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Efficacy and Safety of Coumarin and Troxerutin in the Symptomatic Treatment of Chronic Venous Insufficiency

Primary Purpose

Chronic Venous Insufficiency

Status
Completed
Phase
Phase 4
Locations
Study Type
Interventional
Intervention
Coumarin/troxerutin
Placebo
Sponsored by
Takeda
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Venous Insufficiency focused on measuring Drug therapy

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Consent of subject or legal representative
  2. Men or women of any ethnicity, aged between 18 and 75 years, and body mass index (BMI) equal or less than 40.
  3. Is able to use properly the medication according to protocol.
  4. Has chronic venous insufficiency in the reference leg with the clinical classification C3, or C4a orC4b or C5, provided that in two last situations the present lipodermatosclerosis does not compromise more than 1/3 portion of the leg immersed or immersible in the plethysmometer.
  5. Has stable edema (in a steady state), equivalent to a variation lower than or equal to 10% in partial volume of the reference leg between the screening visit and the randomization visit, and present for at least 6 months.
  6. Scoring in "Severity Score of Local Complaints" equal to or higher than 5 total points.
  7. Women who are using an effective (at the discretion of the investigator), but not hormonal, birth control method (not hormonal intrauterine device (IUD), surgical sterilization, among others), or who are postmenopausal, in addition to condom use (mandatory).

Exclusion Criteria:

  1. Has chronic venous insufficiency classified as C1, C2 in the reference leg or C6 in any leg.
  2. Has chronic venous insufficiency C4b or C5 in the reference leg, with lipodermatosclerosis present in more than 1/3 portion of the leg immersed in the plethysmometer.
  3. Has unstable edema, equivalent to variation of more than 10% of partial volume in the reference leg between the screening visit and randomization visit, prior to start of treatment.
  4. Has venous obstruction and/or deep vein thrombosis (DVT) and/or presence of phlebitis in lower limbs during the last 3 (three) months.
  5. Has developed deep vein insufficiency during the last 3 (three) months.
  6. Has other diseases that may interfere in the findings of the study such as: lymphedema, thrombosis, clotting disorders, edema of lower limbs due to right-sided heart failure, arterial obstruction of lower limbs and other conditions that, at medical discretion, are relevant to exclusion, particularly symptoms which are similar to the symptomatology of chronic venous insufficiency.
  7. Has a history of surgery at the venous system or sclerotherapy or who received any treatment for chronic venous insufficiency during the last 03 months, whether it was by drug, elastic stocking, laser, or surgery.
  8. Has used previously Venalot® and had no benefits with the treatment.
  9. Has a previous history of known or suspected allergy or intolerance to any of the ingredients of the medicinal product under investigation.
  10. Has any clinical finding (history and physical examination) that is interpreted by the physician-investigator as a risk to participant's participation in the study.
  11. Has known serious systemic disease, according to the medical and/or laboratory history.
  12. Has history of a known liver disease such as hepatitis A, hepatitis B, or C.
  13. Has changed at least one lab parameters: aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase (gamma-GT), or alkaline phosphatase 2.5 times above the upper limit of normal range; hemoglobin less than 10 g/dL; clearance of creatinine estimative equal or above 60mL/min/1.73 m^2; platelets below 90,000/mL; and total bilirubin and fractions 1.5 times above the normal values.
  14. Has been using diuretics for a period less than or equal to 6 months due to any disease (hypertension, renal failure, or other).
  15. Has serious chronic liver or kidney disease, according to the medical and/or laboratory history.
  16. Has uncontrolled blood hypertension (systolic blood pressure > 180 mmHg or diastolic blood pressure > 100 mmHg) at randomization or clinical hypertensive urgency.
  17. Has a previous history of diabetes mellitus on use of insulin.
  18. Has received treatment with immunosuppressive drugs, including systemic corticosteroids within 30 days before the start of study (randomization visit), or who are receiving immunosuppressive treatments, or who have known congenital or acquired immunodeficiency.
  19. Has malignant neoplasms, from any etiology, or who are receiving any type of anticancer treatment, unless when properly treated and with no evidence of recurrence during the last five years. Non-melanoma skin cancer is not an exclusion criterion.
  20. Is unable to understand the guidelines specified in this protocol or who cannot attend all the study visits.
  21. Has a previous history of alcoholism, drug abuse, psychological or emotional problems in the last 5 years that can invalidate the Informed Consent Form or restrain participant's ability to comply with the requirements of the protocol.
  22. Pregnant or breastfeeding women, or those who have the potential to become pregnant and are not using an appropriate contraceptive method.
  23. Women who are using hormonal contraceptives or hormone replacement treatment, including phytoestrogens, within the last 3 months.
  24. Took part in clinical trials during the last year.

