Abatacept Conversion in Kidney Transplantation

Study Overview
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Brief Summary
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This is a single center, randomized, controlled phase 2b, conversion trial. This protocol has been developed to answer the question: Can patients be safely converted from monthly belatacept IV infusions to abatacept subcutaneous injections without a decrease in kidney function.The primary objective will be the difference in estimated GFR (eGFR) for abatacept and belatacept groups using a monthly repeated measures model between randomization and 12 months.

Detailed Description
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This is a single center, randomized, controlled phase 2b, conversion trial. This protocol has been developed to answer the question: Can patients be safely converted from monthly belatacept IV infusions to abatacept subcutaneous injections without a decrease in kidney function. Research subjects will be recruited from those who were initiated on belatacept at the time of their kidney transplant and have been stable on belatacept therapy for at least 2 years post-transplant and off CNI therapy for at least 6 months. A total of 86 subjects will be randomized in equal numbers, 43 patients in each arm. Enrollment of all 86 patients is expected to be completed within 1.5 years. All patients will be actively followed in the study for 24 months following randomization. The patient participation is projected to last a total of 3.5 years with data analysis to follow. The primary objective will be the difference in estimated GFR (eGFR) for abatacept and belatacept groups using a monthly repeated measures model between randomization and 12 months.

Official Title
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Late Abatacept Conversion in Kidney Transplant Recipients Receiving Belatacept: a Prospective, Randomized Controlled Non-inferiority Trial. IM101-884

Conditions
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Renal Transplant Recipient

Intervention / Treatment
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* Drug: Belatacept
* Drug: Abatacept


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Individuals who meet all of the following criteria are eligible for enrollment as study participants: Adult (age ≥18 years currently) First-time renal transplant recipients of either living donor or deceased donor Treatment with belatacept from the time of transplant At least 2 years post-transplant and off CNI therapy for at least 6 months Patients at low immunologic risk First time transplant HLA antibody screen with PRA < 80% against class I and class II antigens Negative crossmatch (actual or virtual) No donor specific anti-HLA antibody (DSA) No more than one episode of rejection (Banff grade 1A or greater) No episodes of rejection (borderline or greater) within the last 6 months prior to study participation No rejection of Banff grade IIB or greater Immunosuppression consisting of belatacept (5mg/kg q 1M), mycophenolate mofetil (at least 1000 mg daily), or equivalent mycophenolic acid (720 mg daily) or azathioprine (1- 2 mg/kg daily) dose, and prednisone 5 mg daily. Confirmed Tb screening at the time of transplantation Exclusion Criteria: Individuals who meet any of these criteria are not eligible for enrollment as study participants: Repeat renal transplant, or multi-organ transplant recipient History of more than one episode of biopsy-proven acute rejection (Banff grade 1A or greater), or of any episode of rejection of Banff 97 grade IIB or greater, or any rejection (borderline or greater) within the last 6 months Pregnancy (women of childbearing potential must use adequate contraception during study) GFR less than 35 Serum creatinine at enrollment more than 30% higher than at 3 months (±4 weeks) prior to randomization Recent history of clinically significant proteinuria (urinary protein/Cr ratio >1.0) Receiving belatacept at a dose other than 5 mg/kg body weight Receiving mycophenolate mofetil at a dose of less than 1000 mg po QD (or mycophenolic acid or azathioprine equivalent). Receiving prednisone at a dose greater than 5 mg po qd within 3 months of enrollment Not currently receiving maintenance immunosuppression with prednisone Active infection, or antibiotic or antiviral drug therapy within 1 month of randomization Evidence of CMV viremia or clinical CMV infection within the last 3 months prior to randomization. BK viremia of greater than 4.3 DNA log copies/mL (greater than 20,000 copies/mL) within 3 months of randomization Known hepatitis B surface antigen-positive or PCR-positive for hepatitis B (testing not required) Known HIV-positivity (testing not required) Presence of donor specific antibody by Luminex single antigen bead assay, or antibody screen (% PRA) above 80%. History of substance abuse or psychiatric disorder not compatible with study adherence and follow up. History of medical noncompliance Untreated latent Tb (as determined from prior Tb screening at the time of transplantation)

