........................................................................................13 4. TREATMENT OF SUBJECTS .......................................................................................14 4.1 Investigational product/treatment............................................................................14 4.2 Use of co-intervention (if applicable) ......................................................................14 5. INVESTIGATIONAL MEDICINAL PRODUCT ................................................................15 6. METHODS ....................................................................................................................15 6.1 Study parameters/endpoints ...................................................................................15 6.1.1 Main study parameter/endpoint .......................................................................15 6.1.2 Secondary study parameters/endpoints ..........................................................15 6.1.3 Other study parameters (if applicable) .............................................................15 6.2 Randomisation, blinding and treatment allocation ..................................................15 6.3 Study procedures ...................................................................................................16 6.4 Withdrawal of individual subjects ............................................................................18 6.5 Replacement of individual subjects after withdrawal ...............................................19 7. SAFETY REPORTING ..................................................................................................19 7.1 Section 10 WMO event .........................................................................................19 7.2 Adverse and serious adverse events ....................................................................19 7.3 Data Safety Monitoring Board (DSMB) ..................................................................20 8. STATISTICAL ANALYSIS .............................................................................................21 8.1 Descriptive statistics ...............................................................................................21 8.2 Univariate analysis .................................................................................................21 8.3 Multivariate analysis ...............................................................................................21 8.4 Interim analysis (safety) .........................................................................................21 8.5 Economic Evaluation ..............................................................................................22 9. ETHICAL CONSIDERATIONS ......................................................................................25 9.1 Regulation statement .............................................................................................25 9.2 Recruitment and consent........................................................................................25 9.3 Objection by minors or incapacitated subjects (if applicable) ..................................26 Only patients who have reached a legal age (18 yrs) are included....................................26 9.4 Benefits and risks assessment, group relatedness .................................................26 9.5 Compensation for injury .........................................................................................27 10. ADMINISTRATIVE ASPECTS AND PUBLICATION ......................................................28 10.1 Handling and storage of data and documents ........................................................28 10.2 Amendments ..........................................................................................................28 10.3 Annual progress report ...........................................................................................28


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10.4 End of study report .................................................................................................28 10.5 Public disclosure and publication policy..................................................................29 11. REFERENCES ..........................................................................................................29


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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS ABR

ABR form (Algemene Beoordeling en Registratie) is the application form that is required for submission to the accredited Ethics Committee

AE

Adverse Event

CA

Competent Authority

CCMO

Central Committee on Research Involving Human Subjects

CV

Curriculum Vitae

CEAP

Clinical, Etiological, Anatomical (and segment localization) and Pathophysiological classification

DCE

Discrete Choice Experiment

DSMB

Data Safety Monitoring Board

DVT

Deep Venous Thrombosis

EU

European Union

EudraCT European drug regulatory affairs Clinical Trials GCP Good Clinical Practice ECS

Elastic Compression Stockings

HRQOL

Health Related Quality of Life

IB

Investigator’s Brochure

IC

Informed Consent

LMWH

Low Molecular Weight Heparin

METC

Medical research ethics committee (MREC); in Dutch: medisch ethische toetsing commissie (METC)

PTS

Post Thrombotic Syndrome

SPC

Summary of Product Characteristics (in Dutch: officiële productinfomatie IB1-tekst)

Sponsor

The sponsor is the party that commissions the organisation or performance of the research, for example a pharmaceutical company, academic hospital, scientific organisation or investigator. A party that provides funding for a study but does not commission it is not regarded as the sponsor, but referred to as a subsidising party.

Villalta

Scoring system for PTS

Wbp

Personal Data Protection Act (in Dutch: Wet Bescherming Persoonsgevens)

WMO

Medical Research Involving Human Subjects Act (Wet Medischwetenschappelijk Onderzoek met Mensen

Version: 1.2, date 14 June 2010

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SUMMARY Rationale: In the Netherlands, 25.000 patients each year are diagnosed with Deep Venous Thrombosis (DVT). Elastic compression stocking (ECS) therapy reduces the incidence of post thrombotic syndrome (PTS) following DVT from 50% without ECS to 20-30% after ECS therapy for two years. It is however unclear whether all patients benefit to the same extent from this therapy or what the optimal duration of ECS therapy for individual patients should be. ECS therapy is not only costly, inconvenient and demanding but sometimes also even debilitating. Substantial costs could be saved by tailoring therapy to individual needs and as a result the quality of life for individual patients can be expected to improve. Objective: To assess the costs and effects of tailoring the duration of ECS therapy after DVT to individual patients needs. Study design: a multi-center, randomized, allocation concealed, single-blinded clinical trial in patients with acute proximal DVT with a follow-up of 24 months. Study population: Consecutive, adult outpatients after acute proximal DVT who present themselves at one of the participating centers. Intervention: ECS therapy with a standard duration of 24 months versus tailored ECS therapy following an initial therapeutic period of 6 months, based on signs and symptoms according to a Villalta scale. Main study parameters/endpoints: Primary outcome: percentage of patients with PTS at two year follow-up. Secondary outcomes: 1. Health Related Quality of Life (HRQOL), 2. Recurrent venous thrombosis,3. Mortality due to venous thrombosis, 4. Costs and 5. Patient preference. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The study burden for patients is kept to a minimum and will comprise of regular visits and questionnaires. The study burden for clinicians is low. Patients will be seen at regular intervals (3, 6, 12 and 24 months) at the outpatient clinic. Patients will receive questionnaires preceding their visits. A clinical score to assess post thrombotic complaints will be performed at the out clinic visits. Based on our previous findings we expect that due to individual tailoring of therapy, 50% of patients will need ECS therapy for a period of maximum 12 months, instead of 24 months. HRQOL may be positively affected. Shorter therapy duration is not


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anticipated to have a negative implication on the incidence of PTS during the 24 months period of follow-up (pilot data; J Vasc Surg. 2010 Jul;52(1):132-8).

1. INTRODUCTION AND RATIONALE

Problem definition:

The available evidence: The evidence sustaining the value of ECS therapy following acute DVT is derived from 2 randomized clinical trials. [1, 2] Incidences of PTS were observed to be reduced significantly (approximately 50%) by application of ECS therapy with a duration of 24 months in all patients. However, based on these studies it is still not clear whether all patients benefit to the same extent from ECS therapy or what the optimal duration of ECS therapy for individual patients should be. A significant benefit of early ambulation, measured as mean score on Villalta ( a score containing 5 leg symptoms and 6 objective signs), was found in a follow-up study of a small trial that compared ambulation combined with inelastic compression (Unna boot) or ECS therapy to bed rest without any compression in the acute phase of 9 days, followed by compression therapy for all patients during 2 years of follow up.[3,40] This trial primarily showed the beneficial effects of early ambulation combined with compression. One other study assessed whether ECS therapy in patients with reflux on duplex testing one year after the event of DVT was beneficial for the incidence of PTS and did not find a significant benefit of ECS therapy. [5] Only one study so far assessed whether prolonged duration of ECS therapy was superior to 6 months of ECS therapy following an event of proximal DVT. In this study no significant difference in the incidence of PTS according to the CEAP classification was observed between the two treatment groups. [6]

Our study will provide the lacking information on the individual benefit to patients and the optimal duration of ECS therapy. Alongside the clinical trial, a cost-effectiveness analysis from a societal perspective will elucidate the cost-effectiveness of this approach.


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This protocol concerns all patients with acute proximal DVT who present themselves at the emergency department or outpatient clinic of one of the participating centers. The group of included patients will be a true representation of the general Dutch population with acute proximal DVT. Variations such as in age, gender, BMI and extend of the thrombosis will be addressed in the analysis.

