Belatacept Regimen for Kidney Transplant Recipients

Recruiting at 50 trial locations

Overseen By BMS Study Connect Contact Center www.BMSStudyConnect.com

Age: < 18

Sex: Any

Trial Phase: Phase 3

Sponsor: Bristol-Myers Squibb

Must be taking: Calcineurin inhibitors

Must not be taking: Rituximab, Plasmapheresis

Disqualifiers: EBV negative, Acute rejection, TB, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: Unknown

Duration: 24 months

102 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to evaluate the benefits and risks of conversion of existing adolescent kidney allograft recipients aged 12 to less than 18 years of age to a belatacept-based immunosuppressive regimen as compared to continuation of a calcineurin inhibitor-based regimen and their adherence to immunosuppressive medications.

Will I have to stop taking my current medications?

The trial involves switching from a calcineurin inhibitor-based regimen to a belatacept-based regimen, so you may need to stop or change your current medications. The protocol does not specify a washout period, but you should discuss this with the trial team.

What data supports the effectiveness of the drug regimen for kidney transplant recipients?

Research shows that the extended-release formulation of tacrolimus (Advagraf/Astagraf XL) used with mycophenolate mofetil (CellCept) provides similar patient and graft survival rates compared to the immediate-release version (Prograf). Additionally, using enteric-coated mycophenolate sodium (Myfortic) with tacrolimus has been shown to be effective and safe, with high patient and graft survival rates in kidney transplant recipients. ^{1 2 3 4 5}

Is Belatacept safe for kidney transplant recipients?

Belatacept is generally considered safe for kidney transplant recipients, but it is not recommended for those who are Epstein-Barr virus seronegative due to a higher risk of developing a type of cancer called posttransplant lymphoproliferative disorder. Some studies have shown a higher rate of acute rejection episodes with Belatacept, and a trial was stopped early due to serious adverse events, so risks and benefits should be carefully considered. ^{6 7 8 9 10}

How is the drug Belatacept different from other treatments for kidney transplant recipients?

Belatacept is unique because it is a biological agent used for primary maintenance immunosuppression in kidney transplant patients, allowing for the reduction or withdrawal of calcineurin inhibitors (CNIs) and steroids, which can have harmful side effects. Unlike traditional treatments, Belatacept is administered intravenously and does not require plasma concentration monitoring, although it is less convenient than oral medications. ^{6 8 11 12 13}

Research Team

Bristol-Myers Squibb

Principal Investigator

Bristol-Myers Squibb

Eligibility Criteria

This trial is for adolescents aged 12 to <18 who have had a kidney transplant at least 6 months ago, are vaccinated against SARS-CoV-2, and show no current EBV infection. They must be on a stable calcineurin inhibitor regimen with mycophenolate and possibly corticosteroids. Those previously treated with belatacept or having certain rejection episodes or TB can't participate.

Inclusion Criteria

I've been on a stable medication regimen for my condition for at least 30 days.

I received a kidney transplant more than 6 months ago.

My kidney function has been stable for the last 3 months.

Exclusion Criteria

I have been treated for acute rejection of a transplant within the last 6 months.

I have had a severe rejection episode with my current organ transplant.

I have been treated with belatacept or was in a belatacept trial with my current transplant.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants are converted from a calcineurin inhibitor-based regimen to a belatacept-based regimen or continue with the calcineurin inhibitor-based regimen

24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Belatacept
• Corticosteroids
• Cyclosporine A
• Enteric Coated Mycophenolate Sodium
• Mycophenolate Mofetil
• Tacrolimus

Trial Overview The study compares the effects of switching adolescent kidney transplant recipients from their current calcineurin inhibitor-based treatment (like Tacrolimus) to a Belatacept-based regimen versus continuing their existing treatment. It also looks at how well they stick to their medication schedules.

Participant Groups

Group I: Arm 1: Conversion from a CNI- to belatacept-based regimen after a period of overlap Experimental Treatment 6 Interventions

Conversion followed by tapering and discontinuation of the calcineurin inhibitor (CNI)

Group II: Arm 2: Continue calcineurin inhibitor-based regimen Active Control 5 Interventions

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?

