Study to Assess the Efficacy and Safety of Bleselumab in Preventing the Recurrence of Focal Segmental Glomerulosclerosis in de Novo Kidney Transplant Recipients

Study Overview
=================
Brief Summary
-----------------
The purpose of this study was to assess the efficacy of the bleselumab regimen (basiliximab induction, tacrolimus, steroids and bleselumab) compared with the Standard of Care (SOC) regimen (basiliximab induction, tacrolimus, steroids and mycophenolate mofetil [MMF]) in the prevention of recurrent Focal Segmental Glomerulosclerosis (rFSGS) defined as nephrotic range proteinuria with protein-creatinine ratio (≥ 3.0 g/g) through 3 months post-transplant. Death, graft loss or lost to follow-up were imputed as rFSGS.

Detailed Description
-----------------
The study consisted of the following periods: Screening (Days -21 to -1), Transplant (Day 0), Post-Transplant (Day 0/post-skin closure through 12 months post-transplant). All subjects entered into a Screening Period (Days -21 to -1 prior to transplant), and underwent a Transplant (Day 0 [zero]), and then followed for up to 12 months in the Post-Transplant Period (Day 0 through 12 months post-transplant).

Official Title
-----------------
A Phase 2a, Randomized, Open-Label, Active Control, Multi-Center Study to Assess the Efficacy and Safety of Bleselumab in Preventing the Recurrence of Focal Segmental Glomerulosclerosis in de Novo Kidney Transplant Recipients

Conditions
-----------------
Kidney Transplantation, Primary Focal Segmental Glomerulosclerosis (FSGS)

Intervention / Treatment
-----------------
* Drug: Bleselumab
* Drug: Basiliximab
* Drug: Mycophenolate Mofetil (MMF)
* Drug: Tacrolimus Capsules
* Drug: Methylprednisone
* Drug: Prednisone


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subject is a recipient of a de novo kidney from a living or deceased donor and has biopsy-proven, primary FSGS (pFSGS) as a cause of end stage renal disease (ESRD) in the subject's native kidneys (initial diagnosing biopsy report is required). A subject who has biopsy-proven pFSGS as a cause of ESRD, and the subject's most current graft failure(s) is due to the recurrence of FSGS, is eligible. Subject is anticipated to receive first oral dose of tacrolimus within 48 hours of transplant procedure. Subject must be willing and able to comply with the study requirements including prohibited concomitant medication restrictions. Subject agrees not to participate in another interventional study while on treatment. Exclusion Criteria: Subject has Induction therapy, other than study-assigned basiliximab, planned as part of initial immunosuppressive regimen. Subject has a diagnosis of secondary FSGS (familial, virus associated, medication, etc.) or a defined genetic cause of FSGS. Subject has previously received any organ transplant including a kidney and the most current graft failure(s) is not due to the recurrence of FSGS. Subject will receive a kidney as part of a multi-organ transplant. Subject will receive a dual kidney transplant from a deceased donor. Subject will receive a kidney with an anticipated cold ischemia time (CIT) of > 30 hours. Subject will receive a kidney that meets BOTH Extended Criteria Donor (ECD) and Donation after Cardiac Death (DCD) criteria. (A kidney that meets either ECD OR DCD criteria may be eligible for inclusion.) Subject will receive a blood group system (A, AB, B, O, ABO) incompatible (including A2 into B or O) donor kidney. Recipient or donor is known to be seropositive for human immuno-deficiency virus (HIV). Subject has a current calculated panel reactive antibody (cPRA) level > 50%. Subject has a current malignancy or a history of malignancy (within the past 5 years), except nonmetastatic basal or squamous cell carcinoma of the skin that has been treated successfully, or a renal cell carcinoma that has been treated successfully more than 2 years prior to transplantation. Subject has significant liver disease, defined as having during the past 21 days consistently elevated aspartate aminotransferase (AST) (SGOT) and/or alanine aminotransferase (ALT) (SGPT) levels greater than 1.5 times the upper value of the normal range of the investigational site. Subject is known to have a positive test for latent tuberculosis (TB) and has not previously received adequate anti-microbial therapy/or would require TB prophylaxis after transplant. Subject has an uncontrolled concomitant infection or any other unstable medical condition that could interfere with the study objectives. Subject is concurrently participating in another drug study or has received an investigational drug up to 30 days or 5 half-lives prior to transplant. Subject is currently receiving or has received up to 8 weeks prior to transplant an immunologic biologic compound (i.e., tumor necrosis factor (TNF) inhibitors, [e.g., etanercept, adalimumab], intravenous immunoglobulin (IVIG)). A subject who has previously received a kidney organ transplant and is currently on an immunosuppression regimen that includes MMF, or any of its components, must discontinue MMF. Subject has previously received bleselumab or participated in a clinical study with bleselumab. Subject has a known hypersensitivity to tacrolimus, MMF, basiliximab, corticosteroids, or any of the components. Subject has any form of substance abuse, psychiatric disorder, or a condition that could invalidate communication with the Investigator. Subject has a clinically significant abnormal electrocardiogram (ECG) at Screening. Subject is unlikely to comply with the visits scheduled in the protocol

