<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03833024</url>
  </required_header>
  <id_info>
    <org_study_id>332593-S1</org_study_id>
    <nct_id>NCT03833024</nct_id>
  </id_info>
  <brief_title>The MUFFIN-PTS Trial</brief_title>
  <acronym>MUFFIN-PTS</acronym>
  <official_title>The MUFFIN-PTS Trial: Micronized Purified Flavonoid Fraction for the Treatment of Post-Thrombotic Syndrome</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sir Mortimer B. Davis - Jewish General Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Sir Mortimer B. Davis - Jewish General Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      In this randomized controlled trial (RCT), the investigators will determine whether a 6-month&#xD;
      course of oral Micronized Purified Flavonoid Fraction (MPFF 1000 mg daily), compared with&#xD;
      placebo, improves the symptoms and signs of the post-thrombotic syndrome (PTS) and quality of&#xD;
      life (QOL) at 6 months follow-up.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The post thrombotic syndrome (PTS) is a form of secondary chronic venous insufficiency (CVI)&#xD;
      that develops after a deep vein thrombosis (DVT). It affects up to 50% of patients after a&#xD;
      proximal DVT (i.e. DVT involving popliteal vein or more proximal veins), and 5-10% of&#xD;
      patients develop severe PTS. PTS is a chronic condition that reduces quality of life (QOL)&#xD;
      and for which no curative treatment is available. Cornerstones of PTS treatment include the&#xD;
      use of elastic compression stockings (ECS) to reduce leg symptoms and prevent PTS&#xD;
      progression. However, ECS are incompletely effective, burdensome and costly to patients.&#xD;
      Micronized Purified Flavonoid Fraction (MPFF, Venixxa), a venoactive drug, has been reported&#xD;
      to be effective in reducing venous symptoms and signs and improving QOL in patients with CVI&#xD;
      and has the potential to be effective for the treatment of PTS. Further, use of Venixxa is&#xD;
      safe, with only few very mild and reversible reported side effects. However, studies of MPFF&#xD;
      in patients with CVI have been of low to moderate quality, and there has been little use of&#xD;
      this drug in North America. In addition, the effectiveness of MPFF has never been&#xD;
      specifically evaluated in patients with PTS. Given that the pathophysiological mechanism of&#xD;
      PTS is complex and unique (combination of obstructive and reflux mechanisms as well as&#xD;
      inflammation), it is uncertain if MPFF is effective in patients with PTS, even if it may be&#xD;
      effective for CVI more generally.&#xD;
&#xD;
      The MUFFIN-PTS study will be a multicentre (8-10 centres), randomized, placebo-controlled&#xD;
      trial. Patients will be randomized (1:1 with stratification by centre) to receive 1000 mg of&#xD;
      oral MPFF (Venixxa, one 500mg tablet BID) or an identically appearing placebo (one tablet&#xD;
      BID) for 6 months, in addition to their usual PTS and DVT treatment (i.e. ECS and/or&#xD;
      anticoagulation, at their treating physician's discretion). Its objectives are to evaluate&#xD;
      the effectiveness and safety of MPFF (Venixxa) compared to placebo for the treatment of PTS.&#xD;
&#xD;
      86 patients with lower limb PTS will be enrolled in the study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">February 4, 2022</start_date>
  <completion_date type="Anticipated">December 31, 2023</completion_date>
  <primary_completion_date type="Anticipated">June 30, 2023</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Multicentre, randomized, placebo-controlled trial</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
    <masking_description>Double-blind placebo-controlled trial with oral placebo</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Change in PTS</measure>
    <time_frame>6 months</time_frame>
    <description>Improvement will be defined as a decrease of at least 30% in the Villalta score or a Villalta score &lt;5 in the PTS-affected leg.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Severity of PTS</measure>
    <time_frame>baseline, 3, 6 and 9 months</time_frame>
    <description>Villalta score category (mild, moderate, severe)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in PTS</measure>
    <time_frame>3 and 9 months</time_frame>
    <description>Improvement will be defined as a decrease of at least 30% in the Villalta score or a Villalta score &lt;5 in the PTS-affected leg.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Venous specific Quality of life</measure>
    <time_frame>3, 6 and 9 months</time_frame>
    <description>Venous-disease specific (VEINES-QOL) score</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>General Quality of life</measure>
    <time_frame>3, 6 and 9 months</time_frame>
    <description>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.&#xD;
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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serious Adverse Events (SAE)</measure>
    <time_frame>9 months</time_frame>
    <description>Includes drug-related SAE, DVT, Pulmonary Embolism (PE), death</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient compliance with treatment</measure>
    <time_frame>3 and 6 months</time_frame>
    <description>Judged satisfactory if at least 80% of the study drug was reportedly taken</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patients' overall satisfaction with treatment</measure>
    <time_frame>3 and 6 months</time_frame>
    <description>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)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Villalta score</measure>
    <time_frame>3, 6, 9 months</time_frame>
    <description>Villalta score assessed as a continuous variable (greater score indicates more severe disease, score range 0 to 33)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pain as a symptom of PTS</measure>
    <time_frame>3, 6, 9 months</time_frame>
    <description>Analyzed as individual component of Villalta score (0 absent to 3 severe)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cramps</measure>
    <time_frame>3, 6, 9 months</time_frame>
    <description>Analyzed as individual component of Villalta score (0 absent to 3 severe)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Heaviness</measure>
    <time_frame>3, 6, 9 months</time_frame>
    <description>Analyzed as individual component of Villalta score (0 absent to 3 severe)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Paresthesia</measure>
    <time_frame>3, 6, 9 months</time_frame>
    <description>Analyzed as individual component of Villalta score (0 absent to 3 severe)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pruritus</measure>
    <time_frame>3, 6, 9 months</time_frame>
    <description>Analyzed as individual component of Villalta score (0 absent to 3 severe)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pre-tibial edema</measure>
    <time_frame>3, 6, 9 months</time_frame>
    <description>Analyzed as individual component of Villalta score (0 absent to 3 severe)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hyperpigmentation</measure>
    <time_frame>3, 6, 9 months</time_frame>
    <description>Analyzed as individual component of Villalta score (0 absent to 3 severe)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Redness</measure>
    <time_frame>3, 6, 9 months</time_frame>
    <description>Analyzed as individual component of Villalta score (0 absent to 3 severe)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Skin induration</measure>
    <time_frame>3, 6, 9 months</time_frame>
    <description>Analyzed as individual component of Villalta score (0 absent to 3 severe)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Venous ectasia</measure>
    <time_frame>3, 6, 9 months</time_frame>
    <description>Analyzed as individual component of Villalta score (0 absent to 3 severe)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Venous Ulcer</measure>
    <time_frame>3, 6, 9 months</time_frame>
    <description>Analyzed as individual component of Villalta score (0 absent or 1 present)</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">86</enrollment>
  <condition>Post-Thrombotic Syndrome</condition>
  <arm_group>
    <arm_group_label>Venixxa</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Micronized Purified Flavonoid Fraction (MPFF) for 6 months MPFF 500 mg, BID (morning and evening) for 6 months</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo for 6 months&#xD;
1 Tablet, BID (morning and evening) for 6 months</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Micronized Purified Flavonoid Fraction</intervention_name>
    <description>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</description>
    <arm_group_label>Venixxa</arm_group_label>
    <other_name>Venixxa group</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>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</description>
    <arm_group_label>Placebo</arm_group_label>
    <other_name>Placebo group</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Villalta score ≥5 with at least two of the following four PTS manifestations (daily&#xD;
             heaviness, cramps, pain, and objective edema) in the leg ipsilateral to a previous&#xD;
             objectively diagnosed DVT, or DVT of unknown date but with presence of residual&#xD;
