RFA Funding Successes

Funding to support high-impact Canadian RCTs provided by the ACT Consortium for clinical trial researchers in Canada.

Table of Contents
RFA 3 – Evaluating Canadian Biotechnologies with Randomized Controlled Trials (RCTs)

The Accelerating Clinical Trials (ACT)/ Accélérer les Essais Cliniques (AEC) Consortiumcirculated our third request for applications RFA 3: Evaluating Canadian Biotechnologies with Randomized Controlled Trials (RCTs).  The objective of RFA 3 was to fund partnerships with Canadian-controlled biotechnology companies and ACT/AEC Network clinical trialists.

We received 30 applications that underwent a targeted peer review process where each application was reviewed by a total of 10 independent reviewers – 5 reviewers with experience in clinical trials and 5 reviewers with experience in biotechnology. In total almost $2,000,000 CAD was awarded to support Canadian biotechnology clinical trials. Many thanks to those who submitted applications and to those who were involved in the peer review process.

We are delighted to announce the funded RFA 3 applications (in alphabetical order):

PI: Dr. Hance Clarke, 
Dr. Paul Karanicolas

Biotech: AmacaThera 

Rationale: AmacaThera has developed a novel injectable, local sustained release drug delivery technology, called AmacaGel, which is composed of a physical blend of hyaluronan and methylcellulose. AmacaThera has developed a 3-day release formulation of ropivacaine using AmacaGel that is designed to deliver 3 days of post-operative pain control, to enable a

reduction of opioid usage associated with the current standard of care. To date, AmacaThera has shown human safety of AmacaGel alone in a Phase 1a study, but not yet studied AmacaGel in combination with an active drug. The study proposed here aims to show safety and efficacy of AMT-143 in humans, allowing advancement to surgical pain indications in future trials.

Question: Does AMT-143 provide 3-days of sustained ropivacaine release in humans?

Participants: The study will consist of four cohorts, each representing an ascending single dose of treatment. A total of 28 healthy volunteer participants will be randomized within four cohorts (7 per cohort), starting at the lowest dose. If needed, additional participants will be enrolled to replace dropouts or withdrawals.

Intervention: Subcutaneous (SC) administration of single ascending doses of AMT-143.

Outcomes: The primary objective of this study is to evaluate the safety and tolerability of AMT- 143 following SC administration of single ascending doses at 4 dose levels in healthy participants. The secondary objectives of this study are to assess the pharmacokinetic (PK) profile, pharmacodynamics (PD), and the local analgesic effect of AMT-143.

Impact: AMT-143 has the potential to provide superior control of postoperative pain, simplify pain management, and reduce the need for opioid medications. This trial will provide critical data that will be leveraged to help AmacaThera raise additional capital and provide necessary data to proceed with additional clinical trials examining postoperative pain reduction. The

connection between AmacaThera and Drs. Karanicolas and Clarke, combined with funding from the ACT, will enable advancement of this important technology for non-opioid post-operative pain management, which will benefit patients by providing quicker recovery without the need for opioids.

PI: Dr. Michael Walsh, 
Dr. Peter Margetts, 
Dr. Pavel Roshanov

Biotech: Qidni

Background: 3 million individuals receive dialysis for kidney failure globally but 8 million should be treated with dialysis. The majority of untreated kidney failure is due to inaccessibility of dialysis. Even in developed countries, like Canada, remote dwelling individuals can not easily access dialysis and must relocate, or have dialysis provided at very high cost to the health system. Technological innovations to make dialysis more accessible and affordable are needed. 

Qidni developed a novel dialysis system that is portable and requires only two litres of normal saline (rather than a reverse osmosis filtration unit requiring 500 litres of water per treatment). This technology was successfully trialed in animals for multiple treatments and single treatments of humans with kidney failure. Whether the Qidni system is similarly effective and safe over repeated treatments to conventional hemodialysis is not established. This will determine whether the Qidni system can be used as a simple replacement for conventional dialysis. The Evaluation of Qidni Urea And metabolite cLearance in maintenance Dialysis (EQUAL Dialysis) is a randomized crossover trial of patients receiving chronic hemodialysis. It will evaluate the clearance of small and middle molecules as well as the safety of hemodialysis with the Qidni dialysis system compared to conventional dialysis over a period of three months. 

Primary Objective: to establish whether the Qidni dialysis system provides similar small and middle molecule clearance compared to conventional high-flux dialysis over 3 months.

Secondary Objective: to establish the safety of the Qidni dialysis system. 

Participants: Maintenance hemodialysis patients receiving stable dialysis thrice weekly for at least 90 days prior to randomization. Potential participants are excluded if they are likely to receive a kidney transplant within the next 6 months, likely to die within the next six months according to their attending nephrologist, have an active major medical problem that is untreated, or have missed more than one outpatient dialysis treatment in the last 4 weeks. 

Intervention: dialysis three times per week with the Qidni dialysis system for 12 weeks. 

Control: dialysis three times per week with conventional, high-flux hemodialysis for 12 weeks. 

Outcomes: efficiency of dialysis will be assessed through differences in clearance of a panel of small and middle molecular weight biomarkers We will assess safety by changes in blood tests as markers of hemolysis and inflammation, biophysical markers and serious adverse events. 

Anticipated Impact: This trial will inform the modifications of the current Qidni dialysis system required prior to routine clinical use and its next stage of testing. Ultimately Qidni will increase the availability of dialysis globally, and options for Canadian patients with kidney failure.

PI: Dr. Karen EA Burns, Dr. Andrew Seely

Biotech: Therapeutic Monitoring Systems Inc.

Problem: Extubation (i.e., endotracheal tube removal) that is timely and safe in intensive care unit (ICU) patients is vitally important as prolonged mechanical ventilation and failed attempts at extubation (i.e., re-intubation<48 hrs; 15% incidence) are associated with increased, morbidity, mortality, ICU stays, and hospital costs (~$45k every time it occurs). A Spontaneous Breathing Trial (SBT), performed by respiratory therapists (RTs) is the current standard of care to assess a patient’s readiness for extubation. However, SBTs are performed variably and have poor ability to predict successful extubation. There is an urgent need to improve and standardize extubation decision-making in the ICU. 

Innovation: In a multicentre study (n=721), we found that decreased respiratory rate variability (RRV) during SBTs predicted extubation failure better than other indices. We imbedded this RRV predictive model into a novel software tool called Extubation Advisor (EA), alongside a standardized extubation readiness checklist, RT’s assessments of risk, and individualized risk mitigation strategies. We showed the ability to deliver EA reports to the bedside and the acceptability of the EA tool to respiratory therapists (RTs) and physicians (MDs) in a preparatory observational study (n=117; 2 ICUs) and Phase 1 interventional study (n=29; 3 ICUs),. We are poised to evaluate EA in a multicenter, pilot trial. 

Patients: We will include 100 critically ill adults from 10 centers in Canada who are invasively ventilated for >24 hours and who are ready to undergo an SBT with a view to extubation. 

Intervention: Patients in the intervention arm will undergo an EA assessment and their treating clinicians (RTs, MDs) will receive an EA report for each SBT that is conducted. The EA report will help guide, rather than direct, extubation decision-making by ICU MDs.


Control: Patients in the control arm will receive standard care. SBTs will be directed by clinicians, using current best evidence. No EA assessments will be made and no EA reports will be generated. 

Outcomes: Our primary feasibility outcome will reflect our ability to recruit the desired population. Secondary feasibility outcomes will assess rates of (i) consent (for eligible patients approached), (ii) randomization, (iii) intervention adherence, (iv) crossovers (EA to standard care and standard care to EA), and (v) completeness of clinical outcomes collected. We will also assess the usefulness of the tool to MDs. The future primary outcome of a definitive trial is time to successful ventilatory liberation. 

Timeline: With CIHR funding and ACT funding (to aid in offsetting the 23% CIHR budget cut), we expect to initiate the multicentre pilot trial in August 2023 and bring it to completion by September 2024 with recruitment of 1-2 patients/centre/month. 

Impact: The LEADS trial is novel, low-risk, with potential high impact. It will be the first trial to evaluate a bedside decision support tool to assist ICU clinicians with extubation decision-making. The trial is both clinically and commercially relevant. It aims to inform the design of a future, large-scale RCT that will examine extubation outcome and improve the process of care delivery during ventilator liberation in ICUs.

PI: Dr. Rebecca Auer, Dr. Paul Karanicolas

Biotech: Qu Biologics 

Summary: PERIOP-06 is a Phase 2, multi-center, randomized, placebo-controlled study of 115 participants scheduled to undergo surgical resection of liver metastases from colorectal cancer. It is designed to establish the safety and efficacy of perioperative administration of the Site Specific Immunomodulator QBECO for the attenuation of postoperative immune suppression and improvement of progression-free survival (PFS). The hypothesis of PERIOP-06 is that QBECO will ‘train’ innate immune cells, thereby preventing postoperative immune suppression, resulting in clearance of micrometastatic disease in the early postoperative period.

Primary endpoint: Two‐year progression-free survival (PFS) rate.

Secondary endpoints: Efficacy: a) Clearance of circulating tumour (ct) DNA; b) Five‐year overall survival.
Safety: c) Side‐effect profile of QBECO; d) Quality of recovery and postoperative Morbidity.

Correlative endpoints: a) Immune cell phenotype by mutiparameter flow cytometry; b) Immune cell functional assays,

including Natural Killer Cell Activity (NKA)™, TruCulture™ immunoassays and CD33+ immune cell suppression assay; c) Serum analysis of inflammatory and anti-inflammatory proteins; d) Tumor microenvironment profiling assessing immune gene and protein expression of tissue biopsies.

Treatment: Study treatment will consist of the drug, QBECO (0.1 mL/dose) or placebo, administered by subcutaneous self-injection every second day between 11 – 120 days preoperatively and for 41 days postoperatively. Participants will be randomized 1:1 QBECO:placebo.

PI: Dr. Matthew James, Dr. Neesh Pannu, Dr. Daniel Muruve

Biotech: Arch Biopartners Inc. 

Rationale: People with a variety of chronic diseases frequently require hospitalization, where they are often administered nephrotoxic medications that result in iatrogenic acute kidney injury (AKI) in up to 30% of exposed patients. AKI is associated with several adverse outcomes including prolonged hospitalization, hospital readmission, progression to chronic kidney disease (CKD), kidney failure, cardiovascular (CV) events, and mortality. 

Question: Does cilastatin, a drug repurposed for prevention of nephrotoxic AKI, reduce clinical kidney and cardiovascular (CV) outcomes, in hospitalized patients exposed to nephrotoxic medications. 

Participants: The electronic clinical information system within hospital pharmacies in the six largest tertiary care hospitals in Alberta will be used to screen for patients initiating therapy with one or more agents that mediate AKI via kidney tubular uptake and inflammatory injury. 

