Tacrolimus for Delayed Graft Function
(CINERGY Trial)
Recruiting in Palo Alto (17 mi)
+13 other locations
Overseen byFrédérick D'Aragon
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Université de Sherbrooke
Disqualifiers: Hypersensitivity to tacrolimus, others
Prior Safety Data
Trial Summary
What is the purpose of this 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.
Will I have to stop taking my current medications?
The trial information does not specify whether participants need to stop taking their current medications. It is best to consult with the trial coordinators or your doctor for guidance.
What data supports the effectiveness of the drug Tacrolimus for Delayed Graft Function?
Research shows that Tacrolimus, used in kidney transplant patients, is effective in reducing acute rejection and maintaining graft survival. Studies comparing different formulations of Tacrolimus (Advagraf and Prograf) found similar outcomes in terms of patient survival and graft loss, suggesting its effectiveness in transplant settings.12345
Is tacrolimus safe for use in humans?
Tacrolimus, including its extended-release forms like Advagraf and Astagraf XL, has been used safely in kidney transplant patients, showing similar safety profiles to the immediate-release version, Prograf. It is important to note that while it is generally safe, it can have side effects like increased risk of diabetes and infections, and it is not recommended for liver transplant patients due to higher mortality risk in women.12367
How does the drug tacrolimus for delayed graft function differ from other treatments?
Tacrolimus, particularly in its extended-release form (Advagraf®/Astagraf XL®), is unique because it allows for once-daily dosing, which can improve patient adherence compared to the traditional twice-daily immediate-release formulation. This extended-release version also shows reduced variability in drug concentration levels, potentially leading to better outcomes in preventing graft failure.23678
Eligibility Criteria
This trial is for organ donors who are over 18 years old, have been declared brain dead, and consented to donate their organs. All recipients of the organs must be adults and agree to participate in the study. Donors with potential issues accessing the study drug or known allergies to tacrolimus or certain inactive ingredients cannot join.Inclusion Criteria
I am 18 years old or older.
Donor: Consent for deceased organ donation
Donor: All organ recipients have been identified
See 3 more
Exclusion Criteria
I am donating an organ to someone younger than 18.
I cannot access the study drug due to supply or pharmacy issues.
Donor: One or more organ recipients has not agreed to receive an organ from a donor participating in the study
See 3 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Neurologically deceased donors receive either tacrolimus or placebo 4-8 hours before organ recovery
4-8 hours
1 visit (in-person)
Initial Follow-up
Data is collected from recipients to determine graft function and monitor for adverse events
7 days
Daily monitoring
Long-term Follow-up
Recipients are monitored for vital status, re-transplantation, and dialysis needs
12 months
Periodic assessments
Treatment Details
Interventions
- Placebo (Other)
- Tacrolimus (Calcineurin Inhibitor)
Trial OverviewThe CINERGY-Pilot Trial is testing whether giving a single infusion of tacrolimus (0.02 mg/kg IBW) to brain-dead organ donors can improve transplant outcomes compared to a placebo. The effects will be monitored up until 7 days after transplantation and again at one year post-transplant.
Participant Groups
2Treatment groups
Experimental Treatment
Placebo Group
Group I: TacrolimusExperimental Treatment1 Intervention
Tacrolimus 0.02 mg/kg ideal body weight 4-8 hours before organ recovery
Group II: PlaceboPlacebo Group1 Intervention
0.9% sodium chloride 4-8 hours before organ recovery
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Centre universitaire de santé McGill (CUSM)Montréal, Canada
Hamilton General HospitalHamilton, Canada
St. Joseph's Healthcare HamiltonHamilton, Canada
The Kingston General HospitalKingston, Canada
More Trial Locations
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Who Is Running the Clinical Trial?
