Immunosuppressive Therapy Alone Versus Plus Oral Anticoagulation in the Treatment of VT Associated With Behcet's Disease (BETTER)

Immunosuppressive Therapy Alone Versus Immunosuppressive Therapy Plus Oral Anticoagulation in the Treatment of Lower Extremity Venous Thrombosis Associated With Behcet's Disease

This study is a Phase III, multicenter, prospective, randomized, double-blind, placebo-controlled clinical trial investigating the treatment of lower extremity venous thrombosis associated with Behçet's Disease. The study compares the effectiveness and safety of immunosuppressive therapy alone versus immunosuppressive therapy combined with oral anticoagulation (Rivaroxaban).

Study Overview

• Status: Not yet recruiting
• Conditions: Post Thrombotic Syndrome; Behcet Disease; Deep Venous Thromboses; Behcet Disease and Vascular Involvement
• Intervention / Treatment: Drug: Placebo plus immunosuppression; Drug: Rivaroxaban plus immunosupression

Detailed Description

Behçet's Disease is a systemic inflammatory disorder that can cause vascular complications, including venous thrombosis. Although immunosuppressive therapy is the standard treatment for vascular involvement, the role of anticoagulation remains controversial. This study aims to evaluate whether adding Rivaroxaban to standard immunosuppressive treatment reduces the risk of thrombotic relapse and post-thrombotic syndrome compared to immunosuppressive therapy alone.

This study is a Phase III, multicenter, prospective, randomized, double-blind, placebo-controlled clinical trial investigating the treatment of lower extremity venous thrombosis associated with Behçet's Disease. The study compares the effectiveness and safety of immunosuppressive therapy alone versus immunosuppressive therapy combined with oral anticoagulation (Rivaroxaban).

The study will recruit patients aged 18-50 who have been diagnosed with Behçet's Disease according to International Study Group (ISG) criteria and have a newly diagnosed lower extremity venous thrombosis. Participants will be randomized (1:1) to receive either immunosuppressive therapy with Rivaroxaban or immunosuppressive therapy with a placebo. The treatment duration is 12 months, with follow-up visits at weeks 2, 4, months 2, 3, 6, 9, and 12.

The primary outcome is the rate of thrombotic relapse within 52 weeks, assessed by venous Doppler ultrasound. Secondary outcomes include the development of post-thrombotic syndrome (PTS), quality of life measures, and safety assessments, including bleeding complications.

The study is sponsored by Health Institutes of Türkiye (TÜSEB) and coordinated by Marmara University, Türkiye. Ethics approval has been obtained from Marmara University Clinical Research Ethics Committee.

For further information, please contact the study coordinators.

• Study Type: Interventional
• Enrollment (Estimated): 110
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Fatma Alibaz-Oner, Prof; Phone Number: +90 216 625 45 45; Email: falibaz@gmail.com

Study Locations

• Turkey
  • Istanbul, Turkey
    • Marmara University
  • Istanbul, Turkey
    • Marmara University, School of Medicine, Division of Rheumatology
    • Contact: Email: falibaz@gmail.com
    • Contact: Fatma Alibaz Oner, Prof
    • Contact: Kerem Abacar, MD
    • Contact: Haner Direskeneli, Prof
    • Contact: Ahmet Gül, Prof
    • Contact: Cemal Bes, Prof
    • Contact: Ayten Yazici, Prof
    • Contact: Ömer Karadağ, Prof
    • Contact: Mehmet Akif Öztürk, Prof
    • Contact: Ahmet Omma, Ass. Prof

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Participants must meet the following criteria to be eligible for the study:

Age between 18-50 years old. Diagnosed with Behçet's Disease according to the International Study Group (ISG) criteria.

No prior vascular involvement or no previous immunosuppressive therapy for vascular involvement.

Confirmed venous thrombosis in the lower extremity within the last 14 days before randomization.

