Belatacept for Heart Transplant

Recruiting at 3 trial locations

Overseen By Yvonne Morrison

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Must be taking: Tacrolimus, Mycophenolate, Corticosteroids

Must not be taking: Immunosuppressive biologics

Disqualifiers: HIV, Hepatitis B, Hepatitis C, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 9 months

66 Participants Needed

Trial Summary

Do I need to stop my current medications to join the trial?

The trial involves a gradual withdrawal of tacrolimus over 9 months for those in the belatacept group. Other medications like CellCept® or Myfortic® and corticosteroids will be continued. The protocol does not specify if you need to stop other current medications, so it's best to discuss with the study team.

What data supports the effectiveness of the drug Belatacept for heart transplant patients?

Belatacept is approved for kidney transplants and has shown benefits like better kidney function and lower risk of graft loss and death compared to other drugs. Although primarily used for kidney transplants, there are reports of its use in other transplant settings, suggesting potential benefits for heart transplant patients as well. ^{1 2 3 4 5}

Is Belatacept generally safe for use in humans?

Belatacept has been used safely in kidney transplant patients, showing no increased risk of severe infections, virus reactivation, cancer, or death. However, it may lead to more episodes of cellular rejection and post-transplant lymphoproliferative disorder (a type of immune system disease) in certain patients. ^{3 4 5 6 7}

How is the drug Belatacept different from other treatments for heart transplant patients?

Belatacept is unique because it blocks a specific pathway needed for T cell activation, which helps prevent organ rejection without the kidney-damaging side effects common with other drugs like calcineurin inhibitors. This makes it a promising alternative for heart transplant patients, especially those with kidney concerns. ^{1 3 4 5 8}

What is the purpose of this trial?

This is a phase 2, prospective, multi-center, open-label clinical trial. Sixty-six (66) primary heart transplant recipients will be randomized (1:2) to receive either standard-of-care, tacrolimus-based immunosuppression, or a belatacept-based regimen with gradual tacrolimus withdrawal over 9-months post-transplant. Both study arms will receive CellCept® (mycophenolate mofetil- MMF) or Myfortic® (mycophenolate sodium). Corticosteroids will be continued throughout the study in the belatacept arm. The primary objective is to evaluate whether NULOJIX® (belatacept), when implemented with gradual tacrolimus withdrawal over 9 months, is safe with respect to preventing the composite endpoint of acute cellular rejection (ACR) \>= International Society of Heart and Lung Transplantation (ISHLT) 2R, hemodynamic compromise rejection in the absence of a biopsy or histological rejection, re-transplantation, and death at 18 months post-transplant.

Research Team

Joren C Madsen, MD, DPhil

Principal Investigator

Massachusetts General Hospital

Jon A. Kobashigawa, MD

Principal Investigator

Cedars-Sinai Medical Center

Marlena Habal, MD

Principal Investigator

NYU Langone Health

Christian P. Larsen, MD, DPhil

Principal Investigator

Emory University

Eligibility Criteria

This trial is for primary heart transplant recipients. Participants must be eligible for a heart transplant and fit to undergo the procedure. Specific inclusion or exclusion criteria are not listed, but typically these would exclude individuals with certain medical conditions or those taking conflicting medications.

Inclusion Criteria

Study entry: Subject must be able to understand the purpose of the study and be willing to participate and provide written consent

Study entry: Epstein-Barr Virus (EBV) seropositive

Randomization: Negative crossmatch actual or virtual on the most recent sera

Exclusion Criteria

I have a history of certain medical conditions or treatments.

Study entry: Abnormal white blood cell count or neutrophil count

Randomization: Known hypersensitivity to specific medications

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either standard-of-care tacrolimus-based immunosuppression or a belatacept-based regimen with gradual tacrolimus withdrawal over 9 months post-transplant

9 months

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of chronic kidney disease stage

9 months

Assessed at Baseline, Month 1, 12, and 18

Treatment Details

Interventions

• Belatacept

Trial Overview The study compares standard tacrolimus-based immunosuppression with a belatacept-based regimen where tacrolimus is gradually withdrawn over 9 months post-transplant. Both groups will also receive mycophenolate mofetil/sodium and corticosteroids.

Participant Groups

Group I: Belatacept + Tacrolimus withdrawal Experimental Treatment 4 Interventions

1. Maintenance Immunosuppression: NULOJIX (belatacept) 2. Maintenance Immunosuppression: CellCept (mycophenolate mofetil- MMF), or Myfortic (mycophenolate sodium) 3. Calcineurin Inhibitors (CNI) Taper: Prograf® (tacrolimus), or tacrolimus generic 4. Corticosteroid: Prednisone (no less than 5mg per day continued throughout the study period)

Group II: Standard-of-Care Active Control 3 Interventions

1. Maintenance Immunosuppression: Prograf (tacrolimus), or tacrolimus generic; 2. Maintenance Immunosuppression: CellCept (mycophenolate mofetil- MMF), or Myfortic (mycophenolate sodium); 3. Corticosteroid +/- taper: Prednisone

Belatacept is already approved in United States, European Union for the following indications:

Approved in United States as Nulojix for:

• Prophylaxis of organ rejection in adult patients receiving a kidney transplant

Approved in European Union as Nulojix for:

• Prophylaxis of organ rejection in adult patients receiving a kidney transplant

Who Is Running the Clinical Trial?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3,361

Recruited

5,516,000+

Findings from Research

Belatacept, approved by the FDA in 2011, provides a safer alternative to calcineurin inhibitors for renal transplant patients, showing improved renal function and a 43% reduction in the risk of graft loss and death over seven years in the BENEFIT trial involving multiple centers.

