The MUFFIN-PTS Trial

Study Overview
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Brief Summary
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In this randomized controlled trial (RCT), the investigators will determine whether a 6-month course of oral Micronized Purified Flavonoid Fraction (MPFF 1000 mg daily), compared with placebo, improves the symptoms and signs of the post-thrombotic syndrome (PTS) and quality of life (QOL) at 6 months follow-up.

Detailed Description
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The post thrombotic syndrome (PTS) is a form of secondary chronic venous insufficiency (CVI) that develops after a deep vein thrombosis (DVT). It affects up to 50% of patients after a proximal DVT (i.e. DVT involving popliteal vein or more proximal veins), and 5-10% of patients develop severe PTS. PTS is a chronic condition that reduces quality of life (QOL) and for which no curative treatment is available. Cornerstones of PTS treatment include the use of elastic compression stockings (ECS) to reduce leg symptoms and prevent PTS progression. However, ECS are incompletely effective, burdensome and costly to patients. Micronized Purified Flavonoid Fraction (MPFF, Venixxa), a venoactive drug, has been reported to be effective in reducing venous symptoms and signs and improving QOL in patients with CVI and has the potential to be effective for the treatment of PTS. Further, use of Venixxa is safe, with only few very mild and reversible reported side effects. However, studies of MPFF in patients with CVI have been of low to moderate quality, and there has been little use of this drug in North America. In addition, the effectiveness of MPFF has never been specifically evaluated in patients with PTS. Given that the pathophysiological mechanism of PTS is complex and unique (combination of obstructive and reflux mechanisms as well as inflammation), it is uncertain if MPFF is effective in patients with PTS, even if it may be effective for CVI more generally. The MUFFIN-PTS study will be a multicentre (8-10 centres), randomized, placebo-controlled trial. Patients will be randomized (1:1 with stratification by centre) to receive 1000 mg of oral MPFF (Venixxa, one 500mg tablet BID) or an identically appearing placebo (one tablet BID) for 6 months, in addition to their usual PTS and DVT treatment (i.e. ECS and/or anticoagulation, at their treating physician's discretion). Its objectives are to evaluate the effectiveness and safety of MPFF (Venixxa) compared to placebo for the treatment of PTS. 86 patients with lower limb PTS will be enrolled in the study.

Official Title
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The MUFFIN-PTS Trial: Micronized Purified Flavonoid Fraction for the Treatment of Post-Thrombotic Syndrome

Conditions
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Post-Thrombotic Syndrome

Intervention / Treatment
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* Drug: Micronized Purified Flavonoid Fraction
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Villalta score ≥5 with at least two of the following four PTS manifestations (daily heaviness, cramps, pain, and objective edema) in the leg ipsilateral to a previous objectively diagnosed DVT, or DVT of unknown date but with presence of residual proximal or distal venous obstruction on ultrasound. Females of childbearing age must use medically approved method of birth control and must have negative pregnancy test results at the time of randomization. Exclusion Criteria: Recent acute ipsilateral DVT (<3 months) Active ipsilateral venous ulcer Acute or chronic altered mental status Any venoactive drug intake within 3 months of the start of the study Allergy or hypersensitivity to MPFF/Venixxa Age<18 years Pregnant or breastfeeding women Life expectancy <1 year Refuse or unwilling to provide consent Unable to speak English or French Alcohol/drug abuse Hospitalized patients End-stage kidney disease (dialysis, creatinine clearance < 10ml/min) Liver cirrhosis Child-Pugh class C. Currently enrolled in other clinical trials, other than trials of prevention or treatment of venous thromboembolism