Relevance In the Netherlands each year around 25.000 patients experience a new event of DVT. If not treated with ECS therapy following the event, up to 50% of these patients will develop PTS. This proportion can be reduced to 20-30% after ECS treatment for 2 years. [1, 2] PTS is a serious affliction; it reduces the quality of life and generates substantial healthcare costs. [7-9] The clinical presentation varies from minor signs, including skin discoloration, venous ectasia, discomfort and swelling, to severe manifestations, such as chronic pain, chronic edema or leg ulceration. In order to prevent PTS, common practice is to prescribe custom fitted ECS therapy for 2 years for all patients following DVT. [10, 11] ECS therapy is costly, demanding and sometimes even debilitating. Elderly patients can often not apply the ECS by themselves but need help from family or they even need home care visits (7.5%) [12-14]. Total annual costs of ECS therapy roughly amounts to 2.5 million for stockings (25.000 patients*100 euro) and 21 million for home care (7.5%*25.000 patients*500 visits*20 euro). [12-14] Moreover, the majority of patients do not experience any post thrombotic complaints. [5] The individual benefit to patients and the optimal duration of ECS therapy were never studied properly and as a result it is unclear which patients require therapy for the entire 24 months. Therefore the broad application and the duration of ECS therapy are questioned. We conducted a pilot study in a prospective cohort of 125 consecutive patients with acute DVT to assess the effectiveness of individualized duration of ECS therapy (based on complaints on the Villalta scale [15]) after initial therapy of 6 months on the incidence of PTS [16]. We found that 50% of our patients did not need ECS therapy for as long as 2 years, while the overall incidence of PTS was 21.1% (95% CI 13.528.7). This is comparable to published incidences after 24 months ECS therapy. [2] Over 10 million euro could be saved if 50% of the patients would have ECS therapy Version: 1.2, date 14 June 2010

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for only one year. However, this would only hold true if the incidence of PTS would indeed not rise. Our pilot study was performed in the context of usual care, in consecutive patients without any exclusion criterion. Therefore the results of this pilot study are considered to be highly generalizable. At this moment a randomized clinical trial to assess the effectiveness of ECS versus placebo stockings to prevent PTS is underway. [17] The investigators question the effectiveness of ECS for the prevention of PTS altogether. They state that the trials that published a benefit of ECS for the prevention of PTS following proximal DVT [1,2] lacked a placebo controlled comparison (oversized stockings) and therefore cannot be considered to be undisputable evidence. No individual risk assessment will be performed, nor will differentiation in therapy duration be assessed in that particular study.

Therefore, the study that we plan to perform is not only innovative; for the first time individual tailoring of duration of ECS therapy will be investigated, but also it will provide unique additional knowledge on the safety, effectiveness and costeffectiveness of this approach in the Netherlands.


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2. OBJECTIVES

Our study objective is to assess the safety, the costs and the cost-effectiveness of tailoring therapy duration with elastic compression stockings (ECS) following acute DVT to individual patients needs as compared to usual care (24 months of ECS). To address this objective the following research questions are formulated: - What are the consequences of individualized ECS therapy on safety? (Expressed as differences in PTS incidence) - What are the consequences of individualized ECS therapy on costs? (From a societal perspective) - What are the consequences of individualized ECS therapy on quality of life? (Both generic and specific) - What is the cost-effectiveness of individualized ECS?

3. STUDY DESIGN We propose to perform a multi-center, randomized, allocation concealed, single-blind clinical trial in patients with proximal deep venous thrombosis (DVT). (Flowchart.pdf) We propose to perform a randomized multi-center clinical non-inferiority trial. All patients will have ECS therapy for at least 6 months. Two treatment arms will be compared. One arm will consist of patients treated with ECS therapy for 24 months in total. The other arm will consist of individually tailored treatment based on Villalta clinical scores. In patients with a score of less than or equal to 4 ECS therapy will be discontinued. Randomization will guarantee a fair distribution of patients within each patient group. Stratification will be performed on centre and potentially confounding effects such as age, sex and body mass index. The study will be a multi center study in order to get a good representation of patients and to achieve sufficient patient numbers. The primary outcome will be PTS at 24 months after the event; the observers will be blinded to the allocated treatment arm. The allocation will be concealed from study personnel involved in assessing the leg symptoms and rating the PTS scores. Both randomization and allocation concealment are used as strategies against bias. The study is not double blinded; no inactive stockings will be used in the comparator group. The use of sham stockings will very likely interfere with the quality of life and


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will complicate the assessment of perceived differences between groups. Patients will be followed for the entire study duration; incidence of recurrent DVT and VTE related death during the follow-up period will be documented.

3.1 Population (base) The study population will consist of consecutive outpatients after acute objectively documented proximal DVT. In our hospital approximately 110 new DVT patients present themselves each year. In order to be able to include sufficient patients for the study to be adequately powered we need the input of additional hospitals. We have found 8 hospitals with ample experience in clinical studies on management of patients with DVT willing to participate. The total adherence of these hospitals together is approximately 1.2 million/year. At an annual incidence of 0, 1, we expect to see 1200 patients with DVT each year. The duration of inclusion will be 2, 5 years, if all participating centers will include 30% of all patients who are diagnosed with DVT in their hospital each year, the sample size needed for this trial will be met. The Maastricht-Eindhoven region will contribute with 2 hospitals (220 patients/year), the Amsterdam region with 3 hospitals (600 patients/year), the Nijmegen region with 1 hospital (80 patients/year), and the Almere-Hoorn region with 2 hospitals (270/year). (inclusionscheme.pdf)

3.2 Inclusion criteria •All adult, consenting, consecutive outpatients with acute objectively documented proximal DVT of the leg •All patients should be treated with a minimum of 5 days of Low Molecular Weight Heparins (LMWH) followed by oral anticoagulants with a target international normalized ratio (INR) of 2-3

3.3 Exclusion criteria •Previous DVT in the affected leg •Recurrent DVT in the 6 months following inclusion1 Version: 1.2, date 14 June 2010

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•Pre-existent venous insufficiency (skin signs C3-C6 on CEAP score or requiring ECS therapy2) •Contraindication for elastic compression therapy (e.g. arterial insufficiency3) •Active thrombolysis •Life expectancy < 6 months 1

Recurrent DVT in the ipsilateral leg diagnosed based on ultrasound criteria: incompressibility of a

proximal vein segment previously free from thrombi, or the finding of a more than 4 mm increase of the vein diameter as compared with the last available measurement. If recurrent DVT is located in the contra lateral leg, the criterion is simply the incompressibility of a proximal vein. [18] 2

Skin signs C3-C6 on CEAP scale: C3 (pre-existent oedeem), C4 (huidveranderingen), C5 (genezen

ulcus), C6 (actief ulcus). 3

Arterial insufficiency: asymptomatic patients: a pulse deficit proximal (femoral or popliteal artery)

distal (tibial or pedal artery) or bruit at sites of narrowing at physical examination. Symptomatic patients: intermittent claudication or clinical signs of leg ischemia.

All in – and exclusion criteria will be assessed by the treating physician.

3.4 Sample size calculation The proposed study is a non-inferiority trial and aims to demonstrate that the assessed alternative therapy based on ECS for 6 months followed by individually prolonged ECS therapy based on Villalta scores is not worse than the comparator ECS therapy for a standard duration of 24 months, by more than the prespecified amount of 7.5% (the non-inferiority margin). The published incidence of PTS following two years of ECS lies between 20 and 30%. (Prandoni 24.5% (95% CI 15.633.4), Brandjes 20% (95% CI 12.4-29.2) As it is statistically impossible to demonstrate equivalence (prove the H0 of no difference), Blackwelder proposed a one sided significance test to reject the null hypothesis by a clinically acceptable amount .[19] In common practice differences in effect between the standard and the control treatment are described using a two sided 95% confidence interval, which equals a one sided test at the probability of 0.025. While it can be argued that this protects society from undesired decisions due to the lower p value, there is no good reasoning why a different level of uncertainty should be used in noninferiority


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compared to superiority trials. Moreover if similar rates are observed in both groups the 95% CI will be much smaller than both thresholds allow. Brandjes and Prandoni found a relative reduction of PTS of 26%; 95% CI 22-48. If we allow a difference of 7.5% in the outcome PTS between the group with ECS for 2 years and the group with the alternative therapy, than 70% of the effect will be preserved. This proportion of loss in efficacy is customarily accepted in controlled randomized clinical trials. At a one sided significance level [19,20] of 0.05 and a power of 80%, with a ratio of 1, a total of 847 patients are needed to provide sufficient patients for an adequately powered trial. Loss to follow-up of patients is expected to be less than 2% since the intervention does not have an invasive nature. Therefore a total of 864 patients are needed (432 patients per treatment arm).

