Clinical trial NCT06781944: OBINOTUZUMAB Versus Cyclophosphamide + Glucocorticoids in Primary Membranous Nephropathy(Blossom Study)
Official title: A Multicenter, Open- Label, Randomized, Clinical Trial to Investigate the Efficacy and Safety of OBINOTUZUMAB Versus Cyclophosphamide Combined with Glucocorticoids in Patients with Primary Membranous Nephropathy (Blossom Study)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Primary Membranous Nephropathy
Lead sponsor: Huashan Hospital
Sponsor class: OTHER
First posted: 2025-01-17
Enrollment: 144
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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. 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
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: 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
timeFrame: Month 24
Secondary outcomes:
measure: 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
timeFrame: Month 6
measure: 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
timeFrame: Month 12
measure: The proportion of patients who achieve CR assessed by 24-hour urinary protein to creatinine ratio at Month 12
timeFrame: Month 12
measure: The proportion of patients who achieve PR assessed by 24-hour urinary protein to creatinine ratio at Month 12
timeFrame: Month 12
measure: 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
timeFrame: Month 18
measure: The proportion of patients who achieve CR assessed by 24-hour urinary protein to creatinine ratio at Month 18
timeFrame: Month 18
measure: The proportion of patients who achieve PR assessed by 24-hour urinary protein to creatinine ratio at Month 18
timeFrame: Month 18
measure: The proportion of patients who achieve CR assessed by 24-hour urinary protein to creatinine ratio at Month 24
timeFrame: Month 24
measure: The proportion of patients who achieve PR assessed by 24-hour urinary protein to creatinine ratio at Month 24
timeFrame: Month 24
measure: The proportion of patients who achieve immunological remission (serum anti-PLA2R antibody < 2 RU/ml) assessed by anti-PLA2R at Month 3
timeFrame: Month 3
measure: The proportion of patients who achieve immunological remission (serum anti-PLA2R antibody < 2 RU/ml) assessed by anti-PLA2R at Month 6
timeFrame: Month 6
measure: The proportion of patients who achieve immunological remission (serum anti-PLA2R antibody < 2 RU/ml) assessed by anti-PLA2R at Month 12
timeFrame: Month 12
measure: The proportion of patients who achieve immunological remission (serum anti-PLA2R antibody < 2 RU/ml) assessed by anti-PLA2R at Month 18
timeFrame: Month 18
measure: The proportion of patients who achieve immunological remission (serum anti-PLA2R antibody < 2 RU/ml) assessed by anti-PLA2R at Month 24
timeFrame: Month 24
measure: Time from baseline to CR
timeFrame: ASAP
measure: Time from baseline to PR
timeFrame: ASAP
measure: Time from baseline to immunological remission
timeFrame: ASAP
measure: The proportion of patients who relapse by Month 12
timeFrame: Month 12
measure: The proportion of patients who relapse by Month 18
timeFrame: Month 18
measure: The proportion of patients who relapse by Month 24
timeFrame: Month 24
measure: The proportion of patients who meet the criteria for rescue therapy by Month 24
timeFrame: Month 24
measure: The proportion of patients with a ≥50%, 40%, 30% decrease in eGFR(CKD-EPI) from baseline at Month 12
timeFrame: Month 12
measure: The proportion of patients with a ≥50%, 40%, 30% decrease in eGFR(CKD-EPI) from baseline at Month 24
timeFrame: Month 24
measure: Effect of treatment on renal function, as assessed by the slope of eGFR (CKD-EPI) from baseline to Month 12
timeFrame: Month 12
measure: Effect of treatment on renal function, as assessed by the slope of eGFR (CKD-EPI) from baseline to Month 24
timeFrame: Month 24
measure: eGFR(CKD-EPI) at Month 12
timeFrame: Month 12
measure: eGFR(CKD-EPI) at Month 24
timeFrame: Month 24
measure: Time to relapse after CR or PR by month 24
timeFrame: Month 24
measure: Scores based on EQ-5D-5L questionnaire indicators at baseline and months 6, 12, 18 and 24
timeFrame: Baseline and months 6, 12, 18 and 24
Other outcomes:
measure: Change of anti-PLA2R antibody from baseline to Month 3, 6, 9, 12, 18 and 24 in anti-PLA2R antibody positive patients
timeFrame: Month 3, 6, 9, 12, 18 and 24
measure: Change of 24-hour UPCR from baseline to Month 3, 6, 9, 12, 18 and 24
timeFrame: Month 3, 6, 9, 12, 18 and 24
measure: Change of serum albumin(sALB) from baseline to Month 3, 6, 9, 12, 18 and 24
timeFrame: Month 3, 6, 9, 12, 18 and 24
measure: Time from immunological remission to clinical remission (PR or CR)
timeFrame: Month 24
measure: The relationship between CR or PR (at Month 12 ) and immunological remission (anti-PLA2R antibody < 2RU/ml) status at Month 3 and 6
timeFrame: Month 12
measure: The relationship between CR or PR (at Month 24 ) and immunological remission (anti-PLA2R antibody < 2RU/ml) status at Month 3 and 6
timeFrame: Month 24
measure: The relationship between CR or PR( at Month 12 )and baseline anti-PLA2R antibody titer (low/medium/high)
timeFrame: Month 12
measure: The relationship between CR or PR( at Month 24 )and baseline anti-PLA2R antibody titer (low/medium/high)
timeFrame: Month 24
measure: Proportion of participants achieving CD19+ B cell depletion specified time points
timeFrame: Month 24
measure: Proportion of participants achieving CD19+ B cell depletion specified time points B-cell peripheral blood depletion
timeFrame: Month 24
measure: The relationship between CR and the B cell recovery
timeFrame: Month 24
measure: The relationship between PR and the B cell recovery
timeFrame: Month 24
measure: The relationship between relapse and B cell recovery
timeFrame: Month 24
Locations:
city: Shanghai
country: China
facility: Huashan Hospital, Fudan University
state: Shanghai
Study officials:
References: