Tacrolimus for Delayed Graft Function

(CINERGY Trial)

Recruiting at 15 trial locations

Overseen By Ruth Breau

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Université de Sherbrooke

Disqualifiers: Hypersensitivity to tacrolimus, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

Duration: 4-8 hours

414 Participants Needed

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. ^{1 2 3 4 5}

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. ^{1 2 3 6 7}

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. ^{2 3 6 7 8}

Research Team

Frédérick D'Aragon

Principal Investigator

Université de Sherbrooke

Maureen Meade

Principal Investigator

McMaster University

Markus Selzner

Principal Investigator

University of Toronto

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

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

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
• Tacrolimus

Trial Overview The 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

Group I: Tacrolimus Experimental Treatment 1 Intervention

Tacrolimus 0.02 mg/kg ideal body weight 4-8 hours before organ recovery

Group II: Placebo Placebo Group 1 Intervention

0.9% sodium chloride 4-8 hours before organ recovery

Who Is Running the Clinical Trial?

Université de Sherbrooke

Lead Sponsor

Trials

317

Recruited

79,300+

McMaster University

Collaborator

Trials

936

Recruited

2,630,000+

Findings from Research

A systematic review and network meta-analysis of 68 studies found that long-term outcomes, such as graft loss and patient mortality, are generally comparable between the once-daily tacrolimus formulation (Advagraf) and the twice-daily formulation (Prograf) in kidney transplant recipients.

The analysis showed that the rates of acute rejection and new-onset diabetes mellitus after transplantation varied by treatment, but both Advagraf and Prograf demonstrated similar effectiveness in preventing graft loss and mortality, indicating that either formulation can be a viable option for post-transplant care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. T A, M., Chng, R., Yau, WP.[2022]

Switching from immediate-release (IR) tacrolimus to prolonged-release (PR) tacrolimus in UK renal transplant patients can lead to significant cost savings, averaging GBP 3415 per patient over five years, primarily due to reduced dialysis costs associated with lower graft failure risk.

PR tacrolimus shows reduced variability in tacrolimus trough concentrations compared to IR tacrolimus, which is linked to a lower risk of graft failure, making it a safer and more effective option for renal transplant recipients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Muduma, G., Odeyemi, I., Pollock, RF.[2016]

The extended-release formulation of tacrolimus (Advagraf®/Astagraf XL®) shows similar efficacy to the immediate-release version (Prograf®) in kidney transplant recipients, with no significant differences in patient/graft survival, acute rejection rates, or renal function across studies involving over 2,500 patients.

Advagraf® significantly improves medication adherence compared to Prograf®, which is crucial for long-term transplant success, and it has also been associated with favorable outcomes when combined with mTOR inhibitors, potentially reducing the risk of late-onset cytomegalovirus infection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advagraf® with or without an induction therapy for de novo kidney-transplant recipients. Noble, J., Jouve, T., Rostaing, L., et al.[2021]

Switching from the twice-daily tacrolimus (Prograf) to the once-daily extended-release formulation (Advagraf) in 49 kidney transplant patients led to an increased openness about their transplant experience after 6 months, indicating a potential improvement in quality of life.

However, 8 out of the 49 patients had to switch back to the original formulation due to adverse events, suggesting that while the switch may have benefits, it also carries risks that need to be monitored.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of switching from twice-daily to once-daily tacrolimus formulation on quality of life, anxiety, and transplant benefit perception after kidney transplantation. Calia, R., Lai, C., Aceto, P., et al.[2015]

In a study of 82 heart transplant patients, both Prograf and Advagraf (tacrolimus) showed comparable trough levels after an initial adjustment period, indicating similar drug exposure over time.

The 1-year mortality rates were 20% for Prograf and 15% for Advagraf, suggesting that Advagraf is a safe alternative to Prograf without compromising patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunosuppression with tacrolimus early after orthotopic heart transplantation: a comparison of prograf and advagraf. Ghodsizad, A., Koch, A., Ungerer, MN., et al.[2021]

Extended release tacrolimus (Advagraf©, Astagraf XL©) offers a once-daily dosing option for kidney transplant recipients, potentially improving medication adherence while maintaining a similar safety and efficacy profile to the traditional twice-daily tacrolimus (Prograf©).

While extended release tacrolimus shows comparable pharmacokinetics to the standard formulation, it is not recommended for liver transplant patients due to an increased risk of mortality in female recipients, and there is limited data on its use in heart and lung transplants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overview of extended release tacrolimus in solid organ transplantation. Patel, N., Cook, A., Greenhalgh, E., et al.[2022]

In a study of 638 kidney transplant recipients over 4 years, both tacrolimus formulations (Astagraf XL and Prograf) demonstrated similar patient and graft survival rates, with 93.2% and 91.2% survival respectively, compared to 91.7% for cyclosporine (CsA).

Patients on tacrolimus had a higher incidence of new-onset diabetes after transplantation (41.1% for Astagraf XL and 33.6% for Prograf) compared to 21.3% for CsA, but showed comparable renal function between the two tacrolimus formulations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Silva, HT., Yang, HC., Meier-Kriesche, HU., et al.[2021]

Extended-release tacrolimus (tacrolimus ER) is as effective as the traditional twice-daily formulation in preventing transplant rejection in adult kidney transplant recipients, based on phase III/IV trials with follow-up up to 4 years.

Tacrolimus ER shows better renal function compared to ciclosporin and has a similar tolerability profile to the original formulation, making it a convenient once-daily option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Extended-release tacrolimus: a review of its use in de novo kidney transplantation. McCormack, PL.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

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]

2. England pubmed.ncbi.nlm.nih.gov

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]

3. England pubmed.ncbi.nlm.nih.gov

Advagraf® with or without an induction therapy for de novo kidney-transplant recipients. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Effects of switching from twice-daily to once-daily tacrolimus formulation on quality of life, anxiety, and transplant benefit perception after kidney transplantation. [2015]

5. United States pubmed.ncbi.nlm.nih.gov

Immunosuppression with tacrolimus early after orthotopic heart transplantation: a comparison of prograf and advagraf. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Overview of extended release tacrolimus in solid organ transplantation. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

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]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Extended-release tacrolimus: a review of its use in de novo kidney transplantation. [2022]