4. TREATMENT OF SUBJECTS 4.1 Investigational product/treatment All patients will be initially bandaged for as long as it takes for the acute edema to disappear; afterwards elastic compression stockings will be custom fitted and patients will be advised to wear these stockings during the daytime. The stockings prescribed are custom made flat knitted stockings knee length. A class III pressure is standard. (Mediven ®550, ankle pressure 40 mmHg). All patients will be advised to wear elastic compression stockings for a minimal duration of six months after the acute event. 4.2 Use of co-intervention (if applicable) All patients will be treated with antithrombotic therapy. This treatment consists of an initial treatment with therapeutic doses of LMWH (fraxiparin®, Addendum B1 – Dosing scheme) in combination with vitamin K-antagonists (acenocoumarol® and fenprocoumon®, Addenum B2 – Dosing schemes), followed by treatment with vitamin K-antagonist alone (after completing LMWH treatment of at least 5-7 days and after an INR above 2 has been reached on two consecutive measurements). Anticoagulant treatment will be installed according to national and international guidelines (ACCP 2008 [10], CBO 2008 [11]) tailored based on the character of the event (6 months of therapy for idiopathic DVT and 3 months for provoked DVT). Version: 1.2, date 14 June 2010

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5. INVESTIGATIONAL MEDICINAL PRODUCT No medicinal product will be used in this study.

6. METHODS 6.1 Study parameters/endpoints 6.1.1

Main study parameter/endpoint

The primary outcome will be occurrence of PTS at 24 months after the event (the observers will be blinded to the allocated treatment arm).

6.1.2

Secondary study parameters/endpoints

The secondary outcomes will be: 1. HRQOL, measured by questionnaires (SF-36 [21], EuroQOL-5D [22], Veines-Qol [23] Dutch translated) 2. Recurrent thrombosis, according to criteria as published [18] and assessed by objective tests 3. VTE related death during follow-up, assessed by an independent and blinded adjudication committee 4. Costs [24] 5. Patient preference, assessed with a Discrete Choice Experiment (DCE) [25]

6.1.3

Other study parameters (if applicable)

Potential confounders could be: age, sex and body mass index. These study parameters will be collected. At randomisation these parameters will be stratified for. Patients with previous DVT in the same leg as well as patients with pre-existent venous insufficiency will be excluded.

6.2 Randomisation, blinding and treatment allocation


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In a trials smaller than 1000 subjects simple randomization may not balance the groups well enough. To maintain good balance, blocked randomization therefore will be used. "Blocks" having equal numbers of A‟s and B‟s (A = intervention and B = control) are used, with the order of treatments within the block being randomly permuted. Permuted block randomization ensures that treatment group numbers are evenly balanced at the end of each block. Stratified block randomization will further restrict chance imbalances to ensure the treatment groups are as alike as possible for selected prognostic variables or other patient factors. For subject randomization to treatment allocation, the investigator at the central study site will randomize patients using a computer programme which allocates patients to one of the two treatment arms. Permutated blocks of randomly varying sizes will be used to maintain balance of numbers in each treatment group and to ensure allocation concealment. See Fleiss (1986, sec. 3.1). Stratification will be performed on centre-level and on potentially confounding factors such as age, sex and body mass index. The randomization will be performed

centrally, within a week of obtaining the patient‟s consent. The allocation will be concealed from study personnel involved in assessing the leg symptoms and rating the PTS scores. Both randomization and allocation concealment are used as strategies against bias. The study is not double blinded; no inactive stockings will be used in the comparator group. The use of sham stockings will very likely interfere with the quality of life and will complicate the assessment of perceived differences between groups.

6.3 Study procedures

Treatment

All patients will be treated and followed up in their own hospital, adherent to protocol. Initially all patients will be bandaged for as long as it takes for the acute edema to disappear. Afterwards patients will be advised to wear custom fitted ECS during the daytime (30-40 mmHg ankle pressure). All included patients will have ECS therapy for the duration of at least 6 months. Two treatment arms will be compared.


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One treatment arm (arm 1) will consist of patients allocated to ECS therapy for the duration of 24 months, regardless of scores on the Villalta scale. The other treatment arm (arm 2) will consist of 6 months of initial ECS therapy for all patients followed by individually tailored ECS therapy, based on scores on the Villalta clinical scale. [15] (Addendum 1) After 6 months ECS therapy will be discontinued in patients with a score ≤ 4. Patients with a score of ≥ 5 will continue therapy. If these patients have a score of ≤ 4 on one of the consecutive visits, they will also be allowed to stop ECS therapy. Once stopped, ECS treatment will not be reinstated. Clinical follow-up visits will be matching usual care at 3, 6 and 12 months with an additional visit at 24 months. At each visit signs and symptoms of PTS will be recorded using the Villalta scoring system. [15] This scoring system contains 5 leg symptoms and 6 objective signs. The leg symptoms comprise: pain, cramps, heaviness, pruritus and paresthesia. The objective signs are: pretibial edema, induration, new venous ectasia, redness and pain during calf compression. For all items separately a score of 0 to 3 can be assigned. Patients are classified as having PTS if they have a score ≥ 5 on 2 or more consecutive visits that are at least 3 months apart. All study personnel will be trained on the administration of the Villalta assessment during a one- hour workshop before the start of the study. A plasticized visual scale for the assessment of clinical manifestations of PTS will be supplied to all raters for reference. [26]

Assessment of PTS and ECS compliance

Patients will be asked to refrain from wearing ECS at their visit to the outpatient clinic and not to disclose any information on therapy compliance to the rater during this visit. The subjective ratings on the Villalta scale as well as questions on ECS compliance will be filled out on a scoring list by the patient at the day of the visit. The objective ratings will be performed by a study nurse or by the treating physician. This will guarantee the overall blinding of the assessment. The two score forms will be sent to the central study administration in a prepaid, pre-addressed envelope. The overall score will be calculated centrally and advice on continuation or discontinuation of ECS therapy will be forwarded directly to the patient within two working days of the visit. The patient‟s own doctor will be updated on the actual therapy status of the patient, to safeguard the patient‟s medical status. Version: 1.2, date 14 June 2010

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Because adherence to therapy is of crucial importance the number of contact moments for the assessment of compliance with ECS therapy will be increased by adding telephone contacts to the regular clinical visits, study-supporting staff will make computer-assisted random telephone calls during the entire follow-up period to both the patients in the group with the 2 year ECS intervention and to patients in the group with individualized ECS therapy. The telephone calls will be made randomly to create a surprise effect (patients are off guard) and to allow for a distribution of contacts over the entire study period. Per patient 3 extra contact moments will be created. A standard questionnaire will be used to assess compliance and to address reasons for non-compliance. Cross-over to another therapy arm will be discussed and discouraged.

HRQOL assessments and patient preferences

To assess the impact of ECS therapy and of PTS on the quality of life, three HRQOL questionnaires will be applied. The SF-36 [21], the EuroQOL-5D [22] and Veines-Qol [23] Dutch translated will be used. (Addendum 2) The questionnaires will be applied 5 times (t 0, 3, 6, 12 and 24 months). The HRQOL scores will be related to clinical outcomes. All questionnaires will be offered as a web based application, each patient will have a unique personal entry code. For patients who are not able or willing to use the electronic questionnaires, a paper version will be available. In the latter case the questionnaires can be returned to the investigator using the included prepaid answering envelope. In addition a Discrete Choice Experiment will be performed. [25] This will only be done once, at a predefined point in the study.

6.4 Withdrawal of individual subjects Subjects can leave the study at any time for any reason if they wish to do so without any consequences. The investigator can decide to withdraw a subject from the study for urgent medical reasons. (When thrombosis recurs patient will be withdrawn from the study.)


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6.5 Replacement of individual subjects after withdrawal All patients will be followed for the entire duration of the study. Patients whoare withdrawn from the study will be asked to fill out HRQOL questionnaires, and will if possible be clinically followed at the outpatient clinic for the entire study period.

7. SAFETY REPORTING

7.1 Section 10 WMO event In accordance to section 10, subsection 1, of the WMO, the investigator will inform the subjects and the reviewing accredited METC if anything occurs, on the basis of which it appears that the disadvantages of participation may be significantly greater than was foreseen in the research proposal. The study will be suspended pending further review by the accredited METC. The investigator will take care that all subjects are kept informed.

7.2 Adverse and serious adverse events

Adverse events (AE): At each outpatient visit (3, 6, 12 and 24 months after the event) patients will be questioned by their treating physicians about complaints related to the thrombotic event. Complaints can be indicative of 1. Post thrombotic syndrome (Villalta score above 4), 2. A recurrent event (either pulmonary embolism or deep venous thrombosis) or 3. A venous leg ulcer. All three events could be related to the experimental therapy under study. Of course it is also possible that the subject suffers an adverse event that is not related to the experimental therapy. All adverse events reported spontaneously by the subject or observed by the treating physician or his staff will be recorded on the CRF.

