Network Platforms

Clinical Trials and Shared Platforms

This platform supports pilot studies to inform the design and conduct of full randomized controlled trials. Pilot studies evaluate the feasibility of recruitment and study procedures, and can inform sample size calculations and study logistics. Pilot data can also be reassuring to funders and grant reviewers and help to secure large-scale funding for collaborative multicenter trials.

Since 2016, CanVECTOR has held annual pilot trial competitions that are open to network members. The research teams include trainees and early career investigators, along with patient partners and established investigators. Applications are reviewed by CanVECTOR patient partners and by peer-reviewers from Canada and members of other national networks (through INVENT-VTE).

The Team

Platform Co-Leads

Deborah Siegal (Ottawa, ON)
Grégoire Le Gal (Ottawa, ON)

Pilot Studies

1. COBRRA

Principal Investigator (junior)

Dr. Lana Castellucci (Ottawa)

Principal Investigator (senior)

Dr. Marc Rodger (Ottawa)

Lead Pilot Site Investigators

Hamilton - Dr. Kerstin de Wit
Edmonton - Dr. Cynthia Wu
Sherbrooke - Dr. Genevieve Le Templier

Recently developed new oral anticoagulants (OAC) overcome some of the limitations of established therapy with vitamin K antagonists (VKA) and low-molecular-weight heparin (LMWH) for treatment of acute venous thromboembolism (VTE), due to ease of administration and more predictable pharmacokinetic properties. Many clinical questions about the new OAC remain unanswered because there have not been direct head-to-head comparison trials. For example, although studies have shown that rivaroxaban and apixaban are at least as effective and safe as LMWH and VKA, meta-analyses suggest that apixaban may be associated with lower bleeding risk. Concerns about the potential impact of medication non-adherence have been raised. Compliance with twice daily medications (e.g. apixaban) is often worse than once daily medications (e.g. rivaroxaban). Both of these medications are approved by Health Canada for treatment of VTE yet there is genuine uncertainty about which of the two direct OAC confer the best risk-to-benefit ratio.

This is a multi-centre, prospective randomized open blinded end-point (PROBE) trial assessing clinical feasibility for a larger multi-centred trial comparing bleeding outcomes using apixaban versus rivaroxaban for treatment of acute VTE. The primary objective of the study is to determine if it is feasible to conduct a large randomized multi-centre trial comparing apixaban to rivaroxaban for the treatment of acute VTE. The secondary objectives are to assess safety and superiority of apixaban versus rivaroxaban.

This pilot trial has been completed. It demonstrated feasibility and informed the procedures of the full clinical trial which is funded by a Project Grant from the Canadian Institutes of Health Research (CIHR).

For more details on the full clinical trial see ClinicalTrials.gov: NCT03266783

For more details on the pilot trial see ClinicalTrials.gov: NCT02559856

2. APPLE

Full Title

Assessing the feasibility of a randomized controlled trial evaluating low-molecular-weight-heparin and aspirin versus aspirin alone in women with antiphospholipid syndrome and pregnancy loss

Principal Investigator (fellow)

Dr. Leslie Skeith (Ottawa)

Co-Principal Investigator (supervisor)

Dr. Marc Rodger (Ottawa)

Co-Investigator

Dr. Shannon Bates (Hamilton)

Women with antiphospholipid syndrome (APS) are at increased risk of pregnancy loss compared to the general population. There is poor-quality evidence supporting the use of prophylactic low-molecular weight heparin (LMWH) and aspirin (ASA) in pregnancy for women with APS and past pregnancy loss. Downsides of LMWH include burden of injections (up to 400 injections per pregnancy), cost (more than $4,000 per pregnancy) and side effects of LMWH. When uncertainty exists in pregnancy, health care providers and patients often err on the side of treatment in hopes of preventing complications. the goal of the study is to minimize uncertainty, to provide clear recommendation to women with APS and pregnancy loss based on high-quality evidence.

This APPLE pilot trial was conducted at two centers (Ottawa and Hamilton) to determine if it is feasible to conduct the multicenter randomized APPLE trial in women with APS and previous pregnancy loss. It was estimated that the multicenter trial will target 40 centers and will be completed over 5 years to answer the question of whether the use of prophylactic LMWH and ASA improves the livebirth rate when compared to ASA alone. The APPLE trial would be considered feasible if the APPLE pilot trial demonstrates that recruitment rates average, at a minimum, 1 patient every 2 months per site.

This pilot trial is completed. Please see the published results of the trial here

For more details see ClinicalTrials.gov: NCT03100123

3. HIT

Full Title

Optimizing the Diagnosis of Heparin Induced Thrombocytopenia Using Quantified Anti-Platelet Factor 4 Immunological Testing: A Prospective Cohort Study

Principal Investigator (junior)

Dr. Lisa Duffett (Ottawa)

Co-Investigators

Dr. Esteban Gandara (Ottawa)
Dr. Rick Ikesaka (Fellow, Ottawa)
Dr. Gregoire Le Gal (Ottawa)
Dr. Sudeep Shivakumar (Halifax)

This is a prospective cohort study exploring a novel diagnostic approach to Heparin Induced Thrombocytopenia (HIT) using a combination of pretest probability assessment and quantitative interpretation of the anti-platelet factor 4 Immunological assay (anti-PF4). Patients with a clinical suspicion of HIT will follow the study-specific diagnostic algorithm. The results using the study algorithm will be compared to the Serotonin Release Assay (SRA) gold standard test. Pre-specified criteria will be used to determine if the study algorithm is a safe approach that should be evaluated in a larger randomized controlled trial (RCT). The cohort study will also inform feasibility and recruitment barriers for the larger RCT study. 

This study is recruiting participants. For more details see ClinicalTrials.gov: NCT03148912

4. PLATO

Full Title

Tumour-educated platelets to detect cancer in patients with unprovoked venous thromboembolism

Principal Investigator (PhD student)

Noémie Kraaijpoel

Canadian Co- Investigator (supervisor)

Marc Carrier (Ottawa)

The PLATO pilot study aims to evaluate the feasibility of participating in an INVENT-VTE multi-center, multi-national, prospective, observational cohort study assessing the diagnostic accuracy of platelet mRNA profiling for occult cancer in the setting of venous thromboembolism (VTE). The results of this cohort study will inform and help to design a large multinational randomized controlled trial assessing the efficacy of platelet mRNA to detect occult cancer in patients with unprovoked VTE.

 In the current study, patients of 40 years or older with a first episode of unprovoked deep vein thrombosis (DVT) or pulmonary embolism (PE) will be eligible. Informed consent will be obtained within 10 days of the index unprovoked VTE and blood will be drawn and stored until central platelet mRNA profiling. Patients will undergo standard-of-care limited screening for cancer and be followed for 12 months.The pilot study will assess feasibility in two CanVECTOR sites (Ottawa, London) and the data will enable leverage of additional peer-reviewed funds for participation in the full-scale study and future randomized controlled trial. CanVECTOR Pilot Trial Funding will allow for the recruitment of 50 patients (Ottawa n=25; London n=25) over 6 months (primary objective). Secondary outcomes measures include evaluation of compliance to study procedures and follow-up visits and reasons for non-participation. The primary objective of the full-scale study is to evaluate the sensitivity of platelet mRNA profiling in detecting occult cancer.

This pilot trial has completed recruitment. For more details see ClinicalTrials.gov:  NCT02739867

5. TRIM-Line Pilot

Full Title

A pilot study assessing the feasibility of a randomized controlled trial investigating primary thromboprophylaxis with rivaroxaban in patients with malignancy and central venous catheters

Principal Investigator (fellow)

Dr. Rick Ikesaka (Hamilton)

Co-Principal Investigator (supervisor)

Dr. Marc Carrier (Ottawa)

Co-Investigators

Sudeep Shivakumar (Halifax) 
Cynthia Wu (Edmonton)

The TRIM-Line pilot trial will assess the feasibility of conducting a full-scale, multicentre, randomized controlled trial evaluating a prophylactic dose of direct oral anticoagulant therapy, rivaroxaban, for the primary prevention of venous thromboembolism (VTE) in cancer patients with a central venous catheter (CVC). The pilot trial will be conducted at 3 Canadian centres: Ottawa, Halifax and Edmonton, over a 6-month span. The primary feasibility outcome will be the monthly recruitment rate. The target recruitment will be a total of 10 participants per month with site goals of 4-5 monthly enrollments at each of the established centres of Ottawa and Halifax and 1-2 per month at the emerging centre of Edmonton. Secondary feasibility outcomes and those in keeping with anticipated outcomes for the full-scale trial will also be collected.

