Immunosuppressive Therapy for Kidney Transplant in Children

(ADVANTage Trial)

Recruiting at 47 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests new treatments for children who have undergone a kidney transplant. Researchers aim to determine if the combination of belatacept (an immunosuppressive drug) and sirolimus is safer and more effective than the standard treatment of tacrolimus and Mycophenolate Mofetil (MMF). Eligible participants must be between 13 and 20 years old, have received a kidney from a deceased donor, and meet specific health criteria, such as having had chickenpox or mono in the past. The trial will monitor participants for up to two years to ensure the treatments are effective and safe. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

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.

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

Research has shown that using belatacept and sirolimus together has been tested in children who have had kidney transplants. Earlier studies found that this combination is generally well-tolerated by children. Some experienced side effects like infections, which are common for transplant patients.

Tacrolimus, another treatment option in this study, is often used in kidney transplants and is usually safe. It can cause side effects like shaking and higher blood sugar, but regular check-ups and care can manage these.

Both treatment options in this trial have been used before, and existing evidence suggests they are safe for children with kidney transplants. However, as with any medical treatment, monitoring for side effects is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard of care for kidney transplants in children, which often involves a combination of tacrolimus and mycophenolate mofetil, the investigational treatments in this trial explore new ways to manage immunosuppression. Researchers are excited about Belatacept because it works differently by selectively targeting T-cell co-stimulation, potentially reducing the risk of long-term kidney damage. Sirolimus, another treatment in the study, offers a unique mechanism by inhibiting a protein called mTOR, which may help in reducing side effects associated with traditional immunosuppressants. Together, these treatments could offer a more targeted approach with potentially fewer side effects, making them promising alternatives to current options.

What evidence suggests that this trial's treatments could be effective for kidney transplant in children?

Research shows that using belatacept and sirolimus together may help prevent organ rejection in kidney transplant patients. Early studies in adults and a small group of children have found that this combination can maintain kidney function. In this trial, one group of participants will receive belatacept and sirolimus. Belatacept has been linked to a lower risk of death up to seven years post-transplant compared to other treatments. Sirolimus helps prevent the body's immune system from attacking the new kidney. Researchers are studying these drugs as a potential alternative to traditional treatments. Another group of participants will receive tacrolimus and Mycophenolate Mofetil (MMF), which are part of the standard treatment regimen. ^{1 3 5 6 7}

Who Is on the 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

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 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]

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]

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]

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]

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 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06055608

Advancing Transplantation Outcomes in Children This is a pediatric kidney transplant study comparing the safety and efficacy of an immunosuppressive regimen of belatacept and sirolimus to tacrolimus and ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3884163/

New immunosuppressive agents in pediatric transplantation Of the 666 patients who completed at least 3 years of therapy, 92% of the MI, 92% of the LI, and 89% of the cyclosporine patients survived with a functioning ...

3. answers.childrenshospital.org answers.childrenshospital.org/pediatric-kidney-transplant-clinical-trial/

Finding new medication combinations for pediatric kidney ... The drug has also been successfully used in combination with sirolimus in adults and in a small number of pediatric transplant patients. In the ...

4. amjtransplant.org amjtransplant.org/article/S1600-6135(25)02418-9/fulltext

Belatacept: A New Ring in Pediatric Kidney Transplant ... The primary objective of this study was to evaluate the effectiveness of belatacept in preventing allograft rejection and to assess changes in kidney function.

5. nejm.org nejm.org/doi/full/10.1056/NEJMoa1506027

Belatacept and Long-Term Outcomes in Kidney ... The reduction in the risk of death at 7 years was 38% with the more-intensive belatacept regimen and 45% with the less-intensive regimen as ...

6. reporter.nih.gov reporter.nih.gov/project-details/10282915

Advancing Transplantation Outcomes in Children Based on a recent pilot study using de novo Belatacept therapy in combination with an mTOR inhibitor (mTORi) in pediatric recipients, we will test the ...

7. clinicaltrials.ucsd.edu clinicaltrials.ucsd.edu/trial/NCT06055608

Advancing Transplantation Outcomes in Children This is a pediatric kidney transplant study comparing the safety and efficacy of an immunosuppressive regimen of belatacept and sirolimus to tacrolimus and ...