Efficacy and Safety of Belimumab in Patients With Active Lupus Nephritis

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy, safety, and tolerability of belimumab in adult patients with active lupus nephritis.

Detailed Description
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Study participants receive standard therapy (induction and maintenance) for lupus nephritis in addition to receiving either placebo (no active medicine) or belimumab. Induction therapy starts before the first dose of study drug (belimumab or placebo). Maintenance therapy begins after completion of induction therapy and continues for the remainder of the study. Participants receive study drug throughout the entire study, during both induction and maintenance periods. The controlled period of the study is 104 weeks. The random assignment in this study is 1 to 1 which means you have an equal chance of receiving treatment with belimumab or placebo. Participants who successfully complete the 104-week study may enter into a 6-month open-label extension. All participants in the open-label extension receive belimumab.

Official Title
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A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Belimumab Plus Standard of Care Versus Placebo Plus Standard of Care in Adult Subjects With Active Lupus Nephritis

Conditions
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Lupus Nephritis

Intervention / Treatment
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* Biological: Placebo plus standard therapy
* Biological: Belimumab 10 mg/kg plus standard therapy
* Drug: Standard therapy


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Clinical diagnosis of SLE by American College of Rheumatology (ACR) criteria. Biopsy confirmed active lupus nephritis. Clinically active lupus renal disease at screening requiring /receiving induction therapy with Standard of Care medications. Autoantibody-positive. Key Exclusion Criteria: Pregnant or nursing. On dialysis within the past year. Treatment with belimumab within the past year . Receipt of induction therapy with cyclophosphamide within 3 months prior to induction therapy for the study. Receipt of any B cell targeted therapy (for example, rituximab), investigational biological agent within the past year. Severe active central nervous system (CNS) lupus. Required management of acute or chronic infections within the past 60 days. Current drug or alcohol abuse or dependence. Tested positive for human immunodeficiency virus (HIV), hepatitis B, or hepatitis C. History of severe allergic reaction to contrast agents or biological medicines.

