Immunosuppressive Therapy for Kidney Transplant in Children

(ADVANTage Trial)

Recruiting at 45 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 2

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

Must not be taking: Immunosuppressants, Biologics, Corticosteroids

Disqualifiers: Active infection, Malignancy, Autoimmune disease, 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

Compensation: Varies

Number of Visits: Unknown

Duration: 12-24 months

200 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a pediatric kidney transplant study comparing the safety and efficacy of an immunosuppressive regimen of belatacept and sirolimus to tacrolimus and Mycophenolate Mofetil (MMF). Two hundred participants will be randomized (1:1) to one of two groups within 24 hours following the transplant procedure. The duration of the study from time of transplant to the primary endpoint is 12-24 months.

Will I have to stop taking my current medications?

The trial requires that participants do not use immunosuppressants, biologics, chronic corticosteroids, or investigational drugs within 8 weeks before joining. If you are on these medications, you will need to stop taking them before enrolling.

What data supports the effectiveness of the drug Belatacept for kidney transplant in children?

Belatacept has been shown to maintain stable kidney function and prevent rejection in adolescents, especially those at risk for nonadherence, with good short-term outcomes. It is also effective in cases where traditional drugs cause adverse effects, as seen in a 17-year-old boy who had stable kidney function after switching to Belatacept. ^{1 2 3 4 5}

Is immunosuppressive therapy for kidney transplant in children generally safe?

Belatacept and sirolimus are used in kidney transplants and have shown good safety profiles, though belatacept may increase the risk of infections like CMV. Tacrolimus, another option, is effective but can be hard on the kidneys and may increase diabetes risk. ^{5 6 7 8 9}

How is the drug combination of Belatacept, Sirolimus, and Tacrolimus unique for kidney transplant in children?

This drug combination is unique because it aims to reduce kidney damage by avoiding calcineurin inhibitors, which are commonly used but can be harmful to the kidneys. Belatacept, in particular, offers a different approach by blocking a specific pathway (CD28-mediated T-cell costimulation) to prevent organ rejection, potentially leading to better long-term kidney function and fewer side effects compared to traditional treatments. ^{1 6 7 8 10}

Research Team

David Briscoe, MD

Principal Investigator

Boston Children's Hospital: Pediatric Transplantation

Eileen Chambers, MD

Principal Investigator

Duke University Medical Center: Department of Pediatrics

Eligibility Criteria

This trial is for children aged 13-20 who need a kidney transplant from a deceased donor. They must be able to consent, have immunity to EBV (a type of virus), and use birth control if applicable. Kids under 6 or with living donors might join later if it's safe.

Inclusion Criteria

I have immunity to Epstein-Barr virus as shown by specific blood tests.

I am part of a group that may be included in the study based on safety reviews.

If participant has reproductive potential, agrees to use Food and Drug Administration (FDA) approved methods of birth control for the duration of the study

Exclusion Criteria

I have a kidney condition like FSGS, MPGN, C3 glomerulopathy, or atypical HUS.

I haven't taken immunosuppressants, biologics, chronic steroids, or experimental drugs in the last 8 weeks.

Current or historical anti-HLA antibody to the donor

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Transplantation and Initial Treatment

Participants undergo kidney transplantation and begin initial immunosuppressive treatment

0-4 weeks

In-patient stay for transplantation and initial treatment

Treatment

Participants receive ongoing immunosuppressive regimen of either belatacept and sirolimus or tacrolimus and MMF

12-24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Treatment Details

Interventions

• Belatacept
• Sirolimus
• Tacrolimus

Trial Overview The study compares two drug combos after kidney transplants in kids: belatacept & sirolimus vs tacrolimus & mycophenolate mofetil. It's random which one they get, and they'll be watched for up to two years to see how well the drugs prevent organ rejection.

Participant Groups

Group I: (Group 1): Belatacept+Sirolimus group Experimental Treatment 4 Interventions

Participants in this group will receive antithymocyte globulin (ATG) + steroid taper + belatacept + (tacrolimus bridge, day 0-14) with conversion to sirolimus (day 30 +/-14 days)

Group II: (Group 2): Tacrolimus + Mycophenolate Mofetil (MMF) group Active Control 3 Interventions

Participants in this group will receive anti-thymocyte globulin (ATG) + steroid taper + tacrolimus + MMF

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

Lymphocyte-depleting antibodies, particularly ATG, are the most commonly used induction agents for pediatric kidney transplants in the US, highlighting their importance in improving graft survival despite potential treatment-related toxicities.

