A Study Evaluating the Efficacy and Safety of Obinutuzumab in Participants With Primary Membranous Nephropathy

Study Overview
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Brief Summary
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This study will evaluate the efficacy, safety, pharmacodynamics, and pharmacokinetics (PK) of obinutuzumab compared with tacrolimus in participants with primary membranous nephropathy (pMN).

Official Title
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A Phase III Randomized, Open-Label Active Comparator-Controlled Multicenter Study to Evaluate Efficacy and Safety of Obinutuzumab in Patients With Primary Membranous Nephropathy

Conditions
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Primary Membranous Nephropathy

Intervention / Treatment
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* Drug: Obinutuzumab
* Drug: Tacrolimus
* Drug: Methylprednisolone
* Drug: Acetaminophen
* Drug: Diphenhydramine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of primary membranous nephropathy (pMN) according to renal biopsy prior to or during screening Screening urinary protein-to-creatinine ratio (UPCR) >= 5 g/g from 24-hour urine collection after best supportive care for >= 3 months prior to screening or screening UPCR >= 4 g/g after best supportive care for >= 6 months prior to screening eGFR >= 40 mL/min/1.73m^2 or qualified endogenous creatinine clearance >= 40 mL/min/1.73m^2 based on 24-hour urine collection during screening Other inclusion criteria may apply Exclusion Criteria: Participants with a secondary cause of MN Pregnancy or breastfeeding Evidence of >= 50% reduction in proteinuria during the previous 6 months prior to randomization Severe renal impairment, including the need for dialysis or renal replacement therapy Type 1 or 2 diabetes mellitus Receipt of an excluded therapy, including any anti-CD20 therapy less than 9 months prior to or during screening; or cyclophosphamide, tacrolimus, or cyclosporin less than 6 months prior to or during screening Significant or uncontrolled medical disease which, in the investigator's opinion, would preclude participant participation Known active infection of any kind or recent major episode of infection Major surgery requiring hospitalization within the 4 weeks prior to screening Current active alcohol or drug abuse or history of alcohol or drug abuse within 12 months prior to screening 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Open Label Treatment: Obinutuzumab<br>Participants will be randomized at a 1:1 ratio to receive open-label treatment with obinutuzumab according to region and anti-phospholipase A2 receptor (PLA2R) autoantibody titer (using Euroimmun ELISA). | Drug: Obinutuzumab<br>* Open Label: An intravenous (IV) infusion of 1000 milligram (mg) of obinutuzumab will be administered at Week 0, Week 2, Week 24, and Week 26. Participants who relapse during the open-label treatment period may be eligible for further treatment.<br>* Other names: Gazyva;Drug: Methylprednisolone<br>* Premedication: Methylprednisolone 80 mg IV will be administered between 30 and 60 minutes prior to the obinutuzumab infusion in all study periods.<br>Drug: Acetaminophen<br>* Premedication: Acetaminophen (650-1000 mg, or equivalent dose of a similar agent) PO or IV will be administered between 30 and 60 minutes prior to the obinutuzumab infusion in all study periods.<br>Drug: Diphenhydramine<br>* Premedication: Diphenhydramine (50 mg, or equivalent dose of a similar agent) PO or IV will be administered between 30 and 60 minutes prior to the obinutuzumab infusion in all study periods.<br>|
| Active Comparator: Open Label Treatment: Tacrolimus<br>Participants will be randomized at a 1:1 ratio to receive open-label treatment with tacrolimus according to region and anti-PLA2R autoantibody titer (using Euroimmun ELISA). | Drug: Tacrolimus<br>* Open Label: Participants will receive tacrolimus at a starting oral dose (PO) of 0.05 mg/kilogram (kg) (participant dry weight) per day divided into two equal doses given at 12-hour intervals, titrated to serum trough level 5-7 Nanograms per millilitre (ng/mL). Optimized tacrolimus dose will be maintained for a maximum 52 weeks dependent on response and then tapered over 8 weeks. Participants who relapse during the open-label treatment period will have their dose of tacrolimus tapered over 8 weeks and may be eligible for further treatment.<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 Remission (CR) at Week 104 |  | Week 104 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants who Achieve an Overall Remission at Week 104 |  | Week 104 | 
| Percentage of Participants who Achieve CR at Week 76 |  | Week 76 | 
| Time to Treatment Failure, Meeting Escape Criteria, or Relapse after Complete or Partial Remission |  | Up to 8 years | 
| Time to a Sustained Reduction of Estimated Glomerular Filtration Rate (eGFR) >= 30% from Baseline |  | Up to 8 years | 
| Mean Change in T-score from Baseline in the Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Scale at Week 104 | Self-reported changes in fatigue will be measured using the PROMIS Fatigue Scale. | Baseline to Week 104 | 
| Duration of CR |  | Up to 8 years | 
| Change in anti-PLA2R Autoantibody Titer |  | Baseline to Week 52 | 
| Mean Change from Baseline in the PROMIS Global Assessment of Physical Health Scale at Week 104 | Self-reported changes in physical health will be measured using the PROMIS Physical Health Scale | Baseline to Week 104 | 
| Percentage of Participants with Adverse Events (AEs) | Severity Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0 | Up to 8 years | 
| Percentage of Participants with AEs of Special Interest (AESIs) | AESIs are required to be reported by the investigator to the Sponsor immediately | Up to 8 years | 
| Peripheral B-cell Counts at Specified Timepoints |  | Weeks 0 (baseline), 2, 4, 12, 24, 26, 36, 52, 64, 76, 88, 104, 117, 130, 156, 182, 208 and every 26 weeks thereafter | 
| Serum Concentrations of Obinutuzumab at Specified Timepoints |  | Weeks 0 (baseline), 2, 4, 12, 24, 26, 36, 52, 64, 76, 88, 104, 117, 130, 143, 156, 169, 182, 195, 208, every 26 weeks thereafter | 
| Prevalence of Anti-drug Antibodies (ADAs) to Obinutuzumab at Baseline |  | Open Label: Baseline; Escape Treatment: Week 0 | 
| Incidence of ADAs during the study |  | Weeks 2, 4, 12, 24, 26, 36, 52, 64, 76, 88, 104, 130, 156, 182, 208 and every 26 weeks thereafter |