This trial has been completed and a publication can be found here.

6. PEITHO III

Full Title

A reduced dose of thrombolytic treatment for patients with intermediate to high-risk acute PE

Principal Investigator

Kerstin de Wit (Hamilton) (Principal Investigator, Canada)

*This study is part of an International Collaboration led by Principal Investigators Stavros Konstantinides and Guy Meyer.

Co-Investigators

Lana Castellucci and Marc Rodger (Ottawa)
Ali Mulla
Sudeep Shivakumar (Halifax)
Andrew Hirsch and Susan Kahn (Montreal)

CanVECTOR Patient Partners

Suzanne Dubois (Brantford)

The PEITHO III pilot trial will assess the feasibility of conducting a full-scale, multicentre, randomized controlled trial evaluating the efficacy and safety of reduced dose thrombolytic therapy in patients with intermediate to high-risk acute pulmonary embolism (PE). The aim of the study is to determine whether thrombolysis saves more lives than standard blood thinners alone. It will also report if thrombolysis causes more bleeding. The pilot trial will be conducted at 4 Canadian Centres: Hamilton, Halifax, Montreal, and Ottawa, over a 12-month span. The primary feasibility outcome will be the total recruitment at each site. The target recruitment will be a total of 12 participants with the goal of each site having at least 3 enrollments by the end of the 12-month study period. The study will also report the proportion of screened patients who are eligible, the proportion of eligible patients who are randomized, and the number of patients who are lost to follow up at 30 and 180 days.

7. RIVASVT-100

Full Title

Treatment of portal, mesenteric, and splenic vein thrombosis with rivaroxaban.

Principal Investigator

Dr. Aurélien Delluc (Ottawa)(Principal Investigator, Canada)

Co-Investigators

Dr. Mark Crowther (Hamilton)
Dr. Sébastien Miranda (Ottawa)
Dr. Alejandro Lazo-Langner (London)
Dr. Walter Agendo (Italy) (Principal Investigator, International)

CanVECTOR Patient Partners

Jamie Dossett-Mercer

The pilot study aims to evaluate the feasibility of conducting a multi-center, multi-national, prospective, and observational cohort study that assesses the safety of rivaroxaban for the treatment of splanchnic vein thrombosis (SVT).

The pilot study will be conducted at 3 Canadian Centres: Ottawa, London, and Hamilton. The primary feasibility outcome will be the number of enrolled participants over a 12-month period. The target recruitment total will be a total of 30 participants with the goal of each site having at least 10 enrollments by the end of the 12-month study period. Secondary outcome measures include evaluation of compliance to study procedures and follow-up visits and reasons for non-participation.

Canadian recruitment is now complete.

8. AIRPORT-MPN

Full Title

Thromboprophylaxis with apixaban in polycythemia vera and JAK2-positive essential thrombocythemia patients - A pilot randomized controlled trial assessing feasibility

 

Principal Investigator

Dr. Miriam Kimpton (Ottawa)

Co-Investigators

Dr. Aurelien Delluc (Ottawa)
Dr. Marc Carrier (Ottawa)
Dr. Ranjeeta Mallick (Ottawa)
Dr. Jeannie Callum (Toronto)
Dr. Leslie Skeith (Calgary)
Dr. Sonia Cerquozzi (Calgary)

CanVECTOR Patient Partners

Danielle Morneault

The pilot study aims to evaluate the feasibility of conducting a multi-centre, open-label, randomized controlled trial assessing the superiority of apixaban compared to aspirin as thromboprophylaxis of polycythemia vera (PV) and JAK2-positive essential thrombocythemia (JAK2ET) patients.

The pilot study will be conducted at 3 Canadian Centres: Ottawa, Calgary, and Toronto. The primary feasibility outcome will be the monthly rate of recruitment. The target recruitment total will be a total of 44 patients. Secondary feasibility outcomes will include the proportion of retained patients and of patients with good adherence to the study medication.  

