A Study to Evaluate Efficacy and Safety of Obinutuzumab in Patients with Primary Membranous Nephropathy

• Register: EUCTR
• Last refreshed on: 2 April 2024
• Main ID: EUCTR2020-003233-38-PL
• Date of registration: 24/02/2021
• Prospective Registration: Yes
• Primary sponsor: F.Hoffmann-La Roche Ltd
• Public title: A Study to Evaluate Efficacy and Safety of Obinutuzumab in Patients with Primary Membranous Nephropathy
• Scientific title: A PHASE III, RANDOMIZED, OPEN-LABEL ACTIVE COMPARATOR-CONTROLLED MULTICENTER STUDY TO EVALUATE EFFICACY AND SAFETY OF OBINUTUZUMAB IN PATIENTS WITH PRIMARY MEMBRANOUS NEPHROPATHY
• Date of first enrolment: 13/04/2021
• Target sample size: 140
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2020-003233-38
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: yes Other specify the comparator: Tacrolimus Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Brazil, Canada, China, France, Israel, Italy, Peru, Poland, Russian Federation, Spain, Turkey, Ukraine, United States

Contacts

• Name: Trial Information Support Line-TISL
• Affiliation: F.Hoffmann-La Roche Ltd

• Name: Trial Information Support Line-TISL
• Affiliation: F.Hoffmann-La Roche Ltd

Key inclusion & exclusion criteria

Inclusion criteria:
•Age 18-75 years
•Diagnosis of 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
•Systolic blood pressure <= 140 mmHg and diastolic blood pressure <= 90 mmHg at screening
•eGFR >= 40 mL/min/1.73m2 or qualified endogenous creatinine clearance >= 40 mL/min/1.73m2 based on 24-hour urine collection during screening
•Patients who previously responded to calcineurin inhibitor (CNIs), rituximab, or alkylating agents with either a CR or partial remission and subsequently relapsed are eligible but require discontinuation of CNIs or alkylating agents for >= 6 months and rituximab for >= 9 months prior to screening
•For women of childbearing potential: agreement to remain abstinent or use adequate contraception during the treatment period and for 18 months after the final dose of obinutuzumab and for 28 days after the final dose of tacrolimus
•For men receiving tacrolimus: agreement to remain abstinent or use a condom, as defined below: With a female partner of childbearing potential or pregnant female partner, men must remain abstinent or use a condom during the treatment period and for 28 days after the final dose of tacrolimus to avoid exposing the embryo
•For patients enrolled in the extended China enrollment phase at China's sites: current resident of mainland China and of Chinese ancestry

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 121
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 9

Exclusion criteria:
•Patients with a secondary cause of MN
•Uncontrolled blood pressure, in the opinion of the investigator, during 3 months prior to screening
•Evidence of >= 50% reduction in proteinuria during the previous 6 months prior to randomization
•Receipt of renal replacement therapy
•Type 1 or 2 diabetes mellitus
•Pregnant or breastfeeding, or intending to become pregnant during the study or within 18 months after the final dose of obinutuzumab or 28 days after the final dose of tacrolimus
•History of resistance (no response) to CNIs or B-cell depleting antibodies
•Receipt of previous therapies as follows:
oTreatment with MMF or oral, intramuscular, or intravenous corticosteroids within 1 month prior to or during screening
oAny B-cell depleting therapy such as rituximab, ocrelizumab, or ofatumumab within 9 months prior to or during screening
oTreatment with cyclophosphamide or CNI within 6 months prior to or during screening
oTreatment with any biologic therapy such as belimumab, ustekinumab, or anifrolumab within 6 months prior to or during screening
oTreatment with an inhibitor of Janus-associated kinase, Bruton’s tyrosine kinase, or tyrosine kinase 2, including but not limited to tofacitinib, baricitinib, upadacitinib, filgotinib, ibrutinib, or fenebrutinib within 3 months prior to or during screening
oTreatment with any investigational agent within 28 days of screening or 5 drug-elimination half-lives of the investigational drug, whichever is longer
oReceipt of a live vaccine within 28 days prior to screening or during screening
•Thrombocytopenia, anemia, and/or coagulopathy with high risk for clinically significant bleeding or organ dysfunction or requiring plasmapheresis, intravenous immunoglobulin, or acute blood product transfusions
•Significant or uncontrolled medical disease which, in the investigator’s opinion, would preclude patient participation
•Known HIV infectionfor patients with unknown HIV status, HIV testing will be performed at the local level if required by local regulations or in accordance with local clinical practise
•Tuberculosis infection; testing for latent TB will be performed at screening if required by local regulations or in accordance with local
clinical practice. Latent TB after completion of appropriate treatment is not exclusionary.
•Known active infection of any kind, excluding fungal infection of the nail beds
•Any major episode of infection requiring hospitalization or treatment either with IV anti-infective treatments during the 2 months prior to or during screening or with oral anti-infective treatments during the 2 weeks prior to or during screening
•History of serious recurrent or chronic infection or progressive multifocal leukoencephalopathy
- History of cancer within the past 5 years, including solid tumors,
hematological malignancies, and carcinoma in situ, except non-melanomatous carcinomas of the skin that have been treated or excised and have resolved
•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, including:
oEvidence of intolerance, hypersensitivity to, or toxicity associated with tacrolimus prior to screening
oHistory of severe allergic or anaphylactic reactions to monoclonal antibodies or known hypersensitivity to any component of the obinutuzumab infusion
oIntolerance or contraindication to oral or I

