Tinzaparin Lead-In to Prevent the Post-Thrombotic Syndrome

Phase 4

Terminated

• Conditions: Deep Vein Thrombosis; Post Thrombotic Syndrome
• Interventions: Drug: Rivaroxaban; Drug: tinzaparin

• Registration Number: NCT04794569
• Lead Sponsor: Sunnybrook Health Sciences Centre

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2021-02-24
• Study First Submitted QC: 2021-03-10
• Study First Posted: 2021-03-12
• Study Start: 2021-11-15
• Status Verified: 2023-06
• Primary Completion: 2024-01-19
• Study Completion: 2024-01-19
• Last Update Submitted: 2024-04-02
• Last Update Posted: 2024-04-04

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 9

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

1. Age < 18 years
2. History of ipsilateral DVT (distal and/or proximal)
3. Active cancer
4. Thrombolysis or other invasive early thrombus removal technique to treat DVT or PE
5. Pregnant or breast feeding
6. Impaired renal function (creatinine clearance < 30 ml/min according to Cockcroft-Gault formula)
7. Concomitant use of drugs that interact with rivaroxaban (i.e. keto- or itraconazole, ritonavir)
8. Allergy or hypersensitivity to heparin or rivaroxaban, including heparin induced thrombocytopenia
9. 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)
10. Thrombocytopenia (platelet count < 100 x 109/L)
11. Liver disease (including Child-Pugh Class B and Class C) associated with coagulopathy
12. Body weight > 120 kg or < 40 kg
13. Need for treatment with daily NSAIDs or antiplatelet agent (ibuprofen < 1200 mg/day, aspirin ≤ 160 mg/day or clopidogrel ≤ 75 mg/day are permitted)
14. Treatment with therapeutic doses of anticoagulants for > 72 hours
15. Mechanical heart valve
16. Antiphospholipid syndrome
17. Sulphite sensitivity
18. Lactose sensitivity
19. Life expectancy < 1 year
20. Unable or unwilling to provide informed consent

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Rivaroxaban	Rivaroxaban	Direct oral anticoagulant only (rivaroxaban 15mg po BID for 3 weeks followed by rivaroxaban 20mg po daily ) for at least 3 months
Tinzaparin	tinzaparin	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

Primary Outcome Measures

Name	Time	Method
PTS at 6 months	6 months post randomization	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.
Main feasibility	3 months post randomization	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.

Secondary Outcome Measures

Name	Time	Method
DVT-related leg pain	Two time points: at 10 days and at 3 months post randomization	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
Patient's satisfaction with treatment	Two time points: at 3 weeks and at 6 months post randomization	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).
QOL (Quality of Life) score - SF-36	Three time points: at 3 weeks and at 6 months post randomization	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'.
QOL (Quality of Life) score - VEINES-QOL	Three time points: at 3 weeks and at 6 months post randomization	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'.
PTS severity	6 months post randomization	The Villalta scale will be used to grade the severity of PTS (mild, moderate, severe) at 6 months post randomization.
Villalta score at 10 days	10 days post randomization	Villalta score at 10 days
Global Improvement	Two time points: at 10 days and at 3 months post randomization	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).
SAEs	baseline to 6 months post randomization	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.
Rate of lost to follow-up	6 months post randomization	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.

Trial Locations

Locations (5)

Sunnybrook Health Sciences Centre; 🇨🇦 Toronto, Ontario, Canada

Hamilton General Hospital; 🇨🇦 Hamilton, Ontario, Canada

Juravinski Hospital and Cancer Centre; 🇨🇦 Hamilton, Ontario, Canada

The Ottawa Hospital - Ottawa Hospital Research Institute (OHRI); 🇨🇦 Ottawa, Ontario, Canada

Sir Mortimer B. Davis Jewish General Hospital; 🇨🇦 Montréal, Ontario, Canada