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

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

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.

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.

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.