Immunosuppressive Therapy for Kidney Transplant in Children
(ADVANTage Trial)
Recruiting in Palo Alto (17 mi)
+45 other locations
Age: < 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
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
Prior Safety Data
Breakthrough Therapy
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.12345
Is immunosuppressive therapy for kidney transplant in children generally safe?
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.167810
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
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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
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Trial 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 (Immunosuppressant)
- Sirolimus (Immunosuppressant)
- Tacrolimus (Immunosuppressant)
Trial OverviewThe 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
2Treatment groups
Experimental Treatment
Active Control
Group I: (Group 1): Belatacept+Sirolimus groupExperimental Treatment4 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) groupActive Control3 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Children's Hospital of Los Angeles (Site #: 71036)Los Angeles, CA
Mattel Children's Hospital, UCLA (Site #: 71036)Los Angeles, CA
UCSD Rady Children's Hospital (Site #: 71012)San Diego, CA
Children's National Hospital (Site #: 71039)Washington, United States
More Trial Locations
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Who Is Running the Clinical Trial?
National Institute of Allergy and Infectious Diseases (NIAID)Lead Sponsor
References
Induction and maintenance immunosuppression in pediatric kidney transplantation-Advances and controversies. [2022]Advances in immunosuppression have improved graft survival in pediatric kidney transplant recipients; however, treatment-related toxicities need to be balanced against the possibility of graft rejection. Several immunosuppressive agents are available for use in transplant recipients; however, the optimal combinations of agents remain unclear, resulting in variations in institutional protocols. Lymphocyte-depleting antibodies, specifically ATG, are the most common induction agent used for pediatric kidney transplantation in the US. Basiliximab may be used for induction in immunologically low-risk children; however, pediatric data are scarce. CNIs and antiproliferative agents (mostly Tac and mycophenolate in recent years) constitute the backbone of maintenance immunosuppression. Steroid-avoidance maintenance regimens remain controversial. Belatacept and mTOR inhibitors are used in children under specific circumstances such as non-adherence or CNI toxicity. This article reviews the indications, mechanism of action, efficacy, dosing, and side effect profiles of various immunosuppressive agents available for pediatric kidney transplantation.
Use of belatacept to maintain adequate early immunosuppression in calcineurin-mediated microangiopathic hemolysis post-renal transplant. [2021]We report a 17-yr-old boy who developed a microangiopathic hemolytic anemia presumed secondary to tacrolimus shortly following a living-related donor renal transplant. This was initially managed by plasmapheresis. Reinstitution of calcineurin inhibition using cyclosporine led to recurrence of hemolysis, so an alternative agent was needed. He was commenced on monthly intravenous belatacept, with no further recurrence of the hemolysis, and subsequent stable graft function. Modulation via CTLA-4 offers an alternative immunosuppressive tactic if current regimens produce graft threatening adverse effects. The method of administration and frequency of dosage of belatacept also lends itself well to the high-risk period of adolescence and transition. We propose that belatacept may therefore also have utility in difficult cases complicated by poor concordance, common in the adolescent age group.
Tailored use of belatacept in adolescent kidney transplantation. [2023]Adolescent transplant recipients are at risk for nonadherence, development of de novo donor-specific antibody (dnDSA), and allograft loss. Belatacept, a selective T cell costimulatory blocker, is associated with reduced dnDSA, improved renal function, and prolonged allograft survival when compared to calcineurin inhibitor-based regimens in adults; however, its use in children is scant. Three adolescents were initiated on belatacept between August 2017 and September 2018 at the time of kidney transplantation. Selection criteria included age ≥ 14 and EBV IgG + serostatus. Intraoperative alemtuzumab and methylprednisolone were given as induction therapy. Tailored maintenance therapy included steroid-free belatacept and sirolimus for two patients. One patient was initially maintained steroid-free on belatacept and belimumab, an inhibitor of B cell activating factor to treat concurrent systemic lupus erythematous; steroids were added subsequently. Renal function, biopsy-proven rejection, dnDSA, allograft survival, infection, nonadherence, and proteinuria were monitored. Renal function was 86, 73, 52 mL/min/1.73 m2 at 20, 20, and 8 months, respectively. There was 100% adherence to therapy and no development of dnDSA. All patients had treatable infections. One developed steroid-responsive acute cellular rejection. Belatacept-based regimens can be tailored for adolescent recipients with good short-term clinical outcomes.