Université de SherbrookeLead Sponsor
McMaster UniversityCollaborator
References
Efficacy and Safety of Tacrolimus-Based Maintenance Regimens in De Novo Kidney Transplant Recipients: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials. [2022]BACKGROUND Tacrolimus is an established component of immunosuppressive regimens for kidney transplant recipients (KTRs); however, data comparing long-term outcomes between formulations are lacking. We conducted a systematic literature review and network meta-analysis assessing tacrolimus (primarily Advagraf [once-daily] and Prograf [twice-daily])-based maintenance regimens. MATERIAL AND METHODS Embase, MEDLINE, and Cochrane databases and congress proceedings were searched to identify studies of adult de novo KTRs who received tacrolimus-based therapy in phase II/III randomized controlled trials. Outcomes were acute rejection, graft/patient survival, and incidence of new-onset diabetes mellitus after transplantation (NODAT) and cytomegalovirus (CMV) infection. Bayesian network meta-analysis was used to analyze treatment effects on graft/patient survival. RESULTS Sixty-eight publications (61 primary) were included. Of 21 publications reporting graft rejection following Advagraf or Prograf treatment in ≥1 study arm, 12-month biopsy-proven acute rejection (BPAR) ranged from 3.3% with Prograf to 55.0% with mycophenolic acid (MPA)+corticosteroids (CS); >24 month BPAR ranged from 0% to 58.7% (the latter with bleselumab-based therapy). Fourteen publications reported graft loss following Advagraf (0-9.6%) or Prograf (0-7.5%). Patient mortality ≤24 months after transplantation (14 publications) ranged from 0% to 8.1% with Advagraf or Prograf. Advagraf+MPA+CS and reference treatment, Prograf+MPA+CS, were associated with a similar risk of graft loss (odds ratio 1.19; 95% credible-interval 0.51, 3.06) and mortality (odds ratio 1.21; 95% credible-interval 0.1557, 9.03). Incidence of NODAT and CMV varied by treatment arm. CONCLUSIONS Graft loss and patient mortality rates were generally comparable between Advagraf- and Prograf-based regimens. Further prospective studies are needed to evaluate longer-term outcomes.
A UK analysis of the cost of switching renal transplant patients from an immediate-release to a prolonged-release formulation of tacrolimus based on differences in trough concentration variability. [2016]Randomized controlled trials have shown that a once-daily prolonged-release (PR) tacrolimus formulation (PR tacrolimus; Advagraf * ), is non-inferior to a twice-daily immediate-release (IR) tacrolimus formulation (IR tacrolimus; Prograf † ) in terms of biopsy-proven acute rejection, graft failure and mortality in renal transplant recipients. However, relative to IR tacrolimus, PR tacrolimus exhibits reduced tacrolimus trough concentration variability, which has been associated with reduced graft failure. Based on these data, the present study evaluated the cost of switching UK renal transplant patients from IR tacrolimus to PR tacrolimus.
Advagraf® with or without an induction therapy for de novo kidney-transplant recipients. [2021]Cornerstone immunosuppressive therapy currently relies on immediate-release tacrolimus, a calcineurin inhibitor (CNI) that is potentially nephrotoxic and is more diabetogenic than cyclosporine A. Two new formulations of tacrolimus have been launched: an extended-release formulation (Advagraf®/Astagraf XL®, Astellas company) and a long-lasting formulation (Envarsus®, Veloxis company). Area covered: Herein, we assess the efficacy of an extended-release formulation of tacrolimus (Advagraf®/Astagraf XL®) used in conjunction with or without an induction therapy (i.e., basiliximab) in de novo kidney-transplant recipients. To achieve this, we searched for suitable articles through PubMed. Expert commentary: Phases-III and -IV studies comparing Advagraf®/Astagraf XL® to Prograf® in association with mycophenolate mofetil (more than 2,500 patients) have demonstrated overall similar results with regards to patient/graft survival, biopsy-proven acute-rejection rate, and renal function (p > 0.05). A randomized controlled study in maintenance kidney transplant patients has shown (using electronic monitoring) that, as compared to Prograf®, Advagraf® significantly improved adherence to medication. Other studies report that Advagraf®-treated patients receiving a mTOR-inhibitor agent (sirolimus or everolimus) instead of MMF: this was associated with good allograft outcome, and might also prevent late-onset cytomegalovirus infection. Advagraf®-based immunosuppression given to de novo kidney-transplant recipients, with or without an induction therapy, provided excellent results compared to Prograf®; it also increased patients' adherence to treatment.