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Primary Membranous Nephropathy (pMN)
MedDRA version: 21.1 Level: LLT Classification code 10027170 Term: Membranous nephropathy System Organ Class: 100000004857

Therapeutic area: Diseases [C] - Immune System Diseases [C20]

Intervention(s)

Trade Name: Gazyvaro
Product Name: Obinutuzumab
Product Code: RO5072759
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: OBINUTUZUMAB
CAS Number: 949142-50-1
Current Sponsor code: RO5072759
Other descriptive name: OBINUTUZUMAB/ GA101
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 25-

Product Name: Tacrolimus
Product Code: RO0485337
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Tacrolimus
CAS Number: 104987-11-3
Current Sponsor code: RO0485337
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 0.5-

Product Name: Tacrolimus
Product Code: RO0485337
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Tacrolimus
CAS Number: 104987-11-3
Current Sponsor code: RO0485337
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-

Product Name: Tacrolimus
Product Code: RO0485337
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Tacrolimus
CAS Number: 104987-11-3
Current Sponsor code: RO0485337
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 1-

Primary Outcome(s)

Main Objective: •To evaluate the efficacy of obinutuzumab compared with tacrolimus on the basis of the proportion of patients who achieve a complete remission (CR) at Week 104

Secondary Objective: •To evaluate the efficacy of obinutuzumab compared with tacrolimus on the basis of: achievement an overall remission at Week 104; achievement of CR at Week 76; meeting
escape criteria, or relapse after complete or partial remission; time to a sustained reduction of eGFR>=30% from baseline; mean change in T score from baseline in the Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue scale at Week 104; duration of CR; change in anti-PLA2R autoantibody titer from baseline to Week 52; mean change from baseline in the Patient-Reported Outcomes Measurement Information System (PROMIS) Global Assessment of Physical Health scale and Fatigue scale at Week 104, duration of CR
•To evaluate the safety of obinutuzumab compared with tacrolimus
•To characterize the pharmacodynamic effects of obinutuzumab in pMN patients
•To characterize the pharmacokinetics of obinutuzumab in the pMN population
•To evaluate the immune response to obinutuzumab

Timepoint(s) of evaluation of this end point: 1.At Week 104

Primary end point(s): 1.The proportion of patients who achieve a CR at Week 104

Secondary Outcome(s)

Secondary end point(s): 1.The proportion of patients who achieve an overall remission at Week 104
2.The proportion of patients who achieve CR at Week 76
3.Time to treatment failure, meeting escape criteria, or relapse after
complete or partial remission
4.Time to a sustained reduction of eGFR>=30% from baseline
5. Mean change in T-score from baseline in the Patient-Reported
Outcomes Measurement Information System (PROMIS) Fatigue scale at Week 104
6.Duration of CR
7. Change in anti-PLA2R autoantibody titer from Baseline to Week 52
8. Mean change from baseline in the Patient-Reported Outcomes
Measurement Information System (PROMIS) Global Assessment of
Physical Health scale at Week 104
9.Incidence and severity of adverse events, with severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0
10.Characterization of adverse events of special interest
11.Change from baseline in targeted vital signs
12.Change from baseline in targeted clinical laboratory test results
13. Serum concentrations of obinutuzumab at specified timepoints
14.Peripheral B-cell counts at specified timepoints
15.Prevalence of anti-drug antibodies (ADAs) to obinutuzumab at baseline and incidence of ADAs during the study

Timepoint(s) of evaluation of this end point: 1.At Week 104
2.At Week 76
3-4. Up to 8 years
5. From baseline to Week 104
6. Up to 8 years
7. From Baseline to Week 52
8. From Baseline to Week 104
9-10. Up to 8 years
11-13. Open label: Baseline, Weeks 2, 4, 12, 24, 26, 36, 52, 64, 76, 88,
104; Long-Term Follow-Up (LTFU): Week 117, 130, 143, 156, 169, 182,
195, 208, every 26 weeks thereafter (Q26W); escape treatment: Escape Weeks 0, 2, 4,12, 24, 26, 36, 52, 64, 76, 88, 104, 130, 156, 182, 208,Q26W (each assessment: unplanned visit, study discontinuation)
14-15. Open label: Baseline, Weeks 2, 4, 12, 24, 26, 36, 52, 64, 76, 88,
104; LTFU: Week 130, 156, 182, 208, Q26W; escape treatment: Escape Weeks 0, 2, 4, 12, 24, 36, 52, 76, 104, 130, 156, 182, 208, Q26W (each assessment: unplanned, safety follow up visit, study discontinuation)

Secondary ID(s)

WA41937

2020-003233-38-FR

Source(s) of Monetary Support

F. Hoffmann-La Roche Ltd

Ethics review

Status: Approved
Approval date: 13/04/2021
Contact: