BIIB023 Proof-of-Concept Study in Participants With Lupus Nephritis

Study Overview
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Brief Summary
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The primary objective of the study is to assess the efficacy of BIIB023 as an add-on treatment to background therapy compared with placebo in combination with background therapy in the treatment of participants with active, biopsy-proven lupus nephritis. The secondary objectives of this study are to assess the safety and tolerability of BIIB023 compared with placebo in this study population.

Detailed Description
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Participants who complete this study through Week 52 will be offered the option to enter an Extension study under a separate protocol 211LE202 (NCT0193089).

Official Title
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A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Tolerability of BIIB023 in Subjects With Lupus Nephritis

Conditions
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Lupus Nephritis

Intervention / Treatment
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* Biological: BIIB023
* Biological: Placebo
* Drug: mycophenolate mofetil
* Drug: oral corticosteroids


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Documented diagnosis of systemic lupus erythematosus (SLE) according to current American College of Rheumatology (ACR) criteria. At least 4 ACR criteria must be documented, 1 of which must be a positive antinuclear antibody (ANA), anti Sm, or anti dsDNA antibody. Diagnosis of International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 Class III or IV lupus nephritis with either active or active/chronic disease, confirmed by biopsy within 3 months prior to Screening. Participants are permitted to have co existing Class V lupus nephritis. If a renal biopsy has not been performed within 3 months of the Screening Visit, one can be performed during the Screening Period after all other eligibility criteria have been confirmed. The local histological diagnosis must be confirmed by the central study pathologist. Must have proteinuria at Screening (from a 24 hour urine sample collection) defined as urinary protein:creatinine ratio (uPCR) >1.0 mg/mg. Key Exclusion Criteria: Retinitis, poorly-controlled seizure disorder, acute confusional state, myelitis, stroke or stroke syndrome, cerebellar ataxia, or dementia that is currently active and resulting from SLE at Screening Estimated glomerular filtration rate (eGFR) <30 mL/min per 1.73 m^2 (calculated using the abbreviated Modification of Diet in Renal Disease equation) or the presence of oliguria or end-stage renal disease requiring dialysis or transplantation Subjects requiring dialysis within 12 months prior to Screening History of renal transplant Treatment with any biologic B-cell-depleting therapy (e.g., anti-CD20 [rituximab], anti-CD22 [epratuzumab], anti-BLyS/B-cell activating factor [e.g., briobacept, belimumab] therapy), or TACI-Ig within 12 months prior to Run-in Day 1. NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo intravenous (IV) infusion on Day 1, Week 2, Week 4, Week 8, and every 4 weeks thereafter through Week 48, plus background therapy including oral steroids (prednisone or equivalent) and mycophenolate mofetil (MMF) | Biological: Placebo<br> <br> Drug: mycophenolate mofetil<br>* titrated to a target daily dose of 2 g (1 g twice daily)<br>* Other names: MMF, Cellcept;Drug: oral corticosteroids<br>* oral corticosteroids (prednisone or equivalent) at a target prednisone dose of 10 mg/day<br>|
| Experimental: BIIB023 3 mg/kg<br>BIIB023 3 mg/kg IV on Day 1, Week 2, Week 4, Week 8, and every 4 weeks thereafter through Week 48 plus background therapy including oral steroids (prednisone or equivalent) and MMF. | Biological: BIIB023<br> <br> Drug: mycophenolate mofetil<br>* titrated to a target daily dose of 2 g (1 g twice daily)<br>* Other names: MMF, Cellcept;Drug: oral corticosteroids<br>* oral corticosteroids (prednisone or equivalent) at a target prednisone dose of 10 mg/day<br>|
| Experimental: BIIB023 20 mg/kg<br>BIIB023 20 mg/kg IV on Day 1, Week 2, Week 4, Week 8, and every 4 weeks thereafter through Week 48 plus background therapy including oral steroids (prednisone or equivalent) and MMF. | Biological: BIIB023<br> <br> Drug: mycophenolate mofetil<br>* titrated to a target daily dose of 2 g (1 g twice daily)<br>* Other names: MMF, Cellcept;Drug: oral corticosteroids<br>* oral corticosteroids (prednisone or equivalent) at a target prednisone dose of 10 mg/day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieve a Complete or Partial Renal Response at Week 52 | Complete renal response is defined as: (1) urinary protein:creatinine ratio (uPCR) < 0.5 mg/mg with ≥ 50% reduction of uPCR from Day 1 (Baseline; from a 24 hour urine collection); and (2) estimated glomerular filtration rate (eGFR) within normal range. Partial renal response is defined as: (1) ≥ 50% reduction in uPCR from Day 1 (Baseline; from a 24-hour urine collection) and, (2) with one of the following: (a) uPCR of < 1.0 mg/mg if the Day 1 (Baseline) was ≤ 3.0 mg/mg, or, (b) uPCR < 3.0 mg/mg if the Day 1 (Baseline) ratio was > 3.0 mg/mg; and stabilization of renal function (eGFR + or - 25% of Day 1 [Baseline] or serum creatinine within normal range). | Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieve Complete Renal Response at Week 52 | Complete renal response is defined as uPCR < 0.5 mg/mg with ≥ 50% reduction of uPCR from Baseline (from a 24-hour urine collection) and eGFR within normal range. | Week 52 | 