Intervention: Trial participants will be randomized 1:1 to receive cilastatin or placebo, which will be administered for the duration of nephrotoxic medication exposure and continued for 24 hours following the last dose of the nephrotoxic medication. 

Outcomes: The primary outcome will be a composite of major adverse kidney or CV events at one year. Secondary endpoints will include the components of the major adverse kidney outcome (≥35% decline in glomerular filtration rate, kidney failure, or death) and CV outcomes (myocardial infarction, stroke, heart failure, or death), incidence of AKI, length of hospital stay, all-cause readmission, and death. A Vanguard phase targeting recruitment of 324 patients over one year will be completed to assess feasibility of a large full-scale trial. If successful, the full trial will require recruitment of 1,680 patients (840 each to the cilastatin and placebo arms) to achieve 90% power to detect a 20% reduction in the primary outcome based on a 30% incidence in the eligible participants in the placebo arm, with a type 1 error rate of 0.05 and allowing for a 10% loss to follow-up. 

Anticipated Impact: Nephrotoxic AKI is common and associated with poor outcomes. Cilastatin can prevent nephrotoxic and inflammatory kidney injury, with the potential to improve current approaches to care that lead to drug avoidance, which is suboptimal as it denies patients from receiving otherwise best therapies. If proven effective, cilastatin could prevent more than 10,000 episodes of AKI in Canada each year and avoid major adverse kidney and CV outcomes, saving approximately $78 million annually.

PI: Dr. Sandra Ofori, Dr. Michael McGillion

Biotech: Cloud DX

Background: Patients discharged after non-elective surgeries (i.e., semi-urgent cancer, urgent, or emergent surgeries) are at substantial risk (i.e., 25%) of post discharge acute-hospital care, i.e., emergency department visits or re-admission. We have undertaken RCTs evaluating virtual care and remote automated monitoring (VC-RAM) biotechnologies after surgery. Our VC-RAM research program has demonstrated that it is only credible to expect virtual care with RAM to impact outcomes if these interventions identify problems and lead to changes in patient management. We have gained insights into the biophysical thresholds that should be used to alert healthcare providers and the response pathways to change care and improve outcomes. We propose to undertake the PVC-RAM-2 trial to establish the efficacy of biotechnology-enabled virtual care with RAM after non-elective surgery. 

Primary Objective: Among patients who have undergone non-elective surgery, to determine the effect of virtual care with RAM on the 45-day risk of acute-hospital care (i.e., a composite of hospital readmission and emergency department or urgent-care centre visit).


Methods: We will randomize 2000 patients to virtual care with RAM or standard care as soon as possible after patients undergo non-elective surgery. Patients, health-care providers, and study staff will be aware of treatment assignment, but outcome adjudicators will be masked to treatment allocation. Patients in the experimental group will receive a tablet computer and RAM biotechnology by Cloud DX to measure their daily vital signs and weight. In the first 14 days after discharge, patients will take daily biophysical measurements and wound photographs and interact with nurses virtually. Nurses will escalate care to pre-assigned perioperative physicians if patients’ RAM measurements exceed predetermined thresholds, patients report specific symptoms (e.g., syncope), they identify drug errors, or they have concerns about patients’ health that requires a physician’s attention. Physicians will interact with patients virtually via the tablet computer, and they will add or modify treatments as appropriate. A maximum of two 7-day extensions to the virtual care with RAM intervention will be possible depending on patients’ clinical needs. In the standard care group, patients will receive post-hospital discharge management according to usual care. 

Expertise and Infrastructure: The coordinating centre is the Population Health Research Institute (PHRI), a world-leading research institute with extensive infrastructure and high-qualified personnel specializing in the conduct of large RCTs. The PHRI is linked to our new state-of-the-art virtual care with RAM research facility, the PROTECT Laboratory (funded by the Canadian Foundation for Innovation), which will serve as the central operational command centre for the trial. 

Expected Outcomes: We expect PVC-RAM-2 will demonstrate, among adults who have undergone non-elective surgery that, compared to standard care, virtual care with RAM reduces post discharge acute-hospital care. We also expect improvements in our secondary and tertiary outcomes: index length of hospital stay, medication error detection and correction, surgical site infection, post-operative pain, health services utilization-related costs, re-operation, composite of postoperative complications, death, and health-related quality of life (HRQL).

RFA 2 – Advances in the Conduct of Randomized Controlled Trials

Divided into two distinct streams, our call for proposals from RFA 2 sought to catalyze innovative research. In total, we’ve allocated substantial funding for 13 projects. Stream 1, dedicated to novel designs, boasts a total funding pool of $1.7 million across 9 projects.. Meanwhile, Stream 2, targeting SWATs, holds a funding pool of $400,000 for 5 projects.Our assessment process is tailored to each stream’s unique characteristics.

Stream 1:
The quest for unconventional yet robust trial designs that embrace efficiency without sacrificing credibility. Our emphasis remains on trials with a minimal risk of bias, providing actionable insights.

Stream 1

PI: Dr. Naveen Poonai

Rationale: Lacerations account for almost 50% of procedures in children who present to the emergency department (ED). The most effective anxiolytic is unknown. Even with consistent use of topical anesthetics, most children experience significant distress during laceration repair. Procedural distress is associated with nightmares, anxiety, aggression, and withdrawal in >50% of children for up to a week. Almost 80% of children are physically restrained by healthcare providers (HCPs) for procedures such as laceration repair, despite the anxiolytic midazolam being available for >80% of children. Restraint has moral, ethical, legal, and safety implications and can result in prolonged psychologic stress and physical trauma in children. Needle-related distress may also cause phobias that continue into adulthood, leading to avoidance of preventive healthcare such as vaccinations. Measures to manage distress during laceration repair are associated with higher caregiver satisfaction and less physical restraint. The Canadian Paediatric Society (CPS) strongly recommends managing distress during medical procedures but lacks guidance for laceration repair, which in young children, is resource-intensive, often requiring many HCPs at the bedside. Unfortunately, in the last decade, ED visits have risen by 28% while registered nurses have decreased by 34%. Intranasal midazolam (INM) is the most common anxiolytic for laceration repair in children,2 but its benefit is unclear. In some studies, INM was superior to placebo, while others reported up to 86% of children still required physical restraint. A 2022 systematic review found INM produces “sufficiently intense” sedation for laceration repair but most trials lacked validated measures of anxiolysis. Also, up to 40% of children experience severe nasal pain with administration, even with co-administered anesthetic. Newer agents, intranasal dexmedetomidine (IND) and inhaled nitrous oxide (N2O), have shown more promise. N2O is well tolerated and can be administered by nurses. Its efficacy compared to INM and IND is uncertain, but its rapid onset and offset is potentially advantageous in busy EDs. 

Question: In children 2-12 years with a laceration requiring suture repair in the ED, is INM, IND, or N2O associated with the least behavioral distress on the Observational Scale of Behavioral Distress – Revised (OSBD-R)? 

Methods: The OSBD-R will be scored by 2 independent outcome assessors using video capture of the repair. The vanguard phase will randomize 50 participants at the lead site. We will evaluate feasibility outcomes that may inform protocol modifications for a full-scale 4-center adaptive trial using a Bayesian framework to rank anxiolytics, allowing clinicians to compare their relative benefits with greater power and fewer participants. Based on an interim futility analysis, we will drop the least effective intervention, decreasing the chances of a child being randomized to a less effective anxiolytic, and enroll 159-315 participants. We will conduct an economic analysis using a Bayesian framework to weigh length of stay (LOS), and costs associated with drugs, personnel at the bedside, and managing adverse events (AEs).  

Primary Outcome: OSBD-R during laceration repair 

Feasibility Outcomes: (i) Consent rate; (ii) compliance with primary outcome; (iii) rate of follow-up Secondary Outcomes: (i) Delayed maladaptive behaviors (Post-Hospital Behavior Questionnaire (PHBQ)); (ii) need for additional anxiolytic/sedation; (iii) need for physical restraint; (iv) AEs 

Anticipated Impact: Our findings may improve the healthcare experience for children, enhance patient flow and personnel resource allocation in the ED, and showcase a novel adaptive design that can be translated to other areas. The vanguard phase will optimize recruitment and retention for the full-scale trial.

Stream 1

PI:Dr. Jason Weatherald, Dr. Lisa Mielniczuk

Rationale: Right ventricular (RV) failure is a common cause of death and disability in patients with pulmonary hypertension (PH) regardless of etiology. There are currently few effective therapies that treat RV failure and restore RV function. As such, there is an urgent need to develop new, effective treatments.

Question: Is it feasible to perform a multicentre adaptive platform trial in Canada for testing multiple potential therapies for RV failure due to PH?

Participants: Symptomatic patients with PH due to pulmonary arterial hypertension (group 1 PH), cardiac disease with normal ejection fraction (group 2 PH), lung disease (group 3 PH), or chronic thromboembolic disease (group 4 PH) with RV dilation and dysfunction on echocardiogram, elevated Nterminal

pro-B-type natriuretic peptide (NT-pro-BNP) levels, and who are on stable therapies for underlying PH for at least 1 month.

Interventions: 30 patients will be randomized 1:1:1 to empagliflozin 10 mg daily, ranolazine 500 mg twice daily increasing to 1000 mg twice daily, or placebo plus standard of care.

Outcomes: The primary outcome is feasibility, defined as 1) The proportion of eligible patients approached that consent (target >50%), 2) The proportion of patients who consent that are randomized (target >90%), 3) Average enrolment rate per centre (target 1 patient per centre/month), 4) Loss of follow

up (target at 16 weeks <5%), 5) Ability to capture data for secondary outcomes (Target >95% completion). Secondary outcomes are changes in RV function on echocardiogram, NT-pro-BNP, feasibility and validity of remotely measured 6-minute walk distance with a novel app (Walk.Talk.Track.), patient-reported outcomes, clinical events, and safety/tolerability. In parallel, we will develop and validate a large language model approach to identifying potentially eligible participants based on echocardiogram reports from a community-based echocardiography lab.

Anticipated impact: RV failure is a devastating complication of PH with few treatment options, often resulting in morbidity and mortality. A platform trial design is ideally suited for testing several existing and novel therapies in heterogeneous populations with RV failure. This feasibility trial will set the stage

for a phase 2 CRAVE platform trial, which can improve efficiency over existing approaches and potentially transform the clinical trials landscape in PH and RV failure. Our Canadian network is well positioned to launch and execute this complex initiative based on our highly centralized care structure, a patient-oriented national network of clinical and research centres, and a well-developed pre-clinical pipeline that can feed into the CRAVE platform to test novel future discoveries.

