Tinzaparin Lead-In to Prevent the Post-Thrombotic Syndrome (TILE)

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

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).

Study Overview

• Status: Terminated
• Conditions: Deep Vein Thrombosis; Post Thrombotic Syndrome
• Intervention / Treatment: Drug: tinzaparin; Drug: Rivaroxaban

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 Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8L 2X2
      • Hamilton General Hospital
    • Hamilton, Ontario, Canada, L8V 1C3
      • Juravinski Hospital and Cancer Centre
    • Montréal, Ontario, Canada, H3T 1E2
      • Sir Mortimer B. Davis Jewish General Hospital
    • Ottawa, Ontario, Canada
      • The Ottawa Hospital - Ottawa Hospital Research Institute (OHRI)
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Health Sciences Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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	Drug: tinzaparin; low molecular weight heparin
Active Comparator: Rivaroxaban; Direct oral anticoagulant only (rivaroxaban 15mg po BID for 3 weeks followed by rivaroxaban 20mg po daily ) for at least 3 months	Drug: Rivaroxaban; direct oral anticoagulant

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Collaborators and Investigators

• Sponsor: Sunnybrook Health Sciences Centre
• Collaborators: LEO Pharma; Sunnybrook Research Institute
• Investigators: Principal Investigator: Jean-Philippe Galanaud, MD, Sunnybrook Health Sciences Centre (Toronto, Ontario, Canada); Principal Investigator: Susan R Kahn, MD, Jewish General Hospital (Montreal, Quebec, Canada)

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): November 15, 2021
• Primary Completion (Actual): January 19, 2024
• Study Completion (Actual): January 19, 2024

Study Registration Dates

• First Submitted: February 24, 2021
• First Submitted That Met QC Criteria: March 10, 2021
• First Posted (Actual): March 12, 2021

Study Record Updates

• Last Update Posted (Actual): April 4, 2024
• Last Update Submitted That Met QC Criteria: April 2, 2024
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: tinzaparin
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Disease; Embolism and Thrombosis; Peripheral Vascular Diseases; Venous Insufficiency; Phlebitis; Syndrome; Thrombosis; Venous Thrombosis; Postthrombotic Syndrome; Postphlebitic Syndrome; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Fibrinolytic Agents; Fibrin Modulating Agents; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Rivaroxaban; Heparin, Low-Molecular-Weight; Tinzaparin; Dalteparin
• Other Study ID Numbers: 3315

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No