A Study to Evaluate the Benefits and Risks of Conversion of Existing Adolescent Kidney Transplant Recipients Aged 12 to <18 Years to a Belatacept-based Immunosuppressive Regimen as Compared to Continuation of a Calcineurin Inhibitor-based Regimen, and Their Adherence to Immunosuppressive Medications

Study Overview
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Brief Summary
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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.

Official Title
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A Prospective, Open-label, Multicenter, Randomized Study to Evaluate the Benefits and Risks of Conversion of Existing Adolescent Renal 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

Conditions
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Renal Allograft Recipients

Intervention / Treatment
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* Biological: Belatacept
* Drug: Tacrolimus
* Drug: Cyclosporine A
* Drug: Mycophenolate Mofetil
* Drug: Enteric Coated Mycophenolate Sodium
* Drug: Corticosteroids


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female adolescents 12 to less than 18 years of age Recipients of a renal allograft from a living or deceased donor transplanted at least 6 calendar months prior to enrollment Receiving a stable regimen of a calcineurin inhibitor (CNI), with mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium/mycophenolate mofetil (EC-MPS/MPA), with or without daily corticosteroids for ≥ 30 days prior to randomization Clinically stable renal function during the 12-week period prior to screening, in the opinion of the investigator and based on protocol-defined criteria for proteinuria and estimated glomerular filtration rate (eGFR) Serologic evidence of past exposure to Epstein-Barr virus (EBV) and current absence of EBV DNA replication at or prior to renal transplantation and during the Screening period Completion of an initial course of SARS-CoV-2 vaccination per local standard of care, a minimum of 6 weeks prior to enrollment Exclusion Criteria: Recipients with EBV serostatus negative or unknown at screening or at transplant Treatment for biopsy-proven acute rejection (BPAR) of any degree of severity within 6 calendar months prior to enrollment Biopsy-confirmed antibody-mediated acute rejection at any time with the current allograft Banff 97 grade IIA or higher acute cellular rejection (or equivalent), or treatment with plasmapheresis or rituximab for any acute rejection at any time with the current allograft Current evidence or past history of active or inadequately treated latent tuberculosis (TB) infection Previously treated with belatacept or previously enrolled in a belatacept trial with their present allograft Other inclusion/exclusion criteria apply

