A Study to Evaluate the Efficacy and Safety of Obinutuzumab in Participants With Systemic Lupus Erythematosus

Study Overview
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Brief Summary
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This parallel-group, double-blind, placebo-controlled study will evaluate the efficacy and safety of obinutuzumab versus placebo in participants with active, autoantibody-positive systemic lupus erythematosus (SLE) who are treated with standard-of-care therapy.

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 Systemic Lupus Erythematosus

Conditions
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Systemic Lupus Erythematosus

Intervention / Treatment
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* Drug: Obinutuzumab
* Drug: Placebo
* Drug: Acetaminophen/Paracetamol
* Drug: Diphenhydramine hydrochloride
* Drug: Methylprednisolone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of SLE according to the 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) Classification Criteria >=12 weeks prior to screening Anti-nuclear antibody (ANA) >=1:80, or anti-dsDNA and/or anti-Sm antibodies above the upper limit of normal (ULN), as determined by the central laboratory at screening Low C3 or low C4 or low CH50 complement as determined by the central laboratory at screening High disease activity at screening, based on; BILAG-2004 (Category A disease in >=1 organ system and/or Category B disease in >=2 organ systems), Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) (score >=8) and Physician's Global Assessment (PGA) (score >=1.0 on a 0 to 3 visual analogue scale [VAS]) High disease activity on Day 1, based on; SLEDAI-2K (score >=8) and PGA (score >=1.0 on a 0 to 3 VAS) Current receipt of >=1 of the following classes of standard therapies for the treatment of SLE at stable doses: oral corticosteroid (OCS), antimalarials, conventional immunosuppressants Other inclusion criteria may apply The Medical Monitor may be consulted if there are any questions related to eligibility criteria Exclusion Criteria: Pregnancy or breastfeeding Presence of significant lupus-associated renal disease and/or renal impairment Receipt of an excluded therapy, including any anti-CD20, anti-CD19 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 receive obinutuzumab 1000 milligrams (mg) intravenous (IV) infusions on Day 1 and at Weeks 2, 24 and 26. | Drug: Obinutuzumab<br>* Obinutuzumab will be administered by IV infusion at a dose of 1000 mg on Day 1 and at Weeks 2, 24 and 26.<br>* Other names: Gazyva, GA101, RO5072759;Drug: Acetaminophen/Paracetamol<br>* Acetaminophen 650-1000 mg will be administered as premedication prior to infusions.<br>Drug: Diphenhydramine hydrochloride<br>* Diphenhydramine 50 mg will be administered as premedication prior to infusions.<br>Drug: Methylprednisolone<br>* Methylprednisolone 80 mg IV will be administered as premedication prior to infusions.<br>|
| Placebo Comparator: Placebo<br>Placebo participants will receive obinutuzumab matched placebo on Day 1 and at Weeks 2, 24 and 26. | Drug: Placebo<br>* Placebo matching obinutuzumab will be administered by IV on Day 1 and at Weeks 2, 24 and 26.<br>Drug: Acetaminophen/Paracetamol<br>* Acetaminophen 650-1000 mg will be administered as premedication prior to infusions.<br>Drug: Diphenhydramine hydrochloride<br>* Diphenhydramine 50 mg will be administered as premedication prior to infusions.<br>Drug: Methylprednisolone<br>* Methylprednisolone 80 mg IV 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 who Achieve Systemic Lupus Erythematosus Responder Index (SRI[4]) at Week 52 | SRI(4) requires reduction from baseline of >=4 points in the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), no new systems or organs affected, as defined by >=1 new British Isles Lupus Assessment Group (BILAG) A or >=2 new BILAG B items compared with baseline using BILAG-2004, and no worsening from baseline of >=0.30 points on a 3-point Physician's Global Assessment Visual Analogue Scale (PGA-VAS). | Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants who Achieve SRI(6) at Week 52 | SRI(6) requires reduction from baseline of >=6 points in the SLEDAI-2K, no new systems or organs affected, as defined by >=1 new BILAG A or >=2 new BILAG B items compared with baseline using BILAG-2004, and no worsening from baseline of >=0.30 points on a 3-point PGA-VAS. | Week 52 | 