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Experimental

    Placebo Comparator

    Arm Label

    Coumarin 30 mg + Troxerutin 180 mg

    Placebo

    Arm Description

    Coumarin 30 mg, troxerutin 180 mg fixed-dose combination tablets, orally, three times daily for up to 16 weeks.

    Coumarin + troxerutin placebo-matching tablets, orally, three times daily for up to 16 weeks.

    Outcomes

    Primary Outcome Measures

    Mean Change (Reduction) From Baseline in Volume of Reference Leg at Week 16
    Change in the partial volume of legs will be measured using a water plethysmometer. The volume of water (at 34 ± 0.2 °C) displaced after limb immersion is collected in an empty plastic Beaker which has been previously weighed (scale tare). The equilibrium/stability will be estimated using the absolute difference between measures of volume obtained at the Week 16 visit and Baseline to determine the reduction in edema.

    Secondary Outcome Measures

    Change (Reduction) From Baseline in Local Complaint Severity
    Local Complaint Severity will be assessed using the Severity Score of Local Complaints that comprises 8 items: 1=tired legs, 2=heavy legs, 3= feeling of tension, 4=feeling of swelling, 5=aching legs, 6=tingling, 7=itching, 8=burning of soles of the feet. Each item is classified with a Likert-type scale of 5 levels, where 0=absent, 1=low, 2=medium, 3=high, 4=very high. A total score is calculated from the sum of the scores of all the 8 items and ranges from 0 (complaints absent) to 32 (very high severity).
    Overall Assessment by the Investigator
    The investigator recorded their impression of the overall clinical picture at the end of the treatment period (Week 16), taking into account the clinical picture compared with the Baseline visit. Data is reported for the percentage of participants in each of the following assessment categories: worsening, unchanged, discreet improvement or accentuated improvement.
    Number of Participants With Adverse Events (AEs)
    Adverse events are any unwanted medical occurrences in an individual taking part in a clinical study who is receiving a pharmaceutical product. The adverse event does not have necessarily a causal relationship with the treatment. In this definition, any adverse or unwanted signals and symptoms, or findings that appear from the start or that deteriorate during the clinical study are also included, i.e. any intercurrent diseases (recently diagnosed concomitant diseases or symptoms), accidents and clinically relevant changes in clinical laboratory values.

    Full Information

    First Posted
    May 2, 2013
    Last Updated
    September 21, 2016
    Sponsor
    Takeda
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    1. Study Identification

    Unique Protocol Identification Number
    NCT01848210
    Brief Title
    Efficacy and Safety of Coumarin and Troxerutin in the Symptomatic Treatment of Chronic Venous Insufficiency
    Official Title
    Evaluation of Efficacy and Safety of the Fixed-dose Combination of Coumarin and Troxerutin (Venalot®) Versus Placebo in the Symptomatic Treatment of Chronic Venous Insufficiency - VENACT
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    September 2016
    Overall Recruitment Status
    Completed
    Study Start Date
    May 2013 (undefined)
    Primary Completion Date
    September 2015 (Actual)
    Study Completion Date
    September 2015 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Takeda

    4. Oversight

    Data Monitoring Committee
    No

    5. Study Description

    Brief Summary
    The purpose of this study is to evaluate the efficacy and safety of the fixed-dose combination of coumarin and troxerutin versus placebo in the symptomatic treatment of chronic venous insufficiency.
    Detailed Description
    The drug being tested in this study is the fixed-dose combination of coumarin and troxerutin called Venalot®. Venalot is being tested to treat the symptoms of chronic venous insufficiency. This study will look at symptom relief in people who take Venalot®. The study will enroll approximately 808 patients. Participants will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups-which will remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need): Combination coumarin + troxerutin extended release tablets Placebo (dummy inactive pill) - this is a tablet that looks like the study drug but has no active ingredient. All participants will be asked to take two tablets three times a day throughout the study. This multi-centre trial will be conducted in Brazil. The overall time to participate in this study is up to 18 weeks. Participants will make 6 visits to the clinic.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Chronic Venous Insufficiency
    Keywords
    Drug therapy

