Back to resultsTinzaparin Lead-In to Prevent the Post-Thrombotic Syndrome (TILE)
Primary Purpose
Deep Vein Thrombosis, Post Thrombotic Syndrome
Status
Recruiting
Phase
Phase 4
Locations
Canada
Study Type
Interventional
Intervention
tinzaparin
Rivaroxaban
Sponsored by
About this trial
This is an interventional treatment trial for Deep Vein Thrombosis focused on measuring tinzaparin
Eligibility Criteria
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 > 48 hours (3 injections of LMWH if twice daily therapeutic LMWH used, 2 injections of LMWH if once daily therapeutic LMWH used, 3 doses of twice daily 15 mg of rivaroxaban)
- Mechanical heart valve
- Antiphospholipid syndrome
- Sulphite sensitivity
- Lactose sensitivity
- Life expectancy < 1 year
- Unable or unwilling to provide informed consent
Sites / Locations
- Hamilton General HospitalRecruiting
- Juravinski Hospital and Cancer CentreRecruiting
- Sir Mortimer B. Davis Jewish General HospitalRecruiting
- The Ottawa Hospital - Ottawa Hospital Research Institute (OHRI)Recruiting
- Sunnybrook Health Sciences CentreRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Tinzaparin
Rivaroxaban
Arm Description
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
Direct oral anticoagulant only (rivaroxaban 15mg po BID for 3 weeks followed by rivaroxaban 20mg po daily ) for at least 3 months
Outcomes
Primary Outcome Measures
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.
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.
Secondary Outcome Measures
PTS severity
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
Villalta score at 10 days
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
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).
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).
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'.
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'.
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.
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.
Full Information
NCT ID
NCT04794569
First Posted
February 24, 2021
Last Updated
June 15, 2023
Sponsor
Sunnybrook Health Sciences Centre
Collaborators
LEO Pharma, Sunnybrook Research Institute
1. Study Identification
Unique Protocol Identification Number
NCT04794569
Brief Title
Tinzaparin Lead-In to Prevent the Post-Thrombotic Syndrome
Acronym
TILE
Official Title
Tinzaparin Lead-In to Prevent the Post-Thrombotic Syndrome Phase IV Pilot Study
Study Type
Interventional
2. Study Status
Record Verification Date
June 2023
Overall Recruitment Status
Recruiting
Study Start Date
November 15, 2021 (Actual)
Primary Completion Date
March 31, 2024 (Anticipated)
Study Completion Date
October 31, 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Sunnybrook Health Sciences Centre
Collaborators
LEO Pharma, Sunnybrook Research Institute
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Deep Vein Thrombosis, Post Thrombotic Syndrome
Keywords
tinzaparin
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
Outcomes Assessor
Masking Description
Patients will be instructed not to disclose their treatment to PTS assessors
Allocation
Randomized
Enrollment
60 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Tinzaparin
Arm Type
Experimental
Arm Description
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
Arm Title
Rivaroxaban
Arm Type
Active Comparator
Arm Description
Direct oral anticoagulant only (rivaroxaban 15mg po BID for 3 weeks followed by rivaroxaban 20mg po daily ) for at least 3 months
Intervention Type
Drug
Intervention Name(s)
tinzaparin
Intervention Description
low molecular weight heparin
Intervention Type
Drug
Intervention Name(s)
Rivaroxaban
Intervention Description
direct oral anticoagulant
Primary Outcome Measure Information:
Title
PTS at 6 months
Description
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.
Time Frame
6 months post randomization
Title
Main feasibility
Description
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.
Time Frame
3 months post randomization
Secondary Outcome Measure Information:
Title
PTS severity
Description
The Villalta scale will be used to grade the severity of PTS (mild, moderate, severe) at 6 months post randomization.
Time Frame
6 months post randomization
Title
Villalta score at 10 days
Description
Villalta score at 10 days
Time Frame
10 days post randomization
Title
DVT-related leg pain
Description
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
Time Frame
Two time points: at 10 days and at 3 months post randomization
Title
Global Improvement
Description
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).