Ages Eligible for Study
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Minimum Age: 18 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
Interventional Model Description: Prospective, randomized controlled non-inferiority trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Belatacept group (Control Group)<br>Participants will receive the following: Belatacept: 5 mg/kg i.v. monthly Blood draws for PD studies at baseline/Month 0 and Month 6 fora total of two timepoints. HLA labs at 6, 12 and 24 months Basic chemistry panel (CP Basic) every 3 months per clinical protocol for efficacy analysis Hemoglobin A1c at Screening visit Urine pregnancy test via test kit for WOCP at Screening visit BK and CMV testing at 6, 12, and 24 months | Drug: Belatacept<br>* Belatacept is an immunosuppressive medication and will be given as an intravenous infusion at a dose of 5 mg/kg monthly<br>* Other names: Nulojix;|
| Experimental: Abatacept Group (Conversion Group)<br>Participants will receive the following: Abatacept 125 mg s.c. weekly Safety labs every 2 weeks (months 0-3) then monthly (months 4-12) Blood draws forPK atMonth 6, Month 12, and two random time points in between Month 6 and Month 12 for a total of four time points. Blood draws for PD studies at baseline/Month0 and Month 6 fora total of two timepoints. HLA labs at 6, 12 and 24 months Basic chemistry panel (CP Basic) at each study visit per clinical protocol for efficacy analysis Hemoglobin A1c at Screening visit Urine pregnancy test via test kit for WOCP at screening BK and CMV testing at 6, 12, and 24 months | Drug: Abatacept<br>* Abatacept is an immunosuppressive medication and will be given SQ at a dose of 125 mg s.c. weekly<br>* Other names: Orencia;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in mean estimated GFR (eGFR) between randomization and 12 months post baseline | Difference in estimated GFR (eGFR) for abatacept and belatacept groups using a monthly repeated measures model between randomization and 12 months. | Baseline, 12 months post baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in eGFR between abatacept and belatacept groups at 24 months | The treatment difference in eGFR between abatacept and belatacept groups at 24 months, using a monthly repeated measures model and a pre-specified acceptable difference, or non-inferiority margin of 5 ml/min/1.73m2. | Monthly until 24 months post baseline | 
| Number of subjects with biopsy proven acute rejection: Acute Cellular Rejection (ACR) | Incidence and severity of acute cellular rejection (ACR) | 12 months post baseline, 24 months post baseline | 
| Number of subjects with biopsy proven acute rejection: Antibody Mediated Rejection (AMR) | Incidence and severity of antibody mediated rejection (AMR) analyses | 12 months post baseline, 24 months post baseline | 
| Number of participants with kidney transplant biopsies post baseline | Number of participants with kidney transplant biopsies post baseline | 12 months post baseline, 24 months post baseline | 
| Proportion of subjects treated for ACR/AMR due to clinical suspicion | Proportion of subjects treated for ACR/AMR due to clinical suspicion | 12 months post baseline, 24 months post baseline | 
| Number of subjects with de novo anti-donor human leukocyte antigen (HLA) antibodies | Incidence of de novo anti-donor human leukocyte antigen (HLA) antibodies | 12 months post baseline, 24 months post baseline | 
| First occurrence of graft loss or death post baseline | First occurrence of graft loss or death at 6, 12 and 24 months post baseline | 12 months post baseline, 24 months post baseline | 
| Number of deaths at 6, 12 and 24 months post baseline | Incidence of death with graft function at 6, 12 and 24 months post baseline | 12 months post baseline, 24 months post baseline | 
| Incidence of death-censored graft loss post baseline | Incidence of death-censored graft loss at 12 and 24 months | 12 months post baseline, 24 months post baseline | 
| Compliance with patient-administered subcutaneous abatacept | Compliance with patient-administered subcutaneous abatacept | 12 months post baseline, 24 months post baseline | 
| Incidence of adverse events | Incidence of adverse events | 12 months post baseline, 24 months post baseline | 
| Incidence of serious adverse events | Incidence of serious adverse events | 12 months post baseline, 24 months post baseline | 
| Incidence of events of special interest | Incidence of events of special interest, including CMV viremia, BKV viremia, and serious infections | 12 months post baseline, 24 months post baseline | 
| Incidence of any malignancy | Incidence of any malignancy including PTLD | 12 months post baseline, 24 months post baseline | 
| Incidence of subcutaneous injection site complications | Incidence of subcutaneous injection site complications | 12 months post baseline, 24 months post baseline | 
| Proportion of subjects who develop de-novo, anti-HLA donor specific antibody | Proportion of subjects who develop de-novo, anti-HLA donor specific antibody | 12 months post baseline, 24 months post baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Renal transplant