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 4
    Interventional Study Model
    Parallel Assignment
    Masking
    ParticipantCare ProviderInvestigatorOutcomes Assessor
    Allocation
    Randomized
    Enrollment
    829 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Coumarin 30 mg + Troxerutin 180 mg
    Arm Type
    Experimental
    Arm Description
    Coumarin 30 mg, troxerutin 180 mg fixed-dose combination tablets, orally, three times daily for up to 16 weeks.
    Arm Title
    Placebo
    Arm Type
    Placebo Comparator
    Arm Description
    Coumarin + troxerutin placebo-matching tablets, orally, three times daily for up to 16 weeks.
    Intervention Type
    Drug
    Intervention Name(s)
    Coumarin/troxerutin
    Other Intervention Name(s)
    Venalot®
    Intervention Description
    Coumarin + troxerutin fixed-dose combination tablets
    Intervention Type
    Drug
    Intervention Name(s)
    Placebo
    Intervention Description
    Coumarin + troxerutin placebo-matching tablets
    Primary Outcome Measure Information:
    Title
    Mean Change (Reduction) From Baseline in Volume of Reference Leg at Week 16
    Description
    Change in the partial volume of legs will be measured using a water plethysmometer. The volume of water (at 34 ± 0.2 °C) displaced after limb immersion is collected in an empty plastic Beaker which has been previously weighed (scale tare). The equilibrium/stability will be estimated using the absolute difference between measures of volume obtained at the Week 16 visit and Baseline to determine the reduction in edema.
    Time Frame
    Baseline and Week 16
    Secondary Outcome Measure Information:
    Title
    Change (Reduction) From Baseline in Local Complaint Severity
    Description
    Local Complaint Severity will be assessed using the Severity Score of Local Complaints that comprises 8 items: 1=tired legs, 2=heavy legs, 3= feeling of tension, 4=feeling of swelling, 5=aching legs, 6=tingling, 7=itching, 8=burning of soles of the feet. Each item is classified with a Likert-type scale of 5 levels, where 0=absent, 1=low, 2=medium, 3=high, 4=very high. A total score is calculated from the sum of the scores of all the 8 items and ranges from 0 (complaints absent) to 32 (very high severity).
    Time Frame
    Baseline and Week 16
    Title
    Overall Assessment by the Investigator
    Description
    The investigator recorded their impression of the overall clinical picture at the end of the treatment period (Week 16), taking into account the clinical picture compared with the Baseline visit. Data is reported for the percentage of participants in each of the following assessment categories: worsening, unchanged, discreet improvement or accentuated improvement.
    Time Frame
    Baseline and Week 16
    Title
    Number of Participants With Adverse Events (AEs)
    Description
    Adverse events are any unwanted medical occurrences in an individual taking part in a clinical study who is receiving a pharmaceutical product. The adverse event does not have necessarily a causal relationship with the treatment. In this definition, any adverse or unwanted signals and symptoms, or findings that appear from the start or that deteriorate during the clinical study are also included, i.e. any intercurrent diseases (recently diagnosed concomitant diseases or symptoms), accidents and clinically relevant changes in clinical laboratory values.
    Time Frame
    Baseline to Week 16