Serious Adverse Events (SAE) A SAE is any untoward medical occurrence or effect that :


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-

results in death;

-

is life threatening (at the time of the event);

-

requires hospitalisation or prolongation of existing inpatients‟ hospitalisation;

-

results in persistent or significant disability or incapacity;

-

is a congenital anomaly or birth defect;

The investigator will sent the SAE documents within 15 days after first knowledge of the serious adverse reactions. All SAEs will be gathered by the investigator and will be reported through the webportal “Toetsing Online” to the accredited METC that approved the protocol. SAEs that result in death or are life threatening will be reported as soon as possible. The expedited reporting will occur not later than 7 days after the responsible investigator has first knowledge of the adverse reaction. This is for a preliminary report with another 8 days for completion of the report.

Follow-up of adverse events All adverse events will be followed until they have abated, or until a stable situation has been reached. Depending on the event, follow up may require additional tests or medical procedures.

7.3 Data Safety Monitoring Board (DSMB)

No DSMB is installed for this study. The study endpoints do not include mortality or severe morbidity. The intervention studied is not considered to be of high risk to the patient, pilot data show that equivalence to the current treatment can be expected.


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8. STATISTICAL ANALYSIS

An intention to treat analytical approach will be used for all outcomes. 8.1 Descriptive statistics Descriptive statistics will be computed for baseline characteristics for both groups. 8.2 Univariate analysis For the primary outcome PTS, univariate analysis of all proportions will be performed with logistic regression (chi-squared) analysis.

Cumulative incidences of the post thrombotic syndrome will be calculated according to Kaplan-Meier. The analysis will be adjusted for center in order to compare incidence rates between the two treatment arms. Patients who die or are lost to follow-up will be censored at their last visit. Repeated measures ANOVA will be applied to assess the changes over time for different measurements. 8.3 Multivariate analysis Hazard ratio‟s and 95% confidence intervals for both treatment arms will be calculated by using Cox regression models. Hazard ratio‟s will be adjusted for age, sex, clinical presentation of DVT, extent of the index thrombotic episode.

8.4 Interim analysis (safety) A prespecified safety analysis will be performed when 50% of the subjects have completed the 2 year follow-up. The analysis will be performed by the coordinating centre, and supervised by the principal investigators. The safety analysis will be performed to assess significant enhanced risk of PTS or excess morbidity/mortality in the intervention arm of the study population. Fisher„s exact test will be performed to compare incidence of PTS at a significance level of 0.05 (two sided). The study can


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be stopped in case of significant excess morbidity/mortality in the alternative treatment arm.

8.5 Economic Evaluation The research question for the economic evaluation in this proposal is: What is the cost-effectiveness of individually tailored ECS therapy compared to standard ECS therapy of 24 months in patients with acute DVT?

Since both effects on costs and generic health-related quality of life are to be expected, the method of economic evaluation is a cost-utility analysis (CUA). The analysis will be from a societal perspective. The primary effect parameter is generic health-related quality of life, measured in quality adjusted life years (QALYs).

We will perform two analyses: a trial based CUA with a time horizon of two years (identical to the duration of follow up in the clinical study), and a model-based CUA with a lifelong time horizon. In the trial-based analysis uncertainty surrounding the incremental cost-utility ratio will be estimated by non-parametric bootstrapping. Confidence intervals for the incremental cost-utility ratio will be calculated from the bootstrap results. The implications of sampling uncertainty on decision uncertainty (the probability that individually tailored elastic compression therapy is cost-effective compared to standard elastic compression) will be shown in cost-effectiveness acceptability curves. One-way sensitivity analyses will be used to show the impact of variation in parameters on the incremental cost-utility ratio, such as discount rate, unit prices, and design issues. The impact of variability on the incremental cost-utility ratio arising from diversity and heterogeneity in the patient population will be examined in subgroup analyses, if the data allow this. In addition, we will use decision analytical modelling to extrapolate the findings in the clinical study. We will follow the guidelines of good modelling. [27] We will be able to use a Markov model for diagnostic strategies in DVT, which was developed by our group earlier [28]. Nevertheless, the structure of the Markov model for the research question underlying this proposal will be determined in close collaboration with the


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clinical experts in the project team. Input parameters will be based on the data from the clinical study, the literature, national databases, and, only if no other source is available on expert opinion. One-way sensitivity analyses will be used to show the impact of variation in non-stochastic input parameters on the incremental ratio, such as discount rate, unit prices, and structural features of the model. Probabilistic sensitivity analysis will be used to handle parameter uncertainty. The implications of parameter uncertainty on decision uncertainty will be shown in cost-effectiveness acceptability curves. The impact of variability on the incremental cost-utility ratio arising from diversity and heterogeneity in the patient population will be examined in subgroup analyses, if the data allow this. Excel spreadsheet modelling will be used to perform the task.

2. Cost Analysis Costs in the analysis include direct health care costs (medical costs for prevention, diagnostics, therapy, rehabilitation and care), direct non-health care costs (travel costs) and indirect costs (productivity loss). Resource use will be measured using the case-record forms, hospital data and 5 retrospective cost-questionnaires. In the cost questionnaires the PRODISQ modules will be used to estimate productivity loss. [29] When available, the standard unit costs from the Dutch Manual for Cost Analysis [30] will be used. Resource use for which no standard unit costs are available will be valued using integral cost calculations. Costs from productivity loss will be quantified using the friction cost method.

3. Patient Outcome Analysis A proportion of patients (20–30%) with acute DVT will develop PTS. The syndrome is characterized by leg pain, heaviness, and swelling and, in severe cases, skin ulcers. Therefore, generic health-related quality of life is the primary effect parameter in this economic evaluation. Generic quality of life is measured with the SF36 [21] and the EQ-5D [22]. Measurements will take place at baseline, 3 months, 6 months,12 months and 24 months. Utilities will be calculated from the responses on the EQ-5D and SF36 classification systems using the available multi-attribute utility functions.[ 31, 32]


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Elastic compression therapy can be demanding and patients may experience difficulty putting the stockings on; some patients to the extent that they need (professional) help, which may be experienced as an intrusion of privacy and freedom. Also, patients may experience the stockings as uncomfortable and „ugly‟. From a patient point of view ECS therapy has serious disadvantages, while the duration and (associated) effectiveness are uncertain. Therefore patient preferences will be elicited by conducting a discrete choice experiment (DCE) [25]. The results of the DCE will provide insight in the trade-offs patients make between characteristics of the therapy. More specifically, we will investigate what duration of ECS therapy, with its drawbacks, patients consider to be acceptable. A DCE is a stated preference method to measure preferences for products and services. It is based on the assumption that in general decisions are not based on a single criterion, but on several factors considered jointly. In DCE jargon, these factors are called 'attributes'. A DCE consists of four stages: identifying the attributes of interest and assigning levels to the attributes, experimental design, data collection, and analyzing the responses.

Step 1: identifying the attributes of interest and assigning levels to the attributes Attributes relevant to ECS therapy will be identified in a literature review and in patient interviews. The attributes and levels should be realistic and meaningful. The levels will be set such that persons are willing to trade between attributes. Duration of therapy will be one of the attributes.

Step 2: experimental design. Although the number of attributes and levels is not yet known, a full factorial design would require too many profiles for meaningful research. We therefore use a fractional factorial designs based on an orthogonal main effects design. Profiles will be paired into choice sets using a fold over design. This means that each of the profiles was combined with its 'fold over'. A fold over profile includes the exact opposite attribute levels of the original profile and, therefore, ensures a completely orthogonal design.

Step 3: data collection.


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The patients included in the study will be presented with a series of pair wise profiles (choice sets) involving different levels of the attributes. To assess test-retest reliability a duplicate choice set will be added. A dominant choice set will be included in the questionnaire to test for rationality. Within each choice set, the profiles will be labelled ' A' and ' B', and respondents will be asked to choose between the two profiles. Furthermore, patients may select the 'neither' option if they did not want any of the two profiles (e.g. opt-out). For the patients included in the clinical study, the survey will be administered at one fixed point in time during follow up.

Step 4: data analysis The choices will be used to estimate the overall utility model. Random parameters logit modelling will be used to estimate this model. We will use the software package NLOGIT 3.0 (Econometric Software Inc.). We will calculate the relative importance of the attributes. Heterogeneity in responses will explicitly be considered.