Stream 1

PI: Dr. Samuel Silver, Dr. Amber Molnar

Dial-Bicarb Trial Summary

Background and rationale: Hemodialysis is a life sustaining treatment for people with kidney failure, but many aspects of hemodialysis care lack high quality evidence. One of the critical functions of dialysis is correction of metabolic acidosis. This is achieved by adding bicarbonate to the dialysis solution (dialysate). However, the optimal concentration of dialysate bicarbonate is unknown, and the current concentrations used are highly variable across hemodialysis centres. Observational data suggest when the concentration of dialysate bicarbonate is too high, it may increase the risk of death and hospitalization, but when the concentration is too low, it fails to correct metabolic acidosis.

Research question: In outpatients receiving maintenance hemodialysis, does providing a higher vs. lower dialysate bicarbonate concentration (38 mmol/L vs. 32 mmol/L) as a centre policy alter the risk of all-cause non-elective hospitalization (treated as a recurrent event) or all-cause mortality?

Methods: We will conduct a pragmatic, registry-based, open-label, cluster-randomized trial with altered patient consent that will be embedded into routine care in hemodialysis centres across 5 provinces. The trial has been codesigned with patients as full partners. We will efficiently obtain information on patient characteristics and outcomes from large administrative databases. The vanguard phase of this trial will take place in 20 (~25%) hemodialysis centres across Ontario (sites of Drs Silver, Molnar, and Garg), including a pre-specified subgroup of 100 patients in whom we will obtain patient consent for post-dialysis bloodwork (post-dialysis labs are not routinely done) to measure the relationship between the dialysate bicarbonate concentration and post-dialysis pH, bicarbonate, and other electrolytes.

Potential impact: If a lower dialysate bicarbonate concentration is shown to be superior, it could be easily adopted as the standard of care by hemodialysis units globally at no added cost. Our research team has conducted pragmatic trials in hemodialysis populations using this approach (clinicaltrials.gov NCT04079582 and NCT02628366), which is inclusive (very few patients are excluded), cost-efficient, and methodologically robust (i.e., low risk of bias). The vanguard phase of Dial-Bicarb will ensure intervention fidelity and acceptability in 20 Ontario hemodialysis units before wider trial activities nationally, as well as further develop experience in cluster-randomized registry-based trials that can be translated throughout the ACT Consortium.

Stream 1

PI: Dr. Ann Young

KidneyCareOutreach Trial Summary

Rationale: Despite efforts to improve the recognition of chronic kidney disease, late referrals for specialized kidney care continue to be a problem. Many at-risk individuals in the population are not receiving evidence-based therapies that could significantly slow their disease progression. To help address this, we designed a new KidneyCare Outreach program that will connect individuals at high risk of kidney failure with specialist care. Our 2-year pilot trial will assess program feasibility and process-of-care outcomes. The pilot will serve as the vanguard phase for a larger trial designed to prove that our KidneyCare Outreach program versus usual care reduces the incidence of kidney failure. 

Objectives: To assess the feasibility of our KidneyCare Outreach program features and to compare process-of-care outcomes between individuals randomly allocated to the intervention vs. usual care. 

Participants: Adults in Ontario with a 2-year predicted risk of kidney failure ≥25% or an estimated glomerular filtration rate (eGFR) ≤15 mL/min per 1.73 m2 who are not receiving nephrologist care. We will identify all eligible adults in Ontario using a case-finding algorithm applied to administrative healthcare data at ICES. The sample size for the pilot trial will be 200 eligible individuals with complete contact information. 

Intervention: A concealed allocation scheme will be generated at ICES and eligible individuals will be randomly assigned 1:1 to the intervention group or usual care (control group). Those in the intervention group will be contacted and invited to participate in the KidneyCare Outreach program. Those who agree to participate will complete confirmatory lab tests, be assessed by a trial nephrologist via telemedicine, and be referred to a local nephrologist for ongoing management. 

Outcomes: Key program features (assessed in the intervention group only) will include the contact-to-enrollment ratio, intervention uptake, and the positive predictive value of the case-finding algorithm. Process-of-care measures (assessed in both the intervention and usual-care groups using ICES data) will include outpatient nephrology assessment and new use of kidney-protective medications. 

Impact and Innovation: The KidneyCare Outreach program is designed to serve as a health system safety net for individuals who have not received adequate care for a life-threatening illness. Our trial will provide proof of concept for the novel use of administrative health data to identify high-risk individuals and connect them with specialized care. If successful, this approach may be used more broadly for the early detection of other serious health conditions that can be identified using administrative healthcare data. Our research will also support the modernization of privacy legislation for the judicious use of these data for better patient healthcare.


Stream 1

Dr. Corinne Hohl

Rationale: Coronavirus Disease 2019 (COVID-19) has become endemic and continues to incur substantial acute care resources: Over 5,000 patients were continuously admitted to Canadian hospitals in the winter of 2022/23. Nirmatrelvir/ritonavir (Paxlovid®, called nirmatrelvir) is the only licensed oral therapy for patients with mild to moderate COVID-19 to prevent progression of mild to moderate COVID-19 to severe disease. However, nirmatrelvir has never been evaluated for patients discharged from Emergency Departments (EDs) and remains under-prescribed. This, even though ED discharged patients are at high risk for developing severe disease, Post COVID-19 Condition (PCC), and have 15-fold greater mortality than patients who never seek care in EDs. 

Question: Among adults with mild to moderate COVID-19 who are discharged from EDs is treatment with nirmatrelvir more effective than standard care in reducing a composite endpoint of COVID-19-related hospitalization or mortality at 28 days? 

Participants: We will enroll adults 18-49 years old with mild to moderate COVID-19 and >1 comorbidity who are discharged from an ED, and adults >50 years of age with mild to moderate COVID-19 regardless of comorbidity status. We will exclude patients who meet provincial nirmatrelvir prescribing guidelines. 

Intervention: Nirmatrelvir for a 5-day oral treatment course initiated within 5 days of symptom onset. 

Outcomes: The primary outcome for the pilot trial will be the mean monthly recruitment rate. The primary outcome for the final trial will be a composite of COVID-19-related admissions or mortality; secondary outcomes include PCC, all-cause hospitalization, all-cause mortality, adverse events, and health service use. 

Methods: We are working in close partnership with CanTreatCOVID, a CIHR-funded pan-Canadian adaptive platform trial in primary care to develop a national, pragmatic, individually randomized, open-label ED-based adaptive platform trial. We will evaluate nirmatrelvir as the first treatment arm. A Trial Steering Committee (TSC) will recommend additional treatment arms as new therapeutic agents become available. Patients randomized to the control arm will receive standard care. We will calculate the mean monthly recruitment rate for the proposed pilot and aim to recruit 100 patients from >5 study sites to demonstrate feasibility of the final trial. The primary analysis of the final trial will be a Bayesian logistic regression model stratified by age and vaccination status following intention-to-treat. Given the Bayesian approach, there is no pre-defined sample size. 

Anticipated Impact: EDs are critical access points for the healthcare system for patients with acute respiratory syndromes. The pilot will determine the feasibility of an ED-based adaptive platform trial to evaluate therapies for mild to moderate COVID-19 which would be implemented at 51 CCEDRRN EDs in 8 provinces. The results of the final trial will be applicable to the >13,000 COVID-19 patients per month being discharged from EDs across Canada, while enhancing pre-pandemic preparedness.

Stream 1

PI: Dr. Kristin K Clemens, Dr. Louise Moist

 Rationale: Over half of patients with type 2 diabetes (DM2) live with obesity.1 Obesity not only contributes to cardiovascular events and glycemic complications,2 but mounting evidence supports its causal role in the risk and progression of kidney disease including end-organ failure (end-staged kidney disease or ESKD).3 Obesity can also disqualify patients from accessing life-saving kidney transplantation.4 We have no evidence on how to effectively support weight loss in people with DM2 and advanced CKD (estimated glomerular filtration rate or eGFR <30 ml/min/1.73m2), in a patient-centered and accessible manner. 

We propose a vanguard study to understand the feasibility of conducting a large, pragmatic randomized controlled trial (RCT) on the effectiveness of a weight management program (WMP) in DM2, obesity and high-risk CKD. The primary outcome of our multijurisdictional trial will be % weight change from baseline, with secondary outcomes focused upon access to transplant, cost effectiveness, glycemic control and quality of life. Before proceeding with a multi-site trial of thousands of patients, we will conduct a vanguard study to answer the following questions: 

1) Is participant recruitment into a large multi-centered trial feasible?. 

2) Will participants remain adherent to their assigned treatment arm over 6 months? 

3) Will participants find our program acceptable? 

4) Will safety events preclude us from testing our intervention in a larger RCT? 

Hypothesis: We hypothesize that a large, pragmatic RCT of a co-developed WMP will be feasible, that participants will remain adherent to their treatment assignment, that our program will help patients reach a threshold body mass index (BMI) <35 kg/m2 for transplantation (target measure of most transplant programs),5 and that our WMP will be acceptable and accessible to real-world patients. 

Participants: Adults aged 18 years or older with established DM2, a body mass index (BMI) >35 kg/m2,5 and a >10% risk of ESKD (Kidney Risk Factor Equation) requiring renal replacement therapy in 2 years. 

Intervention and control: Co-developed WMP that offers nutritional support (balanced kidney/DM diet with an aim for 500 kcal deficit/day), subcutaneous weekly semaglutide (minimum 0.25 mg per week), tailored behavioral recommendations, and an individualized

exercise plan. The program will be administered every 4-8 weeks by telemedicine, for a total duration of 6 months. The control arm will receive usual care (usual dietary and exercise advice recommended by kidney care team).

Outcomes: Primary feasibility outcome: Recruitment of at least 60 participants from three clinical centers over 12 months. Secondary outcomes: 1) >75% drug adherence (i.e. semaglutide) in the intervention arm, with <25% cross-over (i.e. initiation of semaglutide) in the usual care arm, 3) Acceptability of intervention to participants of different demographics, gender identities, races and socio-economic backgrounds, 4) Adverse events including kidney injury (AKI), hypoglycemia, gastrointestinal side effects, and frailty (Clinical Frailty Scale).

Anticipated impact: Successful conduct of OK TRANSPLANT-1 will lay the groundwork for a multicentered, pragmatic RCT that uses the same methods and data sources, but on a much larger scale. This trial will have the potential to improve access to transplantation, health and quality of life.


Stream 1

PI: Dr. Emilie Belley-Côté, Dr. Richard Whitlock

Rationale for Stream 1: Recurrent events, particularly hospitalizations, are common in patients with cardiovascular disease. Repeat events are often ignored in cardiovascular trials in favour of time to first event which reduces the power for a given sample size and ignores patients’ true experience as well as the burden to health-care providers and health systems (both on resources and on finances). As one of the first large trials using a total events analysis, SAFE will lead the way for future trials that are more efficient, requiring a smaller sample size and shorter follow-up.

