Deep Vein Thrombosis, Post Thrombotic Syndrome
Conditions
Keywords
tinzaparin
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.
Interventions
DRUGtinzaparin
low molecular weight heparin
DRUGRivaroxaban
direct oral anticoagulant
Sponsors
LEO Pharma
Sunnybrook Research Institute
Sunnybrook Health Sciences Centre
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
Patients will be instructed not to disclose their treatment to PTS assessors
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Villalta score at 10 days | 10 days post randomization | Villalta score at 10 days |
| 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 |
| 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). |
| 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 - 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'. |
| 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. |
| 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'. |
| 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Health Services Research Issues | 6 months post randomization | QOL analyses will be conducted in the pilot study, as it is relevant to comprehensively evaluate chronic burdensome conditions like PTS. Utilities for health states will be derived from QOL measurements |
Countries
Canada
Outcome results
None listed