9. ETHICAL CONSIDERATIONS 9.1 Regulation statement The study will be conducted according to the principles of the Declaration of Helsinki (59th WMA General Assembly, Seoul, October 2008) and in accordance with the Medical Research Involving Human Subjects Act (WMO) and other guidelines, regulations and Acts. Patients will be informed about the risks and possible benefits involved in participating in the study. When patients decline the opportunity of participating in the study, this will have no adverse effects on either the relation with their doctor or their treatment. Whenever patients do decide to participate, they will be allowed to discontinue participation at all times without the need to disclose the reason for discontinuation. We believe that individualized duration of ECS therapy in selected patients is safe and possibly a preferred therapeutic option in patients in relation to outcomes such as HRQOL. 9.2 Recruitment and consent


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Patients with complaints suspected of DVT will present themselves at the emergency room or outpatient department of one of the participating centres. After clinical assessment; a proportion of patients are referred to the radiology department for 2-point CUS. A positive finding on CUS confirms the diagnosis DVT. Patients will return to the emergency room for further instruction and treatment. Patients who fulfil the criteria for our study will be offered information at their first follow-up visit to the outpatient clinic of their own hospital. The treating physician will inform the patient about the study and hand out a patient information form. The patient‟s consent is asked to allow the investigator to contact the patient. The patients are allowed to over think their decision on participation in the study for 24 hours. Standard conservative treatment will be started upon diagnosis. The patient will be contacted by the investigator. After informed consent is given, the patient is randomized to either of the two treatment groups. Randomization will be performed centrally by using a computer based randomization programme. (Patient information letter and consent form are attached as separate documents).

9.3 Objection by minors or incapacitated subjects (if applicable)

Only patients who have reached a legal age (18 yrs) are included.

9.4 Benefits and risks assessment, group relatedness Of the five randomized clinical trials that studied the value of ECS therapy following DVT [1,2, 4-6], only one trial has evaluated variable duration of therapy after initial ECS, and no significant benefit was observed between prolonged treatment and 6 months of ECS in this trial. [6] The authors state however, that their trial was underpowered for the primary outcome measure. A small trial has evaluated the value of initial active compression therapy in combination with ambulation and found a significant benefit in mean Villalta scores for patients with initial active treatment, even after secondary ECS treatment for 2 years in both treatment groups. Another trial has evaluated the late initiation of ECS therapy, at one year following an event of DVT, and did not find a significant benefit of ECS therapy when initiated at this late stage. The positive finding in this latter study was that patients who did not have


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initial ECS therapy and who had not developed PTS one year after the event of thrombosis are unlikely to do so at a later moment in time. The remaining trials all found a significant reduction of PTS after ECS therapy initiated in the acute phase (usually combined with early mobilization). Although the beneficial effect of ECS therapy initiated in the acute phase is clearly demonstrated in groups of unselected patients, the optimal duration of ECS therapy has not been studied properly and therefore is still uncertain as well as the identification of patients who are likely to benefit from ECS therapy beyond the acute phase. Our study will focus on these two remaining issues of uncertainty. We expect that patients will not be harmed by this approach based on results from our previously conducted pilot study and on literature. [16, 5] We expect that a shortened treatment period with ECS will have a positive impact on the HRQOL.

9.5 Compensation for injury The sponsor/investigator has a liability insurance which is in accordance with article 7, subsection 6 of the WMO. The sponsor (also) has an insurance which is in accordance with the legal requirements in the Netherlands (Article 7 WMO and the Measure regarding Compulsory Insurance for Clinical Research in Humans of 23th June 2003). This insurance provides cover for damage to research subjects through injury or death caused by the study. € 450.000,-- (i.e. four hundred and fifty thousand Euro) for death or injury for each subject who participates in the Research; € 3.500.000,-- (i.e. three million five hundred thousand Euro) for death or injury for all subjects who participate in the Research; € 5.000.000,-- (i.e. five million Euro) for the total damage incurred by the organisation for all damage disclosed by scientific research for the Sponsor as „verrichter‟ in the meaning of said Act in each year of insurance coverage.

The insurance applies to the damage that becomes apparent during the study or within 4 years after the end of the study.


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10. ADMINISTRATIVE ASPECTS AND PUBLICATION

10.1 Handling and storage of data and documents Data will be handled confidentially and anonymously. A subject identification list will be used to link the data to the subject. The code will be made up by two numbers that identify the centre (hospital) and three numbers identifying the patient. Patients will be allocated a consecutive number at inclusion. The key to all codes will be safeguarded by the investigator. The handling of data will be executed according to the Dutch Personal Data Protection Act. Material and Data will be kept during a period of 15 years. 10.2 Amendments All amendments will be notified to the METC that gave a favourable opinion. All substantial amendments will be notified to the METC and to the competent authority. Non-substantial amendments will not be notified to the accredited METC and the competent authority, but will be recorded and filed by the investigator.

10.3 Annual progress report The sponsor/investigator will submit a summary of the progress of the trial to the accredited METC once a year. Information will be provided on the date of inclusion of the first subject, numbers of subjects included and numbers of subjects that have completed the trial, serious adverse events other problems, and amendments.

10.4 End of study report The investigator will notify the accredited METC of the end of the study within a period of 8 weeks. The end of the study is defined as the last patient‟s last visit. In case the study is ended prematurely, the investigator will notify the accredited METC, including the reasons for the premature termination. Within one year after the end of the study, the investigator will submit a final study report with the results of the study, including any publications/abstracts of the study, to the accredited METC.


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10.5 Public disclosure and publication policy This trial will be registered in a public trial registry. Both positive and negative results will be published. There are no financial interests in this trial and none of the parties concerned has right of veto. 11. REFERENCES

1. Brandjes DP, Büller HR, Heijboer H, Huisman MV, de Rijk M, Jagt H, ten Cate JW. Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis.Lancet. 1997 Mar 15; 349(9054):759-62. 2. Prandoni P, Lensing AW, Prins MH, Frulla M, Marchiori A, Bernardi E, Tormene D, Mosena L, Pagnan A, Girolami A. Below-knee elastic compression stockings to prevent the post-thrombotic syndrome:a randomized, controlled trial. Ann Intern Med. 2004 Aug 17; 141(4):249-56. 3. Partsch H, BlättlerW. Compression and walking versus bed rest in the treatment of proximal deep venous thrombosis with low molecular weight heparin. Journal of Vascular Surgery 2000; 32(5):861–9. 4. Partsch H, Kaulich M, Mayer W. Immidiate mobilization in acute vein thrombosis reduces post-thrombotic syndrome. Int Angiol 2004; 23: 206-12. 5. Ginsberg JS, Hirsch J, Julian J, vander laandevries M, Magier D, MacKinnon B, Gent M. Prevention and treatment of postphlebitic syndrome. Arch Int Med . 2001 Sept; 161:2105-2109. 6. Aschwanden M, Jeanneret C, Koller MT, Thalhammer C, Bucher HC, Jaeger KA. Effect of prolonged treatment with compression stockings to prevent post-thrombotic sequelae: a randomized controlled trial. J Vasc Surg. 2008 May;47(5):1015-21. Epub 2008 Apr 18. 7. Kahn SR, Hirsch A, Schrier I. Effect of post thrombotic syndrome on health related quality of life after deep venous thrombosis. Arch Intern Med. 2002 May 27; 162 (10): 1144-8 8. Kahn SR, M‟Lan CE, Lamping DL, Kurz X, Berard A, Abendhaim L; The Veines Study Group. The influence of venous thromboembolism on quality of life and severity of chronic venous disease. J Thromb Haemost. 2004 Dec; 2 (12): 2146-51. 9. Bergqvist D, Jendteg S, Johansen L, Persson U, Odegaard K. Cost of long-term complications of deep venous thrombsis of the lower extremities: an analysis of a defined patient population in Sweden. Ann Int Med. 1997 Mar 15; 126 (6): 454-7. 10. Hirsh J, Guyatt G, Albers GW, Harrington R, Schünemann HJ, American College of Chest Physician. Antithrombotic and thrombolytic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008 Jun; 133(6 Suppl):110S-112S. Erratum in: Chest. 2008 Aug; 134(2):473.