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 17 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: Arm 1: Conversion from a CNI- to belatacept-based regimen after a period of overlap<br>Conversion followed by tapering and discontinuation of the calcineurin inhibitor (CNI) | Biological: Belatacept<br>* Specified dose on specified days<br>* Other names: Nulojix;Drug: Tacrolimus<br>* Specified dose on specified days<br>Drug: Cyclosporine A<br>* Specified dose on specified days<br>Drug: Mycophenolate Mofetil<br>* Specified dose on specified days<br>Drug: Enteric Coated Mycophenolate Sodium<br>* Specified dose on specified days<br>Drug: Corticosteroids<br>* Specified dose on Specified days<br>|
| Active Comparator: Arm 2: Continue calcineurin inhibitor-based regimen<br> | Drug: Tacrolimus<br>* Specified dose on specified days<br>Drug: Cyclosporine A<br>* Specified dose on specified days<br>Drug: Mycophenolate Mofetil<br>* Specified dose on specified days<br>Drug: Enteric Coated Mycophenolate Sodium<br>* Specified dose on specified days<br>Drug: Corticosteroids<br>* Specified dose on Specified days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants who survive with a functional graft with estimated glomerular filtration rate (eGFR) > 30 mL/min/1.73 m2 (updated Schwartz formula) at 24 months post-randomization |  | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participant and graft survival: Proportion of participants who survive with a functioning graft |  | 6 and 12 months | 
| Participant and graft survival: Proportion of participants who survive |  | 6, 12, and 24 months | 
| Participant and graft survival: Proportion of participants who experience death-censored graft loss |  | 6, 12, and 24 months | 
| Acute rejection: Incidence of clinically suspected biopsy-proven acute rejection (BPAR) |  | 3, 6, 12, and 24 months | 
| Acute rejection: Severity of clinically suspected, biopsy confirmed rejection as determined by locally and centrally reviewed histopathology |  | 3, 6, 12, and 24 months | 
| Renal function as assessed by: Serum creatinine concentration |  | Up to 24 months | 
| Renal function as assessed by: Estimated GFR (eGFR per updated Schwartz combined equation) |  | Up to 24 months | 
| Renal function as assessed by: eGFR per updated bedside Schwartz approximating equation |  | Up to 24 months | 
| Renal function as assessed by: eGFR per Full Age Spectrum (FAS) equation of Potell et al |  | Up to 24 months | 
| Renal function as assessed by: eGFR per age and sex-dependent equation of Pierce et al |  | Up to 24 Months | 
| Proteinuria, as assessed by urinary protein:creatinine ratio (UPCR), as determined from single-voided urine specimens |  | Up to 24 months | 
| Slope of change in eGFR over time, as assessed by baseline-adjusted mean eGFR determinations at protocol-specified study visits |  | Up to 24 months | 
| Adherence to immunosuppressive medications as assessed by variation in calcineurin inhibitor pre-dose whole blood concentrations by summaries over time of monitored adherence to orally administered immunosuppressive medications |  | up to 24 months | 
| Adherence to immunosuppressive medications, as assessed by: Variations in pre-dose concentrations of calcineurin inhibitor in whole blood |  | Up to 24 months | 
| Adherence to immunosuppressive medications, as assessed by: 7-day recall of missed and late doses of each orally administered immuno-suppressive medication at protocol-specified study visits |  | Up to 24 months | 
| Adherence to immunosuppressive medications, as assessed by: Monitoring of compliance with monthly belatacept infusions |  | Up to 24 months | 
| Adherence to immunosuppressive medications, as assessed by: Periodic review of parents' and patients' perceived barriers to adherence to the prescribed immunosuppressive medications regimen |  | Up to 24 months | 
| Mean blood pressure over time |  | Up to 24 months | 
| Mean blood pressure changes from baseline over time |  | Up to 24 months | 
| Intensity of antihypertensive drug therapy, defined as the total number of medications used to maintain BP control |  | Up to 24 months | 
| Monitoring of safety laboratory parameters over time: Mean fasting lipid profiles |  | Up to 24 months | 
| Monitoring of safety laboratory parameters over time: Fasting blood glucose concentrations |  | Up to 24 months | 
| Monitoring of safety laboratory parameters over time: Hemoglobin A1c concentrations |  | Up to 24 months | 
| Donor Specific antibodies (DSA): Proportion of participants with pre-existing anti-human leukocyte antigen (HLA) DSAs at baseline and with de novo anti-HLA DSA post-randomization |  | 6, 12, and 24 months | 
| Immunogenicity of belatacept as determined by the proportion of participants with detectable serum anti-belatacept antibodies |  | 6, 12, and 24 months | 
| Belatacept pre-dose (C0) serum concentrations |  | Up to 24 months | 
| Mean percent belatacept CD86 receptor occupancy |  | Baseline | 
| Post-randomization changes from baseline percent belatacept CD86 receptor occupancy |  | 6, 12, and 24 months | 
| Safety and tolerability of belatacept following conversion: Incidence of Adverse Events (AEs) |  | up to 24 months | 
| Safety and tolerability of belatacept following conversion: Incidence of Serious Adverse Events (SAEs) |  | Up to 24 months | 
| Safety and tolerability of belatacept following conversion: Incidence of laboratory marked abnormalities |  | Up to 24 months | 
| Proportion of participants within each stage of the Tanner staging scale | The Tanner scale is a measure of pubertal development (sexual maturation) in children and adolescents with components described for each sex, rated separately on a scale of stage one to stage five, with 1 for preadolescent and 5 for mature/adult | Up to 24 months | 
| Linear growth (height) |  | Up to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute rejection, Belatacept, Calcineurin inhibitors (cyclosporine, tacrolimus), Conversion, Donor-specific antibodies, eGFR, Immunosuppressive regimen, Adolescent kidney transplant recipients