             proximal or distal venous obstruction on ultrasound. Females of childbearing age must&#xD;
             use medically approved method of birth control and must have negative pregnancy test&#xD;
             results at the time of randomization.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Recent acute ipsilateral DVT (&lt;3 months)&#xD;
&#xD;
          -  Active ipsilateral venous ulcer&#xD;
&#xD;
          -  Acute or chronic altered mental status&#xD;
&#xD;
          -  Any venoactive drug intake within 3 months of the start of the study&#xD;
&#xD;
          -  Allergy or hypersensitivity to MPFF/Venixxa&#xD;
&#xD;
          -  Age&lt;18 years&#xD;
&#xD;
          -  Pregnant or breastfeeding women&#xD;
&#xD;
          -  Life expectancy &lt;1 year&#xD;
&#xD;
          -  Refuse or unwilling to provide consent&#xD;
&#xD;
          -  Unable to speak English or French&#xD;
&#xD;
          -  Alcohol/drug abuse&#xD;
&#xD;
          -  Hospitalized patients&#xD;
&#xD;
          -  End-stage kidney disease (dialysis, creatinine clearance &lt; 10ml/min)&#xD;
&#xD;
          -  Liver cirrhosis Child-Pugh class C.&#xD;
&#xD;
          -  Currently enrolled in other clinical trials, other than trials of prevention or&#xD;
             treatment of venous thromboembolism&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Susan R Kahn, MD, MSc</last_name>
    <role>Principal Investigator</role>
    <affiliation>Jewish General Hospital (Montreal, Quebec, Canada)</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Jean-Philippe Galanaud, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Susan R Kahn, MD, MSc</last_name>
    <phone>514-340-8222</phone>
    <phone_ext>22790</phone_ext>
    <email>susan.kahn@mcgill.ca</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Jean-Philippe Galanaud, MD, PhD</last_name>
    <phone>514-340-8222</phone>
    <phone_ext>22790</phone_ext>
    <email>Jean-Philippe.Galanaud@sunnybrook.ca</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Vancouver General Hospital</name>
      <address>
        <city>Vancouver</city>
        <state>British Columbia</state>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Agnes Lee, MD</last_name>
      <phone>604-875-4863</phone>
      <email>alee14@bccancer.bc.ca</email>
    </contact>
    <contact_backup>
      <last_name>Mara Westendorp</last_name>
      <phone>604-875-4111</phone>
      <phone_ext>22948</phone_ext>
      <email>mara.westendorp@bccancer.bc.ca</email>
    </contact_backup>
    <investigator>
      <last_name>Agnes Lee, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Queen Elizabeth II Health Sciences Centre</name>
      <address>
        <city>Halifax</city>
        <state>Nova Scotia</state>
        <zip>B3H 3A7</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Sudeep Shivakumar, MD</last_name>
      <phone>902-473-8562</phone>
      <email>sudeep.shivakumar@nshealth.ca</email>
    </contact>
    <contact_backup>
      <last_name>Judy Richard</last_name>
      <email>judy.richard@nshealth.ca</email>
    </contact_backup>
    <investigator>
      <last_name>Sudeep Shivakumar, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Hamilton General Hospital</name>
      <address>
        <city>Hamilton</city>
        <state>Ontario</state>
        <zip>L8L 2X2</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Sam Schulman, MD</last_name>
      <phone>905-527-4322</phone>
      <phone_ext>44479</phone_ext>
      <email>schulms@mcmaster.ca</email>
    </contact>
    <contact_backup>
      <last_name>Michelle Zondag</last_name>
      <phone>905-527-4322</phone>
      <phone_ext>44807</phone_ext>
      <email>zondag@hhsc.ca</email>
    </contact_backup>
    <investigator>
      <last_name>Sam Schulman, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Ottawa Hospital Research Institute</name>
      <address>
        <city>Ottawa</city>
        <state>Ontario</state>
        <zip>K1Y 4E9</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Grégoire Le Gal, MD</last_name>
      <phone>613-737-8899</phone>
      <phone_ext>73034</phone_ext>
      <email>glegal@ohri.ca</email>
    </contact>
    <contact_backup>
      <last_name>Joseph Cyr</last_name>
      <phone>613 737 8899</phone>
      <phone_ext>73828</phone_ext>
      <email>joscyr@ohri.ca</email>
    </contact_backup>
    <investigator>
      <last_name>Grégoire Le Gal, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Sunnybrook Health Sciences Centre</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M4N 3M5</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jean-Philippe Galanaud, MD</last_name>
      <phone>416-480-6100</phone>
