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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Ischemic Reperfusion Injury; Brain Death; Organ Transplant Failure or Rejection
• Intervention / Treatment: Drug: Tacrolimus; Drug: Placebo

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 Type: Interventional
• Enrollment (Estimated): 414
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6Z 1Y6
      • St. Paul's Hospital
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • Vancouver General Hospital
  • Quebec
    • Montréal, Quebec, Canada, H1T 2M4
      • Hôpital Maisonneuve-Rosemont
    • Montréal, Quebec, Canada, H1T 1C8
      • L'institut de cardiologie de Montreal
    • Montréal, Quebec, Canada, H2X 3E4
      • Centre hospitalier universitaire de Montréal
    • Montréal, Quebec, Canada, H4A 3J1
      • Centre universitaire de santé McGill (CUSM)
    • Quebec city, Quebec, Canada, G1V 4G2
      • Centre Hospitalier Universitaire de Québec- Université Laval
    • Québec City, Quebec, Canada, G1V 4G5
      • Institut Universitaire de Cardiologie et de Pneumologie de Quebec (IUCPQ)
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • Centre de recherche CHUS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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: Prograf
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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Université de Sherbrooke
• Collaborators: 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 record dates

Study Major Dates

• Study Start (Actual): July 11, 2022
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): January 1, 2026

Study Registration Dates

• First Submitted: October 18, 2021
• First Submitted That Met QC Criteria: December 7, 2021
• First Posted (Actual): December 8, 2021

Study Record Updates

• Last Update Posted (Actual): April 17, 2025
• Last Update Submitted That Met QC Criteria: April 11, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: organ donation and transplantation
• Additional Relevant MeSH Terms: Neurologic Manifestations; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Postoperative Complications; Pathologic Processes; Neurobehavioral Manifestations; Death; Consciousness Disorders; Unconsciousness; Coma; Delayed Graft Function; Brain Death; Reperfusion Injury; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Calcineurin Inhibitors; Tacrolimus
• Other Study ID Numbers: MP-31-2020-3348

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No