A Study to Evaluate the Safety and Efficacy of Zanubrutinib in Participants With Primary Membranous Nephropathy

Study Overview
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Brief Summary
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The primary objectives of this study are: In Part 1 to evaluate the efficacy of zanubrutinib as measured by proteinuria reduction, and in Part 2 to evaluate the efficacy of zanubrutinib compared with tacrolimus as measured by complete remission rate, in participants with primary membranous nephropathy who are on optimal supportive care.

Official Title
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A Phase 2/3, Multicenter, Randomized, Active-Controlled, Open-label Study to Evaluate the Efficacy and Safety of Zanubrutinib in Patients With Primary Membranous Nephropathy

Conditions
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Primary Membranous Nephropathy

Intervention / Treatment
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* Drug: Zanubrutinib
* Drug: Tacrolimus
* Drug: Zanubrutinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Biopsy-confirmed primary membranous nephropathy UPCR (based on 24-hour urine collection) > 3.5 at initial screening and confirmation assessment Treatment with a maximally tolerated or allowed dose of an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) for ≥ 24 weeks before randomization (12 weeks before initiation of study drug for Part 1) and with adequate blood pressure control Anti-PLA2R antibody > 50 RU/mL at confirmation assessment (Part 1 only) Exclusion Criteria: Participants with a secondary cause of membranous nephropathy Type 1 or 2 diabetes mellitus with hemoglobin A1c (HbA1c) ≥ 7% at screening The eGFR < 40 mL/min/1.73 m2, or initiation of dialysis A known history of a primary immunodeficiency or an underlying condition such as human immunodeficiency virus (HIV) infection or splenectomy that predisposes the participant to infections Positive tuberculosis at screening Known infection with serologic status reflecting active or chronic hepatitis B virus infection, or presence of hepatitis C virus antibody Severe hepatic insufficiency (Child-Pugh C) Clinically significant cardio-cerebrovascular diseases Note: Additional 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
Interventional Model Description: This study consists of 2 parts. Part 1 will evaluate the safety and efficacy of Zanubrutinib in participants with primary membranous nephropathy. Part 2 will evaluate the safety and efficacy of zanubrutinib compared with tacrolimus.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 and Part 2: Zanubrutinib High dose<br>Participants will receive Zanubrutinib twice daily | Drug: Zanubrutinib<br>* Participants will receive zanubrutinib twice daily<br>* Other names: BGB-3111;|
| Experimental: Part 2: Zanubrutinib Low Dose<br>Participants will receive Zanubrutinib once daily | Drug: Zanubrutinib<br>* Participants will receive zanubrutinib once daily<br>* Other names: BGB-3111;|
| Active Comparator: Tacrolimus<br>Participants will receive tacrolimus capsules for 64 weeks | Drug: Tacrolimus<br>* Participants will receive tacrolimus twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Reduction in Urine Protein Creatinine Ratio (UPCR) |  | Week 24 | 
| Part 2: Number of Participants Achieving Complete Remission |  | Week 104 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Number of participants with Treatment Failure |  | Week 24 | 
| Part 1: Number of Participants with Immunological Response | Immunological response is defined as anti- phospholipase A2 receptor (PLA2R) antibody level reduced from baseline to less than 14 RU/ml. | Week 24 | 
| Part 1: Number of Participants with Complete Remission | A complete remission is defined as: UPCR (based on 24-hour urine collection) ≤ 0.3, AND A stable eGFR (remains unchanged or decreases by < 15% compared with the baseline) | Week 24, Week 52, Week 76, and Week 104 | 
| Part 1: Number of Participants with Overall Remission | Participants with overall remission are those achieving either complete remission or partial remission | Week 24, Week 52, Week 76, and Week 104 | 
| Part 1: Number of Participants with Relapse | A relapse is defined as reappearance of UPCR (based on 24-hour urine collection) > 3.5 after complete or partial remission | Week 104 | 
| Part 1: Number Of Participants with Treatment-Emergent Adverse Events (TEAEs) |  | Up to approximately 104 weeks | 
| Part 2: Number of Participants with Overall Remission | Participants with overall remission are those achieving either complete remission or partial remission | Week 24, Week 52, Week 76, and Week 104 | 
| Part 2: Number of Participants with Complete Remission | A complete remission is defined as: UPCR (based on 24-hour urine collection) ≤ 0.3, and A stable eGFR (remains unchanged or decreases by < 15% compared with the baseline) | Week 24, Week 52, and Week 76 | 
| Part 2: Number of participants with Treatment Failure |  | Week 24, Week 52, Week 76, and Week 104 | 
| Part 2: Time to First Complete Remission | Time to First Complete Remission is the time from the date of randomization to the date of the first complete remission | Up to approximately 5.5 years | 
| Part 2: Time to First Overall Remission | Time to first overall remission is the time from the date of randomization to the date of the first overall remission | Up to approximately 5.5 years | 
| Part 2: Number of Participants with Relapse | A relapse is defined as reappearance of UPCR (based on 24-hour urine collection) > 3.5 after complete or partial remission | Week 104 | 
| Part 2: Time to First Relapse | Time to first relapse is the time from the date of first complete or partial remission to the date of the first relapse | Up to approximately 5.5 years | 
| Part 2: Health Related quality of Life (HRQoL) t Using the Kidney Disease and Quality of Life instrument™ - 36 items (KDQoL-36) |  | Up to approximately 5.5 years | 
| Part 2: Health Related quality of Life (HRQoL) Using European Quality of Life 5-Dimensions 5-Levels Health Questionnaire (EQ-5D-5L) |  | Up to approximately 5.5 years | 
| Number of Participants with ≥ 30% ReceptorEstimated Glomerular Filtration Rate (eGFR) Reduction from Baseline |  | Week 52 and Week 104 | 
| Part 2: Number of Participants with TEAEs |  | Up to approximately 5.5 years |