Immunotherapy for De Novo renal transplantation: what's in the pipeline? [2018]Immunosuppressive drugs have been traditionally developed to prevent acute rejection and to improve short-term kidney transplant outcomes. There is still a medical need to improve outcomes among subgroups of patients at higher risk for graft loss and to reduce cardiovascular, infectious and malignancy-associated morbidity and mortality, and improve long-term adherence. Several new immunosuppressive agents and formulations are undergoing clinical investigation and are discussed in this review.A modified release tacrolimus formulation (MR4) for once-daily administration is undergoing phase III trials. It has been developed to be administered de novo or for maintenance using the same therapeutic target tacrolimus trough concentrations as for the original formulation. Belatacept (LEA29Y), a second generation cytotoxic-T-lymphocyte-associated antigen immunoglobulin (CTLA4-Ig), blocks the interaction between CD80/86 and CD28 costimulatory pathways. In phase II trials, belatacept was as effective as ciclosporin (cyclosporine) when administered in combination with basiliximab, mycophenolate mofetil (MMF) and corticosteroids. Currently, belatacept is undergoing phase III trials including one study in recipients of organs from expanded criteria donors. Inhibitors of the Janus protein tyrosine kinase (JAK)-3 show some selectivity for cells of the lymphoid lineage and have been shown to be effective in late preclinical transplant models. The most frequent adverse effects have been related to nonspecific binding to JAK2 kinases. CP-690550, a JAK3 inhibitor is currently in phase II clinical trials.FK778, is a synthetic malononitrilamide that targets the critical enzyme of the de novo pyrimidine synthesis, dihydroorotic acid dehydrogenase, and receptor-associated tyrosine kinases has completed phase II trials. FK778 also shows antiviral activities that have been tested in patients with polyomavirus nephropathy. Fingolimod (FTY720), a synthetic sphingosine phosphate receptor modulator that reduces the recirculation of lymphocytes to blood and peripheral tissues including inflammatory lesions and graft sites is undergoing phase III trials. Although the efficacy of fingolimod is similar to MMF in patients receiving full doses of ciclosporin, safety issues such as a negative chronotropic effect, macular oedema, pulmonary adverse reactions and graft function resulted in premature discontinuation of the development programme for kidney transplantation. Because there was no clear clinical benefit over treatment options, the clinical development programme of FK778 was discontinued.Finally, a new evolving strategy with powerful induction-induced prolonged T-cell depletion followed by low-dose immunosuppressive monotherapy is showing promising results.
Belatacept for the prophylaxis of organ rejection in kidney transplant patients: an evidence-based review of its place in therapy. [2020]Belatacept is a novel immunosuppressive therapy designed to improve clinical outcomes associated with kidney transplant recipients while minimizing use of calcineurin inhibitors (CNIs).
Belatacept in kidney transplantation. [2018]In June 2011 the US Food and Drug Administration approved belatacept (Nulojix; Bristol-Myers Squibb, Princeton, New Jersey, USA) for the prophylaxis of organ rejection in adult kidney transplant recipients. This review will discuss the use of belatacept for the prevention of acute rejection as part of a maintenance immunosuppression regimen.
Belatacept for Simultaneous Calcineurin Inhibitor and Chronic Corticosteroid Immunosuppression Avoidance: Two-Year Results of a Prospective, Randomized Multicenter Trial. [2023]Immunosuppressive therapy in kidney transplantation is associated with numerous toxicities. CD28-mediated T-cell costimulation blockade using belatacept may reduce long-term nephrotoxicity, compared with calcineurin inhibitor-based immunosuppression. The efficacy and safety of simultaneous calcineurin inhibitor avoidance and rapid steroid withdrawal were tested in a randomized, prospective, multicenter study.
Rationale for using belatacept in combination with sirolimus. [2015]Kidney transplantation can be used to replace failing native kidneys; however, it requires long-term immunosuppression, and immunological tolerance for this is not yet achievable. The cornerstone of immunosuppression is based on calcineurin inhibitors, which are nephrotoxic. Therefore, new drugs are being developed that provide efficacious immunosuppression and almost no renal toxicity. The first family of drugs that have these properties are mammalian target of rapamycin inhibitors: these include sirolimus and everolimus. These two drugs, besides their immunosuppressive properties, also have beneficial effects regarding cytomegalovirus (CMV) infection, which is a very common posttransplantation complication. In phase III trials, belatacept, a costimulatory blocker, has also been shown to provide a good immunosuppressive effect and also gives a significantly better cardiovascular profile than cyclosporine-based immunosuppression. However, belatacept can potentially increase infections such as CMV. Thus, herein, we describe the rationale for combining belatacept with sirolimus for kidney transplant patients.
Advagraf® with or without an induction therapy for de novo kidney-transplant recipients. [2021]Cornerstone immunosuppressive therapy currently relies on immediate-release tacrolimus, a calcineurin inhibitor (CNI) that is potentially nephrotoxic and is more diabetogenic than cyclosporine A. Two new formulations of tacrolimus have been launched: an extended-release formulation (Advagraf®/Astagraf XL®, Astellas company) and a long-lasting formulation (Envarsus®, Veloxis company). Area covered: Herein, we assess the efficacy of an extended-release formulation of tacrolimus (Advagraf®/Astagraf XL®) used in conjunction with or without an induction therapy (i.e., basiliximab) in de novo kidney-transplant recipients. To achieve this, we searched for suitable articles through PubMed. Expert commentary: Phases-III and -IV studies comparing Advagraf®/Astagraf XL® to Prograf® in association with mycophenolate mofetil (more than 2,500 patients) have demonstrated overall similar results with regards to patient/graft survival, biopsy-proven acute-rejection rate, and renal function (p > 0.05). A randomized controlled study in maintenance kidney transplant patients has shown (using electronic monitoring) that, as compared to Prograf®, Advagraf® significantly improved adherence to medication. Other studies report that Advagraf®-treated patients receiving a mTOR-inhibitor agent (sirolimus or everolimus) instead of MMF: this was associated with good allograft outcome, and might also prevent late-onset cytomegalovirus infection. Advagraf®-based immunosuppression given to de novo kidney-transplant recipients, with or without an induction therapy, provided excellent results compared to Prograf®; it also increased patients' adherence to treatment.
Early conversion to belatacept-based immunosuppression regimen promotes improved long-term renal graft function in kidney transplant recipients. [2023]Belatacept has been demonstrated as an effective alternative immunosuppressant in kidney transplant recipients. This study focuses on outcomes of early and late conversion to Belatacept-based immunosuppression after kidney transplant.