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
- Trial ID
- 2022-501147-32-00
- Protocol
- BGB-3111-309
- Sponsor
- BeOne Medicines AG
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of **zanubrutinib** in patients with **primary membranous nephropathy** who are on optimal supportive care. This will be assessed in two parts: Part 1 focuses on the reduction of proteinuria, while Part 2 compares the efficacy of zanubrutinib with **tacrolimus** by measuring the complete remission rate. The clinical relevance of this objective lies in determining the potential of zanubrutinib as a therapeutic option for managing proteinuria and achieving remission in this patient population.
Secondary objectives include: Part 1 - evaluating the efficacy of zanubrutinib in terms of complete remission, overall remission, immunological response, and relapse rates; assessing the safety and tolerability of zanubrutinib. Part 2 - comparing the efficacy of zanubrutinib with tacrolimus by measuring overall remission, treatment failure, time to first remission, relapse rates, patient-reported outcomes, and changes in renal function; evaluating the safety and tolerability of zanubrutinib. These secondary objectives aim to provide a comprehensive understanding of the therapeutic profile of zanubrutinib in comparison to tacrolimus, focusing on both efficacy and safety parameters.
Participants
The clinical trial involves a total of **258 participants** diagnosed with **primary membranous nephropathy**. The study population includes both male and female subjects, aged between 18 to 75 years. Participants were selected based on specific criteria, including a biopsy-confirmed diagnosis of primary membranous nephropathy within the last five years and a UPCR greater than 3.5 at initial screening. The trial does not involve a vulnerable population. Participants are required to be on optimal supportive care, with those in Part 1 having been treated with a maximally tolerated or allowed dose of ACEI or ARB for at least 12 weeks prior to the first dose of zanubrutinib, and those in Part 2 for at least 24 weeks before randomization. Adequate blood pressure control is also a prerequisite. Lifestyle considerations such as diet and physical activity are not specified, but female participants of childbearing potential must adhere to strict birth control measures during the study and for at least 30 days after the last dose of treatment. The trial does not specify any particular lifestyle habits or general health status beyond the inclusion criteria.
Plans and Procedures
The clinical trial is designed as a **randomized**, active-controlled, open-label study to evaluate the efficacy and safety of **zanubrutinib** in patients with **primary membranous nephropathy**. The trial is structured in two parts, with Part 1 focusing on the efficacy of zanubrutinib as measured by proteinuria reduction, and Part 2 comparing the efficacy of zanubrutinib with **tacrolimus** based on the complete remission rate. The trial is expected to commence recruitment on January 18, 2024, and conclude by May 26, 2028, with a maximum treatment period of 64 weeks for participants.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, biopsy-confirmed diagnosis, and urine protein creatinine ratio (UPCR). Follow-up visits will be scheduled to monitor treatment efficacy and safety, with primary endpoints assessed at Week 24 for Part 1 and Week 104 for Part 2. Secondary endpoints include treatment failure status, immunological response, and incidence of treatment-emergent adverse events, among others. The end-of-study visit will mark the completion of the trial for each participant.
Participant involvement is expected to last up to 104 weeks, depending on the part of the trial they are enrolled in. Conditions that may lead to early termination from the study include non-compliance with the protocol, withdrawal of consent, or adverse events that necessitate discontinuation of treatment. The trial will adhere to rigorous scientific and ethical standards to ensure the integrity of the data and the safety of the participants.
Treatment
The clinical trial involves the administration of **Zanubrutinib**, an experimental medication, in the form of a capsule. The active substance, **Zanubrutinib**, is of chemical origin and is provided by BEIGENE. The maximum daily dose is 320 mg, with a total maximum dose of 143.3 g over the treatment period. The medication is administered orally, and the treatment duration is set for a maximum of 64 days. Participant compliance with the dosing schedule will be monitored throughout the study.
**Tacrolimus** is used as a comparator treatment in this study. It is also administered in capsule form, with the active substance being of chemical origin. The maximum daily dose is 0.15 mg/kg, with the same total maximum dose over the treatment period of 64 days. Tacrolimus is administered orally. The study will ensure that participants adhere to the prescribed dosing regimen, and compliance will be closely monitored.
