OBINOTUZUMAB Versus Cyclophosphamide + Glucocorticoids in Primary Membranous Nephropathy(Blossom Study)

Phase 3

Recruiting

• Conditions: Primary Membranous Nephropathy
• Interventions: Drug: Cyclophosphamide (CTX); Drug: Glucocorticoids

• Registration Number: NCT06781944
• Lead Sponsor: Huashan Hospital

Brief Summary

This is a randomized, parallel group, active-controlled, open-label, Phase III study comparing the efficacy and safety of obinutuzumab versus cyclophosphamide combined with glucocorticoids in patients with primary membranous nephropathy (pMN). Approximately 144 patients with pMN who have been diagnosed by biopsy or serum anti-PLA2R antibody will be enrolled.

Compare obinutuzumab against cyclophosphamide combined with glucocorticoids in pMN patients. Based on the hypothesis of non-inferiority in terms of the primary endpoint.

Intervention: Intravenous infusion of 1,000 mg obinutuzumab at weeks 0, 2, 24 and 26 Comparator: Cyclical cyclophosphamide and glucocorticoids Methylprednisolone 500 mg iv will be given for 3 consecutive days at the start of month 1,3,5 and followed by prednisone 0.5mg/kg/d (max 40 mg/d) for 27 days.

Oral cyclophosphamide will be given for 30 days in month 2, 4, 6.11 / 68 The dosage is adjusted based on the age and renal function (rounded down to the nearest 25 mg, max 100 mg/day, Cyclophosphamide tablets should not be split; if necessary, alternating doses of 50 mg/day and 100 mg/day can be used)：

* 2.0 mg/kg/d in patients \< 65 years with eGFR ≥60ml/min

* 1.5 mg/kg/d in patients \< 65 years with eGFR\<60ml/min

* 1.5 mg/kg/d in patients ≥ 65 years with eGFR ≥60ml/min

* 1.0 mg/kg/d in patients ≥ 65 years with eGFR\<60ml/min Randomization: Patients will be stratified based on urine protein (24h UPCR \< 8 g/g or ≥ 8 g/g) and randomized in a 1:1 ratio to receive open-label treatment with either obinutuzumab or cyclophosphamide combined with glucocorticoids.

Detailed Description

Not available

Study Timeline

• Status Verified: 2024-10
• Study Start: 2024-10-23
• Study First Submitted: 2024-12-15
• Study First Submitted QC: 2025-01-13
• Last Update Submitted: 2025-01-13
• Study First Posted: 2025-01-17
• Last Update Posted: 2025-01-17
• Primary Completion: 2028-05-31
• Study Completion: 2028-05-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 144

Inclusion Criteria

• Aged 18～75 years (including 18 and 75)old at the time of signing Informed Consent Form
• pMN patients diagnosed according to renal biopsy (original biopsy needs to include light, immunofluorescence, and electron microscopy) within 5 years or serum anti-PLA2R antibody (≥14 RU/ml )
• 24-hour UPCR ≥ 4 g/g and serum albumin (sALB) < 30 g/L,despite being treated with ACEi and/or ARB for ≥ 6 months prior to screening, or 24-hour UPCR ≥ 5 g/g and sALB < 30 g/L , despite being treated with ACEi and/or ARB for ≥ 3 months prior to screening; or 24-hour UPCR ≥ 8 g/g and sALB < 25 g/L, despite being treated with ACEi and/or ARB for ≥ 1 month prior to screening,.
• eGFR ≥40 mL/min/1.73m2 (CKD-EPI), a renal biopsy is required to exclude renal damage due to other co-morbidities if eGFR <60mL/min/1.73 m2.
• Ability to comply with the study protocol, in the investigator's judgment

Exclusion Criteria

• Patients with a secondary cause of MN (e.g. hepatitis B, systemic lupus erythematosus, medications, malignancies)

• Type 1 or 2 diabetes mellitus

• eGFR <40 mL/min/1.73m2 (CKD-EPI) or dialysis or kidney transplantation

• Evidence of 50% reduction in proteinuria or serum anti-PLA2R antibody within 6 months prior to screening

• Pregnant or breastfeeding, or intending to become pregnant during the study or within 18 months after the final dose of obinutuzumab

• Women of childbearing potential, including those who have had a tubal ligation, must have a negative pregnancy test result within 1 day prior to infusion of study drug

• Women of childbearing age not willing to use contraception

• Active gastrointestinal ulcer

• Receipt of previous therapies as follows :

  • A history of obinutuzumab or alkylating agents (e.g. Cyclophosphamide )
  • Treatment with any biologic therapy including but not limited to ocrelizumab, ofatumumab，rituximab, belimumab, ustekinumab, anifrolumab, telitacicept, or Janus associated kinase (JAK) inhibitor, Bruton tyrosine kinase (BTK) or tyrosine kinase 2 (TYK2) inhibitor, tofacitinib, baricitinib, upadacitinib, filgotinib (investigational), ibrutinib, fenebrutinib (investigational) during 9 months prior to screening
  • Received glucocorticoids, mycophenolate mofetil or CNI within 3 months prior to screening
  • Treatment with any investigational agent within 28 days of screening or 5 half-lives of the investigational drug, whichever is longer
  • Receipt of a live vaccine during the 2 months prior to 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

• The patients using of SGLT2-i agents or GLP-1 agonist, non-steroidal MRA, may not be excluded, but the dose should be stable for ≥30 days prior to randomization

• Significant or uncontrolled medical disease which, in the investigator's opinion, would preclude patient participation

• HIV infection (Require negative HIV antibody test within 1 month prior to screening)

• Previous or existing syphilis infection (Require negative syphilis test within 1 month prior to screening)

• Any type of active infection, excluding nail bed fungal infections

• History of serious recurrent or chronic infection

• Active tuberculosis (TB) infection

  • Patients with latent TB are not exclusionary. But prophylactic treatment with Isoniazid should be started after the randomization for 6 months. For the patients allergic to isoniazid or the liver injury happens, levofloxacin could be used instead

• History of cancer, including solid tumors, hematological malignancies, and carcinoma in situ

• 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:

  • ntolerance or contraindication to oral or IV corticosteroids, cyclophosphamide
  • Lack of peripheral venous access

• Laboratory parameters

  • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 ✖ the upper limit of normal (ULN)
  • HbA1C≥6.5%
  • CD19+ B cells <5/μL
  • Neutrophils <1.5 ×103/μL
  • Positive hepatitis B surface antigen (HBsAg); patients who are HBsAg negative and hepatitis B core antibody positive with no detectable HBV DNA will be allowed into the study but will require regular HBV DNA monitoring （at least per 3 months) and start prophylactic use of Entecavir after the randomization
  • Positive hepatitis C-RNA or positive hepatitis C antibody
  • Hemoglobin < 9 g/dL
  • Platelet count <100,000/μL
  • Positive serum human chorionic gonadotropin measured at screening

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Obinutuzumab	Cyclophosphamide (CTX)	Intravenous infusion of 1,000 mg obinutuzumab at weeks 0, 2, 24 and 26.
Premedications	Glucocorticoids	The following premedication will be administered prior to all obinutuzumab infusions in all study periods. The administration of all premedication must be completed between 30 and 60 minutes prior to the obinutuzumab infusion: * Methylprednisolone 80 mg IV infusion and * Acetaminophen PO (650-1000 mg, or equivalent dose of a similar agent) and * Ebastine PO (10 mg, or equivalent dose of a similar agent).

Primary Outcome Measures

Name	Time	Method
The proportion of patients who achieve overall remission (OR) (Complete remission [CR] or artial remission[PR]) assessed by 24-hour urinary protein to creatinine ratio at Month 24	Month 24	Collect 24-hour urine from patients in the 24th month and measure the 24-hour urinary protein to creatinine ratio (24-hour UPCR) to evaluate the proportion of patients achieving total response (OR) (complete response \[CR\] or partial response \[PR\]).; CR is defined as a urinary protein-to-creatinine ratio (UPCR) ≤0.3 g/g (24-hour urine).; PR is defined as reduction of urinary protein-to-creatinine ratio (UPCR) (24-hour urine) from baseline ≥ 50% ,plus ≤3.5 g/g but \>0.3 g/g.

Secondary Outcome Measures

Name	Time	Method
The proportion of patients who achieve overall remission (OR) (Complete remission [CR] or artial remission[PR]) assessed by 24-hour urinary protein to creatinine ratio at Month 6	Month 6	Collect 24-hour urine from patients in the 6th month and measure the 24-hour urinary protein to creatinine ratio (24-hour UPCR) to evaluate the proportion of patients achieving total response (OR) (complete response \[CR\] or partial response \[PR\]).; * CR is defined as a urinary protein-to-creatinine ratio (UPCR) ≤0.3 g/g (24-hour urine).; * PR is defined as reduction of urinary protein-to-creatinine ratio (UPCR) (24-hour urine) from baseline ≥ 50% ,plus ≤3.5 g/g but \>0.3 g/g.
The proportion of patients who achieve overall remission (OR) (Complete remission [CR] or artial remission[PR]) assessed by 24-hour urinary protein to creatinine ratio at Month 12	Month 12	Collect 24-hour urine from patients in the 12th month and perform 24-hour urinary protein to creatinine ratio (24-hour UPCR) testing to evaluate the proportion of patients who achieve OR(Complete remission \[CR\] or artial remission\[PR\]) .; * CR is defined as a urinary protein-to-creatinine ratio (UPCR) ≤0.3 g/g (24-hour urine); * PR is defined as reduction of urinary protein-to-creatinine ratio (UPCR) (24-hour urine) from baseline ≥ 50% ,plus ≤3.5 g/g but \>0.3 g/g
The proportion of patients who achieve CR assessed by 24-hour urinary protein to creatinine ratio at Month 12	Month 12	Collect 24-hour urine from patients in the 12th month and measure the 24-hour urinary protein to creatinine ratio (24-hour UPCR) to evaluate the proportion of patients achieving CR.; · CR is defined as a urinary protein-to-creatinine ratio (UPCR) ≤0.3 g/g (24-hour urine).
The proportion of patients who achieve PR assessed by 24-hour urinary protein to creatinine ratio at Month 12	Month 12	Collect 24-hour urine from patients in the 12th month and measure the 24-hour urinary protein to creatinine ratio (24-hour UPCR) to evaluate the proportion of patients achieving PR.; * PR is defined as reduction of urinary protein-to-creatinine ratio (UPCR) (24-hour urine) from baseline ≥ 50% ,plus ≤3.5 g/g but \>0.3 g/g.
The proportion of patients who achieve overall remission (OR) (Complete remission [CR] or artial remission[PR]) assessed by 24-hour urinary protein to creatinine ratio at Month 18	Month 18	Collect 24-hour urine from patients in the 18th month and perform 24-hour urinary protein to creatinine ratio (24-hour UPCR) testing to evaluate the proportion of patients who achieve OR(Complete remission \[CR\] or artial remission\[PR\]) .; * CR is defined as a urinary protein-to-creatinine ratio (UPCR) ≤0.3 g/g (24-hour urine).; * PR is defined as reduction of urinary protein-to-creatinine ratio (UPCR) (24-hour urine) from baseline ≥ 50% ,plus ≤3.5 g/g but \>0.3 g/g.
The proportion of patients who achieve CR assessed by 24-hour urinary protein to creatinine ratio at Month 18	Month 18	Collect 24-hour urine from patients in the 12th month and measure the 24-hour urinary protein to creatinine ratio (24-hour UPCR) to evaluate the proportion of patients achieving CR.; · CR is defined as a urinary protein-to-creatinine ratio (UPCR) ≤0.3 g/g (24-hour urine).
The proportion of patients who achieve PR assessed by 24-hour urinary protein to creatinine ratio at Month 18	Month 18	Collect 24-hour urine from patients in the 18th month and measure the 24-hour urinary protein to creatinine ratio (24-hour UPCR) to evaluate the proportion of patients achieving PR.; · PR is defined as reduction of urinary protein-to-creatinine ratio (UPCR) (24-hour urine) from baseline ≥ 50% ,plus ≤3.5 g/g but \>0.3 g/g.