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11. CBO Richtlijn Diagnostiek, preventie en behandeling van veneuze tromboembolie en secundaire preventie van arteriele trombose. ISBN: 978-90-8523-193-6, 2008 Kwaliteitsinstituut voor de Gezondheidszorg CBO. 12. Raju S, Hollis k, Neglen P. Use of compression stockings in chronic venous disease: patient compliance and efficacy. Ann Vasc Surg. 2007 Nov;21 (6): 790-5. 13. Blättler W. Aspects of cost effectiveness in therapy of acute leg/pelvic vein thrombosis. Wien Med Wochenschr. 1999; 149 (2-4):61-5. 14. Gelderblom GJ, Hagedoren-Meuwissen EAV. Kousen uittrekhulpmiddel EasyLever. Een onderzoek naar bruikbaarheid, effecten en belemmeringen, in opdracht van ZonMw juni 2005. 15. Villalta S, Bagatella P, Picolli A, Lensing A, Prins M, Prandoni P. Assessment of validity and reproducibility of a clinical scale for the post thrombotic syndrome (abstract). Haemostasis 1994; 24:158a. 16. ten Cate-Hoek AJ, ten Cate H, Tordoir J, Hamulyák K, Prins MH. Individually tailored duration of elastic compression therapy in relation to incidence of the post thrombotic syndrome. In academic thesis ISBN 978 90 5278 760 2; page 209-226. ( accepted by J Vasc Surg) 17. Kahn SR, Shbaklo H, Shapiro S, Wells PS, Kovacs MJ, Rodger MA, Anderson DR, Ginsberg JS, Johri M, Tagalakis V. Effectiveness of compression stockings to prevent the post-thrombotic syndrome ( the Sox trial and Bio-sox biomarker substudy ): a randomized controlled trial. BMC cardiovascular disorders 2007.7:21. 18. Prandoni P, Lensing AWA, Bernardi E, Villalta S, Bagatelli P, Girolami A. the diagnostic value of compression ultrasonography in patients with suspected recurrent deep vein thrombosis. Thromb Haemost 2003;360:1914-20. 19. Blackwelder WC. “Proving the null hypothesis” in clinical trials. Control Clin Trials. 1982 Dec; 3(4): 345-53. 20. Laster LL, Johnson MF. Non-inferiority trials: the 'at least as good as' criterion. Stat Med. 2003 Jan 30;22(2):187-200. 21. Aaronson NK, Muller M, Cohen PD, Essink-Bot ML, Fekkes M, Sanderman R, Sprangers MA, te Velde A, Verrips E. Translation, validation, and norming of the Dutch language version of the SF-36 Health Survey in community and chronic disease populations. J Clin Epidemiol. 1998 Nov;51(11):1055-68. 22. Brooks R. EuroQol: the current state of play. Health Policy 1996;37(1):53-72. The Euroqol Group. Euroqol - a new facility for the measurement of health-related quality of life. Health Policy 1990;16(3):199-208. 23. Kahn Sr, Lamping DL, Ducruet T, Arsenault L, Miron MJ, Roussin A, Desmarais S, Joyal F, Kassis J, solynoss S, Desjardins L, Johri M, Shrier I. VeinesQol/ Sym questionnaire was a reliable and valid disease specific quality of life measure for deep veinous thrombosis. J clin Epidemiol 2006; 59: 1049-56. 24. Brouwer W. Handleiding voor het gebruik van PRODISQ versie 2.1 (PROductivity and DISease Questionnaire). Een modulaire vragenlijst over de relatie tussen ziekte en productiviteitskosten. Toepasbaar bij economische evaluaties van


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gezondheidszorgprogramma‟s voor patiënten en werknemers. Rotterdam/ Maastricht; 2004. 25. Lancaster K. A new approach to consumer theory. J Polit Econ 1966; 74:132157. 26. Kahn SR. Measurement properties of the Villalta scale to define and classify the severity of the post-thrombotic syndrome. J Thromb Haemost 2009: 7;884-8. 27. Weinstein MC, O'Brien B, Hornberger J, Jackson J, Johannesson M, McCabe C, Luce BR; ISPOR Task Force on Good Research Practices--Modeling Studies. Principles of good practice for decision analytic modeling in health-care evaluation: report of the ISPOR Task Force on Good Research Practices--Modeling Studies. Value Health. 2003 Jan-Feb;6(1):9-17. 28. Ten Cate-Hoek AJ, Toll DB, Büller HR, Hoes AW, Moons KG, Oudega R, Stoffers HE, van der Velde EF, van Weert HC, Prins MH, Joore MA. Cost-effectiveness of ruling out deep venous thrombosis in primary care versus care as usual. J Thromb Haemost. 2009 Dec;7(12):2042-9. 29. Koopmanschap MA, Meerding WJ, Evers S, Severens J, Burdorf A, Brouwer W. Handleiding voor het gebruik van PRODISQ versie 2.1 (PROductivity and DISease Questionnaire). Een modulaire vragenlijst over de relatie tussen ziekte en productiviteitskosten. Toepasbaar bij economische evaluaties van gezondheidszorgprogramma‟s voor patiënten en werknemers. Rotterdam/Maastricht; 2004. 30. Oostenbrink JB, Bouwmans CM, Koopmanschap MA, Rutten FFH. Manual for Cost Analysis. Amstelveen: College voor Zorgverzekeringen. (In Dutch); 2004. 31. Dolan, P. Modelling valuations for EuroQol health states. Med Care 1997;35:1095-108. 32. Brazier J, Roberts J, Deverill M. The estimation of a preference-based measure of health from the SF-36. J Health Econ 2002;21:271-92.


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Addendum A: List of participating centers List of participating centers 1. MUMC+-Maastricht 2. MMC-Eindhoven 3. UMC-Nijmegen 4. AMC-Amsterdam 5. OLVG-Amsterdan 6. Slotervaart-Amsterdam 7. FlevoZH-Almere 8. WFGasthuis-Hoorn

contact: Dr. A. J. ten Cate-Hoek contact: Dr. L. Tick contact: Dr. M. Janssen contact: Dr. P.W. Kamphuizen contact: Dr.W. Terpstra contact: Dr. V. Gerdes contact: Dr. M. Ten Wolde contact: Dr. S. Van den Heiligenberg

Addendum B: Qualiweb protocol 8052 “Diagnostiek en behandeling van DVT”

Ten aanzien van behandeling van DVT zijn er een aantal aanbevelingen. De behandeling is individueel en afhankelijk van gewicht (LMWG) en metabolisme (vit K antagonisten). Medicamenteuze behandeling Deze bestaat uit de combinatie Laag Moleculair Gewicht Heparine (LMWH) en coumarine derivaten (vitamine K antagonisten). Voor deze indicatie is de eerste keuze LMWH Fraxiparine. LMWH wordt 1 x daags toegediend op geleide van het lichaamsgewicht met als basisschema: B1 – LMWH doseerschema < 50 kg: 50-70 kg: > 70 kg:

1dd 0,8 ml Fraxiparine 1dd 0,6 ml Fraxodi 1dd 0,8 ml Fraxodi

LMWH dient tenminste 5-7 dagen gecombineerd met de vitamine K antagonist te worden gegeven en kan daarna worden gestopt indien de INR tenminste 2 opeenvolgende dagen in de gewenste range ligt. Er is geen lab controle nodig voor het gebruik van LMWH's, tenzij sprake is van specifieke situaties zoals sterk afwijkend lichaamsgewicht, nierinsufficiëntie (klaring<20 ml/min) met bloedingsneiging, zwangerschap of verdenking heparine geïnduceerde trombopenie (HIT). In deze gevallen overleg met (dienstdoende) hematoloog of vasculair geneeskundige. Als alternatieve behandeling bij een HIT is de eerste keuze Orgaran (LMW heparinoid, doseringen zijn terug te vinden in het Farmacotherapeutisch kompas). De vitamine K antagonisten (Sintrommitis of Marcoumar) worden tegelijk met de LMWH gestart.


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B2 – Vitamine K antagonist (coumarine derivaat) doseerschema’s Startdosering Sintrommitis (acenocoumarol) Startdosering Marcoumar (phenprocoumon)

6 - 4 - 4 controle INR 4 - 2 - 2 controle INR

Bij een bekende proteïne C/S deficiëntie geen oplaaddosis coumarines geven i.v.m. risico op huidnecrose. De controle frequentie en het verdere doseringsadvies vindt plaats via de trombosedienst. De duur van de orale antistolling wordt individueel bepaald en bedraagt minimaal 3 maanden, de duur hangt af van de ingeschatte kans op recidief versus de kans op ernstige bloedingen. Langdurige orale antistolling wordt gegeven bij recidiverende spontane veneuze tromboëmbolie met persisterende risicofactoren. De dosering van de orale antistolling vindt plaats op geleide van de INR (range 2.0 - 3.0), bij recidief veneuze tromboembolie tijdens adequate antistolling dient overleg plaats te vinden met (dienstdoende) hematoloog of vasculair geneeskundige (zie Orale antistolling). Bij patiënten met een bekende maligniteit (solide tumoren m,u.v. prostaatca.) wordt in principe niet gestart met coumarine derivaten, maar uitsluitend met LMWH behandeld. Het definitieve behandelprotocol wordt poliklinisch met de behandelend oncoloog afgesproken.