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard of Care (SOC) Regimen<br>Participants received SOC regimen (basiliximab induction, MMF, Tacrolimus, Methylprednisone, Prednisolone). Basiliximab 20 milligrams (mg) administered by intravenous injection prior to transplantation or intra- operatively before revascularisation as induction therapy and 20mg on day 3 or 4 or 5 post-transplant. MMF 1 gram (g) administered orally or intravenously twice daily until 12 months post transplant. Tacrolimus 0.1 milligram per kilogram per day (mg/kg/day) (two equally divided doses at 0.05 mg/kg/day every 12 hours with a target trough level of 4 - 11 nanogram per milliliter (ng/mL) administered orally within 48 hours post-transplant until 12 months post transplant. Methylprednisone 500, 250, 125 and 60mg administered orally or intravenously on days 0, 1, 2 and 3 respectively and continue through 12 months post transplant. Prednisolone administered orally by tapered doses of 20-30 mg on days 4-14, 10-20mg on days 15-28, 5-10mg on days 29 through 12 months post transplant. | Drug: Basiliximab<br>* Bolus injection<br>* Other names: Simulect®;Drug: Mycophenolate Mofetil (MMF)<br>* Oral Intravenous<br>* Other names: MMF;Drug: Tacrolimus Capsules<br>* Oral Capsule<br>* Other names: Prograf®;Drug: Methylprednisone<br>* Oral or Intravenous<br>Drug: Prednisone<br>* Oral Tablet<br>|
| Experimental: Bleselumab Regimen<br>Participants received bleselumab regimen (basiliximab induction, bleselumab, Tacrolimus, Methylprednisone, Prednisolone). Basiliximab 20mg administered by intravenous injection prior to transplantation or intra - operatively before revascularisation as induction therapy and 20mg on day 3 or 4 or 5 post-transplant. Bleselumab 200mg administered by intravenous infusion on day 0, 7, 14, 28, 42, 56, 70, 90 and once per month until month 12. Tacrolimus 0.1 mg/kg/day (two equally divided doses at 0.05 mg/kg/day every 12 hours with a target trough level of 4 - 11 ng/mL) administered orally within 48 hours post transplant until 12 months post transplant. Methylprednisone 500, 250, 125 and 60mg administered orally or intravenously on days 0, 1, 2 and 3 respectively and continue through 12 months post transplant. Prednisolone administered orally by tapered doses of 20-30 mg on days 4-14, 10-20mg on days 15-28, 5-10mg on days 29 through 12 months post transplant. | Drug: Bleselumab<br>* Intravenous infusion<br>* Other names: ASKP1240;Drug: Basiliximab<br>* Bolus injection<br>* Other names: Simulect®;Drug: Tacrolimus Capsules<br>* Oral Capsule<br>* Other names: Prograf®;Drug: Methylprednisone<br>* Oral or Intravenous<br>Drug: Prednisone<br>* Oral Tablet<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Recurrence of Focal Segmental Glomerulosclerosis (rFSGS) or Death or Graft Loss or Lost to Follow-up Through 3 Months Post Transplant | rFSGS was defined as nephrotic range proteinuria with a protein/creatinine ratio (≥ 3.0 g/g). Death, graft loss or lost to follow-up was imputed as rFSGS. | At 3 Months post transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With rFSGS or Death or Graft Loss or Lost to Follow-up Through 6 and 12 Months Post Transplant | rFSGS was defined as nephrotic range proteinuria with a protein/creatinine ratio (≥ 3.0 g/g). Death, graft loss or lost to follow-up was imputed as rFSGS. | At 6 and 12 Months post transplant | 
| Percentage of Participants With Biopsy-Proven Acute Rejection (BPAR) Through 3, 6, and 12 Months Post Transplant | All episodes of kidney dysfunction based on clinical signs and symptoms were evaluated for possible BPAR. BPAR was confirmed if participants Banff criteria >=1. | At 3, 6 and 12 Months post transplant | 
| Percentage of Participants With Efficacy Failure Through 12 Months Post Transplant | Efficacy failure was defined as BPAR, death, graft loss or lost to follow-up through 12 months post transplant. | 12 Months post transplant | 
| Percentage of Participants With Biopsy Proven rFSGS Through 3, 6 and 12 Months Post-Transplant | Percentage of participants with biopsy-proven rFSGS determined by a blinded central review of images from electron microscopy (EM) and slides for light microscopy (LM) by an independent pathologist. | At 3, 6 and 12 Months post transplant | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Bleselumab, ASKP1240, Efficacy and Safety