Venous thrombosis diagnosis confirmed by:

Non-compressible venous segment in ultrasound, OR A significant (>4 mm) increase in thrombus diameter in an already abnormal segment, OR New intraluminal filling defect on venography, CT, or MR angiography.

Female participants must:

Not be pregnant or breastfeeding. Use effective contraception if of childbearing potential. Be postmenopausal (no menses for at least 1 year) or have undergone surgical sterilization.

Ability to provide written informed consent and comply with study requirements.

Exclusion Criteria:

• Participants will be excluded if they meet any of the following criteria:

Presence of any aneurysm. Chronic multisystemic disease other than Behçet's Disease. History of intolerance to Rivaroxaban. Use of immunosuppressive drugs (azathioprine, mycophenolate mofetil, cyclosporine, cyclophosphamide, TNF inhibitors, or interferon-gamma) within the last 6 months.

Prolonged corticosteroid use (>3 months) for Behçet's Disease mucocutaneous symptoms.

Prior anticoagulant therapy:

Low molecular weight heparin, fondaparinux, or unfractionated heparin for >48 hours before randomization.

More than one dose of vitamin K antagonists before randomization. Thrombectomy, vena cava filter placement, or fibrinolytic therapy for the current thrombotic episode.

Planned administration of a live vaccine within 30 days after randomization. Clinically significant acute or uncontrolled chronic diseases (e.g., cardiovascular, pulmonary, hematologic, gastrointestinal, hepatic, renal, neurological, malignancy, or infectious diseases) that may interfere with study results.

Planned surgical procedure or significant medical condition deemed unsuitable for the study by the investigator.

History of malignancy within the last 5 years (except adequately treated basal or squamous cell carcinoma or carcinoma in situ of the cervix).

Renal impairment (Creatinine clearance <30 ml/min). Severe liver disease (e.g., acute hepatitis, active chronic hepatitis, cirrhosis, or ALT >3 times the upper limit).

Active bleeding or high bleeding risk contraindicating anticoagulant therapy. Uncontrolled hypertension (SBP >180 mmHg or DBP >110 mmHg). Severe anemia (Hemoglobin <10 mg/dL). Women who are pregnant, breastfeeding, or of childbearing potential without contraception.

Use of strong CYP3A4 inhibitors or inducers (e.g., protease inhibitors, systemic ketoconazole, rifampin, carbamazepine, phenytoin).

Participation in another experimental drug study within the last 30 days. Life expectancy of less than 3 months. History of serious infections within the last 60 days (e.g., bacterial endocarditis, tuberculosis, opportunistic infections).

Active substance or alcohol abuse or history of substance dependence within the last year.

Positive screening for Hepatitis B surface antigen, Hepatitis C antibody, or known HIV-1 infection.

Known coagulation disorders or laboratory abnormalities (e.g., DMID toxicity scale Grade 3 or higher).