Background: Atrial fibrillation (AF) is a tachyarrhythmia that impairs cardiac function and, over time, causes the left atrium to dilate and lose its transport function promoting thrombus formation. AF ablation is the creation of scars to the atrial tissue to try and disrupt the faulty electrical signals causing

arrhythmia. Restoring sinus rhythm through surgical ablation of AF may prevent cardiovascular complications such as heart failure and stroke. Of the 10% of patients undergoing cardiac surgery who have AF, only one third receive concomitant AF ablation. Despite promising observational data and small randomized controlled trials, AF ablation’s benefit has never been definitively confirmed. Cardiac surgery provides the only opportunity to study AF ablation in a blinded manner, generating important data for the cardiac surgery and arrhythmia fields.

Study Design and Methods: The Surgical Ablation of Atrial Fibrillation Efficacy (SAFE) trial will evaluate whether concomitant surgical AF ablation in adult patients with a history of AF undergoing cardiac surgery impacts hospital readmissions with heart failure. Patients with persistent or paroxysmal AF will be eligible. Before cardiac surgery, participants will be randomized to surgical AF ablation or no ablation. All participants will undergo left atrial appendage occlusion, receive antithrombotic and heart failure therapies according to guidelines, and will be followed for a median of 4 years.

Objectives and Outcomes: The primary objective of the SAFE vanguard trial is: Is a large trial evaluating the impact of concomitant surgical AF ablation feasible? The feasibility outcomes are: 1) The average enrolment rate of 3 patients per centre per month, 2) the proportion of patients that crossover is <5%. The primary objective of the SAFE main trial is to examine the impact of concomitant surgical ablation of AF on hospital readmissions for heart failure. Other important outcomes include death, stroke, freedom from atrial tachycardias and quality of life measures.

Sample Size and Statistical Considerations: The SAFE vanguard trial will enroll 100 patients. Unless there are major protocol changes, these patients will be rolled in the main trial. The sample size for the SAFE main trial is 2000. The LAAOS III trial suggests that 11% patients have 1 or more hospital readmission for heart failure at a median of 3.8 years of follow-up. We estimated the negative binomial dispersion parameter and the common baseline hazard using Weibull distribution parameters for sample size calculation. Using 𝛂 = 0.05, and treating the outcome as a recurrent event, we used Cox proportional hazards models as extended by Andersen-Gill to calculate the sample size. SAFE will enroll 2000 patients which will provide 85% power to detect a 30% relative risk reduction.


Stream 1

PI: Dr. Jessica Spence, Dr. Deborah Siegal

Rationale: About 50% of patients undergoing cardiac surgery require red blood cell (RBC) transfusion, with an average of 3 RBC units administered per patient. Given the limited blood supply and harms of transfusion, evidence-based blood conservation strategies are a priority. Retrograde autologous priming (RAP) is a simple technique whereby the patient’s own blood, rather than crystalloid fluid, is used to prime the cardiopulmonary bypass (CPB) circuit, thereby minimizing hemodilution, a potentially modifiable contributor to RBC transfusion. In small randomized controlled trials, RAP reduced the incidence of RBC transfusion by 40% and the mean number of RBC units transfused by 38%. However, RAP is not routinely used due to uncertainty about overall benefit and potential harms. Routine RAP may be beneficial, but this needs to be confirmed in a large pragmatic randomized trial. The goal of this vanguard pilot trial is to assess the feasibility of a full-scale multicentre randomized cluster crossover trial to determine whether an institutional policy of routine RAP reduces the number of RBC units transfused up to 72 hrs after cardiac surgery compared to crystalloid priming. Provided no major protocol modifications are required, vanguard participants will be included in the full trial, for which we will seek separate funding after proving feasibility.

Study population: Hospitals (clusters) conducting ≥200 adult cardiac surgery cases per year will be eligible for inclusion. All adult patients undergoing cardiac surgery on CPB in a participating hospital during the trial period will be included through a waiver of individual participant consent.

Interventions: TheRAPy will compare 2 hospital-based policies for the initiation of CPB:

Routine RAP Policy (intervention) 

(i) Use of arterial and venous autologous CPB priming in all adult patients undergoing cardiac surgery (minimum 300mL)

(ii) Crystalloid priming acceptable for patients with a contraindication to RAP (≤ 10% expected)

Crystalloid Priming Policy (control)

(i) Use of crystalloid priming in all patients undergoing cardiac surgery

(ii) RAP acceptable in patients with a contraindication to crystalloid priming (≤ 10% expected)

Outcomes: Primary feasibility outcome: the mean proportion of patients managed per assigned policy (i.e., protocol adherence), defined at the center-level during 12 x 4-week crossover periods (progression criterion ≥90% in each arm). Primary outcome of full-scale trial: mean number of RBC units transfused up to 72 hours after cardiac surgery per patient within a centre.

Sample size: Each of the 4 sites enrolled in this pilot vanguard trial will complete 12 separate 4-week crossover periods. Based on known case volumes, we anticipate a sample of ~4,500 patients.

Impact: Cardiac surgery accounts for a substantial proportion of the ~1 million units of RBCs transfused in Canada each year. Assuming conservatively that 10% of RBCs in Canada are used in cardiac surgery and that RAP reduces transfusion by 10%, universal implementation would save 9,250 RBC and $7,000,000 each year.


Stream 1

PI: Dr. Sylvie Aucoin

Rationale: More than 100,000 Canadians with frailty have surgery each year and experience a 2- to 5-fold increase in adverse events (AEs) and impaired recovery. Many of these AEs occur around the time of transition home from hospital, a time where patients and caregivers express the need for improved continuity and support to ensure they can effectively recover from surgery.  

Question: The VICTORY Pilot Trial will assess the feasibility of a frailty-specific Virtual Recovery After Surgery (VRAS) to improve patient-centered outcomes for surgical patients with frailty. This multicenter vanguard trial will directly inform the future, fully powered VICTORY Trial, which will employ registry linkage and sequential Bayesian learning, to innovatively estimate the efficacy of frailty-specific VRAS to increase the number of days alive and at home experienced by surgical patients with frailty. 

Participants: People >60 years with frailty (CFS>4) having planned, inpatient non-cardiac surgery. 

Intervention: A frailty-specific VRAS program, based remote monitoring (vital signs and wound assessment) plus virtual nursing care and ‘4Ms’ geriatric assessment will be used to follow surgical patients with frailty for up to 14 days after discharge. 

Control: Control participants will receive institution-standard surgical and post-discharge care. 

Outcomes: Vanguard outcomes reflect trial feasibility (enrollment, intervention fidelity, complete follow-up). Full trial outcomes will include Days Alive at Home 30-days (primary); resource use (length of stay, readmissions, total hospital days, ED use), patient-reported (delirium, quality of life, pain interference, satisfaction, goal attainment) and safety (medication adverse events). 

Anticipated Impact: The results of this 96-patient, 3-center vanguard randomized trial will directly inform the feasibility of a full multicenter trial powered for patient-centered and important outcomes, including whether we are likely to meet minimal (based on precision from the lower limit of the 95% confidence interval) enrollment (>20%), intervention fidelity (>7 complete assessments per participant) and complete follow-up (>90%). Results of the VICTORY vanguard will be disseminated to key stakeholders (e.g. Ontario Ministry of Health Surgical Transitions working group) and our Canadian network of centres delivering VRAS. As such, we will be positioned to complete the full VICTORY Trial, which will address key, high-priority knowledge gaps relevant to one of the most vulnerable groups who routinely have surgery (i.e., those with frailty).  prioritized by patients (having adequate support and continuity to achieve improved recovery resulting in more time at home), the clinical community (evaluation of frailty-specific interventions for surgical patients with frailty), and the healthcare system (improving outcomes and reducing resource use). Furthermore, use of a virtual care model aligns with ongoing, systematic changes to healthcare delivery in the 21st century.

Stream 2:
The focus here is on generating sound evidence that enhances trial conduct. We sought interventions that streamline processes, elevate participant engagement, and elevate data quality. Stay tuned as we usher in a new era of innovative trial designs and methodologies that will transform how we approach clinical research!

Stream 2

PI: Dr. Sylvain Lother

CAPTIVATE is a multi-centre, open-label, study within a trial (SWAT) which is nested within 3 large Canadian adaptive platform trials (APTs) that will innovate the conduct of future randomized controlled trials (RCT) by improving informed consent methods. Traditional RCT informed consent forms (ICF) are lengthy, complicated, and structured to mitigate institutional legal risk. They aren’t easily modifiable to suit the needs of APTs where complex trial procedures are encountered, and frequent trial adaptations are needed. Study question: Can a novel, patient-centered, modular audiovisual consent method be applied across different APTs, and does this novel consent strategy improve patient-perceived acceptability of the consent process compared with standard ICFs? Participants: Patients who screen eligible for one of three Canadian APTs, including AntiThrombotic Therapy to Ameliorate Clinical Complications in Community Acquired Pneumonia (ATTACC-CAP), Platform of Randomized Adaptive Clinical Trials in Critical Illness (PRACTICAL), and Randomized Embedded Multicenter Adaptive Platform Trial for Community Acquired Pneumonia (REMAP-CAP) will be approached for enrolment. Patients who are able to provide first person consent, or their authorized 3rd party, will be eligible. Intervention: Participants will be randomized 1:1 to receive a novel consent method or the standard ICF. Those randomized to the novel consent group will have their choice of viewing a video consent or reviewing a pamphlet that is predominantly composed of infographics with brief text. Outcomes: The primary outcomes will be participant-perceived evaluation of the consent process. A 10-question brief survey will be administered following the consent decision to evaluate the process and acceptability or burden of the consent process. Secondary outcomes will include participant knowledge (based on recall questionnaire), consent decision for the parent RCT, and research staff satisfaction with the informed consent process. Time to a consent decision and research personnel time to administer consent will also be recorded. Anticipated impact: This SWAT will democratize the consent process of future RCTs by influencing key stakeholders away from institutionally derived ICFs, in favor of innovative consent processes informed and designed by patients. It will provide a consent template which can be customized to future APTs, to reduce the burden on patients and research teams, to enhance the understanding of consent elements, and to improve recruitment, retention, and scientific discoveries for the future.

Stream 2

Dr. Paul Karanicolas

Background/Rationale: Patient-reported outcome measures (PROMs) are a crucial component of pragmatic, patient-centered clinical trials. Traditional methods to complete PROMs (i.e. paper- based) are resource-intensive and prone to error. Technology allows integrated, online capture of      PROMs through email and text messages directly to trial participants, but response rates with these methods are suboptimal, limiting applicability. Better strategies to improve completion of online PROMs are vital to ensure trial validity and maximize efficiency of trial conduct. We propose a study within a trial (SWAT) to test specific interventions to maximize the response rates of PROM surveys. 

Questions: 1) What is the effect of using different tones in email reminders to participants on the PROM response rate? 2) What is the effect of offering participants a monetary or non-monetary incentive on the PROM response rate? 