Efficacy
The efficacy of the investigational product, **Zanubrutinib**, in patients with primary membranous nephropathy will be assessed through a series of predefined endpoints. In Part 1 of the trial, the primary endpoint is the change from baseline in urine protein creatinine ratio (UPCR) at Week 24. In Part 2, the primary endpoint is the complete remission status at Week 104. Secondary endpoints for Part 1 include treatment failure status, immunological response status, complete remission status, overall remission status, relapse status, and the incidence and severity of treatment-emergent adverse events, all measured at various timepoints up to Week 104. For Part 2, secondary endpoints include overall remission status, complete remission status, treatment failure status, time to first complete and overall remission, relapse status, time to first relapse, patient-reported symptoms and overall health status using the Kidney Disease and Quality of Life instrument™ - 36 items (KDQoL-36) and European Quality of Life 5-Dimensions 5-Levels Health Questionnaire (EQ-5D-5L), and a ≥ 30% reduction in eGFR from baseline to Week 52 and Week 104.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Part 1 and 2: 18 to 75 years of age (inclusive) on the day of signing the ICF
- Part 1 and 2: Patients must sign the ICF and be capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in the protocol
- Part 1 and 2: Biopsy-confirmed primary membranous nephropathy within 5 years before the initial screening (ie, the day the informed consent is signed)
- Part 1 and 2: UPCR (based on 24-hour urine collection) > 3.5 at the initial screening and at the confirmation assessment.
- Part 1 and 2: Female patients of childbearing potential must be willing to use a highly effective method of birth control for the duration of the study and for ≥ 30 days after the last dose of treatment. They must also have a negative urine or serum pregnancy test result (Section 8.3.5). Note: a woman is considered of childbearing potential (ie, fertile, following menarche and until becoming postmenopausal) unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. Nonsterile male patients must be willing to use a highly effective method of birth control for the duration of the study and for ≥ 30 days after the last dose of study drug.
- Part 1 only: Treatment with maximally tolerated or allowed dose of ACEI or ARB for ≥ 12 weeks before the first dose of zanubrutinib and with adequate blood pressure control (blood pressure < 130/80 mmHg, measured on ≥ 2 occasions [not on the same day] within 4 weeks before the assignment of study treatment).
- Part 1 only: Anti-PLA2R antibody > 50 RU/mL at confirmation assessment
- Part 2 only : Treatment with maximally tolerated or allowed dose of ACEI or ARB for ≥ 24 weeks before randomization and with adequate blood pressure control (blood pressure < 130/80 mmHg, measured on ≥ 2 occasions [not on the same day] within 4 weeks before randomization). See protocol for details.
Exclusion Criteria
- Part 1 and 2: Lactating or pregnant female patients
- Part 2 only: Evidence of ≥ 50% reduction in 24-hour urine protein within 24 weeks before randomization
- Part 2 only: History of resistance or intolerance to tacrolimus.
- Part 1 and 2: Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction.
- Part 2 only: Hypersensitivity to zanubrutinib, tacrolimus, or other macrolides, or their formulation excipients (eg, HCO-60 [polyoxyl 60 hydrogenated castor oil]).
- Part 1 and 2: Ongoing treatment with a strong CYP3A inhibitor or inducer (refer to Appendix 4).
- Part 1 and 2: Prior exposure to a BTK inhibitor.
- Part 1 and 2: Any infections requiring hospitalization or treatment with intravenous anti-infectives not completed ≥ 4 weeks before the assignment of study treatment.
- Part 1 and 2: Receipt of any prohibited drug within specified time (refer to Table 3 and Appendix 9).
- Part 1 and 2: A known history of a primary immunodeficiency or an underlying condition such as human immunodeficiency virus (HIV) infection or splenectomy that predisposes the patient to infections.
- Part 1 and 2: Patients at risk for tuberculosis (see protocol for details)
- Part 1 and 2: Unwilling or unable to follow the dietary guidance per investigator.
- Part 1 only: The eGFR < 30 mL/min/1.73 m2 (according to the CKD-EPI formula), or initiation of dialysis.
- Part 1 and 2: Severe hepatic insufficiency (Child-Pugh C).
- Part 1 and 2: Current alcohol, drug, or chemical abuse, or a history of such abuse within 1 year before the assignment of study treatment.
