Calcineurin Inhibitor in NEuRoloGically Deceased Donors to Decrease Kidney delaYed Graft Function (CINERGY)
- Conditions
- Organ Transplant Failure or RejectionIschemic Reperfusion InjuryBrain Death
- Interventions
- Drug: Placebo
- Registration Number
- NCT05148715
- Lead Sponsor
- Université de Sherbrooke
- 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.
- 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.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 414
- ≥18 years of age;
- Neurologically deceased;
- Consent for deceased organ donation;
- All organ recipients have been identified;
- ≥ 1 kidney allocated to a recipient.
Donor
- Known hypersensitivity to tacrolimus or polyoxyl 60 hydrogenated castor oil;
- One or more organs allocated to a non-participating transplant program;
- Unlikely access to study drug (e.g., due to supply issues, or pharmacist availability);
- One or more organ recipients has not agreed to receive an organ from a donor participating in the study;
- One or more organs are allocated to a recipient under the age of 18;
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Placebo 0.9% sodium chloride 4-8 hours before organ recovery Tacrolimus Tacrolimus Tacrolimus 0.02 mg/kg ideal body weight 4-8 hours before organ recovery
- Primary Outcome Measures
Name Time Method 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
Name Time Method 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.
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.
Recipient survival 12 months post transplant Recipient death
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 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 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/
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.
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
Graft survival 12 months post transplant Need to be re-transplanted or to be on the re-transplant list.
Recipients requiring dialysis 12 months post transplant Recipient requirement for dialysis at 12 months
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 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 heart recipients with severe primary graft dysfunction Within 1 days post transplant Dependence on mechanical support
Percentage of kidney recipients with delayed graft function Within 7 days post transplant Requirement of ≥ 1 hemodialysis session
Percentage of pancreas recipients with delayed graft function At hospital discharge, an average of 7 days Requirement of ≥1 exogenous insulin at hospital discharge
Trial Locations
- Locations (9)
L'Institut de Cardiologie de Montréal
🇨🇦Montréal, Quebec, Canada
Hôpital Maisonneuve-Rosemont
🇨🇦Montréal, Quebec, Canada
Centre Hospitalier Universitaire de Montréal
🇨🇦Montréal, Quebec, Canada
Centre universitaire de santé McGill (CUSM)
🇨🇦Montréal, Quebec, Canada
Centre Hospitalier Universitaire de Québec- Université Laval
🇨🇦Quebec city, Quebec, Canada
Institut universitaire de cardiologie et de pneumologie de Québec (IUCPQ)
🇨🇦Québec City, Quebec, Canada
Centre de recherche CHUS
🇨🇦Sherbrooke, Quebec, Canada
Vancouver General Hospital
🇨🇦Vancouver, British Columbia, Canada
St. Paul's Hospital
🇨🇦Vancouver, British Columbia, Canada