Effects of switching from twice-daily to once-daily tacrolimus formulation on quality of life, anxiety, and transplant benefit perception after kidney transplantation. [2015]This study investigated whether switching from the twice-daily (Prograf; TAC) to the once-daily formulation of tacrolimus with extended release (Advagraf; XL) affected quality of life, anxiety, and transplant benefit perception after allogeneic kidney transplantation.
Immunosuppression with tacrolimus early after orthotopic heart transplantation: a comparison of prograf and advagraf. [2021]We compared trough levels and clinical outcomes in patients who received Prograf or Advagraf (tacrolimus) de novo following heart transplantation surgery.
Overview of extended release tacrolimus in solid organ transplantation. [2022]Tacrolimus (Prograf(©), Astellas Pharma Europe Ltd, Staines, United Kingdom; referred to as tacrolimus-BID) is an immunosuppressive agent to prevent and treat allograft rejection in kidney transplant recipients in combination with mycophenolate mofetil, corticosteroids, with or without basiliximab induction. The drug has also been studied in liver, heart and lung transplant; however, these are currently off-label indications. An extended release tacrolimus formulation (Advagraf(©), Astagraf XL(©)) allows for once-daily dosing, with the potential to improve adherence. Extended release tacrolimus has similar absorption, distribution, metabolism and excretion to tacrolimus-BID. Phase I pharmacokinetic trials comparing extended release tacrolimus and tacrolimus-BID have demonstrated a decreased maximum concentration (Cmax) and delayed time to maximum concentration (tmax) with the extended release formulation; however, AUC0-24 was comparable between formulations. Overall extended release tacrolimus has a very similar safety and efficacy profile to tacrolimus-BID. It is not recommended in the use of liver transplant patient's due to the increased risk of mortality in female recipients. There has been minimal data regarding the use of extended release tacrolimus in heart and lung transplant recipients. With the current data available for all organ groups the extended release tacrolimus should be dosed in a 1:1 fashion, the exception may be the cystic fibrosis population where their initial dose may need to be higher.
Long-term follow-up of a phase III clinical trial comparing tacrolimus extended-release/MMF, tacrolimus/MMF, and cyclosporine/MMF in de novo kidney transplant recipients. [2021]In a phase III, open-label, comparative, noninferiority study, 638 subjects receiving de novo kidney transplants were randomized to one of three treatment arms: tacrolimus extended-release (Astagraf XL) qd, tacrolimus (Prograf) bid, or cyclosporine (CsA) bid. All subjects received basiliximab induction, mycophenolate mofetil, and corticosteroids. Safety and efficacy follow-up data through 4 years are reported.
Extended-release tacrolimus: a review of its use in de novo kidney transplantation. [2022]Extended-release tacrolimus (tacrolimus ER) [Advagraf(®); Astagraf XL(®); Graceptor(®); Prograf XL(®)] is a once-daily formulation of the immunosuppressive calcineurin inhibitor, which is approved in many countries worldwide for the prophylaxis of transplant rejection in adult de novo kidney transplant recipients. It is absorbed more slowly than the conventional, twice-daily, immediate-release formulation, initially producing lower exposure when administered at the same daily dosage, but providing equivalent exposure upon repeat administration with therapeutic drug monitoring. In randomized, controlled, phase III/IV trials, with extended follow-up to 4 years, the efficacy of tacrolimus ER was similar to that of twice-daily tacrolimus with regard to the prevention of acute rejection or graft dysfunction in adult de novo kidney transplant recipients. Renal function was significantly better with tacrolimus ER, but not tacrolimus, than with ciclosporin. The tolerability profile of tacrolimus ER was descriptively similar to that of the original twice-daily formulation, with no notable differences. Therefore, tacrolimus ER retains the immunosuppressive activity of the original formulation in the prophylaxis of transplant rejection in adult de novo kidney transplant recipients and offers the benefits of once-daily administration.