| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Primary Membranous Nephropathy (pMN) |
|
| E.1.1.1 | Medical condition in easily understood language |
| pMN is a kidney-specific, autoimmune glomerular disease that presents with increased protein in the urine associated with an injury in glomeruli |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027170 |
| E.1.2 | Term | Membranous nephropathy |
| E.1.2 | System Organ Class | 100000004857 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| •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 |
|
| E.2.2 | Secondary objectives of the trial |
•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
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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
|
|
| E.4 | Principal 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 IV corticosteroids and premedications
oIntolerance or hypersensitivity to tacrolimus and its excipients
oLack of peripheral venous access
•Laboratory parameters
oaspartate aminotransferase or alanine transaminase > 2.5 ×the upper limit of normal (ULN)
oAmylase or lipase > 2 × ULN
oNeutrophils < 1.5 × 10^3/micro L
oCD19+ B cells < 5/micro L
oPositive for hepatitis B surface antigen (HBsAg) at screening
oPositive hepatitis C virus antibody at screening
oHemoglobin < 9 g/dL
oPlatelet count < 75,000/micro L
oPositive serum human chorionic gonadotropin measured at screening |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1.The proportion of patients who achieve a CR at Week 104 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | 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 |
|
| E.5.2.1 | 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) |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 22 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Peru |
| Ukraine |
| Brazil |
| Canada |
| China |
| Israel |
| Russian Federation |
| Turkey |
| United States |
| France |
| Italy |
| Poland |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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