Study Design, Participants and Interventions: This SWAT will use a two-by-two factorial randomized controlled trial (RCT) design. Participants will be randomized to receive a duty-laden or encouragement-laden reminder if they do not respond to the initial PROM survey, and a small monetary (gift card) incentive or non-monetary (entry into a lottery) incentive upon completion of their PROM survey. Clinical Evaluation of Adults Undergoing Elective Surgery Utilizing Intraoperative Incisional Wound Irrigation (CLEAN Wound), the parent trial for this SWAT, is a multicentre, pragmatic, participant and adjudicator-blinded, three-arm RCT examining the effect of intraoperative incisional wound irrigation on the incidence of surgical site infection in patients undergoing abdominal surgery. It is fully funded and is primed to begin recruiting across 15 sites in Ontario imminently with a total sample size up to 2500 participants (Clinicaltrials.gov registration: NCT04548661). 

Outcomes: Proportion of complete responses received, participant perception of interventions .

Anticipated Impact: Improved trial efficiency and quality through proficient and complete data collection.

Stream 2

PI: Dr. Nick Daneman

Rationale: Existing RCT consent forms are long, complicated, and may overwhelm patients with too much information. This can lead to counter-productive effects such as deterring patients from participation, or unintentionally discriminating against patients with less privileged backgrounds. 

Research question: For potential participants (or surrogate decision makers [SDMs]) of a large platform trial, does use of a simplified layered consent process compared to a conventional consent form lead to an increased informed consent rate without compromising participant understanding and satisfaction? 

Study design: This study is a pragmatic, multi-centre, open-label, two-arm parallel-group RCT, nested within the larger Staphylococcus aureus Network Adaptive Platform (SNAP) trial at select sites in Canada. Participants will be all potential participants of the SNAP trial at participating sites. SDMs will be approached for potential participants with no decision-making capacity. 

Interventions: In the experimental arm, the simplified layered consent process will be used, where summarized information is provided in a 4-page concise information sheet, with links to additional information that can be accessed separately for those who wish to read more. In the control arm, the conventional informed consent form (ICF) will be used, with all information provided upfront.  

Outcomes: Primary outcome will be recruitment into the SNAP trial. Secondary outcomes are a) participant satisfaction with consent process, b) research staff satisfaction with consent process, c) time taken for entire consent process, and d) participant understanding of the clinical trial. 

Anticipated Impact: We expect the results of this trial to be broadly applicable to comparative effectiveness trials across all disciplines. We are hopeful that simplified consent processes would lower the barrier for trial entry for more diverse population groups, improve trial efficiency by streamlining consent processes with potential savings in terms of resources and human effort, and provide a more positive patient experience with a patient-centred approach to consent.

Stream 2

PI: Prof. Shrikant Bangdiwala, Prof. Susan Jack

Rationale: Recruitment of participants into randomized controlled trials (RCTs) is challenging, and when experienced, there have been few approaches to systematically identify barriers, followed by the implementation of strategies to enhance recruitment. The ongoing Bariatric surgery for the Reduction of cArdioVascular Events (BRAVE) trial is the first large RCT examining the effects of bariatric surgery compared to medical therapy on cardiovascular disease (CVD) and mortality in patients with severe obesity and known CVD. To-date, methodological and clinical challenges have inhibited recruitment. These challenges include navigating multidisciplinary teams involving different health care professionals, and the need for multiple, complex medical investigations to assess suitability for bariatric surgery. We initiated a vanguard phase to assess feasibility of enrolment (target enrolment of 1.0 per center per month), but to date, only 2 out of the 8 recruiting centers have met this target.  

Methods: This protocol outlines a “study within a trial” (SWAT) to the BRAVE trial, that consists of three components: 1) a qualitative descriptive study to identify context-specific factors that influence recruitment; findings from this component will then inform; 2) the identification of clear obstacles and hidden barriers followed by the development of strategies to minimize these and enhance recruitment; and 3) the implementation and evaluation of these strategies using a modified stepped wedge RCT design. The approach will be based on the Qualitative Recruitment Intervention (QRI), which has been used in several previous trials in the United Kingdom (UK), where recruitment difficulty was anticipated. While the QRI has shown promising increases in recruitment, it has not been evaluated using a randomized controlled approach, as traditional designs are not suitable. In our proposal, we will use a novel randomized design (Stepped Wedge In Flexible baTches – or SWIFT) to evaluate and implement a process similar to the QRI (mod-QRI) to enhance recruitment in BRAVE.

Question: The overall objective is to formatively develop (using qualitative methods) and test a novel intervention, tailored specifically to the BRAVE trial, to address barriers and improve the rates of recruitment across about 16 centers. Our questions are: a) What are the factors (patients, health care providers and systems) that influence the enrolment of individuals with severe obesity and known CVD into BRAVE; b) What are the possible strategies to minimize barriers and maximize facilitating factors; and c) Are these strategies effective in enhancing recruitment into the trial?

Participants: Patients with severe obesity (BMI>35) and CVD at 16 centers.

Intervention: A complex, multifaceted intervention to improve recruitment by overcoming barriers to enrolment of patients in BRAVE.

Outcomes: Rates of consent to participate in the BRAVE RCT.

Anticipated Impact: Meaningful (20% to 25%) increase in current rates of consent after implementation of the mod-QRI.

Stream 2

PI: Dr. Balpreet Singh

Rationale: Approaching families regarding research opportunities in a Neonatal Intensive Care Unit (NICU) comes with significant challenges. Families are particularly vulnerable during a NICU stay, as are their babies. While this is often a difficult time for families, recruiting infants that require NICU care for research studies is essential to the ongoing improvement of care and can provide families with a sense of involvement/purpose during a particularly stressful time. The general public often does not have a well-rounded understanding of how research and clinical trials can inform healthcare practices and can struggle to consume and comprehend complex clinical trial details shared during their NICU stay. Providing families with easy-to-consume clinical trial information may improve recruitment rates to large, randomized control trials (RCTs) in high-risk health environments.  

Research Question: Does the use of a digital media intervention (2.5-3 min. video) targeting parent-reported questions regarding a complex RCT improve the overall recruitment rate for a large RCT  (WHEAT International Trial) taking place in 16 NICUs across Canada? 

Participants: Parents/Primary caregivers approached for participation in the WHEAT International Trial; those with infants born at <30 weeks gestation at participating Canadian NICU sites.  

Intervention: Participating NICU sites will be randomized to either the Video arm (intervention) or the No-Video arm (comparator). Those in the Video arm will provide approached families with trial information through their usual consent approach (informed consent/opt-out consent documents) and a QR code linking to a 2.5-3-minute video. The video will be co-developed with a parent-partner group and will utilize digital media to highlight the importance of research in NICUs and share trial-related details in an easy-to-consume, visually appealing way. Sites in the No-Video arm will give approached families trial information through their usual informed consent/opt-out consent documents. All approached families will complete a short questionnaire of open-ended questions regarding trial comprehension and experiences with the consenting process. 


  • Primary Outcome – Rate of refusal to participate in the WHEAT International Trial pre-randomization. 
  • Secondary Outcomes – 1) Rate of withdrawal from the WHEAT International Trial post-randomization; 2) Parental comprehension of trial-specific details; 3) Parental experience with the consent process 

Anticipated Impact: If results show that the developed video reduces the refusal rate for participation in a large RCT such as the WHEAT International Trial, the video could be easily replicated for future trials to improve recruitment rates and parental understanding of clinical trial details.  

RFA 1 – Supporting the Completion of High-Impact Randomized Controlled Trials

We received 43 outstanding applications from across Canada.  We undertook a targeted peer review process whereby each application was reviewed and scored by 5 independent individuals, who had previously led a high-impact clinical trial.  24 experts in relevant clinical trial fields were identified and agreed to serve as reviewers.  Each application was reviewed separately by five of these expert reviewers and scored according to:

  • The trial will be publicly reported by January 15, 2025 (mark: 30 out of 100)
  • The trial is high-quality in its design and execution (mark: 30 out of 100)
    e.g., concealed random allocation, complete follow-up, complete data collection, adequate statistical power for meaningful effect.
  • There is a high probability that the trial will lead to meaningful impact (mark: 40 out of 100) e.g., intervention likely to improve the effectiveness, safety, people-centeredness, timeliness, equitability, efficiency, or integration of care.

Mean scores for each application were calculated and applications were ranked.  The top 10 ranked applications were each awarded their requested budget.  The 11th ranked application became eligible for funding due to some successful applications that requested budgets less than $200,000.

  • ACHIEVE: Aldosterone bloCkade for Health Improvement EValuation in End-stage renal disease (ACHIEVE) trial
    Dr. Michael Walsh

    Trial Summary 

    Background: Globally, 2.5 million people with kidney failure receive dialysis, 6 million more would receive dialysis if it were accessible and these numbers are projected to triple over the next 15 years. Although dialysis is lifesaving, the median survival is less than 4 years. Cardiovascular disease is common and accounts for over half of deaths. Treatments to prevent cardiovascular deaths by controlling risk factors for atherosclerotic disease did not demonstrate benefits. However, antagonizing the mineralocorticoid receptor, a treatment for heart failure, appears promising in small trials. 

    We are determining if spironolactone, an inexpensive, widely available mineralocorticoid receptor antagonist reduces cardiovascular deaths and heart failure hospitalizations in patients with kidney failure in an international, placebo controlled, randomized controlled trial called the Aldosterone bloCkade for Health Improvement EValuation in End-stage renal disease (ACHIEVE). 

    Methods: ACHIEVE is an international, randomized, placebo-controlled trial enrolling people with kidney failure receiving dialysis (end-stage kidney disease). Eligible participants enroll in an open label run-in to assess tolerance of and adherence to spironolactone 25 mg daily. Participants that are eligible after run-in are randomly allocated to either spironolactone 25 mg daily or matching placebo. Follow-ups occur at 3 and 6 months then 6 monthly thereafter concentrating on assessing safety, encouraging study medication adherence, ascertaining outcomes and resupplying study medication with a subsample undergoing biobanking of serial blood samples from run-in to the end of the first year. 

    Eligibility: Eligible participants are ≥45 years or ≥18 years with diabetes mellitus (ensures participants are at risk of cardiovascular death), have received dialysis for at least 90 days (ensures dialysis is not temporary) and receive hemodialysis at least twice weekly or peritoneal dialysis at least daily (ensures true kidney failure and risk of cardiovascular death). Participants who have recent severe hyperkalemia, develop severe hyperkalemia during run-in, are non-adherent to the run-in medication, have a scheduled kidney transplant, a sensitivity to spironolactone, an absolute indication or contraindication for spironolactone, a life expectancy less than 6 months, or are pregnant or breastfeeding are excluded from ACHIEVE (to ensure safety and the possibility of benefit). 

    Intervention: Participants are randomly allocated to either spironolactone 25 mg daily or matching placebo. The dose of spironolactone is based on positive results in prior small trials in dialysis and the mean dose received in prior trials of mineralocorticoid receptor antagonist trials in heart failure trials. Participants who are unable to tolerate the full dose after randomization have the option to reduce the dose, temporarily or permanently, to 25 mg thrice weekly. 