History of suicidal behavior in the last 6 months or suicidal ideation (C-SSRS type 4 or 5) in the last 2 months.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Immunosuppressive Therapy + Placebo; Azathioprine (2.5 mg/kg/day, maximum 200 mg/day, oral) Methylprednisolone (0.5 mg/kg/day, oral, tapered over 12 weeks according to protocol) + Placebo	Drug: Placebo plus immunosuppression; Participants in this arm will receive placebo plus standard immunosuppressive therapy consisting of: Azathioprine (2.5 mg/kg/day, maximum 200 mg/day, oral) Methylprednisolone (0.5 mg/kg/day, oral, tapered over 12 weeks according to protocol) This intervention represents the standard treatment for venous thrombosis associated with Behçet's Disease and serves as the control arm of the study.
Active Comparator: Immunosuppressive Therapy + Rivaroxaban; Azathioprine (2.5 mg/kg/day, maximum 200 mg/day, oral) Methylprednisolone (0.5 mg/kg/day, oral, tapered over 12 weeks according to protocol), plus Rivaroxaban (20 mg/day, oral, for 12 months)	Drug: Rivaroxaban plus immunosupression; Participants in this arm will receive standard immunosuppressive therapy as described above, plus Rivaroxaban (20 mg/day, oral, for 12 months). This intervention aims to evaluate whether the addition of oral anticoagulation (Rivaroxaban) to immunosuppressive therapy reduces the risk of thrombotic relapse and post-thrombotic syndrome compared to immunosuppressive therapy alone.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Thrombotic Relapse at 52 Weeks	The primary outcome is the rate of thrombotic relapse within 52 weeks, assessed via lower extremity venous Doppler ultrasound. Thrombotic relapse is defined as: A new thrombotic event in a previously unaffected ipsilateral or contralateral vein. Re-thrombosis in a previously affected vein that was classified as well-recanalized (≥50% compressibility on Doppler ultrasound). Venous Doppler ultrasound assessments will be performed at baseline, months 1, 3, 6, 9, and 12.	52 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Development of Post-Thrombotic Syndrome (PTS) at 52 Weeks	The occurrence of Post-Thrombotic Syndrome (PTS) will be assessed using standardized clinical scoring systems, including: Villalta Scale (PTS severity assessment) Venous Clinical Severity Score (VCSS) Venous Disability Score (VDS) Venous Insufficiency Epidemiological and Economic Study Quality of Life (VEINES-QOL) PTS is defined as a Villalta score ≥5 or the presence of a venous ulcer.	52 weeks
Rate of Venous Recanalization at 52 Weeks	Venous recanalization will be assessed via Doppler ultrasound to evaluate the extent of clot resolution in affected veins. Partial or complete recanalization will be determined based on compressibility and flow characteristics. Measured at baseline, months 1, 3, 6, 9, and 12.	52 weeks
Incidence of Major and Clinically Relevant Non-Major Bleeding Events	The frequency of major bleeding (as per ISTH criteria) and clinically relevant non-major bleeding will be recorded. Major bleeding: 2.0 g/dL hemoglobin drop; 2 units of red blood cell transfusion Intracranial, retroperitoneal, or fatal bleeding Clinically relevant non-major bleeding: Epistaxis >5 minutes, spontaneous hematomas >25 cm², gastrointestinal bleeding not meeting major criteria.	52 weeks

Collaborators and Investigators

• Sponsor: Marmara University
• Collaborators: Health Institutes of Turkey
• Investigators: Principal Investigator: Fatma Alibaz-Oner, Prof, Marmara University

Study record dates

Study Major Dates

• Study Start (Estimated): April 30, 2025
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): April 1, 2028

Study Registration Dates

• First Submitted: April 7, 2025
• First Submitted That Met QC Criteria: April 7, 2025
• First Posted (Actual): April 13, 2025

Study Record Updates

• Last Update Posted (Actual): April 13, 2025
• Last Update Submitted That Met QC Criteria: April 7, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: Rivaroxaban; Deep venous thrombosis; Behcet's disease; Anticoagulant therapy
• Additional Relevant MeSH Terms: Mouth Diseases; Stomatognathic Diseases; Vascular Diseases; Cardiovascular Diseases; Genetic Diseases, Inborn; Eye Diseases; Embolism and Thrombosis; Skin Diseases; Skin Diseases, Vascular; Skin Diseases, Genetic; Peripheral Vascular Diseases; Uveal Diseases; Vasculitis; Panuveitis; Venous Insufficiency; Phlebitis; Uveitis, Anterior; Uveitis; Hereditary Autoinflammatory Diseases; Thrombosis; Venous Thrombosis; Postthrombotic Syndrome; Postphlebitic Syndrome; Behcet Syndrome; Molecular Mechanisms of Pharmacological Action; Protease Inhibitors; Enzyme Inhibitors; Anticoagulants; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Rivaroxaban
• Other Study ID Numbers: 09.2023.1733

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data (IPD) will not be shared to ensure patient confidentiality and compliance with data protection regulations

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No