Advancing Transplantation Outcomes in Children

Study Overview
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Brief Summary
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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.

Official Title
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Advancing Transplantation Outcomes in Children (CTOT-41)

Conditions
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Kidney Transplant

Intervention / Treatment
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* Drug: Sirolimus
* Biological: Belatacept
* Drug: Mycophenolate Mofetil
* Drug: Tacrolimus (Group1)
* Drug: Anti-Thymocyte Globulin (ATG)
* Drug: Tacrolimus (Group 2)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant and/or parent/guardian must be able to understand and provide informed consent Male or female, 13-20 years of age at time of enrollment Candidate for primary renal allograft from a deceased donor EBV IgG seropositive, defined as evidence of acquired immunity shown by the presence of IgG antibodies to viral capsid antigen (VCA) and EBV nuclear antigen (EBNA) at time of enrollment If a female participant of childbearing potential, a negative pregnancy test within 48 hours of enrollment If participant has reproductive potential, agrees to use Food and Drug Administration (FDA) approved methods of birth control for the duration of the study Negative test result for latent tuberculosis infection by tuberculosis skin test (purified protein derivative [PPD]) or Tuberculosis (TB) blood test (interferon gamma release assay [IGRA] i.e., QuantiFERON, T- SPOT.TB) within 12 months In the absence of contraindication, vaccinations must be up to date per the Centers for Disease Control and Prevention (CDC) Guidelines and Division of Allergy, Immunology, and Transplantation (DAIT) Guidance for Patients in Transplant Trials Enrollment criteria for donor source and age will be expanded using a stepwise approach determined by safety monitoring. Expansion criteria will include recipients down to age 6 and living donors. Safety data from each step will be reviewed by the study team, DSMB and FDA. If no safety concerns are identified, inclusion criteria will be expanded. Exclusion Criteria: Inability or unwillingness to comply with study protocol Active infection requiring treatment, or viremia History of malignancy Current or historical anti-HLA antibody to the donor Peak calculated Panel Reactive Antibody (cPRA) greater than 80 percent Receipt of any licensed or investigational live attenuated vaccine(s) within 4 weeks of enrollment Prior history of organ transplantation Active systemic autoimmune disease at time of enrollment Idiopathic Focal Segmental Glomerulosclerosis (FSGS), Membranoproliferative Glomerulonephritis (MPGN), C3 glomerulopathy, or atypical Hemolytic Uremic Syndrome (HUS) suspected at risk for recurrence Use of immunosuppressants, biologics (including IVIG), chronic corticosteroids or investigational drug(s) within 8 weeks of enrollment Known bleeding disorder Platelet count < 75,000 cells/microliters within 3 months of enrollment History of inherited hypercoagulability requiring therapy more than aspirin Clinically significant unrepaired congenital heart disease causing hemodynamic compromise Uncontrolled diagnosed psychiatric disorder or self-reported drug or alcohol abuse that, in the opinion of the investigator, would interfere with the participant's ability to comply with study requirements Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study Randomization Exclusion Criteria: Individuals who meet any of these criteria are not eligible for randomization. Sustained WBC <1500 or >20,000 per microliter within 3 months of randomization Sustained liver function tests (AST and/or ALT) > 2x normal within 3 months of randomization Active systemic autoimmune disease at time of transplant Known bleeding disorder Platelet count < 75,000 cells/microliters within 3 months of enrollment Current or historical anti-HLA antibody to the donor at the time of transplant Recent recipient of any licensed or investigational live attenuated vaccine(s) within 4 weeks of randomization Panel Reactive Antibody (cPRA) greater than 80 percent If a female participant of childbearing potential, a positive pregnancy test within 48 hours of randomization (all female participants of childbearing potential must complete a pregnancy test within 48 hours of randomization) Treatment with immunosuppressants, including biologics (including IVIG), within 8 weeks of randomization

Ages Eligible for Study
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Minimum Age: 13 Years
Maximum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: (Group 1): Belatacept+Sirolimus group<br>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) | Drug: Sirolimus<br>* Participants in Group 1 will transition to sirolimus therapy on day 14 (+/- 5 days) - weight <40 kg will receive 3mg/m^ 2, with maintenance dose of 1 mg/m^2 divided BID - weight >= 40kg will receive 6mg/m^ 2, with maintenance dose of 2 mg daily<br>* Other names: Rapamycin;Biological: Belatacept<br>* Belatacept will be administered as an intravenous infusion over 30 minutes. The belatacept dose for the study is 10 mg/kg on post-operative day (POD) 1, 5, 14, 28, 56, 84 for the first 3 months, followed by 5 mg/kg every 4 weeks (+/-4 days), starting on month 4 until month 24<br>* Other names: Nulojix;Drug: Tacrolimus (Group1)<br>* Participants will receive Prograf® (tacrolimus), or generic, initiated at 0.1 mg/kg BID within 48 hours of transplantation to attain target trough levels. Participants in Group 1 will be transitioned to sirolimus 2-4 weeks post-transplant<br>* Other names: Prograf;Drug: Anti-Thymocyte Globulin (ATG)<br>* Participants will receive induction therapy with anti-thymocyte globulin (1.5 mg/kg/dose, maximum 125 mg) starting intraoperatively on day 0 and continuing on days 2 and 3 (total dose 4.5 mg/kg). Total dose may be extended to 6 mg/kg over 1-2 days for delayed graft function<br>|
| Active Comparator: (Group 2): Tacrolimus + Mycophenolate Mofetil (MMF) group<br>Participants in this group will receive anti-thymocyte globulin (ATG) + steroid taper + tacrolimus + MMF | Drug: Mycophenolate Mofetil<br>* Mycophenolate Mofetil-MMF will be initiated at 600 mg/m^2 BID until tacrolimus is at therapeutic levels, then 450 mg/m^2 BID<br>* Other names: MMF;Drug: Anti-Thymocyte Globulin (ATG)<br>* Participants will receive induction therapy with anti-thymocyte globulin (1.5 mg/kg/dose, maximum 125 mg) starting intraoperatively on day 0 and continuing on days 2 and 3 (total dose 4.5 mg/kg). Total dose may be extended to 6 mg/kg over 1-2 days for delayed graft function<br>Drug: Tacrolimus (Group 2)<br>* Participants will receive Prograf® (tacrolimus), or generic, initiated at 0.1 mg/kg BID within 48 hours of transplantation to attain target trough levels<br>* Other names: Prograf;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of de novo Donor Specific Antibody (dnDSA) (central lab) OR decline in estimated glomerular filtration rate (eGFR) >7.5 mL/min/1.73m^2 (central lab) |  | At 2 years post-transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of clinical biopsy proven allograft rejection (central lab) |  | Within 2 years post-transplant | 
| Time to development of clinical biopsy proven allograft rejection (central lab) |  | Within 2 years post-transplant | 
| Incidence of subclinical biopsy proven allograft rejection (central lab) |  | Within 2 years post-transplant | 
| Time to development of subclinical biopsy proven allograft rejection (central lab) |  | Within 2 years post-transplant | 
| Incidence of Post-Transplant Lymphoproliferative Disease (PTLD) |  | Within 2 years post-transplant | 
| Time to development of the PTLD |  | Within 2 years post-transplant | 
| Incidence of Grade 3 and above opportunistic infections bacterial, viral, fungal, pneumocystis pneumonia, or parasitic infections assessed as a composite |  | Within 2 years post-transplant | 
| Time to development of Grade 3 and above opportunistic infections bacterial, viral, fungal, pneumocystis pneumonia, or parasitic infections assessed as a composite |  | Within 2 years post-transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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kidney transplant, belatacept, sirolimus