The article reviews various immunosuppressive agents, including CNIs and antiproliferative agents, emphasizing that while they form the backbone of maintenance therapy, the optimal combinations and steroid-avoidance strategies remain uncertain, indicating a need for tailored approaches in pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Induction and maintenance immunosuppression in pediatric kidney transplantation-Advances and controversies. Balani, SS., Jensen, CJ., Kouri, AM., et al.[2022]

A 17-year-old boy developed a serious blood condition called microangiopathic hemolytic anemia after receiving tacrolimus following a kidney transplant, which was initially treated with plasmapheresis.

Switching to monthly intravenous belatacept successfully prevented the recurrence of hemolysis and maintained stable kidney function, suggesting that belatacept could be a valuable alternative immunosuppressive treatment for patients experiencing adverse effects from standard therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of belatacept to maintain adequate early immunosuppression in calcineurin-mediated microangiopathic hemolysis post-renal transplant. Reynolds, BC., Talbot, D., Baines, L., et al.[2021]

In a study involving three adolescent kidney transplant recipients, the use of belatacept as a selective T cell costimulatory blocker resulted in good short-term clinical outcomes, including 100% adherence to therapy and no development of de novo donor-specific antibodies (dnDSA).

Renal function was maintained at acceptable levels over the monitoring period, with one patient experiencing treatable infections and another having a steroid-responsive acute cellular rejection, indicating that belatacept can be a viable option for managing transplant care in adolescents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tailored use of belatacept in adolescent kidney transplantation. Blew, KH., Chua, A., Foreman, J., et al.[2023]

A modified release tacrolimus formulation (MR4) is currently in phase III trials and aims to improve kidney transplant outcomes by allowing once-daily administration while maintaining the same therapeutic target levels as the original formulation.

Belatacept (LEA29Y), a second-generation immunosuppressant, has shown comparable efficacy to ciclosporin in phase II trials and is now in phase III trials, indicating its potential as a viable alternative for kidney transplant patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunotherapy for De Novo renal transplantation: what's in the pipeline? Tedesco Silva, H., Pinheiro Machado, P., Rosso Felipe, C., et al.[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]

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]

In a study of 316 kidney transplant recipients over 2 years, belatacept-based immunosuppression showed a significantly lower incidence of reduced kidney function (eGFR <45 ml/min) compared to tacrolimus, indicating better long-term kidney health.

However, belatacept was associated with a higher rate of biopsy-proven acute rejection compared to tacrolimus, suggesting a trade-off between reduced nephrotoxicity and increased rejection risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Belatacept for Simultaneous Calcineurin Inhibitor and Chronic Corticosteroid Immunosuppression Avoidance: Two-Year Results of a Prospective, Randomized Multicenter Trial. Kaufman, DB., Woodle, ES., Shields, AR., et al.[2023]

Mammalian target of rapamycin (mTOR) inhibitors like sirolimus and everolimus offer effective immunosuppression for kidney transplant patients with minimal renal toxicity, making them a promising alternative to traditional calcineurin inhibitors.

Combining belatacept, which has a favorable cardiovascular profile, with sirolimus may enhance immunosuppression while mitigating the risk of cytomegalovirus (CMV) infections, although belatacept alone can increase infection risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rationale for using belatacept in combination with sirolimus. Wéclawiak, H., Kamar, N., Ould-Mohamed, A., et al.[2015]

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]

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]

References

1. Denmark pubmed.ncbi.nlm.nih.gov

Induction and maintenance immunosuppression in pediatric kidney transplantation-Advances and controversies. [2022]

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

Use of belatacept to maintain adequate early immunosuppression in calcineurin-mediated microangiopathic hemolysis post-renal transplant. [2021]

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

Tailored use of belatacept in adolescent kidney transplantation. [2023]

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

Immunotherapy for De Novo renal transplantation: what's in the pipeline? [2018]

5. 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]

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

Belatacept in kidney transplantation. [2018]

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

Belatacept for Simultaneous Calcineurin Inhibitor and Chronic Corticosteroid Immunosuppression Avoidance: Two-Year Results of a Prospective, Randomized Multicenter Trial. [2023]

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

Rationale for using belatacept in combination with sirolimus. [2015]

9. England pubmed.ncbi.nlm.nih.gov

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

10. 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]