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Maximum Age & Unit of Time
    75 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Consent of subject or legal representative Men or women of any ethnicity, aged between 18 and 75 years, and body mass index (BMI) equal or less than 40. Is able to use properly the medication according to protocol. Has chronic venous insufficiency in the reference leg with the clinical classification C3, or C4a orC4b or C5, provided that in two last situations the present lipodermatosclerosis does not compromise more than 1/3 portion of the leg immersed or immersible in the plethysmometer. Has stable edema (in a steady state), equivalent to a variation lower than or equal to 10% in partial volume of the reference leg between the screening visit and the randomization visit, and present for at least 6 months. Scoring in "Severity Score of Local Complaints" equal to or higher than 5 total points. Women who are using an effective (at the discretion of the investigator), but not hormonal, birth control method (not hormonal intrauterine device (IUD), surgical sterilization, among others), or who are postmenopausal, in addition to condom use (mandatory). Exclusion Criteria: Has chronic venous insufficiency classified as C1, C2 in the reference leg or C6 in any leg. Has chronic venous insufficiency C4b or C5 in the reference leg, with lipodermatosclerosis present in more than 1/3 portion of the leg immersed in the plethysmometer. Has unstable edema, equivalent to variation of more than 10% of partial volume in the reference leg between the screening visit and randomization visit, prior to start of treatment. Has venous obstruction and/or deep vein thrombosis (DVT) and/or presence of phlebitis in lower limbs during the last 3 (three) months. Has developed deep vein insufficiency during the last 3 (three) months. Has other diseases that may interfere in the findings of the study such as: lymphedema, thrombosis, clotting disorders, edema of lower limbs due to right-sided heart failure, arterial obstruction of lower limbs and other conditions that, at medical discretion, are relevant to exclusion, particularly symptoms which are similar to the symptomatology of chronic venous insufficiency. Has a history of surgery at the venous system or sclerotherapy or who received any treatment for chronic venous insufficiency during the last 03 months, whether it was by drug, elastic stocking, laser, or surgery. Has used previously Venalot® and had no benefits with the treatment. Has a previous history of known or suspected allergy or intolerance to any of the ingredients of the medicinal product under investigation. Has any clinical finding (history and physical examination) that is interpreted by the physician-investigator as a risk to participant's participation in the study. Has known serious systemic disease, according to the medical and/or laboratory history. Has history of a known liver disease such as hepatitis A, hepatitis B, or C. Has changed at least one lab parameters: aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase (gamma-GT), or alkaline phosphatase 2.5 times above the upper limit of normal range; hemoglobin less than 10 g/dL; clearance of creatinine estimative equal or above 60mL/min/1.73 m^2; platelets below 90,000/mL; and total bilirubin and fractions 1.5 times above the normal values. Has been using diuretics for a period less than or equal to 6 months due to any disease (hypertension, renal failure, or other). Has serious chronic liver or kidney disease, according to the medical and/or laboratory history. Has uncontrolled blood hypertension (systolic blood pressure > 180 mmHg or diastolic blood pressure > 100 mmHg) at randomization or clinical hypertensive urgency. Has a previous history of diabetes mellitus on use of insulin. Has received treatment with immunosuppressive drugs, including systemic corticosteroids within 30 days before the start of study (randomization visit), or who are receiving immunosuppressive treatments, or who have known congenital or acquired immunodeficiency. Has malignant neoplasms, from any etiology, or who are receiving any type of anticancer treatment, unless when properly treated and with no evidence of recurrence during the last five years. Non-melanoma skin cancer is not an exclusion criterion. Is unable to understand the guidelines specified in this protocol or who cannot attend all the study visits. Has a previous history of alcoholism, drug abuse, psychological or emotional problems in the last 5 years that can invalidate the Informed Consent Form or restrain participant's ability to comply with the requirements of the protocol. Pregnant or breastfeeding women, or those who have the potential to become pregnant and are not using an appropriate contraceptive method. Women who are using hormonal contraceptives or hormone replacement treatment, including phytoestrogens, within the last 3 months. Took part in clinical trials during the last year.
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Medical Director
    Organizational Affiliation
    Takeda
    Official's Role
    Study Director

    12. IPD Sharing Statement

    Citations:
    PubMed Identifier
    33141449
    Citation
    Martinez-Zapata MJ, Vernooij RW, Simancas-Racines D, Uriona Tuma SM, Stein AT, Moreno Carriles RMM, Vargas E, Bonfill Cosp X. Phlebotonics for venous insufficiency. Cochrane Database Syst Rev. 2020 Nov 3;11(11):CD003229. doi: 10.1002/14651858.CD003229.pub4.
    Results Reference
    derived

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    Efficacy and Safety of Coumarin and Troxerutin in the Symptomatic Treatment of Chronic Venous Insufficiency

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