PTS scoring scales Addendum C1.

Villalta PTS scale

Symptoms and Clinical signs Symptoms Pain Cramps Heaviness Paresthesia Pruritus

None 0 points 0 points 0 points 0 points 0 points

Mild 1 point 1 point 1 point 1 point 1 point

Moderate 2 points 2 points 2 points 2 points 2 points

Severe 3 points 3 points 3 points 3 points 3 points

Clinical signs Pretibial edema Skin induration Hyperpigmentation Redness Venous ectasia Pain on calf compression Venous ulcer

0 points 0 points 0 points 0 points 0 points 0 points Absent

1 point 1 point 1 point 1 point 1 point 1 point Present

2 points 2 points 2 points 2 points 2 points 2 points

3 points 3 points 3 points 3 points 3 points 3 points

Points are summed into a total score (range 0–33). PTS is deﬁned by a total score of ≥5 or the presence of a venous ulcer. PTS is classiﬁed as mild if the Villalta score is 5–9, moderate if the Villalta score is 10–14, and severe if the Villalta score is ≥15 or a venous ulcer is present. To use the Villalta score as a continuous measure, it is recommended that patients who meet criteria for severe PTS based solely on the presence of an ulcer (i.e. total Villalta score is <15)


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Addendum C1b CEAP scale

Class C0 C1 C2 C3 C4 C5 C6

Clinical signs No signs of venous disease Teleangiectasies/reticular veins varicous veins Edema Lipodermatosclerosis Healed ulcer Active ulceration

Addendum D Questionnaires used in the trial Health-related QOL questionnaires Addendum D1.

SF-36 vragenlijst

De volgende vragen gaan over uw standpunten ten aanzien van uw gezondheid. Met behulp van deze gegevens kan worden bijgehouden hoe u zich voelt en hoe goed u in staat bent uw gebruikelijke bezigheden uit te voeren. Beantwoordt elke vraag op de aangegeven manier. Als u niet zeker weet hoe u een vraag moet beantwoorden, geef dan het best mogelijke antwoord. 1. Hoe zou u over het algemeen uw gezondheid noemen? (Omcirkel één cijfer) Uitstekend Zeer goed Goed Matig Slecht 1 2 3 4 5 2. Hoe beoordeelt u NU uw gezondheid over het algemeen, vergeleken met EEN WEEK GELEDEN? (omcirkel één cijfer) Veel beter NU dan een WEEK GELEDEN 1 Wat beter NU dan een WEEK GELEDEN 2 Ongeveer hetzelfde NU als een WEEK GELEDEN 3 Wat slechter NU dan een WEEK GELEDEN 4 Veel slechter NU dan een WEEK GELEDEN 5 3. De volgende vragen gaan over bezigheden die u misschien doet op een doorsnee dag. Wordt u door uw gezondheid OP DIT MOMENT beperkt bij deze bezigheden? Zoja, in welke mate? (Omcirkel één cijfer op elke regel) Ja, ernstig Ja, een beetje Nee, helemaal beperkt beperkt niet beperkt BEZIGHEDEN a. Forse inspanning, zoals hardlopen, 1 2 3 tillen van zware voorwerpen, een veeleisende sport beoefenen


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b. Matige inspanning, zoals een tafel verplaatsen, stofzuigen, zwemmen of fietsen c. Boodschappen tillen of dragen d. Een paar trappen oplopen e. Eén trap oplopen f. Bukken, knielen of hurken g. Meer dan een kilometer lopen h. Een paar honderd meter lopen i. Ongeveer honderd meter lopen j. Uzelf wassen of aankleden

Short title

1

2

3

1 1 1 1 1 1 1 1

2 2 2 2 2 2 2 2

3 3 3 3 3 3 3 3

4. Heeft u in de AFGELOPEN WEEK, één van de volgende problemen bij uw werk of andere dagelijkse bezigheden gehad, ten gevolge van uw lichamelijke gezondheid? (Omcirkel één cijfer op elke regel) JA NEE a. U besteedde minder tijd aan werk of andere 1 2 bezigheden b. U heeft minder bereikt dan u zou willen 1 2 c. U was beperkt in het soort werk of andere bezigheden 1 2 d. U had moeite om uw werk of andere bezigheden uit te 1 2 voeren (het kostte u b.v. extra inspanning) 5. Heeft u in de AFGELOPEN WEEK één van de volgende problemen ondervonden biJ uw werk of andere dagelijkse bezigheden ten gevolge van uw emotionele problemen (zoals depressieve of angstige gevoelens)? (Omcirkel één cijfer op elke regel) JA NEE a. U besteedde minder tijd aan werk of andere 1 2 bezigheden b. U heeft minder bereikt dan u zou willen 1 2 c. U deed uw werk of andere bezigheden niet zo 1 2 zorgvuldig als gewoonlijk 6. In hoeverre hebben uw lichamelijke gezondheid of emotionele problemen u gedurende de AFGELOPEN WEEK gehinderd in uw normale omgang met familie, ` vrienden of buren of bij activiteiten in groepsverband? (Omcirkel één cijfer) Helemaal niet Enigszins Nogal Veel Heel erg veel 1 2 3 4 5 7. Hoeveel lichamelijke pijn heeft u de AFGELOPEN WEEK gehad? (Omcirkel één cijfer) Geen Heel licht Licht Nogal Ernstig 1 2 3 4 5

Heel ernstig 6

8. In welke mate bent u de AFGELOPEN WEEK door pijn gehinderd in uw normale werk (zowel werk buitenshuis als huishoudelijk werk)? (Omcirkel één cijfer) Helemaal niet Een klein beetje Nogal Veel Heel erg veel 1 2 3 4 5


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9. Deze vragen gaan over hoe u zich voelt en hoe het met u ging in de AFGELOPEN WEEK. Wilt u a.u.b. bij elke vraag het antwoord geven dat het best benadert hoe u zich voelde. Hoe vaak gedurende de AFGELOPEN WEEK...... (Omcirkel één cijfer op elke regel) Altijd Meestal Vaak Soms Zelden a. Voelde u zich levenslustig? 1 2 3 4 5 b. Was u erg zenuwachtig? 1 2 3 4 5 c. Zat u zo in de put dat niets u kon 1 2 3 4 5 opvrolijken? d. Voelde u zich rustig en tevreden? 1 2 3 4 5 e. Had u veel energie? 1 2 3 4 5 f. Voelde u zich somber en 1 2 3 4 5 neerslachtig? g. Voelde u zich uitgeput? 1 2 3 4 5 h. Was u een gelukkig mens? 1 2 3 4 5 i. Voelde u zich moe? 1 2 3 4 5

Ideal DVT study

Nooit 6 6 6 6 6 6 6 6 6

10. Hoe vaak hebben uw lichamelijke gezondheid of emotionele problemen u gedurende de AFGELOPEN WEEK gehinderd bij uw sociale activiteiten (zoals vrienden of familie bezoeken, enz)? (Omcirkel één cijfer) Altijd Meestal Soms Zelden Nooit 1 2 3 4 5 11. Hoe juist of onjuist is elk van de volgende uitspraken voor u? (Omcirkel één cijfer op elke regel) Volkomen Grotendeels Weet ik juist juist niet a. Ik lijk wat gemakkelijker ziek 1 2 3 te worden dan andere mensen b. Ik ben even gezond als 1 2 3 andere mensen die ik ken c. Ik verwacht dat mijn 1 2 3 gezondheid achteruit zal gaan d. Mijn gezondheid is uitstekend 1 2 3


Grotendeels onjuist 4

Volkomen onjuist 5

4

5

4

5

4

5

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AddendumD2.