Bristol-Myers Squibb

Lead Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Findings from Research

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]

In a study of 65 Korean patients undergoing de novo renal transplantation, enteric-coated mycophenolate sodium (Myfortic) demonstrated a low incidence of biopsy-confirmed acute rejection at 10.8% within 6 months, indicating its efficacy in preventing rejection.

The safety profile showed that while 38.8% of patients experienced gastrointestinal discomfort, only 4.5% had reactions directly linked to the drug, and the overall patient and graft survival rates were high at 98.1% and 97.0%, respectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A 6-month, open-label, multicenter clinical study in Korean de novo renal transplant patients evaluating the efficacy, safety, and tolerance of myfortic concomitantly used with tacrolimus. Ju, MK., Park, SH., Kim, SJ., 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]

In a 6-month trial involving 237 stable renal transplant recipients, converting from mycophenolate mofetil (MMF) to enteric-coated mycophenolate sodium (EC-MPS) was found to be safe, with only 10% of patients requiring dose reductions due to adverse events.

The incidence of adverse events was 59.9%, with gastrointestinal issues being the most common at 22%, but the overall need for dose adjustments was low, indicating that EC-MPS is a tolerable alternative for patients previously on MMF.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety assessment of the conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in stable renal transplant recipients. Massari, P., Duro-Garcia, V., Girón, F., et al.[2016]

In a 24-month study of 101 kidney transplant recipients, the enteric-coated formulation of mycophenolate sodium (EC-MPS) showed a significantly lower incidence of serious infections compared to mycophenolate mofetil (MMF), with rates of 40% for EC-MPS and 49% for MMF.

The therapeutic effects of EC-MPS were found to be similar to those of MMF, as indicated by comparable serum creatinine levels and rates of biopsy-proven acute rejection, suggesting that EC-MPS is a safe and effective alternative in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enteric-coated mycophenolate sodium given in combination with tacrolimus has a lower incidence of serious infections in Asian renal-transplant recipients compared with mycophenolate mofetil. Feng, JJ., Zhang, LW., Zhao, P., et al.[2016]

Belatacept is a newly approved immunosuppressive therapy for kidney transplant recipients that has been shown to improve long-term graft function and is effective in preventing kidney allograft rejection, based on data from Phase II and III clinical trials.

Unlike traditional therapies, belatacept may reduce the risk of chronic side effects associated with calcineurin inhibitors and steroids, making it a promising option for long-term immunosuppression, although it is contraindicated in patients with unknown Epstein-Barr virus serostatus due to increased risk of complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Belatacept utilization recommendations: an expert position. Grinyó, JM., Budde, K., Citterio, F., et al.[2015]

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 significantly improves renal function in kidney transplant recipients compared to traditional cyclosporine-based therapy, with a notable increase in estimated glomerular filtration rate (eGFR) of 13-15 mL/min at 1 year and 23-27 mL/min at 7 years, as shown in the BENEFIT study involving standard criteria donors.

In addition to enhancing kidney function, belatacept therapy is associated with lower rates of hypertension, high cholesterol, and new-onset diabetes compared to cyclosporine, although concerns about the risk of posttransplantation lymphoproliferative disorder and the cost of treatment may limit its widespread use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Belatacept for the prophylaxis of organ rejection in kidney transplant patients: an evidence-based review of its place in therapy. Hardinger, KL., Sunderland, D., Wiederrich, JA.[2020]

Converting from tacrolimus to belatacept in kidney transplant patients with stable low eGFR (< 40 mL/min) resulted in a significant improvement in eGFR, with an average increase of 11.0 mL/min compared to 4.8 mL/min in the control group over 4 months.