| Percentage of Participants Entering the Study on Prednisone >= 10 mg/day (or equivalent) who Achieve Sustained Corticosteroid Control | No treatment with prednisone >=7.5 mg/day (or equivalent) and no receipt of intravenous, intramuscular, or intra-articular corticosteroids. | From Week 40 to Week 52 | 
| Time to First BILAG Flare over 52 Weeks | Flare is defined as the occurrence of >=1 new BILAG A or >=2 new BILAG B manifestations from the previous visit | From baseline to Week 52 | 
| Percentage of Participants who Achieve a Sustained SRI(4) Response | Achievement of SRI(4) at all study visits from Week 40 through Week 52. | From Week 40 to Week 52 | 
| Percentage of Participants who Achieve British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) at Week 52 | Reduction of all baseline BILAG-2004 A items to B/C/D and baseline BILAG-2004 B items to C/D; no new systems or organs affected, as defined by >=1 new BILAG A or >=2 new BILAG B items compared with baseline; no net increase in SLEDAI-2K score from baseline; and no worsening from baseline of >=0.30 points on a 3-point PGA-VAS. | Week 52 | 
| Percentage of Participants who Achieve SRI(8) at Week 52 |  | Week 52 | 
| Percentage of Participants who Achieve SRI(4) at Week 24 |  | Week 24 | 
| Percentage of Participants who Achieve Clinical SRI(4) at Week 52 |  | Week 52 | 
| Percentage of Participants who Achieve SRI(4) at Week 52 on Low-dose Corticosteroids |  | Week 52 | 
| Percentage of Participants who Achieve Lupus Low Disease Activity State (LLDAS) at Week 52 |  | Week 52 | 
| Percentage of Participants who Achieve Definition of Remission in SLE (DORIS) at Week 52 |  | Week 52 | 
| Change in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Scale |  | From baseline to Week 24 and from baseline to Week 52 | 
| Change in 36-Item Short Form Survey, Version 2 (SF-36 v2) Bodily Pain Domain Scale |  | From baseline to Week 24 and from baseline to Week 52 | 
| Change in SF-36 v2 Physical Component Summary Scale |  | From baseline to Week 24 and from baseline to Week 52 | 
| Change in Active Joint Count (Swollen plus Tender) |  | From baseline to Week 24 and from baseline to Week 52 | 
| Percentage of Participants who Achieve a >= 50% Reduction in Active Joint Counts (Swollen plus Tender) at Each Study Visit |  | From baseline to Week 52 | 
| Percentage of Participants who Achieve a >= 50% Reduction in Cutaneous Lupus Erythematosus Disease Area and Severity (CLASI) Total Activity Score at each Study Visit, among Participants with CLASI Total Activity Score >=10 at Baseline |  | From baseline to Week 52 | 
| Percentage of Participants who Achieve Sustained Corticosteroid Control |  | From Week 40 through Week 52 | 
| Cumulative Corticosteroid use (in Equivalent Milligrams of Prednisone) |  | From baseline to Week 52 | 
| Annualized flare rate through Week 52 |  | At Week 52 | 
| Percentage of Participants with Adverse Events |  | From baseline to approximately 6 years | 
| Percentage of Participants with Adverse Events of Special Interest (AESIs) |  | From baseline to approximately 6 years | 
| Serum Concentration of Obinutuzumab |  | Double blind period: At Weeks 2, 4, 12, 24, 26, 36, 52 and at early study discontinuation visit; Open label period: At Weeks 54, 56, 58, 66, 78, 90, 104 and at early study discontinuation visit | 
| Percentage of Participants with Anti-drug Antibodies (ADAs) at Baseline |  | Baseline | 
| Percentage of Participants with ADAs During the Study |  | Up to approximately 6 years |