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Health Related Quality of life Questionnaire  EuroQOL-5D


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Addendum D3. Dutch translated Veines Qol questionnaire

Datum (dd-mm-jj):

Randomisatie nr:

Tijdstip

:

T0 ☐

T3 ☐

T6 ☐

T12 ☐

U heeft een veneuze trombose doorgemaakt. In dit onderzoek zijn wij geïnteresseerd in de effecten van uw beenprobleem op uw dagelijkse activiteiten, zowel thuis als op het werk. Deze informatie geeft ons een beter idee over hoe wij dergelijke problemen kunnen behandelen.

Dank voor uw deelname aan dit onderzoek. Deze vragenlijst bevat vragen over uw gezondheid in het algemeen en over uw beenproblemen evenals over uw dagelijks leven en gewoonlijke activiteiten. Het zal u ongeveer 10 minuten kosten om deze vragenlijst in te vullen. Al uw antwoorden zijn vertrouwelijk. Schrijf a.u.b. niet uw naam op de vragenlijst!

Hartelijk dank voor uw hulp.


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INSTRUCTIES VOOR HET BEANTWOORDEN VAN DE VRAGEN: Beantwoord elke vraag door het antwoord te markeren zoals aangegeven. Indien u onzeker bent over hoe u een vraag moet beantwoorden, geef dan alstublieft het beste antwoord dat u kunt geven. Deze vragen gaan over uw beenprobleem (beenproblemen).

1. Gedurende de afgelopen 4 weken, hoe vaak heeft u een van de volgende beenproblemen gehad?

(kruis steeds 1 hokje op elke lijn aan)

Elke dag

Een aantal

Ongeveer

Minder dan

keer per

één keer

één keer

week

per week

per week

Nooit

1. Zware benen

☐1

☐2

☐3

☐4

☐5

2. Pijnlijke benen

☐1

☐2

☐3

☐4

☐5

3. Zwelling

☐1

☐2

☐3

☐4

☐5

4. Nachtelijke krampen

☐1

☐2

☐3

☐4

☐5

5.

☐1

☐2

☐3

☐4

☐5

6. Rusteloze benen

☐1

☐2

☐3

☐4

☐5

7. Kloppend gevoel

☐1

☐2

☐3

☐4

☐5

8. Jeuk

☐1

☐2

☐3

☐4

☐5

9. Tintelend gevoel

☐1

☐2

☐3

☐4

☐5

Warm of branderig gevoel

(speldenprik gevoel)

2. Op welk tijdstip van de dag is uw beenprobleem het meest intens? (kruis 1 mogelijkheid aan) ☐1

bij het ontwaken

☐2

midden op de dag

☐3

aan het eind van de dag

☐4

gedurende de dag ☐5

gedurende elk moment van de dag ☐6

nooit

3. Vergeleken met de situatie van 1 jaar geleden, hoe zou u uw beenprobleem in het algemeen nu beoordelen? (kruis 1 mogelijkheid aan) ☐1

veel beter nu dan 1 jaar geleden

☐4

iets slechter nu dan 1 jaar geleden

☐2

iets beter nu dan 1 jaar geleden

☐5

☐3

ongeveer hetzelfde nu als 1 jaar geleden ☐6

veel slechter nu dan 1 jaar geleden ik had vorig jaar geen enkel

beenprobleem


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4. De volgende vragen gaan over activiteiten die u op een normale dag zou kunnen uitvoeren. Beperkt uw beenprobleem u nu bij het uitvoeren van deze activiteiten? Zo ja, hoeveel?


a. Dagelijkse activiteiten op werk

Ik werk niet

JA, ernstig

JA, enigzins

NEE, helemaal

beperkt

beperkt

niet beperkt

☐1

☐2

☐3

☐1

☐2

☐3

☐1

☐2

☐3

☐1

☐2

☐3

☐0

b. Dagelijkse activiteiten thuis (bv: huishouden, strijken, klusjes/reparaties uitvoeren in en rond het huis, tuinieren etc....) c. Sociale activiteiten of vrijetijdsbesteding waarbij u langdurig staat (bv: feestjes, bruiloften, openbaar vervoer, winkelen etc....) d. Sociale activiteiten of vrijetijdsbesteding waarbij u langdurig zit (bv: naar de bioscoop of het theater gaan, reizen etc....)

5. Heeft u gedurende de afgelopen 4 weken een van de volgende problemen ondervonden met uw werk of andere normale dagelijkse activiteiten ten gevolge van uw beenprobleem?


JA

NEE

a. Vermindering van hoeveelheid tijd die u normaal besteed aan

☐1

☐2

b. Minder bereikt dan u zou willen

☐1

☐2

c.

☐1

☐2

☐1

☐2

werk of andere activiteiten

c.

Was beperkt in het soort werk of andere activiteiten

d. Had moeite met het uitvoeren van werk of andere activiteiten (bv: het kostte meer moeite)

6. Gedurende de afgelopen 4 weken, in welke mate heeft uw beenprobleem u beperkt in uw normale sociale activiteiten met familie, vrienden, buren of andere groepen? (kruis 1 mogelijkheid aan) ☐1

helemaal niet

☐4

best veel

☐2

enigzins

☐5

ernstig

☐3

matig

7. Hoeveel beenpijn heeft u gedurende de afgelopen 4 weken gehad? (kruis 1 mogelijkheid aan) ☐1

geen


☐4

matig

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☐2

zeer mild

☐5

ernstig

☐3

mild

☐6

zeer ernstig

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8. Deze vragen gaan over hoe u zich voelt en over hoe het met u gegaan is gedurende de afgelopen 4 weken als gevolg van uw beenprobleem. Geef voor elke vraag het antwoord dat het dichtst in de buurt komt van hoe u zich gevoeld heeft. Hoe vaak gedurende de afgelopen 4 weken -


De hele

Het

Vrij

tijd

grootste

vaak

Soms

Heel

Nooit

af en

gedeelte

toe

van de tijd ☐1

☐2

☐3

☐4

☐5

☐6

b. was u prikkelbaar?

☐1

☐2

☐3

☐4

☐5

☐6

c. heeft u zich tot last van uw

☐1

☐2

☐3

☐4

☐5

☐6

☐1

☐2

☐3

☐4

☐5

☐6

☐1

☐2

☐3

☐4

☐5

☐6

a. was u bezorgd over hoe uw been (benen) eruit ziet (zien)?

familie of vrienden gevoeld? d. bent u bang geweest ergens tegenaan te stoten? e.

heeft hoe uw been (benen) eruit ziet (zien) uw kledingkeuze beïnvloed?

Dank u voor uw hulp.

Schrijf hier a.u.b. de datum van vandaag.


[_____/_____/__________] (dag/maand/jaartal)

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D4.Extra vragen over werkverzuim/arbeidsongeschiktheid & doktersbezoeken

1. Heeft u momenteel een betaalde baan? a. ja,

ik verricht ongeveer …… uur betaald werk per week;

Functieniveau:

Basisonderwijs Middelbaar Beroepsonderwijs HBO/WO

b. nee

2. Hoeveel dagen heeft u uw dagelijkse werkzaamheden (betaald werk, school, huishoudelijk werk, vrijwilligerswerk) verzuimd na de operatie, als gevolg van de operatie? Tot 6 weken

:

____ dagen.

3. Heeft u als gevolg van de operatie thuis extra hulp gehad? Tot 6 weken: a. nee b. ja, wijkverpleging, ….. uur per week, gedurende ….. weken c. ja, vrijwilliger, ….. uur per week, gedurende ….. weken 4. Heeft u als gevolg van de operatie verbandmiddelen nodig gehad? Tot 6 weken: a. nee b. ja, gedurende …… dagen 5. Heeft u als gevolg van de operatie extra medicijnen nodig gehad? Tot 6 weken: a. nee b. ja, pijnstillers (naam: _______________________ ), voor …… dagen c. ja, antibiotica (naam: _______________________ ), voor …… dagen d. anders ……………................................................................................ 6. Hoe vaak heeft u als gevolg van de operatie een bezoek aan de huisarts gebracht? Tot 6 weken: a. nooit b. …… keer, omdat __________________________________


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7. Hoe vaak heeft u als gevolg van de operatie de specialist bezocht? Tot 6 weken:

a. b. c. d.

nooit dermatoloog, ….. keer, omdat _______________________________ chirurg, …. keer, omdat ____________________________________ anders, ….. keer, omdat ___________________________________

8. Ander zorggebruik dan in bovenstaande vragen? Tot 6 weken: Nee Ja, graag specificeren ____________________________


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