Tinzaparin Lead-In to Prevent the Post-Thrombotic Syndrome

Study Overview
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Brief Summary
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The TILE pilot study will be a multicenter, open-label, assessor-blinded RCT (randomized control trial) comparing extended LMWH (Low Molecular Weight Heparin) vs. DOAC (Direct Oral Anticoagulants) to PTS (prevent post thrombotic syndrome) in patients with DVT (Deep Vein Thrombosis).

Detailed Description
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The TILE pilot study will investigate the magnitude of difference in effectiveness between LMWH (low molecular weight heparin, tinzaparin) plus DOAC (Direct Oral Anticoagulants, rivaroxaban) vs. DOAC alone to determine the sample size and assess feasibility for a larger study assessing the effectiveness of an initial 3-week lead-in course of LMWH (tinzaparin) compared to DOAC alone (rivaroxaban) in patients with proximal DVT (Deep Vein Thrombosis) at high risk of developing PTS (Post-Thrombotic Syndrome). PTS is a frequent, costly and burdensome complication of DVT, especially for patients with iliac or femoral vein DVT who have a high risk of developing PTS and severe PTS. Anticoagulant therapy appears to influence this risk, with a higher frequency of PTS in patients with DVT who receive suboptimal treatment with a VKA (Vitamin K Antagonist). DOAC are expected to avoid this and other limitations of VKA therapy and have become the standard of care for patients with DVT. Extended treatment of DVT with LMWH, by providing more effective anticoagulation and by reducing inflammation, appears to restore venous patency and reduce venous reflux compared to VKA and probably to DOAC. Extended treatment of DVT with LMWH, therefore, has the potential to reduce PTS.

Official Title
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Tinzaparin Lead-In to Prevent the Post-Thrombotic Syndrome Phase IV Pilot Study

Conditions
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Deep Vein Thrombosis, Post Thrombotic Syndrome

Intervention / Treatment
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* Drug: tinzaparin
* Drug: Rivaroxaban


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Patients with objectively confirmed acute (i.e. onset of symptoms <10 days) symptomatic iliac or common femoral DVT (DVT diagnosis will be made with a Compression Ultrasound (CUS) according to standardized consensus criteria) Exclusion Criteria: Age < 18 years History of ipsilateral DVT (distal and/or proximal) Active cancer Thrombolysis or other invasive early thrombus removal technique to treat DVT or PE Pregnant or breast feeding Impaired renal function (creatinine clearance < 30 ml/min according to Cockcroft-Gault formula) Concomitant use of drugs that interact with rivaroxaban (i.e. keto- or itraconazole, ritonavir) Allergy or hypersensitivity to heparin or rivaroxaban, including heparin induced thrombocytopenia Anticoagulant therapy contraindicated because of presence of active bleeding or condition with high risk of bleeding (e.g. peptic ulcer, acute or subacute septic endocarditis, uncontrolled severe hypertension, other) Thrombocytopenia (platelet count < 100 x 109/L) Liver disease (including Child-Pugh Class B and Class C) associated with coagulopathy Body weight > 120 kg or < 40 kg Need for treatment with daily NSAIDs or antiplatelet agent (ibuprofen < 1200 mg/day, aspirin ≤ 160 mg/day or clopidogrel ≤ 75 mg/day are permitted) Treatment with therapeutic doses of anticoagulants for > 72 hours Mechanical heart valve Antiphospholipid syndrome Sulphite sensitivity Lactose sensitivity Life expectancy < 1 year Unable or unwilling to provide informed consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tinzaparin<br>initial 3-week lead-in course of low molecular weight heparin (tinzaparin 175 units/Kg sc daily) followed by a direct oral anticoagulant (rivaroxaban 20mg po daily) for at least 3 months | Drug: tinzaparin<br>* low molecular weight heparin<br>|
| Active Comparator: Rivaroxaban<br>Direct oral anticoagulant only (rivaroxaban 15mg po BID for 3 weeks followed by rivaroxaban 20mg po daily ) for at least 3 months | Drug: Rivaroxaban<br>* direct oral anticoagulant<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PTS at 6 months | Proportion of patients with PTS at 6 months using the Villalta scale. PTS will be diagnosed using the Villalta scale. This clinical scale is the recommended standard to diagnose PTS. | 6 months post randomization | 
| Main feasibility | Main feasibility outcomes: a. Proportion of eligible patients, among patients screened b. Proportion of recruited patients, among patients who are eligible c. Proportion of patients who are compliant with tinzaparin, among recruited patients assigned to tinzaparin arm. | 3 months post randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PTS severity | The Villalta scale will be used to grade the severity of PTS (mild, moderate, severe) at 6 months post randomization. | 6 months post randomization | 
| Villalta score at 10 days | Villalta score at 10 days | 10 days post randomization | 
| DVT-related leg pain | DVT-related leg pain will be assessed using an 11-point Likert rating scale (0 no pain, 10, worst possible pain, during the last 24 hours). This relates to sub-acute DVT pain and not a pain that could have been caused by LMWH injection | Two time points: at 10 days and at 3 months post randomization | 
| Global Improvement | Assessing Patient's global improvement using the Patient's global improvement scale (On a scale of 1 to 7, where 1 is extremely improved and 7 is extremely deteriorated). | Two time points: at 10 days and at 3 months post randomization | 
| Patient's satisfaction with treatment | Patient's satisfaction with treatment and patient's global improvement will be assessed using a 7-point Likert visual analog scale questionnaire (1 = extremely satisfied to 7 = extremely dissatisfied). | Two time points: at 3 weeks and at 6 months post randomization | 
| QOL (Quality of Life) score - SF-36 | Generic QOL will be measured using Short-Form Health Survey-36 (SF-36) instrument. Physical and Mental Component Summary scores reflect physical and mental health status, respectively. To only take into account change in QOL related to DVT, at the 3 week visit, we will change the first sentence (i.e. stem) of the SF-36 questionnaire from 'over the past 4 weeks' to 'over the past 3 weeks'. | Three time points: at 3 weeks and at 6 months post randomization | 
| QOL (Quality of Life) score - VEINES-QOL | Venous disease-specific QOL will be assessed with VEINES-QOL, a 25-item self-completed measure. To only take into account change in QOL related to DVT, at the 3 week visit, we will change the first sentence (i.e. stem) of the VEINES-QOL questionnaire from 'over the past 4 weeks' to 'over the past 3 weeks'. | Three time points: at 3 weeks and at 6 months post randomization | 
| SAEs | Serious adverse events (SAE) will be defined as per the Health Canada definition. SAEs will be reported as required by local regulations, with copies sent to Health Canada, Therapeutic Product Directorate (Ottawa), Leo Pharma (maker of tinzaparin) and Bayer (maker of rivaroxaban). SAEs from baseline to 3 weeks and from 3 weeks to 6 months, including recurrent DVT, PE (Pulmonary Embolism), major bleeding and clinically relevant non-major bleeding, death will be assessed. | baseline to 6 months post randomization | 
| Rate of lost to follow-up | The number of patients randomized that do not attend (in person or over the phone) the 6-month follow-up visit; Patients who withdraw consent are not considered as lost to follow-up. | 6 months post randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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tinzaparin