Tinzaparin Lead-In to Prevent the Post-Thrombotic Syndrome

Deep Vein Thrombosis Clinical Trial

— TILE  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04794569
• Other study ID #: 3315
• Status: Terminated
• Phase: Phase 4
• Start date: November 15, 2021
• Est. completion date: January 19, 2024

Study information

• Verified date: June 2023
• Source: Sunnybrook Health Sciences Centre
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 9
• Est. completion date: January 19, 2024
• Est. primary completion date: January 19, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Deep Vein Thrombosis
• Post Thrombotic Syndrome
• Postphlebitic Syndrome
• Postthrombotic Syndrome
• Syndrome
• Thrombosis
• Venous Thrombosis

Intervention

Drug:
• tinzaparin
low molecular weight heparin
• Rivaroxaban
direct oral anticoagulant

Locations

Country	Name	City	State
Canada	Hamilton General Hospital	Hamilton	Ontario
Canada	Juravinski Hospital and Cancer Centre	Hamilton	Ontario
Canada	Sir Mortimer B. Davis Jewish General Hospital	Montréal	Ontario
Canada	The Ottawa Hospital - Ottawa Hospital Research Institute (OHRI)	Ottawa	Ontario
Canada	Sunnybrook Health Sciences Centre	Toronto	Ontario

Sponsors (3)

Lead Sponsor	Collaborator
Sunnybrook Health Sciences Centre	LEO Pharma, Sunnybrook Research Institute

Country where clinical trial is conducted

Canada, 

References & Publications (4)

Hull RD, Townshend G. Long-term treatment of deep-vein thrombosis with low-molecular-weight heparin: an update of the evidence. Thromb Haemost. 2013 Jul;110(1):14-22. doi: 10.1160/TH12-12-0931. Epub 2013 Apr 25. — View Citation

Kahn SR, Comerota AJ, Cushman M, Evans NS, Ginsberg JS, Goldenberg NA, Gupta DK, Prandoni P, Vedantham S, Walsh ME, Weitz JI; American Heart Association Council on Peripheral Vascular Disease, Council on Clinical Cardiology, and Council on Cardiovascular and Stroke Nursing. The postthrombotic syndrome: evidence-based prevention, diagnosis, and treatment strategies: a scientific statement from the American Heart Association. Circulation. 2014 Oct 28;130(18):1636-61. doi: 10.1161/CIR.0000000000000130. Epub 2014 Sep 22. No abstract available. Erratum In: Circulation. 2015 Feb 24;131(8):e359. — View Citation

Kahn SR, Partsch H, Vedantham S, Prandoni P, Kearon C; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of post-thrombotic syndrome of the leg for use in clinical investigations: a recommendation for standardization. J Thromb Haemost. 2009 May;7(5):879-83. doi: 10.1111/j.1538-7836.2009.03294.x. Epub 2009 Jan 19. — View Citation

Makedonov I, Kahn SR, Galanaud JP. Prevention and Management of the Post-Thrombotic Syndrome. J Clin Med. 2020 Mar 27;9(4):923. doi: 10.3390/jcm9040923. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Health Services Research Issues	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	6 months post randomization
Primary	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
Primary	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	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
Secondary	Villalta score at 10 days	Villalta score at 10 days	10 days post randomization
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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