CINERGY Pilot Trial
Study Details
Study Description
Brief Summary
The investigators hypothesize that preconditioning neurologically deceased organ donors with the calcineurin inhibitor tacrolimus will improve short and long-term transplant survival without causing harm. Organ donors will be randomized to receive either 0.02 mg/kg ideal body weight (IBW) of tacrolimus single infusion or placebo before organ recovery. All corresponding recipients are enrolled and data is collected up to 7 days post-transplant to determine graft function and at 1 year to collect outcomes of vital status, re-transplantation and dialysis. The CINERGY Pilot Trial assesses feasibility for the main trial.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
Background: Organ donation saves lives, and improves quality of life for thousands of people. But organ donation falls short of expectations for some patients who suffer early graft loss. During organ donation surgery, the supply of blood with oxygen and nutrients is suspended. When restored during transplant surgery, a cascade of inflammation perturbs the newly transplanted organ -causing ischemia-reperfusion injury. When severe, it can hinder transplant function in the early post-operative period, lead to profound critical illness, increase the risks of transplant rejection and chronic disease, and reduce the transplant lifespan. Administration of tacrolimus, a calcineurin inhibitor, to neurologically deceased donors may reduce ischemia-reperfusion injury in transplant recipients.
Objectives: The CINERGY Pilot Trial will test the feasibility of comparing tacrolimus to placebo for the prevention of delayed graft function in kidney recipients and establish the foundation for a large, multi-centre randomized controlled trial (RCT).
Methods: 90 neurologically deceased kidney donors will be randomized to either tacrolimus (0.02 mg/kg) or the corresponding placebo 4-8 hours before organ recovery. To be included in the CINERGY Pilot RCT, donors will need to meet inclusion criteria. All corresponding recipients are enrolled and their data is collected in the first 7 days and at 12 months after transplantation.
Outcomes: Feasibility: Donor accrual rate and consent rate of organ recipients. Safety: acute kidney injury, hyperkalemia and anaphylaxis in donors and recipients. Clinical: graft function within 7 days in all recipients, vital status, re-transplantation and need for dialysis at 12 months.
Relevance: This pilot study will inform the feasibility and design of a larger trial. Moreover, the CINERGY Pilot RCT will pave the way for future trials linking organ donation and transplantation across Canada.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Tacrolimus Tacrolimus 0.02 mg/kg ideal body weight 4-8 hours before organ recovery |
Drug: Tacrolimus
Single dose intravenous tacrolimus over 4 hour infusion at a dose of 0.02 mg/kg ideal body weight diluted with 0.9% sodium chloride starting 4-8 hours before scheduled organ recovery.
Other Names:
|
| Placebo Comparator: Placebo 0.9% sodium chloride 4-8 hours before organ recovery |
Drug: Placebo
Single dose of intravenous 0.9% sodium chloride over 4 hour infusion, starting 4-8 hours before scheduled organ recovery.
|
Outcome Measures
Primary Outcome Measures
- Organ donor accrual rates [6 to 12 months after the beginning of the trial]
One primary objective of this pilot study is to determine if a national multi-centre placebo randomized controlled trial (RCT) will be feasible with respect to: organ donor accrual.
- Recipient consent rate [6 to 12 months after the beginning of the trial]
Another primary objective of this pilot study is to determine if a national multi-centre placebo controlled RCT will be feasible with respect to the consent rates of organ recipients. Recipient consent rates will be assessed during analysis, analyzing the rate and reasons for non-enrolment.
Secondary Outcome Measures
- Correlation between two methods for obtaining survival status [12 months post transplant]
We will compare 2 methods (Hospital records, Canadian Institute for Health Information) for obtaining recipient survival at 12 months post-transplant.
- Unexpected adverse events [Within 7 days post transplant]
In donors and recipients, unexpected adverse events as identified by clinical staff will be reported and analyzed.
- Percentage of donors with acute kidney injury (AKI) [Within 4 hours after the end of the study drug infusion]
AKI defined as defined as Kidney disease: Improving global outcome (KDIGO) stage II (or more): serum creatinine ≥ 2.0 times baseline OR a urine output <0.5mL/kg/h for ≥12 hours
- Percentage of donors with hyperkalemia [Within 4 hours after the end of the study drug infusion]
Hyperkalemia defined as a potassium level > 5 mmol/L
- Percentage of donors hypertension during tacrolimus infusion [Within 4 hours after the initiation of study drug infusion]
Hypertension (systolic blood pressure ≥ 160 mmHg or mean arterial pressure ≥ 90 mmHg for > 15 minutes)
- Percentage of donors with cardiac arrhythmia associated with tacrolimus infusion [Within 4 hours after the initiation of study drug infusion]
Cardiac arrhythmias defined as new onset of atrial fibrillation or flutter, ventricular tachycardia or fibrillation
- Percentage of donors with anaphylaxis [Within 4 hours after the initiation of study drug infusion]
Anaphylaxis defined as per The American Academy of Allergy, Asthma and Immunology
- Percentage of recipients with acute kidney injury [Within 7 days post transplant]
AKI defined as defined as KDIGO stage II or more: serum creatinine ≥ 2.0 times baseline OR a urine output <0.5mL/kg/h for ≥12 hours
- Percentage of recipients with hyperkalemia [Within 7 days post transplant]
Hyperkalemia defined as a potassium level > 5 mmol/L
- Percentage of recipients with anaphylaxis [Within 7 days post transplant]
Anaphylaxis defined as per The American Academy of Allergy, Asthma and Immunology
- Recipient serum tacrolimus levels [Within 7 days post transplant]
Clinical research staff will abstract routine serum tacrolimus levels (when measured) from hospital records over the first 7 days, along with local thresholds for toxic level.