- Part 1 and 2: Known infection with serologic status reflecting active or chronic HBV, or presence of hepatitis C virus (HCV) antibody (see protocol for details)
- Part 1 and 2: History of a cancer, apart from cervical cancer in situ, basal or squamous cell skin cancer treated with curative therapy ≥ 2 year prior to the assignment of study treatment.
- Part 1 and 2: History of intracranial hemorrhage.
- Part 1 and 2: Clinically significant cardio-cerebrovascular diseases (see protocol for details)
- Part 1 and 2: History of severe bleeding disorder such as hemophilia A, hemophilia B, and von Willebrand disease, or history of spontaneous bleeding requiring blood transfusion or other medical intervention.
- Part 2 only: The eGFR < 40 mL/min/1.73 m2 (according to the CKD-EPI formula), or initiation of dialysis.
- Part 1 and 2: Patients with a secondary cause of membranous nephropathy (eg, diabetic nephropathy, lupus nephritis) or with other primary glomerular diseases, such as Immunoglobulin A (IgA) nephropathy, etc.
- Part 1 and 2: Unable to understand the purpose and risks of the study and to provide a signed and dated ICF and authorization to use protected health information (in accordance with national and local patient privacy regulations), except to the extent that surrogate consents and assents are obtained in accordance with national and local laws and regulations. For clarity, the surrogate consents and assents may include, but are not limited to the following: court-appointed guardians, healthcare proxies, durable powers of attorney, or family members/next-of-kin.
- Part 1 and 2: Major surgery within 4 weeks before the assignment of study treatment.
- Part 1 and 2: Vaccination with a live vaccine within 4 weeks before the assignment of study treatment. See protocol for details on COVID 19 vaccination
- Part 1 and 2: Concurrent participation in another therapeutic clinical trial.
- Part 1 and 2: Positive test result for COVID-19 as determined by antigen testing or polymerase chain reaction (PCR) testing by a licensed method within 4 weeks before the assignment of study treatment.
- Part 1 and 2: Unwilling or unable to participate in all required study evaluations and procedures.
- Part 1 and 2: Active granulomatous infection before the assignment of study treatment; nontuberculous mycobacterial infection or opportunistic infection requiring hospitalization or parenteral antimicrobial treatment within 1 year before the assignment of study treatment.
- Part 1 and 2: Any conditions that in the opinion of the investigator, will either alone or in combination (see protocol for the full list)
- Part 1 and 2: Any of the following conditions within 14 days before the assignment of study treatment: Part 1 and 2: Alanine aminotransferase ≥ 3 x the upper limit of normal (ULN). Aspartate aminotransferase ≥ 3 x ULN. Total bilirubin ≥ 2 x ULN.
- Part 1 only: Hypersensitivity to zanubrutinib, or its formulation excipients
- Part 1 and 2: Type 1 or 2 diabetes mellitus with hemoglobin A1c (HbA1c) ≥ 7% at screening.
- Part 1 only: Evidence of ≥ 50% reduction in 24-hour urine protein within 12 weeks before the assignment of zanubrutinib.
- Part 1 and 2: Severe renal disease as determined by rapid decline in eGFR (defined as > 15 mL/min/1.73 m2 within 24 weeks prior to randomization, not otherwise explained)
- Part 1 and 2: In the absence of colony-stimulating factor or blood transfusion, any of the following within 14 days before the assignment of study treatment: • hemoglobin ≤ 80 g/L (8.0 g/dL), • platelet count ≤ 100 x 10^9/L (100,000 cells/mm³), • white blood cell count ≤ 2.0 x 10^9/L (2,000 cells/mm³), • neutrophils ≤ 1.5 x 10^9/L (1500 cells/mm³), • CD4+ T cell count ≤ 0.4 x 10^9/L (400 cells/mm³)
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Czechia | Not Recruiting | 18 Jan 2024 | 4 |
 Italy | Not Recruiting | 18 Jan 2024 | 2 |
 Poland | Not Recruiting | 18 Jan 2024 | 9 |
 Spain | Not Recruiting | 18 Jan 2024 | 6 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Zanubrutinib | Test | CAPSULE | ORAL | 320 | 64 | PRD4470763 |
TACROLIMUS | Comparator | — | ORAL | 0.15 | 64 | SUB10797MIG |