However, while the belatacept group showed a modest increase in kidney function, there was a higher incidence of acute rejection (16.7%) compared to the control group, indicating potential safety concerns with this conversion strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early Conversion to Belatacept in Kidney Transplant Recipients With Low Glomerular Filtration Rate. Abdelwahab Elhamahmi, D., Heilman, RL., Smith, B., et al.[2022]

In a study involving 19 renal transplant recipients, the belatacept-based immunosuppressive regimen showed a higher frequency of acute cellular rejection episodes compared to the tacrolimus regimen, with 10 episodes in the belatacept groups versus only 1 in the tacrolimus group.

Despite similar estimated kidney function (GFR) at week 52 between the groups, the study was halted early due to a high rate of serious adverse events, highlighting the need for careful consideration of risks in immunosuppressive therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lessons Learned: Early Termination of a Randomized Trial of Calcineurin Inhibitor and Corticosteroid Avoidance Using Belatacept. Newell, KA., Mehta, AK., Larsen, CP., et al.[2023]

Belatacept, an immunosuppressant approved for preventing kidney graft rejection, showed similar graft survival rates compared to ciclosporin after 3 years in two large trials with over 1,200 patients, but only a high dose of belatacept improved renal function, which is not the authorized dose.

However, belatacept was associated with a higher risk of certain lymphomas and severe infections, such as progressive multifocal leukoencephalopathy and tuberculosis, making ciclosporin a more established and safer choice for long-term immunosuppressive therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Belatacept. [2019]

Early conversion to belatacept-based immunosuppression after kidney transplantation significantly improved kidney function, as measured by eGFR, from 26.73 to 45.3 ml/min/1.73 m² within one year, while late conversion showed no significant change.

Both early and late conversion groups had a one-year allograft survival rate of 100%, but early conversion was associated with a higher rate of acute T-cell-mediated rejections, suggesting that the choice of immunosuppressants may influence rejection types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early conversion to belatacept-based immunosuppression regimen promotes improved long-term renal graft function in kidney transplant recipients. Moein, M., Dvorai, RH., Li, BW., et al.[2023]

Belatacept shows improved renal function and lower rates of new onset diabetes compared to traditional calcineurin inhibitors (CNI) in kidney transplant recipients, based on a meta-analysis of six randomized controlled trials.

There were no significant differences in acute rejection rates between belatacept and CNIs, suggesting that belatacept may reduce CNI-related toxicity without compromising transplant success.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Does belatacept improve outcomes for kidney transplant recipients? A systematic review. Talawila, N., Pengel, LH.[2018]

References

1. England pubmed.ncbi.nlm.nih.gov

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

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

A 6-month, open-label, multicenter clinical study in Korean de novo renal transplant patients evaluating the efficacy, safety, and tolerance of myfortic concomitantly used with tacrolimus. [2022]

3. 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]

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

Safety assessment of the conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in stable renal transplant recipients. [2016]

5. England pubmed.ncbi.nlm.nih.gov

Enteric-coated mycophenolate sodium given in combination with tacrolimus has a lower incidence of serious infections in Asian renal-transplant recipients compared with mycophenolate mofetil. [2016]

6. England pubmed.ncbi.nlm.nih.gov

Belatacept utilization recommendations: an expert position. [2015]

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

Belatacept in kidney transplantation. [2018]

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

Belatacept for the prophylaxis of organ rejection in kidney transplant patients: an evidence-based review of its place in therapy. [2020]

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

Early Conversion to Belatacept in Kidney Transplant Recipients With Low Glomerular Filtration Rate. [2022]

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

Lessons Learned: Early Termination of a Randomized Trial of Calcineurin Inhibitor and Corticosteroid Avoidance Using Belatacept. [2023]

11. France pubmed.ncbi.nlm.nih.gov

Belatacept. [2019]

12. Netherlands pubmed.ncbi.nlm.nih.gov

Early conversion to belatacept-based immunosuppression regimen promotes improved long-term renal graft function in kidney transplant recipients. [2023]

13. Switzerland pubmed.ncbi.nlm.nih.gov

Does belatacept improve outcomes for kidney transplant recipients? A systematic review. [2018]