- Percentage of liver recipients with early graft function [Within 7 days post transplant]
At least ≥ 1 of the following criteria: Bilirubin ≥ 10 mg/dL , International normalized ratio (INR) ≥ 1.6 AST or ALT level > 2000 IU/
- Graft survival [12 months post transplant]
Need to be re-transplanted or to be on the re-transplant list.
- Recipient survival [12 months post transplant]
Recipient death
- Recipients requiring dialysis [12 months post transplant]
Recipient requirement for dialysis at 12 months
- Percentage of lungs recipients with severe primary graft dysfunction [Within 3 days post transplant]
PaO2/FiO2 ratio <200 and diffuse infiltration/pulmonary edema on chest radiograph
- Percentage of kidney recipients with delayed graft function [Within 7 days post transplant]
Requirement of ≥ 1 hemodialysis session
- Percentage of heart recipients with severe primary graft dysfunction [Within 1 days post transplant]
Dependence on mechanical support
- Percentage of pancreas recipients with delayed graft function [At hospital discharge, an average of 7 days]
Requirement of ≥1 exogenous insulin at hospital discharge
Eligibility Criteria
Criteria
Neurologically deceased donors who meet the inclusion and exclusion criteria will be eligible for participating in this study along with the correlating organ recipients who meet inclusion criteria.
Donor Inclusion Criteria:
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≥18 years of age;
-
Neurologically deceased;
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Consent for deceased organ donation;
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All organ recipients have been identified;
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≥ 1 kidney allocated to a recipient.
Donor Exclusion Criteria:
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Known hypersensitivity to tacrolimus or polyoxyl 60 hydrogenated castor oil;
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One or more organs allocated to a non-participating transplant program;
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Unlikely access to study drug (e.g., due to supply issues, or pharmacist availability);
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One or more organ recipients has not agreed to receive an organ from a donor participating in the study;
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One or more organs are allocated to a recipient under the age of 18;
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A transplant physician has judged that donor tacrolimus will be unsuitable for an intended recipient.
Recipient Inclusion Criteria
- Organ/Transplant graft originated from a donor enrolled in this study.
No exclusion criteria.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Hamilton General Hospital | Hamilton | Ontario | Canada | L8L 2X2 |
| 2 | St. Joseph's Healthcare Hamilton | Hamilton | Ontario | Canada | L8N 4A6 |
| 3 | The Kingston General Hospital | Kingston | Ontario | Canada | K7L 2V7 |
| 4 | London Health Sciences | London | Ontario | Canada | N6A 5W9 |
| 5 | The Ottawa Hospital | Ottawa | Ontario | Canada | K1H 8L6 |
| 6 | St. Michael's Hospital, UHN | Toronto | Ontario | Canada | M5B 1W8 |
| 7 | Toronto General Hospital, UHN | Toronto | Ontario | Canada | M5G 2C4 |
| 8 | L'Institut de Cardiologie de Montréal | Montréal | Quebec | Canada | H1T 1C8 |
| 9 | Hôpital Maisonneuve-Rosemont | Montréal | Quebec | Canada | H1T 2M4 |
| 10 | Centre Hospitalier Universitaire de Montréal | Montréal | Quebec | Canada | H2X 3E4 |
| 11 | Centre universitaire de santé McGill (CUSM) | Montréal | Quebec | Canada | H4A 3J1 |
| 12 | Centre Hospitalier Universitaire de Québec- Université Laval | Quebec city | Quebec | Canada | G1V 4G2 |
| 13 | Institut universitaire de cardiologie et de pneumologie de Québec (IUCPQ) | Québec City | Quebec | Canada | G1V 4G5 |
| 14 | Centre de recherche CHUS | Sherbrooke | Quebec | Canada | J1H 5N4 |
Sponsors and Collaborators
- Université de Sherbrooke
- McMaster University
Investigators
- Principal Investigator: Frédérick D'Aragon, Université de Sherbrooke
- Principal Investigator: Maureen Meade, McMaster University
- Principal Investigator: Markus Selzner, University of Toronto
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- MP-31-2020-3348