      <phone_ext>3056</phone_ext>
      <email>jean-philippe.galanaud@sunnybrook.ca</email>
    </contact>
    <contact_backup>
      <last_name>Barbara Huth</last_name>
      <phone>416-480-4298</phone>
      <email>Barbara.Huth@sunnybrook.ca</email>
    </contact_backup>
    <investigator>
      <last_name>Jean-Philippe Galanaud, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Toronto General Hospital</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5G 1Z5</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jameel Abdulrehman, MD</last_name>
      <phone>416-714-0194</phone>
      <email>jameel.abdulrehman@uhn.ca</email>
    </contact>
    <contact_backup>
      <last_name>Crystal Wang</last_name>
      <phone>(416) 946-4501</phone>
      <phone_ext>5868</phone_ext>
      <email>crystal.wang@uhn.ca</email>
    </contact_backup>
    <investigator>
      <last_name>Jameel Abdulrehman, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Sir Mortimer B. Davis - Jewish General Hospital</name>
      <address>
        <city>Montreal</city>
        <state>Quebec</state>
        <zip>H3T 1E2</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Susan R. Kahn, M.D., M.Sc.</last_name>
      <phone>514-340-8222</phone>
      <phone_ext>24667</phone_ext>
    </contact>
    <investigator>
      <last_name>Susan R. Kahn, M.D., M.Sc.</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <reference>
    <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>
    <PMID>29459016</PMID>
  </reference>
  <reference>
    <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>
    <PMID>29545327</PMID>
  </reference>
  <reference>
    <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.</citation>
    <PMID>25246013</PMID>
  </reference>
  <reference>
    <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>
    <PMID>28844444</PMID>
  </reference>
  <reference>
    <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>
    <PMID>22315114</PMID>
  </reference>
  <reference>
    <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>
    <PMID>27048768</PMID>
  </reference>
  <reference>
    <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. Erratum In: Phlebology. 2017 Dec;32(10 ):NP36.</citation>
    <PMID>28211296</PMID>
  </reference>
  <reference>
    <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>
    <PMID>25972136</PMID>
  </reference>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>January 30, 2019</study_first_submitted>
  <study_first_submitted_qc>February 5, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 6, 2019</study_first_posted>
  <last_update_submitted>February 15, 2023</last_update_submitted>
  <last_update_submitted_qc>February 15, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 17, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Sir Mortimer B. Davis - Jewish General Hospital</investigator_affiliation>
    <investigator_full_name>Dr. Susan Kahn</investigator_full_name>
    <investigator_title>Professor of Medicine</investigator_title>
  </responsible_party>
  <keyword>deep vein thrombosis</keyword>
  <keyword>chronic venous insufficiency</keyword>
  <keyword>venoactive drug</keyword>
  <keyword>Micronized Purified Flavonoid Fraction</keyword>
  <keyword>DVT</keyword>
  <keyword>post thrombotic syndrome</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Postthrombotic Syndrome</mesh_term>
    <mesh_term>Postphlebitic Syndrome</mesh_term>
    <mesh_term>Syndrome</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_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</ipd_description>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03833024
org study id: 332593-S1
nct id: NCT03833024
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
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.
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.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Multicentre, randomized, placebo-controlled trial
primary purpose: Treatment
masking: Triple (Participant, Investigator, Outcomes Assessor)
masking description: Double-blind placebo-controlled trial with oral placebo
measure: Change in PTS
time frame: 6 months
description: 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.
measure: Severity of PTS
time frame: baseline, 3, 6 and 9 months
description: Villalta score category (mild, moderate, severe)
measure: Change in PTS
time frame: 3 and 9 months
description: 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.
measure: Venous specific Quality of life
time frame: 3, 6 and 9 months
description: Venous-disease specific (VEINES-QOL) score
measure: General Quality of life
time frame: 3, 6 and 9 months
description: 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.