The primary objective of the full-size RCT will be the rate of thrombotic events (arterial and venous). The secondary objective will be the rate of major bleeding (per the International Society of Thrombosis and Haemostasis).

This trial is recruiting participants. For more details see ClinicalTrials.govNCT04243122

Standardization and Best Practices in VTE Research

14. Common Data Elements

ISTH VTE CDEs

Common Data Elements for Venous Thromboembolism (ISTH VTE CDE) were presented in The Journal of Thrombosis and Haemostasis as an official communication from the Scientific and Standardization Committee (SSC) of the International Society on Thrombosis and Haemostasis (ISTH). This culminated a year-long international effort to collaboratively create global common research data standards for VTE clinical research. The project’s Steering Committee, including CanVECTOR members Dr. Grégoire Le Gal (Chair), Dr. Lana Castellucci, and Dr. Marc Carrier, oversaw seven Working Groups comprising a team of over 50 international VTE experts. Twelve CanVECTOR members contributed as working group members and many others participated in the public comment period.

Access the ISTH Common Data Elements here.

Publication(s)

  • Le Gal, GCarrier, MCastellucci, LA, et al; for the ISTH CDE Task ForceDevelopment and implementation of common data elements for venous thromboembolism research: Official Communication from the SSC of the ISTHJ Thromb Haemost202119297– 303https://doi.org/10.1111/jth.15138

ASH COVID Toolkit 

 A toolkit including data elements and endpoints related to venous thrombosis, arterial thrombosis, anticoagulation, bleeding, and associated laboratory tests, was published in Blood Advances in December 2020. The toolkit, designed to be easy to use by trialists who are not thrombosis specialists, was a product of The ASH Research Collaborative (ASH RC) and the International Society on Haemostasis and Thrombosis (ISTH), led by Dr. Deborah Siegal, and a team consisting of several CanVECTOR members.

Learn more about the toolkit here

Publication(s)

  • Deborah M. Siegal, Geoffrey D. Barnes, Nicole J. Langlois, Adrienne Lee, Saskia Middeldorp, Leslie Skeith, William A. Wood, Grégoire Le Gal; A toolkit for the collection of thrombosis-related data elements in COVID-19 clinical studies. Blood Adv 2020; 4 (24): 6259–6273. doi: https://doi.org/10.1182/bloodadvances.2020003269

 

15. Standardized Outcomes

PE-related Death

Pulmonary embolism (PE)‐related death is often a component of the primary outcome in venous thromboembolism (VTE) clinical studies. Definitions for PE‐related death vary widely, which may lead to biased risk estimates of clinical outcomes, thereby affecting both internal and external validity of study results. We here provide a standardized definition of PE‐related death and propose guidance for classification and reporting of the cause of death for clinical studies in VTE. The proposal was developed in a four‐step process, including a systematic review of definitions used for PE‐related death in previous studies, two subsequent surveys with VTE experts, and meetings held within the Scientific and Standardization Committee (SSC) working group until consensus on the proposal was reached. The proposed classification comprises three categories:

  • Category A: PE‐related death;
  • Category B: undetermined cause of death, and;
  • category C: cause of death other than PE.

Category A includes A1: autopsy‐confirmed PE in the absence of another more likely cause of death; A2: objectively confirmed PE before death in the absence of another more likely cause of death; and A3: PE is not objectively confirmed, but is most likely the main cause of death. Category B includes B1: cause of death is undetermined, despite available information; and B2: insufficient clinical information available to determine the cause of death. The use of the proposed definition will hopefully improve the accuracy of study outcomes, between‐study comparisons, meta‐analyses, and validity of future clinical VTE studies.