The proportion of patients who achieve CR assessed by 24-hour urinary protein to creatinine ratio at Month 24	Month 24	Collect 24-hour urine from patients in the 12th month and measure the 24-hour urinary protein to creatinine ratio (24-hour UPCR) to evaluate the proportion of patients achieving CR.; * CR is defined as a urinary protein-to-creatinine ratio (UPCR) ≤0.3 g/g (24-hour urine).
The proportion of patients who achieve PR assessed by 24-hour urinary protein to creatinine ratio at Month 24	Month 24	Collect 24-hour urine from patients in the 24th month and measure the 24-hour urinary protein to creatinine ratio (24-hour UPCR) to evaluate the proportion of patients achieving PR.; · PR is defined as reduction of urinary protein-to-creatinine ratio (UPCR) (24-hour urine) from baseline ≥ 50% ,plus ≤3.5 g/g but \>0.3 g/g.
The proportion of patients who achieve immunological remission (serum anti-PLA2R antibody < 2 RU/ml) assessed by anti-PLA2R at Month 3	Month 3	Immunological remission：serum anti-PLA2R antibody \< 2 RU/ml
The proportion of patients who achieve immunological remission (serum anti-PLA2R antibody < 2 RU/ml) assessed by anti-PLA2R at Month 6	Month 6	Immunological remission:serum anti-PLA2R antibody \< 2 RU/ml.
The proportion of patients who achieve immunological remission (serum anti-PLA2R antibody < 2 RU/ml) assessed by anti-PLA2R at Month 12	Month 12	Immunological remission:serum anti-PLA2R antibody \< 2 RU/ml.
The proportion of patients who achieve immunological remission (serum anti-PLA2R antibody < 2 RU/ml) assessed by anti-PLA2R at Month 18	Month 18	Immunological remission:serum anti-PLA2R antibody \< 2 RU/ml.
The proportion of patients who achieve immunological remission (serum anti-PLA2R antibody < 2 RU/ml) assessed by anti-PLA2R at Month 24	Month 24	Immunological remission:serum anti-PLA2R antibody \< 2 RU/ml.
Time from baseline to CR	ASAP	CR is defined as a urinary protein-to-creatinine ratio (UPCR) ≤0.3 g/g (24-hour urine).
Time from baseline to PR	ASAP	PR is defined as reduction of urinary protein-to-creatinine ratio (UPCR) (24-hour urine) from baseline ≥ 50% ,plus ≤3.5 g/g but \>0.3 g/g.
Time from baseline to immunological remission	ASAP	Immunological remission:serum anti-PLA2R antibody \< 2 RU/ml.
The proportion of patients who relapse by Month 12	Month 12	Relapse is defined as an increase in the UPCR to \> 3.5 g/g 24 hours after achievement of a CR or PR . For patients achieving PR, a concomitant increase in UPCR \> 50% (50% increase using the lowest value of the 24-hour UPCR during PR as the baseline) or, in the opinion of the investigator (after consulting with the medical monitor), additional or altered immunosuppressive therapy is required.
The proportion of patients who relapse by Month 18	Month 18	Relapse is defined as an increase in the UPCR to \> 3.5 g/g 24 hours after achievement of a CR or PR . For patients achieving PR, a concomitant increase in UPCR \> 50% (50% increase using the lowest value of the 24-hour UPCR during PR as the baseline) or, in the opinion of the investigator (after consulting with the medical monitor), additional or altered immunosuppressive therapy is required.
