Tacrolimus for Delayed Graft Function

(CINERGY Trial)

Not currently recruiting at 21 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether administering tacrolimus to brain-dead organ donors can improve the survival of transplanted organs. Tacrolimus is an immunosuppressant drug. Donors will receive either tacrolimus or a placebo (a harmless substance) before organ recovery. The trial will evaluate organ function shortly after the transplant and again after a year. Potential participants include neurologically deceased donors who have agreed to donate their organs and their identified organ recipients. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that tacrolimus is generally safe for people. In past studies, no unexpected safety problems arose when tacrolimus was used in kidney transplant patients. For example, one study found that both patients and their new kidneys had high survival rates after one year. Another study showed that after two years, no surprising safety issues emerged.

However, some risks exist. For instance, using tacrolimus during pregnancy can increase the chance of miscarriage and early birth.

Overall, evidence suggests that tacrolimus is quite safe for organ transplants, but like any medication, it carries some risks. People considering joining a trial should weigh these potential risks against the benefits. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about Tacrolimus for delayed graft function because, unlike standard treatments that focus mainly on managing symptoms after they occur, Tacrolimus is administered before organ recovery. This preemptive approach aims to protect organs during the transplant process, potentially reducing the chance of complications. Additionally, Tacrolimus works by suppressing the immune response, which is crucial in preventing the body from rejecting a new organ. This makes it a promising option for improving transplant outcomes.

What evidence suggests that tacrolimus might be an effective treatment for delayed graft function?

Research has shown that tacrolimus, which participants in this trial may receive, can greatly benefit organ transplant patients. Studies have found high survival rates, with 98.6% of patients surviving the first year and 96.7% of transplanted organs remaining functional. This indicates that tacrolimus effectively maintains the health of both patients and their new organs. The treatment also consistently reduces issues with delayed organ function, a common problem with transplants from deceased donors. Overall, tacrolimus holds strong potential to enhance the success and longevity of transplants. ^{1 2 3 6 7}

Who Is on the Research Team?

Frédérick D'Aragon

Principal Investigator

Université de Sherbrooke

Maureen Meade

Principal Investigator

McMaster University

Markus Selzner

Principal Investigator

University of Toronto

Are You a Good Fit for This Trial?

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

Donor: Consent for deceased organ donation

Donor: All organ recipients have been identified

You received an organ or tissue transplant from a donor who is also taking part in this study.

Exclusion Criteria

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

My doctor thinks tacrolimus isn't right for my transplant.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 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]

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]

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]

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]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC3979830/

Long-Term Follow-Up of a Phase III Clinical Trial ...

In the Astagraf XL, Prograf, and CsA groups, patient survival was 93.8% (95% CI: 90.5%, 97.2%), 93.2% (95% CI: 89.8%, 96.7%), and 92.5% (95% CI: 88.6%, 96.3%), ...

2.

sciencedirect.com

sciencedirect.com/science/article/pii/S1600613522146149

One-Year Results with Extended-Release Tacrolimus/MMF ...

One-year patient and graft survival were 98.6% and 96.7% in the XL/MMF group, 95.7% and 92.9% in TAC/MMF group and 97.6% and 95.7% in CsA/MMF group. The safety ...

3.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC4801790/

Overview of extended release tacrolimus in solid organ ...

Graft survival rates were 94.6% and 93.6% at 24 wk and 92.8% and 91.5% at 12 mo respectively. The incidence of delayed graft function, serum creatinine (SrCr) ...

4.

amjtransplant.org

amjtransplant.org/article/S1600-6135(22)14614-9/pdf

One-Year Results with Extended-Release Tacrolimus/MMF ...

Regardless of treatment group, >90% of episodes of delayed graft function occurred in patients who received grafts from de- ceased donors. Renal function ...

5.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/24521771/

Long-term follow-up of a phase III clinical trial comparing ...

In this 4-year follow-up report, patients receiving Astagraf XL and Prograf showed comparable efficacy and safety profiles, with a higher incidence of new- ...

6.

clinicaltrials.gov

clinicaltrials.gov/study/NCT00720408

A Randomized Study to Assess the Safety and Efficacy of ...

A Randomized, Open-Label, Comparative, Multi-Center Study to Assess the Safety and Efficacy of Prograf (Tacrolimus)/MMF and Extended Release (XL) Tacrolimus / ...

7.

accessdata.fda.gov

accessdata.fda.gov/drugsatfda_docs/label/2020/204096s009lbl.pdf

ASTAGRAF XL (tacrolimus) Label - accessdata.fda.gov

Safety data from the TPRI and postmarketing surveillance suggest infants exposed to tacrolimus in utero have an increased risk for miscarriage, pre-term ...