    Outcome Measures: The primary composite outcome is cardiovascular death or hospitalization for heart failure. Secondary and tertiary outcomes include, cardiovascular death, hospitalization for heart failure, all cause death, all cause hospitalization, hospitalization for hyperkalemia, health related quality of life, dialysis recovery time, new onset atrial fibrillation, stroke and myocardial infarction. 

    Follow-up and Duration of Study: Participants are enrolled in 49 to 100 day active run-in period. Eligible participants are then randomly allocated and seen at 3 months, 6 months and then 6 monthly to the end of the trial (follow-up range between 1 and 7 years; median follow-up 3 years). 

    Sample Size: ACHIEVE is event driven with 650 primary outcome events required to identify a hazard ratio of 0.75 with 90% power. After accounting for non-adherence, kidney transplantation, losses to 

    follow-up and the length of the enrollment period, a total of 2500 participants randomized are required with a median follow-up of 3 years.

  • ARTESIA: Trial Apixaban for the Reduction of Thrombo-Embolism in Patients with Device-Detected Sub-Clinical Atrial Fibrillation
    Dr. Jeff Healey

    Trial Summary 

    ARTESIA is a randomized-controlled, double-blind, double-dummy trial comparing Apixaban (at guideline-indicated dosing) versus Aspirin (80-100 mg/day) in patients with pacemaker or defibrillator-detected sub-clinical AF lasting between 6 minutes and 24 hours in duration 4. Eligible patients could not have a history of clinical AF or atrial flutter, or another indication for chronic anticoagulation (e.g. mechanical heart valve). Patients must also have a history of stroke, TIA or systemic embolism, OR be over the age of 75 years; aged 65-74 years with at least 2 additional stroke risk factors*; or aged 55-64 with 3 additional stroke risk factors*. (* stroke risk factors are: hypertension, heart failure, diabetes mellitus, female sex or coronary/peripheral arterial disease). Patients could not have severe kidney disease (eGFR < 25 mL/min) or serious bleeding in the prior 6 months. 

    Patients are followed every 6 months for the primary efficacy outcome of stroke (all-cause) or systemic embolism. The outcome of stroke includes neurologic events lasting < 24 hours if there is evidence of stroke on brain imaging. The primary safety outcome is major bleeding (using the ISTH definition), which will also be sub-classified based on severity and outcomes. Several secondary outcomes include all-cause and cardiovascular mortality, and a 1000-patient sub-study will evaluate the effect of randomized therapy on cognitive function, using serial measures of the Montreal Cognitive Assessment (MoCA). 

    ARTESIA, which is coordinated by the Population Health Research Institute in Hamilton, Ontario, and will complete its follow-up of 4012 patients by August 2023. Its principal investigator is Dr. Jeff Healey, who is a Canadian citizen from McMaster University, who is a member of CSPIN (The Canadian Stroke Prevention Intervention Network). Close-out activities, data cleaning and statistical analysis will take place in the summer/fall of 2023, with a plan to present the results at the American Heart Association Sessions in November 2023 and have a simultaneous publication in a top journal. 

    The circumstances of the COVID pandemic created many hardships for ARTESIA, which have contributed to it being in a significant financial deficit despite CIHR, CSPIN and industry (BMS/Pfizer and Medtronic) funding. It is an investigator initiated and sponsored study, so no additional funds were available from industry, particularly since the study drug is now off-patent. At present, over one million dollars of deficit is being marked against budget residuals from the PIs’ other trials and salary support awards. 

    Enrollment in ARTESIA slowed dramatically during the pandemic, and the completion of enrollment was delayed approximately 1 year, finishing in July 2021. This delay lead to a corresponding increase in central coordinating costs. The restrictions on in-person visits and concerns that the predominantly elderly subjects in ARTESIA had about discretionary visits to the hospital posed great challenges for study drug re-supply. However, thanks to engaged local research assistants, strong national leaders and innovative research staff at PHRI, the number of patients coming off study drug due to re-supply challenges was kept to an extremely small number. While vital to preserving the integrity of this clinical trial, these strategies (which often involved shipment of medication) were costly. Additional costs were also incurred to ascertain patient status, since many were not attending clinic or study visits.  

    Funds from this ACT grant competition will close the funding shortfall due to these multiple circumstances. 

  • B-Free: Benzodiazepine-free cardiac anesthesia for reduction of postoperative delirium
    Dr. Jessica Spence

    Background: Delirium is an acute disorder of cognition and attention. It affects ~15% of patients after cardiac surgery and is associated with prolonged length of stay, cognitive and functional decline, and death.1 Receiving benzodiazepines before and after cardiac surgery is associated with postoperative delirium, such that guidelines recommend avoiding their use.2,3 Benzodiazepine use during cardiac surgery remains common because of their amnestic effects and favourable hemodynamic profile.4 Randomized evidence from the intensive care unit (ICU) suggests that a benzodiazepine-free approach after cardiac surgery may reduce delirium;2 no evidence informs intraoperative benzodiazepine use. 

    Objective: To evaluate whether a policy of restricted intraoperative benzodiazepine use reduces postoperative delirium when compared with a policy of liberal benzodiazepine use. 

    Trial design: Multicentre, randomized, cluster crossover trial. 

    Inclusion/exclusion criteria: All patients undergoing cardiac surgery at an enrolled site during the trial period are included in data collection through a waiver of individual patient consent; percutaneous procedures and secondary operations are excluded. Hospitals are included if: i) they perform ≥250 cardiac surgeries a year; ii) their cardiac anesthesia group agrees to manage patients as per both benzodiazepine policies as per their randomization schedule; and iii) if cardiac surgery patients are assessed for postoperative delirium using a validated scale ≥ 12 hours in routine clinical care. 

    Trial interventions: B-Free compares 2 hospital-based cardiac anesthesia policies, both of which fall within the standard of care. Both policies allow deviations to occur when mandated by patient condition. The study expects that only 90% of patients will be treated according to the assigned policy due to appropriate deviations as described below: The “Restricted Benzodiazepine Policy” arm consists of the following: 1. No routine use of any intraoperative benzodiazepines. 2. Accepted benzodiazepine use in the case of seizure, alcohol withdrawal, severe anxiety, history of awareness during anesthesia, or known benzodiazepine dependence. 3. Accepted benzodiazepine use in patients who are hemodynamically unstable and/or have cardiac anatomy that puts them at high risk on induction of anesthesia using other agents. 

    The “Liberal Benzodiazepine Policy” arm consists of the following: 1. Intraoperative administration of the equivalent of at least 0.03mg/kg midazolam equivalent. Any benzodiazepine may be used. 2. Accepted avoidance of benzodiazepine use in patients who have contraindications to the administration of these medications (e.g., documented allergy, previous adverse reaction). 

    Randomization: We randomize sites to one of the two policies to be used by all anesthetists. Sites cross-over to the other policy at random. An independent statistician randomizes each site to twelve to eighteen (according to local feasibility), 4-week crossover periods, such that each policy is applied an equal number of times. 

    Outcomes: The primary outcome is the incidence of delirium up to 72 hours after cardiac surgery. The secondary outcomes are ICU and hospital length-of-stay and in-hospital mortality. 

    Trial status: We completed enrollment December 11/2022 and are finalizing data collection and database cleaning. Currently, 17,452 patients have complete data in the trial database and 2,248 patients still require some data entry. We have drafted a statistical analysis plan but have not yet begun undertaking analyses. 

    Trial leadership: B-Free is led by a group of Canadian female early career investigators, including Principal Investigator Dr. Jessica Spence and co-Principal Investigators Drs. Emilie Belley-Côté and Shun Fu Lee, all of whom are members of the Perioperative Care Clinical Trial Network. The trial is coordinated by the Population Health Research Institute in Hamilton, Ontario, Canada. 18/20 (90%) of sites and 17489/19700 (88.8%) of patients are Canadian.

  • CLEAR: A 2×2 factorial placebo-controlled trial of colchicine and spironolactone in patients with acute myocardial infarction (MI)
    Dr. Sanjit Jolly

    CLEAR Trial: A 2x2 factorial placebo-controlled trial of colchicine and spironolactone in patients with acute myocardial infarction (MI).

    PI: Sanjit Jolly, Professor of Medicine, McMaster University, member of Canadian Association of Interventional trials network

    Rationale: Colchicine: Inflammation is likely a key mechanism in atherosclerosis. Available randomized trials suggests that colchicine may reduce cardiovascular events but there are concerns regarding non CV mortality that need to be resolved from the largest trial. The finding of increased non-CV mortality may be spurious similar to the statin story or real and we are poised to resolve this in the CLEAR trial. Spironolactone: Similar to angiotensin receptor blockers, routine use of spironolactone in patients with acute MI (without heart failure), may be beneficial in preventing ventricular remodelling, heart failure and death.

    Primary outcomes: The primary outcome for colchicine is CV death, MI or stroke and for spironolactone is CV death or new or worsening heart failure.

    Power: The trial will have 80% power to detect a 25% relative risk reduction for a control event rate of 9%.

    Blinding and Concealed Allocation: Patients, physicians and study staff are blinded as matching placebo is used. The Population Health Research Institute is the co-ordination site and uses computer randomization with variable block size ensuring concealed allocation.

    Progress: We have recruited 7063 patients from 14 countries and completed recruitment on November 8, 2022. We expect to complete follow up in May 2024 with a median of 3 years of follow up and present in fall 2024. . There is 1.2 visits per patient left (approximately 8800 for 7062 patients) that are are due to happen before study close out.

    Experience of Team and Co-ordination Centre: The group has successfully completed a number of large scale randomized trials including TOTAL, COMPLETE, OASIS 5, 6, 7 and 8 trials. Dr. Sanjit Jolly (PI), Jessica Tyrwhitt (Study manager) and Elizabeth Skuriat (Study Coordinator) are managing day to day operations of the trial. Senior clinical trialists Drs. Salim Yusuf, John Cairns, Shamir Mehta, John Eikelboom, PJ Devereaux are providing senior leadership on the steering committee of the trial. Senior statisticians Lehana Thabane and Shirikant Bangdiwala are providing biostatistical leadership for the trial. Dr. Lavi chairs the adjudication committee. Drs. Welsh, Sheth, Natarajan, Bertrand, Conen, Graham, Madan and Cantor are key recruiters. Dr. Schwalm is a KT expert and will develop strategies post trial implementation into practice.

    Importance: Based on randomized trials, colchicine has a class IIB recommendation in patients with coronary artery disease. CLEAR will be the largest trial of colchicine and determine whether colchicine in acute myocardial infarction should be a class I indication. Both colchicine and spironolactone are widely available, inexpensive medications that can rapidly deployed to help the health of Canadians with acute myocardial infarction.