The proportion of patients who relapse by Month 24	Month 24	Relapse is defined as an increase in the UPCR to \> 3.5 g/g 24 hours after achievement of a CR or PR . For patients achieving PR, a concomitant increase in UPCR \> 50% (50% increase using the lowest value of the 24-hour UPCR during PR as the baseline) or, in the opinion of the investigator (after consulting with the medical monitor), additional or altered immunosuppressive therapy is required.
The proportion of patients who meet the criteria for rescue therapy by Month 24	Month 24	For the patients who do not achieve either PR/CR or the rescue criteria at month 12, will receive the rescue evaluation with UPCR at month 15 , 18 and 21. During the period from month 12 to month 24, the patients will receive the rescue therapy and enter the rescue follow up throughout the study period once the rescue criteria is met.; Rescue criteria： Month 12 and 15：24-hour UPCR \>3.5 g/g and \<30% reduction from baseline hour UPCR \>3.5 g/g and \<30% reduction from baseline.; Month 18 and 21：24-hour UPCR \>3.5 g/g and \<50% reduction from baseline. Month 12 ～ 24：Relapse, defined as the recurrence of UPCR \>3.5 g/g (24-hour collection) following a CR or a PR.
The proportion of patients with a ≥50%, 40%, 30% decrease in eGFR(CKD-EPI) from baseline at Month 12	Month 12	CKD-EPI formula：GFR = 141 × min(Scr/κ, 1)\^α × max(Scr/κ, 1)\^-1.209 × 0.993\^Age × 1.018 \[if female\] × 1.159 \[if black\].
The proportion of patients with a ≥50%, 40%, 30% decrease in eGFR(CKD-EPI) from baseline at Month 24	Month 24	CKD-EPI formula：GFR = 141 × min(Scr/κ, 1)\^α × max(Scr/κ, 1)\^-1.209 × 0.993\^Age × 1.018 \[if female\] × 1.159 \[if black\].
Effect of treatment on renal function, as assessed by the slope of eGFR (CKD-EPI) from baseline to Month 12	Month 12	CKD-EPI formula：GFR = 141 × min(Scr/κ, 1)\^α × max(Scr/κ, 1)\^-1.209 × 0.993\^Age × 1.018 \[if female\] × 1.159 \[if black\].
Effect of treatment on renal function, as assessed by the slope of eGFR (CKD-EPI) from baseline to Month 24	Month 24	CKD-EPI formula：GFR = 141 × min(Scr/κ, 1)\^α × max(Scr/κ, 1)\^-1.209 × 0.993\^Age × 1.018 \[if female\] × 1.159 \[if black\].
eGFR(CKD-EPI) at Month 12	Month 12	CKD-EPI formula：GFR = 141 × min(Scr/κ, 1)\^α × max(Scr/κ, 1)\^-1.209 × 0.993\^Age × 1.018 \[if female\] × 1.159 \[if black\].
eGFR(CKD-EPI) at Month 24	Month 24	CKD-EPI formula：GFR = 141 × min(Scr/κ, 1)\^α × max(Scr/κ, 1)\^-1.209 × 0.993\^Age × 1.018 \[if female\] × 1.159 \[if black\].
Time to relapse after CR or PR by month 24	Month 24	CR is defined as a urinary protein-to-creatinine ratio (UPCR) ≤0.3 g/g (24-hour urine).; PR is defined as reduction of urinary protein-to-creatinine ratio (UPCR) (24-hour urine) from baseline ≥ 50% ,plus ≤3.5 g/g but \>0.3 g/g.; For the patients who do not achieve either PR/CR or the rescue criteria at month 12, will receive the rescue evaluation with UPCR at month 15 , 18 and 21. During the period from month 12 to month 24, the patients will receive the rescue therapy and enter the rescue follow up throughout the study period once the rescue criteria is met.; Rescue criteria： * Month 12 and 15：24-hour UPCR \>3.5 g/g and \<30% reduction from baseline hour UPCR \>3.5 g/g and \<30% reduction from baseline.; * Month 18 and 21：24-hour UPCR \>3.5 g/g and \<50% reduction from baseline.; * Month 12 ～ 24：Relapse, defined as the recurrence of UPCR \>3.5 g/g (24-hour collection) following a CR or a PR.
Scores based on EQ-5D-5L questionnaire indicators at baseline and months 6, 12, 18 and 24	Baseline and months 6, 12, 18 and 24	EuroQol 5-Dimension Questionnaire, 5-Level Version (EQ-5D-5L)

Trial Locations

Locations (1)

Huashan Hospital, Fudan University; 🇨🇳 Shanghai, Shanghai, China