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Multicentre, randomized, placebo-controlled trial
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Venixxa<br>Micronized Purified Flavonoid Fraction (MPFF) for 6 months MPFF 500 mg, BID (morning and evening) for 6 months | Drug: Micronized Purified Flavonoid Fraction<br>* After randomization (1:1 with stratification by centre) patients will receive 1000 mg of oral MPFF (Venixxa, one 500mg tablet BID) for 6 months, in addition to their usual PTS and DVT treatment<br>* Other names: Venixxa group;|
| Placebo Comparator: Placebo<br>Placebo for 6 months 1 Tablet, BID (morning and evening) for 6 months | Drug: Placebo<br>* After randomization (1:1 with stratification by centre) patients will receive an oral placebo (one tablet BID) for 6 months, in addition to their usual PTS and DVT treatment<br>* Other names: Placebo group;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in PTS | Improvement will be defined as a decrease of at least 30% in the Villalta score or a Villalta score <5 in the PTS-affected leg. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Severity of PTS | Villalta score category (mild, moderate, severe) | baseline, 3, 6 and 9 months | 
| Change in PTS | Improvement will be defined as a decrease of at least 30% in the Villalta score or a Villalta score <5 in the PTS-affected leg. | 3 and 9 months | 
| Venous specific Quality of life | Venous-disease specific (VEINES-QOL) score | 3, 6 and 9 months | 
| General Quality of life | Generic QOL (EQ-5D-5L) score. The EQ-5D-5L consists of the EQ-5D-5L descriptive system and the EQ Visual Analogue scale (EQ VAS). The descriptive system comprises 5 dimensions (mobility, self care, usual activities, pain/discomfort, anxiety/depression). Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. This decision results in a 1-digit number expressing the level selected for that dimension. The digits for 5 dimensions can be combined in a 5-digit number describing the respondent's health state. The EQ VAS records the respondent's self-rated health on a 20 cm vertical, visual analogue scale with endpoints labelled 'the best health you can imagine' and 'the worst health you can imagine'. This information can be used as a quantitative measure of health as judged by the individual respondents. | 3, 6 and 9 months | 
| Serious Adverse Events (SAE) | Includes drug-related SAE, DVT, Pulmonary Embolism (PE), death | 9 months | 
| Patient compliance with treatment | Judged satisfactory if at least 80% of the study drug was reportedly taken | 3 and 6 months | 
| Patients' overall satisfaction with treatment | Assessed with a 5-point Likert visual analog scale questionnaire (1 indicate patient is very satisfied with treatment and 5 that he is very unsatisfied) | 3 and 6 months | 
| Villalta score | Villalta score assessed as a continuous variable (greater score indicates more severe disease, score range 0 to 33) | 3, 6, 9 months | 
| Pain as a symptom of PTS | Analyzed as individual component of Villalta score (0 absent to 3 severe) | 3, 6, 9 months | 
| Cramps | Analyzed as individual component of Villalta score (0 absent to 3 severe) | 3, 6, 9 months | 
| Heaviness | Analyzed as individual component of Villalta score (0 absent to 3 severe) | 3, 6, 9 months | 
| Paresthesia | Analyzed as individual component of Villalta score (0 absent to 3 severe) | 3, 6, 9 months | 
| Pruritus | Analyzed as individual component of Villalta score (0 absent to 3 severe) | 3, 6, 9 months | 
| Pre-tibial edema | Analyzed as individual component of Villalta score (0 absent to 3 severe) | 3, 6, 9 months | 
| Hyperpigmentation | Analyzed as individual component of Villalta score (0 absent to 3 severe) | 3, 6, 9 months | 
| Redness | Analyzed as individual component of Villalta score (0 absent to 3 severe) | 3, 6, 9 months | 
| Skin induration | Analyzed as individual component of Villalta score (0 absent to 3 severe) | 3, 6, 9 months | 
| Venous ectasia | Analyzed as individual component of Villalta score (0 absent to 3 severe) | 3, 6, 9 months | 
| Venous Ulcer | Analyzed as individual component of Villalta score (0 absent or 1 present) | 3, 6, 9 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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deep vein thrombosis, chronic venous insufficiency, venoactive drug, Micronized Purified Flavonoid Fraction, DVT, post thrombotic syndrome