| Duration of Renal Response in Participants Who Achieve Complete Renal Response at Week 52 | Duration of response was calculated as the days in between the date of Week 52 visit and the date when the participant last became complete renal responder on or before Week 52 visit. Complete renal response: (1) uPCR <0.5 mg/mg with ≥ 50% reduction of uPCR from Day 1 (Baseline) (from a 24 hour urine collection); and (2) eGFR within normal range. | Week 52 | 
| Time to Renal Response (Partial or Complete) in Participants Who Achieve Renal Response at Week 52 | Onset of renal response was calculated as weeks elapsed from baseline date to first visit where renal response was achieved. Complete renal response is defined as: (1) uPCR <0.5 mg/mg with ≥ 50% reduction of uPCR from Day 1 (Baseline) (from a 24 hour urine collection); and (2) eGFR within normal range. Partial renal response is defined as: (1) ≥ 50% reduction in uPCR from Day 1 (Baseline; from a 24-hour urine collection) and, (2) with one of the following: (a) uPCR of < 1.0 mg/mg if the Day 1 (Baseline) was ≤ 3.0 mg/mg, or, (b) uPCR < 3.0 mg/mg if the Day 1 (Baseline) ratio was > 3.0 mg/mg; and stabilization of renal function (eGFR + or - 25% of Day 1 [Baseline] or serum creatinine within normal range). Estimated from the Kaplan-Meier Curve. | Baseline to Week 52 | 
| Percentage of Participants With uPCR > 3.0 mg/mg at Baseline Who Achieve uPCR <1.0 mg/mg at Week 52 |  | Baseline (Day 1), Week 52 | 
| Percentage of Participants With Active Urinary Sediment at Baseline Who Have Inactive Urinary Sediment at Week 52 | Active urinary sediment is defined by 1 of the following (in the absence of a urinary tract infection or menses): > 5 red blood cell/high power field (RBC/HPF) or above the reference range for the laboratory, and > 5 white blood cell/high power field (WBC/HPF) or above the reference range for the laboratory, and presence of cellular casts (RBC or WBC). Inactive urinary sediment is defined as: < 5 RBC/HPF and < 5 WBC/HPF, or within the laboratory reference range, and no cellular casts (no RBC or WBC casts). | Baseline, Week 52 | 
| Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Study Discontinuation During the Run-In Period | AEs that had an onset on or after dosing of MMF on run-in Day 1 up to the first double-blind dose, or any pre-existing condition that worsened. AE: any untoward medical occurrence that does not necessarily have a causal relationship with this treatment. SAE: any untoward medical occurrence that at any dose: results in death; in the view of the Investigator, places the participant at immediate risk of death (a life-threatening event); requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; or results in a congenital anomaly/birth defect. An SAE may also be any other medically important event that, in the opinion of the Investigator, may jeopardize the participant or may require intervention to prevent one of the other outcomes listed above. | Day 1 to Week 12 | 
| Number of Participants With AEs, SAEs and AEs Leading to Study Discontinuation During the Double-Blind Period | AEs that had an onset on or after dosing of BIIB023 or placebo, or any pre-existing condition that worsened. AE: any untoward medical occurrence that does not necessarily have a causal relationship with this treatment. SAE: any untoward medical occurrence that at any dose: results in death; in the view of the Investigator, places the participant at immediate risk of death (a life-threatening event); requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; or results in a congenital anomaly/birth defect. An SAE may also be any other medically important event that, in the opinion of the Investigator, may jeopardize the participant or may require intervention to prevent one of the other outcomes listed above. | Week 12 to Week 56 | 
| Duration of Renal Response in Participants Who Achieve Partial or Complete Renal Response at Any Time During the Study | Number of days between first visit with response to last consecutive visit with partial or complete response. Complete renal response is defined as: (1) uPCR <0.5 mg/mg with ≥ 50% reduction of uPCR from Day 1 (Baseline) (from a 24 hour urine collection); and (2) eGFR within normal range. Partial renal response is defined as: (1) ≥ 50% reduction in uPCR from Day 1 (Baseline; from a 24-hour urine collection) and, (2) with one of the following: (a) uPCR of < 1.0 mg/mg if the Day 1 (Baseline) was ≤ 3.0 mg/mg, or, (b) uPCR < 3.0 mg/mg if the Day 1 (Baseline) ratio was > 3.0 mg/mg; and stabilization of renal function (eGFR + or - 25% of Day 1 [Baseline] or serum creatinine within normal range). Estimated from the Kaplan-Meier Curve. | up to Week 52 |