measure: Serious Adverse Events (SAE)
time frame: 9 months
description: Includes drug-related SAE, DVT, Pulmonary Embolism (PE), death
measure: Patient compliance with treatment
time frame: 3 and 6 months
description: Judged satisfactory if at least 80% of the study drug was reportedly taken
measure: Patients' overall satisfaction with treatment
time frame: 3 and 6 months
description: 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)
measure: Villalta score
time frame: 3, 6, 9 months
description: Villalta score assessed as a continuous variable (greater score indicates more severe disease, score range 0 to 33)
measure: Pain as a symptom of PTS
time frame: 3, 6, 9 months
description: Analyzed as individual component of Villalta score (0 absent to 3 severe)
measure: Cramps
time frame: 3, 6, 9 months
description: Analyzed as individual component of Villalta score (0 absent to 3 severe)
measure: Heaviness
time frame: 3, 6, 9 months
description: Analyzed as individual component of Villalta score (0 absent to 3 severe)
measure: Paresthesia
time frame: 3, 6, 9 months
description: Analyzed as individual component of Villalta score (0 absent to 3 severe)
measure: Pruritus
time frame: 3, 6, 9 months
description: Analyzed as individual component of Villalta score (0 absent to 3 severe)
measure: Pre-tibial edema
time frame: 3, 6, 9 months
description: Analyzed as individual component of Villalta score (0 absent to 3 severe)
measure: Hyperpigmentation
time frame: 3, 6, 9 months
description: Analyzed as individual component of Villalta score (0 absent to 3 severe)
measure: Redness
time frame: 3, 6, 9 months
description: Analyzed as individual component of Villalta score (0 absent to 3 severe)
measure: Skin induration
time frame: 3, 6, 9 months
description: Analyzed as individual component of Villalta score (0 absent to 3 severe)
measure: Venous ectasia
time frame: 3, 6, 9 months
description: Analyzed as individual component of Villalta score (0 absent to 3 severe)
measure: Venous Ulcer
time frame: 3, 6, 9 months
description: Analyzed as individual component of Villalta score (0 absent or 1 present)
arm group label: Venixxa
arm group type: Active Comparator
description: Micronized Purified Flavonoid Fraction (MPFF) for 6 months MPFF 500 mg, BID (morning and evening) for 6 months
arm group label: Placebo
arm group type: Placebo Comparator
description: Placebo for 6 months
1 Tablet, BID (morning and evening) for 6 months
intervention type: Drug
intervention name: Micronized Purified Flavonoid Fraction
description: 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
arm group label: Venixxa
other name: Venixxa group
intervention type: Drug
intervention name: Placebo
description: 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
arm group label: Placebo
other name: Placebo group
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Susan R Kahn, MD, MSc
role: Principal Investigator
affiliation: Jewish General Hospital (Montreal, Quebec, Canada)
last name: Jean-Philippe Galanaud, MD, PhD
role: Principal Investigator
affiliation: Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
last name: Susan R Kahn, MD, MSc
phone: 514-340-8222
phone ext: 22790
email: susan.kahn@mcgill.ca
last name: Jean-Philippe Galanaud, MD, PhD
phone: 514-340-8222
phone ext: 22790
email: Jean-Philippe.Galanaud@sunnybrook.ca
facility: 
status: Recruiting
contact: 
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country: Canada
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.
PMID: 29459016
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.
PMID: 29545327
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.
PMID: 25246013
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.
PMID: 28844444
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.
PMID: 22315114
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.
PMID: 27048768
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. Erratum In: Phlebology. 2017 Dec;32(10 ):NP36.
PMID: 28211296
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.
PMID: 25972136
responsible party type: Principal Investigator
investigator affiliation: Sir Mortimer B. Davis - Jewish General Hospital
investigator full name: Dr. Susan Kahn
investigator title: Professor of Medicine
mesh term: Postthrombotic Syndrome
mesh term: Postphlebitic Syndrome
mesh term: Syndrome
sharing ipd: No
ipd 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