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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo plus standard therapy<br>Placebo IV plus standard therapy; placebo administered on Days 0, 14, 28, and then every 28 days thereafter through Week 100, with a final evaluation at Week 104 in the double-blind period. In the open-label extension period, placebo patients who opt to participate will receive belimumab 10 mg/kg IV every 28 days for an additional 6 months. | Biological: Placebo plus standard therapy<br>* Placebo plus standard therapy<br>Drug: Standard therapy<br>* The standard therapies allowed in this study are: - High-dose steroids (for example, methylprednisolone) plus cyclophosphamide for induction therapy followed by azathioprine for maintenance therapy OR - High-dose steroids plus mycophenolate for induction therapy followed by mycophenolate for maintenance therapy<br>|
| Experimental: Belimumab 10 mg/kg plus standard therapy<br>Belimumab 10 mg/kg IV plus standard therapy; belimumab administered on Days 0, 14, 28, and then every 28 days thereafter through Week 100, with a final evaluation at Week 104 in the double-blind period. In the open-label extension period, patients who opt to participate will continue to receive belimumab 10 mg/kg IV every 28 days for an additional 6 months. | Biological: Belimumab 10 mg/kg plus standard therapy<br>* Belimumab 10 mg/kg plus standard therapy<br>* Other names: BENLYSTA™;Drug: Standard therapy<br>* The standard therapies allowed in this study are: - High-dose steroids (for example, methylprednisolone) plus cyclophosphamide for induction therapy followed by azathioprine for maintenance therapy OR - High-dose steroids plus mycophenolate for induction therapy followed by mycophenolate for maintenance therapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Double-blind Period: Percentage of Participants With Primary Efficacy Renal Response (PERR) at Week 104 | PERR is defined as urinary protein creatinine ratio <=0.7, estimated glomerular filtration rate (eGRF) was not more than 20 percent (%) below the pre-flare value or >=60 milliliters per minute per 1.73 square meter (mL/min/1.73m^2) and was not a treatment failure. Analysis was performed using a logistic regression model for the comparison between Belimumab and Placebo with covariates treatment group, induction regimen (CYC vs. MMF), race (Black vs. Non-Black), Baseline urine protein-creatinine ratio (uPCR), and Baseline eGFR. Modified Intent-to-treat (mITT) Population consisted of all randomized participants who received at least one dose of study treatment and were not excluded due to Good Clinical Practice (GCP) non-compliance. Percentage of participants with PERR at Week 104 has been presented. | Week 104 | 
| Open-label Period: Number of Participants Reporting Adverse Events (AEs) and Serious AEs (SAEs) | An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporarily associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE is any untoward medical occurrence that, at any dose: resulting in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, any other situation according to medical or scientific judgment or all events of possible drug-induced liver injury with hyperbilirubinemia were categorized as SAE. Number of participants with AEs and SAEs have been reported. | From first open-label dose (Day 1) up to open-label Week 32 (8 weeks after last dose) | 
| Open-label Period: Number of Participants Reporting Adverse Events of Special Interest (AESI) | An AESI is one of scientific and medical concern specific to the product, for which ongoing monitoring and rapid communication by investigator to sponsor can be appropriate. A summary of protocol defined AESIs include malignant neoplasms including and excluding non-melanoma skin cancer (NMSC), post-infusion systemic reactions (PISR), all infections of special interest (opportunistic infections [OI], Herpes Zoster [HZ], tuberculosis [TB], and sepsis), depression (including mood disorders and anxiety)/suicide/self-injury and deaths. | From first open-label dose (Day 1) up to open-label Week 32 (8 weeks after last dose) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Double-blind Period: Percentage of Participants With Complete Renal Response (CRR) at Week 104 | CRR is defined as urinary protein creatinine ratio <0.5, eGRF was not more than 10% below the pre-flare value or >=90 mL/min/1.73m^2 and was not a treatment failure. Analysis was performed using a logistic regression model for the comparison between Belimumab and Placebo with covariates of induction regimen (CYC vs. MMF), race (Black vs. Non-Black), Baseline uPCR and Baseline eGFR. Percentage of participants with CRR at Week 104 has been presented. | Week 104 | 
| Double-blind Period: Percentage of Participants With PERR at Week 52 | PERR is defined as urinary protein creatinine ratio <=0.7, eGRF was not more than 20% below the pre-flare value or >=60 mL/min/1.73m^2 and was not a treatment failure. Analysis was performed using a logistic regression model for the comparison between Belimumab and Placebo with covariates of induction regimen (CYC vs. MMF), race (Black vs. Non-Black), uPCR, and Baseline eGFR. Percentage of participants with PERR at Week 52 has been presented. | Week 52 | 
| Double-blind Period: Number of Participants With Time to Death or Renal Related Event | Events are defined as the first event experienced among the following: death, progression to end stage renal disease, doubling of serum creatinine from Baseline, renal worsening or renal-related treatment failure. Participants who discontinued randomized treatment, withdrew from the study, were lost to follow-up, or had a non renal-related treatment failure were censored. Participants who completed the 104-week treatment period were censored at the Week 104 visit. Time to event is defined as event date minus treatment start date plus one. Analysis was performed using Cox proportional hazards model for the comparison between Belimumab and Placebo adjusting for induction regimen, race, Baseline uPCR and Baseline eGFR. Number of participants with time to death or renal related event up to Week 104 has been presented. | Up to Week 104 | 
| Double-blind Period: Percentage of Participants With Ordinal Renal Response (ORR) at Week 104 | ORR is defined with respect to reproducible responses that included CRR, partial RR (PRR) and non responder. CRR is reported when uPCR was <0.5, eGFR was not more than 10% below pre-flare GFR or within normal range and not a treatment failure. PRR is >=50% decrease from Baseline in uPCR and one of the following: value <1 if Baseline <=3, or value <3 if the Baseline was >3, eGFR not more than 10% below Baseline GFR or within normal range and not a treatment failure and not a CRR. Non responder is reported when neither CRR nor PRR criteria was met. Percentage of participants reporting CRR, PRR and non responders at Week 104 has been presented. | Week 104 | 
| Double-blind Period: Number of Participants Reporting On-treatment AEs and SAEs | An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporarily associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE is any untoward medical occurrence that, at any dose: resulting in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, any other situation according to medical or scientific judgment or all events of possible drug-induced liver injury with hyperbilirubinemia were categorized as SAE. Number of participants with on-treatment AEs and SAEs has been reported. | Up to Week 104 | 
| Double-blind Period: Number of Participants Reporting AESI | An AESI is one of scientific and medical concern specific to the product, for which ongoing monitoring and rapid communication by investigator to sponsor can be appropriate. A summary of protocol defined AESIs include malignant neoplasms including and excluding non-melanoma skin cancer (NMSC), post-infusion systemic reactions (PISR), all infections of special interest (opportunistic infections [OI], Herpes Zoster [HZ], tuberculosis [TB], and sepsis), depression (including mood disorders and anxiety)/suicide/self-injury and deaths. On-treatment data is displayed. | Up to Week 104 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Antibodies, Systemic Lupus Erythematosus, Autoimmune Disease, Glomerulonephritis, Belimumab, Lupus, Nephritis, Kidney Diseases, SLE