Clinical trial NCT03833024: The MUFFIN-PTS Trial
Official title: The MUFFIN-PTS Trial: Micronized Purified Flavonoid Fraction for the Treatment of Post-Thrombotic Syndrome
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Post-Thrombotic Syndrome
Keywords: deep vein thrombosis
chronic venous insufficiency
venoactive drug
Micronized Purified Flavonoid Fraction
DVT
post thrombotic syndrome
Lead sponsor: Sir Mortimer B. Davis - Jewish General Hospital
Sponsor class: OTHER
First posted: 2019-02-06
Enrollment: 88
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multicentre, randomized, placebo-controlled trial
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in PTS
timeFrame: 6 months
Secondary outcomes:
measure: Severity of PTS
timeFrame: baseline, 3, 6 and 9 months
measure: Change in PTS
timeFrame: 3 and 9 months
measure: Venous specific Quality of life
timeFrame: 3, 6 and 9 months
measure: General Quality of life
timeFrame: 3, 6 and 9 months
measure: Serious Adverse Events (SAE)
timeFrame: 9 months
measure: Patient compliance with treatment
timeFrame: 3 and 6 months
measure: Patients' overall satisfaction with treatment
timeFrame: 3 and 6 months
measure: Villalta score
timeFrame: 3, 6, 9 months
measure: Pain as a symptom of PTS
timeFrame: 3, 6, 9 months
measure: Cramps
timeFrame: 3, 6, 9 months
measure: Heaviness
timeFrame: 3, 6, 9 months
measure: Paresthesia
timeFrame: 3, 6, 9 months
measure: Pruritus
timeFrame: 3, 6, 9 months
measure: Pre-tibial edema
timeFrame: 3, 6, 9 months
measure: Hyperpigmentation
timeFrame: 3, 6, 9 months
measure: Redness
timeFrame: 3, 6, 9 months
measure: Skin induration
timeFrame: 3, 6, 9 months
measure: Venous ectasia
timeFrame: 3, 6, 9 months
measure: Venous Ulcer
timeFrame: 3, 6, 9 months
Other outcomes:
Locations:
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
city: Halifax
country: Canada
facility: Queen Elizabeth II Health Sciences Centre
state: Nova Scotia
city: Hamilton
country: Canada
facility: Hamilton General Hospital
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Hospital Research Institute
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
city: Montreal
country: Canada
facility: Sir Mortimer B. Davis - Jewish General Hospital
state: Quebec
Study officials:
affiliation: Jewish General Hospital (Montreal, Quebec, Canada)
name: Susan R Kahn, MD, MSc
role: PRINCIPAL_INVESTIGATOR
affiliation: Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
name: Jean-Philippe Galanaud, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kahn SR, Pengo V. Special issue: Late consequences of venous thromboembolism. Thromb Res. 2018 Apr;164:99. doi: 10.1016/j.thromres.2018.02.005. Epub 2018 Feb 13. No abstract available.
citation: Rabinovich A, Kahn SR. How I treat the postthrombotic syndrome. Blood. 2018 May 17;131(20):2215-2222. doi: 10.1182/blood-2018-01-785956. Epub 2018 Mar 15.
citation: Kahn SR, Comerota AJ, Cushman M, Evans NS, Ginsberg JS, Goldenberg NA, Gupta DK, Prandoni P, Vedantham S, Walsh ME, Weitz JI; American Heart Association Council on Peripheral Vascular Disease, Council on Clinical Cardiology, and Council on Cardiovascular and Stroke Nursing. The postthrombotic syndrome: evidence-based prevention, diagnosis, and treatment strategies: a scientific statement from the American Heart Association. Circulation. 2014 Oct 28;130(18):1636-61. doi: 10.1161/CIR.0000000000000130. Epub 2014 Sep 22. No abstract available. Erratum In: Circulation. 2015 Feb 24;131(8):e359. doi: 10.1161/CIR.0000000000000185.
citation: Galanaud JP, Monreal M, Kahn SR. Epidemiology of the post-thrombotic syndrome. Thromb Res. 2018 Apr;164:100-109. doi: 10.1016/j.thromres.2017.07.026. Epub 2017 Jul 24.
citation: Cohen JM, Akl EA, Kahn SR. Pharmacologic and compression therapies for postthrombotic syndrome: a systematic review of randomized controlled trials. Chest. 2012 Feb;141(2):308-320. doi: 10.1378/chest.11-1175.
citation: Martinez-Zapata MJ, Vernooij RW, Uriona Tuma SM, Stein AT, Moreno RM, Vargas E, Capella D, Bonfill Cosp X. Phlebotonics for venous insufficiency. Cochrane Database Syst Rev. 2016 Apr 6;4(4):CD003229. doi: 10.1002/14651858.CD003229.pub3.
citation: Bush R, Comerota A, Meissner M, Raffetto JD, Hahn SR, Freeman K. Recommendations for the medical management of chronic venous disease: The role of Micronized Purified Flavanoid Fraction (MPFF). Phlebology. 2017 Apr;32(1_suppl):3-19. doi: 10.1177/0268355517692221.
citation: Rabe E, Agus GB, Roztocil K. Analysis of the effects of micronized purified flavonoid fraction versus placebo on symptoms and quality of life in patients suffering from chronic venous disease: from a prospective randomized trial. Int Angiol. 2015 Oct;34(5):428-36. Epub 2015 May 14.
citation: Galanaud JP, Abdulrehman J, Lazo-Langner A, Le Gal G, Shivakumar S, Schulman S, Kahn S. MUFFIN-PTS trial, Micronized Purified Flavonoid Fraction for the Treatment of Post-Thrombotic Syndrome: protocol of a randomised controlled trial. BMJ Open. 2021 Sep 13;11(9):e049557. doi: 10.1136/bmjopen-2021-049557.