Time Frame
Two time points: at 10 days and at 3 months post randomization
Title
Patient's satisfaction with treatment
Description
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).
Time Frame
Two time points: at 3 weeks and at 6 months post randomization
Title
QOL (Quality of Life) score - SF-36
Description
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'.
Time Frame
Three time points: at 3 weeks and at 6 months post randomization
Title
QOL (Quality of Life) score - VEINES-QOL
Description
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'.
Time Frame
Three time points: at 3 weeks and at 6 months post randomization
Title
SAEs
Description
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.
Time Frame
baseline to 6 months post randomization
Title
Rate of lost to follow-up
Description
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.
Time Frame
6 months post randomization
Other Pre-specified Outcome Measures:
Title
Health Services Research Issues
Description
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
Time Frame
6 months post randomization
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Jean-Philippe Galanaud, MD
Phone
416-480-6100
Ext
3056
Email
Jean-Philippe.Galanaud@sunnybrook.ca
First Name & Middle Initial & Last Name or Official Title & Degree
Sonya Mergler
Phone
(416) 480-5627
Email
tile@sunnybrook.ca
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jean-Philippe Galanaud, MD
Organizational Affiliation
Sunnybrook Health Sciences Centre (Toronto, Ontario, Canada)
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Susan R Kahn, MD
Organizational Affiliation
Jewish General Hospital (Montreal, Quebec, Canada)
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hamilton General Hospital
City
Hamilton
State/Province
Ontario
ZIP/Postal Code
L8L 2X2
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sam Schulman, MD
Phone
905-527-4322
Ext
44479
Email
schulms@mcmaster.ca
First Name & Middle Initial & Last Name & Degree
Michelle Zondag
Phone
905-527-4322
Ext
44807
Email
zondag@hhsc.ca
Facility Name
Juravinski Hospital and Cancer Centre
City
Hamilton
State/Province
Ontario
ZIP/Postal Code
L8V 1C3
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Peter Gross, MD
Phone
905-521-2100
Ext
40779
Email
pgross@mcmaster.ca
First Name & Middle Initial & Last Name & Degree
Erjona Kruja
Phone
905-521-2100
Ext
43761
Email
kruja@HHSC.CA
Facility Name
Sir Mortimer B. Davis Jewish General Hospital
City
Montréal
State/Province
Ontario
ZIP/Postal Code
H3T 1E2
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Susan Kahn, MD
Phone
514 340 8222
Ext
24667
Email
susan.kahn@mcgill.ca
First Name & Middle Initial & Last Name & Degree
Elena Shulikovsky
Phone
514 340 8222
Ext
23703
Email
eshulikovsky@jgh.mcgill.ca
Facility Name
The Ottawa Hospital - Ottawa Hospital Research Institute (OHRI)
City
Ottawa
State/Province
Ontario
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Aurélien Delluc, M.D. Ph. D.
Phone
613-737-8899
Ext
79076
Email
adelluc@toh.ca
First Name & Middle Initial & Last Name & Degree
Daniel Warner
Phone
613-737-8899
Ext
79590
Email
dawarner@ohri.ca
Facility Name
Sunnybrook Health Sciences Centre
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M4N 3M5
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jean-Philippe Galanaud, MD
Phone
416-480-5953
Email
Jean-Philippe.Galanaud@sunnybrook.ca
First Name & Middle Initial & Last Name & Degree
Jonathan Sasitharan
Email
jonathan.sasitharan@sri.utoronto.ca
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
32230912
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.
Results Reference
background
PubMed Identifier
25246013
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.
Results Reference
background
PubMed Identifier
23615656
Citation
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.
Results Reference
background
PubMed Identifier
19175497
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.
Results Reference
background
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Tinzaparin Lead-In to Prevent the Post-Thrombotic Syndrome
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