While primarily used in renal transplantation, emerging reports suggest successful long-term use of belatacept in other transplant settings, including kidney-after-heart transplants, indicating its potential versatility beyond just kidney transplants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

De Novo Belatacept in a Kidney-After-Heart Transplant Recipient. Schenk, AD., Anderson, DJ., Cole, RT., et al.[2020]

In a study involving 4 liver transplant patients who were switched from belatacept to triple therapy, all experienced acute rejection and graft dysfunction after a mean of 10.3 weeks on MMF monotherapy, indicating that belatacept does not provide sufficient immunomodulatory effects to allow for safe withdrawal.

Despite initial superior kidney function (eGFR of 105.1 mL/min/1.73 m²) in belatacept patients compared to controls (58 mL/min/1.73 m²), kidney function declined significantly after switching to CNI therapy, highlighting the need for careful management of immunosuppressive therapy in liver transplant recipients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Belatacept treatment for two yr after liver transplantation is not associated with operational tolerance. Schwarz, C., Rasoul-Rockenschaub, S., Soliman, T., et al.[2016]

Belatacept is an effective immunosuppressant for kidney transplant recipients, showing noninferior patient and allograft survival compared to cyclosporine in Phase 3 trials, with improved kidney function over three years.

While belatacept may offer benefits like better renal function and cardiometabolic health, it carries a risk of higher early rejection rates and potential increased risk of posttransplant lymphoproliferative disease, particularly in certain patient populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Belatacept in kidney transplantation. Wojciechowski, D., Vincenti, F.[2018]

Belatacept, a new immunosuppressant for kidney transplantation, has shown superior graft function and better preservation of renal structure compared to traditional treatments like cyclosporine, based on phase II and III clinical trials.

However, belatacept is associated with a higher risk of cellular rejection and post-transplant lymphoproliferative disorder (PTLD), particularly in patients who are EBV seronegative, indicating the need for careful patient selection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Belatacept: from rational design to clinical application. Wekerle, T., Grinyó, JM.[2017]

An accurate and precise assay for measuring belatacept serum concentrations was developed, showing a measurement range of 0.9-30 mg/L and high accuracy (91%-99%).

This assay was applied in a pharmacokinetic study involving 5 renal transplant recipients, allowing for the visualization of belatacept concentrations over time, which is crucial for optimizing immunosuppressive therapy post-transplant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Fully Automated Method for the Determination of Serum Belatacept and Its Application in a Pharmacokinetic Investigation in Renal Transplant Recipients. Klaasen, RA., Egeland, EJ., Chan, J., et al.[2019]

In a study of 27 kidney transplant recipients, the combination of belatacept (Bela) with mycophenolate (MPA) led to a high rate of acute rejection, resulting in the early closure of this treatment arm, with 4 out of 9 patients experiencing rejection.

Conversely, the regimen of belatacept with low-dose tacrolimus (Tac) showed a trend towards improved kidney function, with an increase in estimated glomerular filtration rate (eGFR), suggesting that low-dose Tac may be necessary to prevent rejection when using belatacept in steroid-free regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early calcineurin-inhibitor to belatacept conversion in steroid-free kidney transplant recipients. Tawhari, I., Hallak, P., Bin, S., et al.[2023]

In a study of 34 patients at high cardiovascular risk, Belatacept treatment led to a significant increase in estimated glomerular filtration rate (eGFR) compared to a matched control group on calcineurin inhibitors, indicating better kidney function with Belatacept.

Belatacept was found to be safe, with no significant increase in risks for renal allograft rejection, severe infections, or other serious complications, making it a promising immunosuppressive option for renal transplant patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Belatacept Treatment in Renal Allograft Recipients at High Cardiovascular Risk-A Single Center Experience. Neuwirt, H., Leitner-Lechner, I., Kerschbaum, J., et al.[2020]

Belatacept, approved by the FDA in 2011 for kidney transplantation, selectively blocks T cell costimulation and has shown promising results in improving both short- and long-term outcomes in renal transplants, while having a better side effect profile compared to traditional calcineurin inhibitors (CNIs).

The use of belatacept may help reduce the nephrotoxicity and metabolic side effects associated with CNIs, addressing the significant issues of chronic kidney disease and its related complications in solid organ transplant patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Belatacept As an Alternative to Calcineurin Inhibitors in Patients with Solid Organ Transplants. Kumar, D., LeCorchick, S., Gupta, G.[2020]

References

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

De Novo Belatacept in a Kidney-After-Heart Transplant Recipient. [2020]

2. Denmark pubmed.ncbi.nlm.nih.gov

Belatacept treatment for two yr after liver transplantation is not associated with operational tolerance. [2016]

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

Belatacept in kidney transplantation. [2018]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Belatacept: from rational design to clinical application. [2017]

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

A Fully Automated Method for the Determination of Serum Belatacept and Its Application in a Pharmacokinetic Investigation in Renal Transplant Recipients. [2019]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Early calcineurin-inhibitor to belatacept conversion in steroid-free kidney transplant recipients. [2023]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Belatacept Treatment in Renal Allograft Recipients at High Cardiovascular Risk-A Single Center Experience. [2020]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Belatacept As an Alternative to Calcineurin Inhibitors in Patients with Solid Organ Transplants. [2020]