A Study To Evaluate The Efficacy And Safety Of Obinutuzumab In Patients With ISN/RPS 2003 Class III Or IV Lupus Nephritis

Study Overview
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Brief Summary
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This study will evaluate the efficacy, safety, and pharmacokinetics of obinutuzumab compared with placebo in patients with International Society of Nephrology/Renal Pathology Society (ISN/RPS) class III or IV lupus nephritis (LN) when added on to standard-of-care therapy consisting of mycophenolate mofetil (MMF) and corticosteroids.

Official Title
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A Phase III, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study To Evaluate The Efficacy And Safety Of Obinutuzumab In Patients With ISN/RPS 2003 Class III Or IV Lupus Nephritis (REGENCY)

Conditions
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Lupus Nephritis

Intervention / Treatment
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* Drug: Obinutuzumab
* Drug: MMF
* Drug: Prednisone
* Drug: Placebo
* Drug: Methylprednisolone
* Drug: Acetaminophen
* Drug: Diphenhydramine


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Diagnosis of active or active/chronic ISN/RPS 2003 Class III or IV proliferative LN as evidenced by renal biopsy performed within 6 months. Participants may co-exhibit Class V disease in addition to either Class III or Class IV disease Urine protein to creatinine ratio greater than or equal to (>/=) 1 on a 24-hour collection Other inclusion criteria may apply Key Exclusion Criteria: Pregnancy or breastfeeding Severe renal impairment or the need for dialysis or renal transplantation Receipt of an excluded therapy, including any anti-CD20 therapy less than 9 months prior to screening or during screening; or cyclophosphamide, tacrolimus, ciclosporin, or voclosporin during the 2 months prior to screening or during screening Significant or uncontrolled medical disease which, in the investigator's opinion, would preclude patient participation Known active infection of any kind or recent major episode of infection Intolerance or contraindication to study therapies Other 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 |
| --- | --- |
| Experimental: Obinutuzumab<br>Participants will be randomized into 2 groups. Group 1 will receive obinutuzumab 1000 mg IV at baseline and Weeks 2, 24, 26, 50, and 52 plus MMF and oral prednisone. Group 2 receive obinutuzumab 1000 mg IV at baseline and Weeks 2, 24, 26, and 52 plus MMF and oral prednisone. Group 2 participants will receive a placebo infusion at their Week 50 visit. Participants with an adequate response at Week 76 will continue receiving blinded obinutuzumab infusions every 6 months starting at Week 80. Participants without an adequate response at Week 76 may be eligible for open-label obinutuzumab starting at Week 80. | Drug: Obinutuzumab<br>* Obinutuzumab will be administered by IV infusion at a dose of 1000 mg at Baseline and Weeks 2, 24, 26, 50 (group 2: placebo), and 52 and subsequently from Week 80 and every 6 months thereafter, based on response.<br>* Other names: Gazyva, GA101, RO5072759;Drug: MMF<br>* MMF willl be administered at a target dose of 2.0 - 2.5 g/day in divided doses through Week 80.<br>Drug: Prednisone<br>* Prednisone 0.5 mg/kg/day (maximum 60 mg/day) will be started on Day 2. Beginning on Day 15, prednisone will be tapered to 5 mg/day and continued until Week 80.<br>Drug: Methylprednisolone<br>* Methylprednisolone 80 mg IV will be administered as predmedication prior to infusions.<br>Drug: Acetaminophen<br>* Acetaminophen 650-1000 mg will be administered as premedication prior to infusions.<br>Drug: Diphenhydramine<br>* Diphenhydramine 50 mg will be administered as premedication prior to infusions.<br>|
| Placebo Comparator: Placebo<br>Placebo participants will receive obinutuzumab matched placebo at baseline and Weeks 2, 24, 26, 50, and 52 plus MMF and oral prednisone. Participants with an adequate response at Week 76 will continue receiving blinded obinutuzumab infusions every 6 months starting at Week 80. Participants without an adequate response at Week 76 may be eligible for open-label obinutuzumab starting at Week 80. | Drug: Obinutuzumab<br>* Obinutuzumab will be administered by IV infusion at a dose of 1000 mg at Baseline and Weeks 2, 24, 26, 50 (group 2: placebo), and 52 and subsequently from Week 80 and every 6 months thereafter, based on response.<br>* Other names: Gazyva, GA101, RO5072759;Drug: MMF<br>* MMF willl be administered at a target dose of 2.0 - 2.5 g/day in divided doses through Week 80.<br>Drug: Prednisone<br>* Prednisone 0.5 mg/kg/day (maximum 60 mg/day) will be started on Day 2. Beginning on Day 15, prednisone will be tapered to 5 mg/day and continued until Week 80.<br>Drug: Placebo<br>* Placebo matching obinutuzumab will be administered by IV infusion at baseline and Weeks 0, 2, 24, 26, 50 and 52 and subsequently from Week 80 and every 6 months thereafter based on response.<br>Drug: Methylprednisolone<br>* Methylprednisolone 80 mg IV will be administered as predmedication prior to infusions.<br>Drug: Acetaminophen<br>* Acetaminophen 650-1000 mg will be administered as premedication prior to infusions.<br>Drug: Diphenhydramine<br>* Diphenhydramine 50 mg will be administered as premedication prior to infusions.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants with Complete Renal Response (CRR) |  | At Week 76 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants who Achieve a Proteinuric Response |  | At Week 76 | 
| Percentage of Participants who Achieve Complete Renal Response (CRR) with Successful Prednisone Taper at Week 76 |  | At Week 76 | 
| Percentage of Participants who Achieve an Overall Renal Response (ORR), Defined as Achievement of Either CRR or Partial Renal Response (PRR) |  | At Week 50 | 
| Percentage of Participants who Experience Death or Renal-related Events |  | From baseline to Week 76 | 
| Mean Change in Estimated Glomerular Filtration Rate (eGFR) |  | From baseline to Week 76 | 
| Change in Anti-dsDNA Titer |  | From baseline to Week 50 | 
| Change in Complement C3 |  | From baseline to Week 50 | 
| Change in Systematic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) |  | From baseline to Week 76 | 
| Time to Onset of CRR |  | From baseline to Week 76 | 
| Change in Fatigue (FACIT-F) Scale |  | From baseline to Week 76 | 
| Percentage of Participants who Achieve CRR with Serum Creatinine Criteria |  | At Week 76 | 
| Percentage of Participants with Adverse Events According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 |  | From baseline to Week 76 | 
| Percentage of Participants with Adverse Events of Special Interest (Infusion Related Reactions, Neutropenia, Infections, Thrombocytopenia) |  | From baseline to Week 76 | 
| Maximum Serum Concentration of Obinutuzumab |  | Baseline, Week 2, 4, 12, 26, 36, 50, 52, 64, 76 and early study discontinuation | 
| Percentage of Participants with Anti-Drug Antibodies (ADAs) at Baseline and ADAs Post-Treatment |  | From baseline to Week 76 | 
| Change from Baseline in Total Peripheral B-Cell Count |  | Baseline, Week 4, 12, 24, 50 and 76 |