Publication(s)

  • Systematic Review: Kraaijpoel N, Tritschler T, Guillo E, Girard P, Le Gal G. Definitions, adjudication, and reporting of pulmonary embolism-related death in clinical studies: A systematic review. J Thromb Haemost. 2019 Oct;17(10):1590-1607. doi: 10.1111/jth.14570. Epub 2019 Jul 31. PMID: 31301689.
  • Definitions and Methods: Tritschler, T, Kraaijpoel, N, Girard, P, et al Definition of pulmonary embolism‐related death and classification of the cause of death in venous thromboembolism studies: Communication from the SSC of the ISTH. J Thromb Haemost. 2020; 18: 1495– 1500. https://doi.org/10.1111/jth.14769

Establishing an International Core Outcome Set for Clinical Trials of Interventions for Venous Thromboembolism in Adults (VTE-COS)

Blood clots in the veins (called venous thromboembolism or VTE) are common and affect up to 70,000 Canadians per year. This condition can be fatal if a blood clot in the leg or arm travels to the lungs. Treatment mostly relies on anticoagulants (blood thinners), which are very effective but involve risks and inconvenience for patients. Clinical trials are vital for determining the effectiveness of new treatments. Researchers measure outcomes that they believe are important for decision-making. Two problems that we have identified in clinical trials of VTE treatment are: 1) inconsistent measurement of outcomes, and 2) they may not be measuring all outcomes that are important, especially to patients but also to other stakeholders such as policy makers. The development of "core outcome sets" is gaining popularity as a strategy to address these problems. They are an agreed upon collection of standardized outcomes that should be measured and reported for a condition. A variety of perspectives are required to create a useful core outcome set. CanVECTOR, a national VTE research network, plans to involve researchers, clinicians, patients and other stakeholders to decide together on the best outcomes for VTE studies. We will seek input from international groups to develop a core outcome set that is applicable worldwide. Our project has several steps: 1) Review VTE studies to create a comprehensive list of outcomes; 2) Hold small group sessions with patients to identify outcomes that are meaningful to them; 3) Survey a large group of clinicians, researchers, patients and policy makers to prioritize the list of outcomes; 4) Hold a consensus meeting with representatives of each group to decide on the final core outcome set; and 5) Introduce and promote the core outcome set to Canadian and International researchers and stakeholders in our Canadian and global networks.

  1. Inconsistent measurement of outcomes, and
  2. They may not be measuring all outcomes that are important, especially to patients but also to other stakeholders such as policy makers.

The development of "core outcome sets" is gaining popularity as a strategy to address these problems. They are an agreed upon collection of standardized outcomes that should be measured and reported for a condition. A variety of perspectives are required to create a useful core outcome set. CanVECTOR, a national VTE research network, plans to involve researchers, clinicians, patients and other stakeholders to decide together on the best outcomes for VTE studies. We will seek input from international groups to develop a core outcome set that is applicable worldwide. The project has several steps including:

  1. Review VTE studies to create a comprehensive list of outcomes;
  2. Hold small group sessions with patients to identify outcomes that are meaningful to them;
  3. Survey a large group of clinicians, researchers, patients and policy makers to prioritize the list of outcomes;
  4. Hold a consensus meeting with representatives of each group to decide on the final core outcome set;
  5. Introduce and promote the core outcome set to Canadian and International researchers and stakeholders in our Canadian and global networks.

COMET Registry

Clinical trials of venous thromboembolism (VTE) treatment in adults suffer from inconsistent measurement of outcomes and they may not be measuring all outcomes that are important, especially to patients and stakeholders. A COS for VTE does not exist as a resource for investigators.

This project is a mixed-methods Core Outcome Set development study with the goal of defining a core set of valid, homogeneous and relevant outcomes for use in clinical trials of interventions for venous thromboembolism in adults, then promoting these outcomes internationally with researchers, knowledge users and all relevant stakeholders.

The scoping review has been registered at the University of Ottawa: http://hdl.handle.net/10393/40459. Learn more here.

Publication(s)

  • Tritschler T, Langlois N, Hutton B, et al Protocol for a scoping review of outcomes in clinical studies of interventions for venous thromboembolism in adults BMJ Open 2020;10:e040122. doi: 10.1136/bmjopen-2020-040122

16. Adjudication Platform

Currently, adjudication is done with paper-based forms at face-to-face meetings; this is time consuming, inconvenient, and reduces independent evaluation by dual adjudicators. We have developed and are currently testing a web-based adjudication platform that will allow adjudicators to do this work on their own time, more efficiently, and with a lower potential for biased interpretation.