Clinical trial NCT05148715: Calcineurin Inhibitor in NEuRoloGically Deceased Donors to Decrease Kidney delaYed Graft Function (CINERGY)
Official title: Calcineurin Inhibitor in NEuRoloGically Deceased Donors to Decrease Kidney delaYed Graft Function (CINERGY)-Pilot Trial
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Organ Transplant Failure or Rejection
Brain Death
Ischemic Reperfusion Injury
Keywords: organ donation and transplantation
Lead sponsor: Université de Sherbrooke
Sponsor class: OTHER
Collaborators: name: McMaster University
First posted: 2021-12-08
Enrollment: 414
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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:

* ≥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.

Primary outcomes:
measure: Organ donor accrual rates
timeFrame: 6 to 12 months after the beginning of the trial
measure: Recipient consent rate
timeFrame: 6 to 12 months after the beginning of the trial
Secondary outcomes:
measure: Correlation between two methods for obtaining survival status
timeFrame: 12 months post transplant
measure: Unexpected adverse events
timeFrame: Within 7 days post transplant
measure: Percentage of donors with acute kidney injury (AKI)
timeFrame: Within 4 hours after the end of the study drug infusion
measure: Percentage of donors with hyperkalemia
timeFrame: Within 4 hours after the end of the study drug infusion
measure: Percentage of donors hypertension during tacrolimus infusion
timeFrame: Within 4 hours after the initiation of study drug infusion
measure: Percentage of donors with cardiac arrhythmia associated with tacrolimus infusion
timeFrame: Within 4 hours after the initiation of study drug infusion
measure: Percentage of donors with anaphylaxis
timeFrame: Within 4 hours after the initiation of study drug infusion
measure: Percentage of recipients with acute kidney injury
timeFrame: Within 7 days post transplant
measure: Percentage of recipients with hyperkalemia
timeFrame: Within 7 days post transplant
measure: Percentage of recipients with anaphylaxis
timeFrame: Within 7 days post transplant
measure: Recipient serum tacrolimus levels
timeFrame: Within 7 days post transplant
measure: Percentage of liver recipients with early graft function
timeFrame: Within 7 days post transplant
measure: Graft survival
timeFrame: 12 months post transplant
measure: Recipient survival
timeFrame: 12 months post transplant
measure: Recipients requiring dialysis
timeFrame: 12 months post transplant
measure: Percentage of lungs recipients with severe primary graft dysfunction
timeFrame: Within 3 days post transplant
measure: Percentage of kidney recipients with delayed graft function
timeFrame: Within 7 days post transplant
measure: Percentage of heart recipients with severe primary graft dysfunction
timeFrame: Within 1 days post transplant
measure: Percentage of pancreas recipients with delayed graft function
timeFrame: At hospital discharge, an average of 7 days
Other outcomes:
Locations:
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
city: Vancouver
country: Canada
facility: St. Paul's Hospital
state: British Columbia
city: Montréal
country: Canada
facility: L'Institut de Cardiologie de Montréal
state: Quebec
city: Montréal
country: Canada
facility: Hôpital Maisonneuve-Rosemont
state: Quebec
city: Montréal
country: Canada
facility: Centre Hospitalier Universitaire de Montréal
state: Quebec
city: Montréal
country: Canada
facility: Centre universitaire de santé McGill (CUSM)
state: Quebec
city: Quebec city
country: Canada
facility: Centre Hospitalier Universitaire de Québec- Université Laval
state: Quebec
city: Québec City
country: Canada
facility: Institut universitaire de cardiologie et de pneumologie de Québec (IUCPQ)
state: Quebec
city: Sherbrooke
country: Canada
facility: Centre de recherche CHUS
state: Quebec
Study officials:
affiliation: Université de Sherbrooke
name: Frédérick D'Aragon
role: PRINCIPAL_INVESTIGATOR
affiliation: McMaster University
name: Maureen Meade
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Toronto
name: Markus Selzner
role: PRINCIPAL_INVESTIGATOR
References: