The MUFFIN-PTS Trial (MUFFIN-PTS)

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Post-Thrombotic Syndrome
• Intervention / Treatment: Drug: Micronized Purified Flavonoid Fraction; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 88
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada
      • Vancouver General Hospital
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 3A7
      • Queen Elizabeth II Health Sciences Centre
  • Ontario
    • Hamilton, Ontario, Canada, L8L 2X2
      • Hamilton General Hospital
    • Ottawa, Ontario, Canada, K1Y 4E9
      • Ottawa Hospital Research Institute
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Health Sciences Centre
    • Toronto, Ontario, Canada, M5G 1Z5
      • Toronto General Hospital
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • Sir Mortimer B. Davis - Jewish General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Venixxa; Micronized Purified Flavonoid Fraction (MPFF) for 6 months MPFF 500 mg, BID (morning and evening) for 6 months	Drug: Micronized Purified Flavonoid Fraction; 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; Other Names: Venixxa group
Placebo Comparator: Placebo; Placebo for 6 months 1 Tablet, BID (morning and evening) for 6 months	Drug: Placebo; 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; Other Names: Placebo group

What is the study measuring?

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
Villalta score	Villalta score assessed as a continuous variable (greater score indicates more severe disease, score range 0 to 33)	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
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
Pain as a symptom of PTS	Analyzed as individual component of Villalta score (0 absent to 3 severe)	3, 6, 9 months

Collaborators and Investigators

• Sponsor: Sir Mortimer B. Davis - Jewish General Hospital
• Investigators: Principal Investigator: Susan R Kahn, MD, MSc, Jewish General Hospital (Montreal, Quebec, Canada); Principal Investigator: Jean-Philippe Galanaud, MD, PhD, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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. Erratum In: Phlebology. 2017 Dec;32(10 ):NP36.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): February 4, 2022
• Primary Completion (Estimated): March 30, 2024
• Study Completion (Estimated): May 30, 2024

Study Registration Dates

• First Submitted: January 30, 2019
• First Submitted That Met QC Criteria: February 5, 2019
• First Posted (Actual): February 6, 2019

Study Record Updates

• Last Update Posted (Actual): November 30, 2023
• Last Update Submitted That Met QC Criteria: November 29, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: deep vein thrombosis; DVT; venoactive drug; chronic venous insufficiency; Micronized Purified Flavonoid Fraction; post thrombotic syndrome
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Disease; Embolism and Thrombosis; Venous Thrombosis; Thrombosis; Peripheral Vascular Diseases; Venous Insufficiency; Phlebitis; Syndrome; Postthrombotic Syndrome; Postphlebitic Syndrome
• Other Study ID Numbers: 332593-S1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Open access to individual patient data is not planned, but all requests for the trial's data will be considered on an individual basis by the trial steering committee

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No