    Trial funding: The trial was funded by 2 CIHR grants (total $5,204,224) and a grant from Boston Scientific ($7,284,00) and received in kind donation of study drugs from Tiofarma. However, due to 20% across the board cut from CIHR and delays due to COVID, we have a deficit and so this funding will be important to help us to complete the trial and allow us to complete median 3 year follow up. We confirm that we can complete the trial with this additional funding.

    Will the trial be publicly reported by January 15, 2025: With recruitment complete and final visit expected in May 2024 for a median of 3 years of follow, the target would be a simultaneous publication and presentation in the fall of 2024 at major international meeting and a top tier journal (NEJM, JAMA or Lancet).

    Co-ordination centre: The trial will be coordinated at the Population Health Research Institute (PHRI), McMaster University. The PHRI has coordinated large practice-changing trials in cardiology. Examples include HOPE[1] (N=9000), CURE[2] (N=12500), OASIS 5[3]and 6[4] (N=25000 & 12000, respectively), and RELY (N=18113), TOTAL[5] (N=10732) and COMPLETE[6] (N=4041). The study operations team will be supervised by Jessica Tyrhitt who has >10yrs of experience in managing large multicenter trials in ACS. All the data points required for this trial, from baseline to the follow-up visit, are being collected centrally by PHRI in electronic Case Report Forms (eCRFs), using the iDataFax database and randomization by the ROME electronic system.

  • COP-AF: Colchicine For The Prevention Of Perioperative Atrial Fibrillation In Patients Undergoing Thoracic Surgery
    Dr. David Conen

    Registration: ClinicalTrials.gov

    Applicant / Principal investigator: David Conen MD MPH, McMaster University, Member of the perioperative network within ACT, permanent resident of Canada 

    Data Coordinating Centre: Population Health Research Institute, McMaster University, Canada 

    Current status: As of March 30 2023, 2,920 of 3,200 (91%) patients have been enrolled, and >2,800 of 3,200 final visits have been completed. We expect the last patient last visit around June 30, 2023. 

    Study Design: Multi-centre, international, blinded, randomized controlled trial 

    Primary Objectives: To determine whether the administration of colchicine compared with placebo reduces the occurrence of the co-primary outcomes 1) perioperative atrial fibrillation/atrial flutter (AF), and 2) myocardial injury after noncardiac surgery (MINS), both within 14 days of randomization. 

    Secondary Objectives: The secondary trial objectives are to determine whether the administration of colchicine compared with placebo reduces the following within 14 days of randomization: 1) composite of all-cause mortality, nonfatal MINS, or nonfatal stroke; 2) composite of all-cause mortality, nonfatal myocardial infarction (MI), or nonfatal stroke; 3) MINS not fulfilling the 4th universal definition of MI; 4) MI; 5) time to chest tube removal; and 6) duration of stay in ICU, step-down, and in-hospital. 

    Main Safety Outcomes: The two main COP-AF safety outcomes are 1) the occurrence of sepsis/infection; and 2) non-infectious diarrhea within 14 days of randomization 

    Inclusion Criteria: Patients are eligible if they: 1) are undergoing thoracic surgery with general anesthesia; 2) are ≥55 years of age at randomization; 3) are expected to require at least an overnight hospital admission after surgery; and 4. provide written informed consent. 

    Exclusion Criteria: 1) prior history of AF; 2) taking anti-arrhythmic medication; 3) undergoing minor thoracic interventions/procedures; 4) contraindications to colchicine; 5) not expected to take oral medications for >24 hours after surgery; 6) scheduled for lung transplantation; 7) currently taking non-study colchicine before surgery; 8) severe hepatic dysfunction; 9) aplastic anemia; 10) women of childbearing potential who are not taking effective contraception, pregnant or breast-feeding; 11) scheduled to take during the first 10 days after surgery clarithromycin, erythromycin, telithromycin, cyclosporine, ketoconazole or itraconazole; or 12) HIV patients treated with antiretroviral therapy. 

    Treatment: Oral colchicine (0.5 mg) or matching placebo is given within 4 hours before surgery. Thereafter, patients will receive colchicine 0.5 mg or placebo twice daily for a total of 10 days. 

    Follow-up: Patients will be followed while in hospital and at 14 days after randomization.

  • CYCLE: Critical Care Cycling to Improve Lower Extremity Strength
    Dr. Michelle Kho

    Trial Summary: CYCLE - Critical Care Cycling to Improve Lower Extremity Strength

    Survivors of critical illness may face physical disability up to 5 years following their discharge from the intensive care unit (ICU).1 Muscle mass decreases within the first 72 hours of a patient’s ICU stay.2 Leg muscles account for 75% of total skeletal muscle mass3 and are most vulnerable to weakness from immobility.4 Therefore, addressing immobility while patients are in the ICU is an important opportunity to optimize physical function.4 The Society of Critical Care Medicine guidelines recommend rehabilitation or mobilization in the ICU for critically ill adults, as the benefits likely outweigh the risks.5 However, the guidelines did not recommend specific types or timing of rehabilitation activities due to heterogeneous evidence. Further, two recent prominent randomized controlled trials (RCTs)6,7 and a systematic review8 raised concerns for an increased risk of safety events in patients randomized to early rehabilitation interventions, prompting discussion within the critical care and rehabilitation communities. Data from high-quality, rigorous clinical trials, performed in the Canadian context are urgently needed.

    CYCLE (Critical Care Cycling to Improve Lower Extremity Strength) is a Canadian, physiotherapist-led, CIHR-funded research program started in 2013. In-bed cycling is an underused, promising intervention aimed at minimizing immobility and improving physical function post-ICU discharge. The CYCLE research program has culminated in an international RCT with the following objectives: 1) to determine if early in-bed cycling and usual care physiotherapy (PT) compared to usual care PT alone in critically ill, mechanically ventilated adults improves the primary outcome of physical function, and 2) to conduct an economic evaluation of the CYCLE RCT.

    Characteristics of CYCLE RCT:

    Study design: 360-patient, 17 site (14 Canada, 1 Australia, 2 United States), concealed, open-label, parallel-group.

    Population: Adults (³18 years old) within the first 7 days of ICU admission, first 4 days of mechanical ventilation, and who could ambulate independently before their critical illness (with or without a gait aid). Intervention: 30 minutes per day of cycling, 5 days per week in addition to usual care PT activities. A specialized in-bed cycle ergometer provides passive (no patient induced muscular contribution), active-assisted (partial patient), or active cycling (full patient). Starting at enrollment, individual participants receive in-bed cycling for the duration of their index ICU admission, or until the patient can march on the spot for two consecutive days, or to a maximum of 28 days, whichever occurs first. ICU physiotherapists deliver the intervention as part of their usual clinical role.

    Comparison: Patients allocated to the control arm receive usual care PT activities per current institutional practice.

    OutcomesPrimary: Physical Function ICU Test-Scored,9 a reliable and valid measure in critically ill patients, 3-days post ICU discharge completed by assessors blinded to treatment allocation. Secondary: Safety, muscle strength, physical function, frailty, psychological distress, quality of life (EQ-5D),10-12 mortality, and healthcare utilization (ICU and hospital length of stay). Follow-up: 90-days post-randomization.

    Meaningful impact: CYCLE is the largest study of critical care in-bed cycling rehabilitation in the world. Results of the CYCLE RCT will provide Canadian efficacy and safety evidence to determine whether inbed cycling during critical illness improves short-term physical and functional outcomes and accelerates recovery in ICU survivors.

    Given recent concerns raised regarding the safety of ICU rehabilitation, additional data are urgently needed to inform contemporary clinical practice.

  • EnAKT (Effect of a Multi-Component Quality Improvement Intervention on Patient Access to Kidney Transplantation and Living Kidney Donation: The EnAKT LKD Randomized Clinical Trial
    Dr. Amit Garg
    Western University

    Trial Summary 

    Importance: Patients with advanced chronic kidney disease (CKD) have the best chance for a longer and healthier life if they receive a kidney transplant. However, many barriers prevent patients from receiving a transplant.

    Objective: To evaluate the effect of a multi-component quality improvement intervention designed to help eligible patients complete key steps toward receiving a kidney transplant.

    Design, setting, and participants: A pragmatic, two-arm, parallel-group, open-label, registry-based, superiority, cluster-randomized trial (November 1, 2017, to December 31, 2021). The trial included all 26 CKD programs in Ontario. These programs care for patients approaching the need for or receiving maintenance dialysis.

    Intervention: Using stratified, covariate-constrained randomization, we allocated the CKD programs (1:1) to provide the intervention or usual care for 4.2 years. The intervention had 4 main components: (1) administrative support to establish local teams to drive performance; (2) transplant educational resources; (3) an initiative for transplant recipients and living donors to share stories and experiences; and (4) program-level performance reports and oversight by administrative leaders.

    Primary outcome: Total steps completed toward receiving a kidney transplant. Each patient could complete up to 4 steps: step 1, referred to a transplant centre for evaluation; step 2, had a potential living donor contact a transplant centre for evaluation; step 3, added to the deceased donor waitlist; and step 4, received a transplant from a living or deceased donor.

    Results to date: The 26 CKD programs (13 intervention, 13 usual care) cared for 20,375 potentially transplant-eligible patients with advanced CKD (intervention [n=9780 patients], usual care [n=10 595 patients]). The provincial core operations group met over 100 times during the trial. Each of the 13 CKD programs established a local quality improvement team, developed a charter with their goals and activities, and indicated that team members met regularly to review and improve transplant performance. Together, the programs reported that 1740 patients completed the educational program Explore Transplant Ontario (etontario.org). Transplant ambassadors (prior kidney transplant recipients and living kidney donors) recorded 5471 meaningful interactions with patients with advanced CKD and 719 meaningful interactions with potential living kidney donors (transplantambassadors.ca). Each CKD program received regular performance reports and had annual performance meetings with the provincial renal agency. We are currently analyzing and preparing the results for publication.

  • HEMOTION: HEMOglobin transfusion threshold in Traumatic brain Injury OptimizatioN
    Dr. Alexis Turgeon

    HEMOTION Trial: HEMOglobin transfusion threshold in Traumatic brain Injury OptimizatioN

    The problem: In Canada, trauma causes more than 15,000 deaths every year. Most deaths are related to traumatic brain injury (TBI). Although the management of TBI patients has improved, mortality remains unacceptably high (20 to 50%), and half of survivors are left with major functional impairment. Current guidelines for the management of TBI are based on limited evidence and practice is highly variable, including strategies to improve brain oxygen delivery such as blood transfusion. Most critically ill patients with TBI will develop anemia, which may decrease oxygen delivered to a fragile traumatized brain. While clinical practice is moving towards transfusing patients at low hemoglobin (Hgb) levels, experts have expressed concerns regarding restrictive strategies and the low level of evidence on which they are based. Indeed, there is concern that anemia might adversely affect clinical outcomes in TBI.

