Calcineurin Inhibitor in NEuRoloGically Deceased Donors to Decrease Kidney delaYed Graft Function (CINERGY)-Pilot Trial

Study Overview
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Brief Summary
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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
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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.

Official Title
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Calcineurin Inhibitor in NEuRoloGically Deceased Donors to Decrease Kidney delaYed Graft Function (CINERGY)-Pilot Trial

Conditions
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Organ Transplant Failure or Rejection, Brain Death, Ischemic Reperfusion Injury

Intervention / Treatment
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* Drug: Tacrolimus
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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: ≥18 years of age; Neurologically deceased; Consent for deceased organ donation; All organ recipients have been identified; ≥ 1 kidney allocated to a recipient. Donor Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tacrolimus<br>Tacrolimus 0.02 mg/kg ideal body weight 4-8 hours before organ recovery | Drug: Tacrolimus<br>* 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.<br>* Other names: Prograf;|
| Placebo Comparator: Placebo<br>0.9% sodium chloride 4-8 hours before organ recovery | Drug: Placebo<br>* Single dose of intravenous 0.9% sodium chloride over 4 hour infusion, starting 4-8 hours before scheduled organ recovery.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Organ donor accrual rates | 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. | 6 to 12 months after the beginning of the trial | 
| Recipient consent rate | 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. | 6 to 12 months after the beginning of the trial | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation between two methods for obtaining survival status | We will compare 2 methods (Hospital records, Canadian Institute for Health Information) for obtaining recipient survival at 12 months post-transplant. | 12 months post transplant | 
| Unexpected adverse events | In donors and recipients, unexpected adverse events as identified by clinical staff will be reported and analyzed. | Within 7 days post transplant | 
| Percentage of donors with acute kidney injury (AKI) | 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 | Within 4 hours after the end of the study drug infusion | 
| Percentage of donors with hyperkalemia | Hyperkalemia defined as a potassium level > 5 mmol/L | Within 4 hours after the end of the study drug infusion | 
| Percentage of donors hypertension during tacrolimus infusion | Hypertension (systolic blood pressure ≥ 160 mmHg or mean arterial pressure ≥ 90 mmHg for > 15 minutes) | Within 4 hours after the initiation of study drug infusion | 
| Percentage of donors with cardiac arrhythmia associated with tacrolimus infusion | Cardiac arrhythmias defined as new onset of atrial fibrillation or flutter, ventricular tachycardia or fibrillation | Within 4 hours after the initiation of study drug infusion | 
| Percentage of donors with anaphylaxis | Anaphylaxis defined as per The American Academy of Allergy, Asthma and Immunology | Within 4 hours after the initiation of study drug infusion | 
| Percentage of recipients with acute kidney injury | 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 | Within 7 days post transplant | 
| Percentage of recipients with hyperkalemia | Hyperkalemia defined as a potassium level > 5 mmol/L | Within 7 days post transplant | 
| Percentage of recipients with anaphylaxis | Anaphylaxis defined as per The American Academy of Allergy, Asthma and Immunology | Within 7 days post transplant | 
| Recipient serum tacrolimus levels | 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. | Within 7 days post transplant | 
| Percentage of liver recipients with early graft function | At least ≥ 1 of the following criteria: Bilirubin ≥ 10 mg/dL , International normalized ratio (INR) ≥ 1.6 AST or ALT level > 2000 IU/ | Within 7 days post transplant | 
| Graft survival | Need to be re-transplanted or to be on the re-transplant list. | 12 months post transplant | 
| Recipient survival | Recipient death | 12 months post transplant | 
| Recipients requiring dialysis | Recipient requirement for dialysis at 12 months | 12 months post transplant | 
| Percentage of lungs recipients with severe primary graft dysfunction | PaO2/FiO2 ratio <200 and diffuse infiltration/pulmonary edema on chest radiograph | Within 3 days post transplant | 
| Percentage of kidney recipients with delayed graft function | Requirement of ≥ 1 hemodialysis session | Within 7 days post transplant | 
| Percentage of heart recipients with severe primary graft dysfunction | Dependence on mechanical support | Within 1 days post transplant | 
| Percentage of pancreas recipients with delayed graft function | Requirement of ≥1 exogenous insulin at hospital discharge | At hospital discharge, an average of 7 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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organ donation and transplantation