    Study hypothesis: We hypothesize that, among critically ill adult patients with TBI, a liberal RBC transfusion strategy (triggered by Hgb ≤100g/L) improves long-term functional outcomes compared to a restrictive strategy (triggered by Hgb ≤70g/L).

    Trial design: We are conducting a multicenter international pragmatic open blinded-endpoint (PROBE) randomized trial in critically ill patients with TBI.

    Eligibility criteria: We enroll adult patients (≥18 years old) admitted to the ICU with an acute (hospital admission within 24 hours of injury) moderate or severe (Glasgow Coma Score (GCS) ≤12) blunt TBI and a Hb level ≤100 g/L. We exclude patients who receive transfusion after ICU admission, have contraindications or known objection to transfusions or have no fixed address.

    Interventions: Experimental intervention: liberal transfusion strategy: patients in the liberal transfusion strategy group receive an RBC transfusion if their Hgb is ≤100 g/L. Control intervention: restrictive transfusion strategy: patients in the restrictive transfusion strategy group receive an RBC transfusion only if their Hgb is ≤70 g/L. The trial intervention is initiated within 3 hours in patients meeting the threshold for transfusion in their respective group to avoid prolonged exposure to Hgb levels below this threshold. The allocated transfusion strategy is applied from the time of randomization to death or discharge from the ICU. Methods to minimize biases and ensure feasibility have been put in place.

    Primary outcome: We are using the Glasgow Outcome Scale extended (GOSe) to assess neurological outcome at 6 months.1,2 The GOSe scale comprises eight ranking levels from 1 (death, least favorable outcome) to 8 (upper good recovery, most favorable outcome) and is the gold standard outcome measure in TBI.

    Secondary outcomes: We are assessing ICU, hospital and 6-month mortality. At 6 months, we measure the Functional Independence Measure (FIM), the quality of life using the EuroQoL 5-Dimension 5-Level (EQ- 5D-5L) (generic scale) and the Quality of Life after Brain Injury (QOLIBRI) (TBI-specific scale), and the self-reported Patient Health Questionnaire (PHQ-9) to evaluate depression.

    Tertiary outcomes: We are capturing the number of RBC units transfused in the ICU, lowest daily Hb, infections, duration of mechanical ventilation and ICU and hospital length of stay. We are also assessing complications related to transfusion.

    Sample size: We will include 742 adult patients at 34 sites in 4 countries (Canada, UK, France, Brazil).

  • RAFF4: A Randomized Trial of Anti-Arrhythmic Agents to Improve Management of Emergency Department Patients with Acute Atrial Fibrillation
    Dr. Ian Stiell
    University of Ottawa


    ClinicalTrials.gov Identifier: NCT04485195 

    Our study question, comparing IV vernakalant to IV procainamide, has equipoise amongst Canadian ED physicians and has never been directly studied. Background: Atrial fibrillation (AF) causes a rapid, irregular heart rate and is the most common arrhythmia seen in the emergency department (ED). We will focus on acute-onset episodes of AF, which usually have onset <48 hours and are highly symptomatic. Most Canadian ED physicians attempt cardioversion (CV) to sinus rhythm, either with drugs or electrically. If drug CV fails, then patients usually undergo electrical CV which is effective but is often associated with significant delays and adverse events (13.9%; Stiell CJC 2022). The most commonly used drug is the older intravenous (IV) procainamide which has a conversion rate of 52.2%, median time to conversion 55 minutes, and incidence adverse events 9.8%. The newer IV vernakalant reportedly has a conversion rate of 65%, median time to conversion 12 minutes, and adverse events <1%; it was approved in Canada in 2017 but has seen modest uptake. 

    Most acute AF patients occupy valuable ED cardiac monitors for a prolonged period. Our hope is that IV vernakalant will result in more rapid cardioversions in our extremely crowded Canadian EDs. We hypothesize that our study will reveal that IV vernakalant is superior with a higher conversion rate, faster conversion times, and far fewer adverse events. RAFF4 is an open-label pragmatic trial so that we can see the actual performance of these drugs in real clinical circumstances. 

    Recruitment has been delayed over the past year due to the pandemic but we have enrolled 190 patients, 75% in Ottawa. We have funded the RAFF4 study using funds from a CIHR Foundation award held by the PI (IGS) - this expires in early 2023, hence the current application is essential to ensure trial completion. Cipher Pharmaceuticals Inc. (Canada) offers unrestricted support by providing vernakalant at no cost for all study sites but gives no money. 

    Study Objective: To compare IV vernakalant to IV procainamide for acute AF patients. 

    Primary Outcomes: conversion to and maintenance of sinus rhythm for at least 30 minutes after the drug infusion. Other: length of stay in the ED, adverse events, and 30-day follow-up status. 

    Primary Analysis: on an intention-to-treat basis, using multiple logistic regression controlling for the following variables: age, sex, first or repeat episode, time from onset, and history of heart failure. 

    Methods: Design: Pragmatic comparative effectiveness trial with an open label, randomized (1:1) comparison of drug CV with: i) IV vernakalant, and ii) IV procainamide. Stratified by site. 

    Interventions: a) IV Vernakalant. Given as an initial infusion of 3 mg/kg over 10 minutes, followed if necessary by a second infusion of 2 mg/kg. b) IV Procainamide. Given as an infusion of 15 mg/kg, over 60 minutes. If patients have not converted to sinus rhythm by 30 minutes after the end of either drug infusion, they will be offered electrical CV. 

    Setting: 12 tertiary care EDs in 5 provinces. 

    Subjects: 340 patients with acute AF where acute rhythm control is a safe option.

    Importance: If IV vernakalant proves to be more effective, faster, and safer than IV procainamide, this will give clinicians an important alternative for drug cardioversion of acute AF. The study results should lead to higher rhythm conversion rates and more rapid discharges from our crowded EDs and should change clinical practice worldwide.

  • REVISE: Re-Evaluating the Inhibition of Stress Erosions in the ICU Trial
    Dr. Deborah Cook

    REVISE is a global Canadian-led randomized clinical trial [NCT03374800] conducted by the Canadian Critical Care Trials Group, an ACT Partner. The Global Principal Investigator (Dr. D Cook) and Canadian Principal Investigator (Dr. G Guyatt) are Canadian. The Global Methods Center is in Hamilton, Canada. Randomization is ongoing. As of March 29, 2023, 3,992 of 4,800 patients have been recruited in 63 international centers; 808 patients remain to enrol. The manuscript submission is anticipated in September 2024. 

    Structured Abstract Summary 

    Background: For 40 years, pharmacologic prevention of stress ulcer-related gastrointestinal (GI) bleeding with acid suppression has been the standard of care for mechanically ventilated patients in the intensive care unit (ICU) [1]. Proton pump inhibitors (PPIs) are more commonly used than histamine-2-receptor antagonists (H2RAs). Observational studies and our recent networkmeta-analysis suggest that PPIs may increase the risk of ventilator-associated pneumonia (VAP) and Clostridioides difficile infection (CDI) [2,3]. Moreover, a recent large trial raised concerns about an increased risk of death associated with pantoprazole in the most severely ill patients [4]. Although in this trial GI bleeding events were less frequent in the pantoprazole group, the bleeds may not have been patient-important, and investigators identified no other benefits. Moreover, a cluster-crossover trial of 26,771 patients evaluating PPIs versus H2RAs also suggested an increased risk of death in the most severely ill patients receiving PPIs, raising further misgivings about PPIs in the ICU setting [5]. Given that the widespread use of PPIs may not be in the best interest of critically ill patients, successfully completing the REVISE trial is crucial from a clinical, ethical and policy perspective. 

    Objectives: To determine, in mechanically ventilated patients, the effect of pantoprazole versus placebo on the primary efficacy outcome of clinically important upper GI bleeding, and the primary safety outcome of 90-day mortality. Secondary outcomes are patient-important GI bleeding, VAP and CDI, treatment with renal replacement therapy and hospital mortality. Tertiary outcomes are red blood cell transfusions, serum creatinine, duration of mechanical ventilation, duration of ICU stay and duration of hospital stay. 

    Methods: REVISE is a high-impact global randomized trial of 4,800 ICU patients >18 years old who have an anticipated duration of mechanical ventilation of ≥48 hours. Exclusion criteria are acute or recent GI bleeding, dual antiplatelet therapy, combined antiplatelet and anticoagulant therapy, intent to withdraw advanced life support or hopeless prognosis, and previous enrolment in this or a confounding trial. The protocol allows either a priori informed consent or informed consent to continue with study drug. Patients are randomized in a fixed 1:1 allocation, stratified by center and whether or not they were using acid suppression prior to hospitalization. Stratification by pre-hospital acid suppression will allow evaluation of possible rebound gastric acid hypersecretion upon acid suppression termination [6] and possible microbiome and infection risk modification by long-term acid suppression [7]. Study Pharmacists obtain concealed allocation from a password-protected website; all researchers and clinicians, patients and families are blinded. With a priori or deferred consent, patients are randomized to pantoprazole 40 mg or placebo intravenously daily while in ICU up to 90days or until successful discontinuation of mechanical ventilation for >48 hours; development of clinically important GI bleeding; or 3) death in ICU. 

    International Collaboration: REVISE is conducted under the auspices of the International Forum for Acute Care Trialists in collaboration with the Canadian Critical Care Trials Group [www.ccctg.ca], the Australian and New Zealand Critical Care Trials Group [www.anzicsctg.com].

  • Risk Estimation Following Infarction Non-invasive Evaluation – ICD Efficacy (REFINE-ICD)
    Dr. Derek Exner
    University of Calgary

    Trial Synopsis REFINE ICD is testing whether an implantable cardioverter defibrillator (ICD), in addition to usual care, will alter mortality as compared to usual care alone. A total of 700 patients with an LVEF 36% to 50% plus impaired HRT and abnormal TWA, measured at least 2 months after MI, are being randomized. Patients with normal HRT +/- TWA are not eligible for randomization but are followed in a registry. 

    Primary hypothesis. An ICD in addition to usual care will increase the probability of survival in subjects with LVEF values of 36% to 50%, impaired HRT and abnormal TWA measured at least 2 months after the index MI. 

    Outcome. Mortality is the standard by which most cardiac interventions are judged since it is unbiased and unambiguous. In the event of a positive outcome, quality of life should be assessed to aid in the overall interpretation of the results. As such, these outcomes comprise secondary outcomes and will only be assessed if the primary outcome is positive. 

    Inclusion Criteria: 18-80 years old, clinically appropriate ICD candidate, LVEF 36% to 50% measured 2 months post-MI and at least 3 months after angioplasty or bypass surgery, revascularization where clinically indicated, appropriate medical therapy, sinus rhythm in the 8 weeks prior to the Holter assessment, and abnormal HRT and TWA on the Holter assessment performed 2 months after MI (core lab with expert over-read). The trial is registered at clinicaltrials.gov (NCT00673842)