Rituximab Combined With Cyclosporine Versus Rituximab Alone in the Treatment of iMN

Sponsor

Peking Union Medical College Hospital (Other)

Overall Status

Recruiting

CT.gov ID

NCT04743739

Collaborator

Beijing Tongren Hospital (Other), Chinese Academy of Medical Sciences, Fuwai Hospital (Other), The Luhe Teaching Hospital of the Capital Medical University (Other), The Seventh Affiliated Hospital of Sun Yat-sen University (Other), First Affiliated Hospital of Xinjiang Medical University (Other), Nanyang Nanshi Hospital of Henan University (Other), Shanghai Fosun Pharmaceutical Industrial Development Co. Ltd. (Industry)

126

Enrollment

Locations

Arms

46.6

Anticipated Duration (Months)

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The primary objective of this study is to determine whether or not cyclosporine (CsA) combined with RTX is more effective than RTX alone in the treatment of idiopathic membranous nephropathy (iMN).

Condition or Disease	Intervention/Treatment	Phase
Idiopathic Membranous Nephropathy	Drug: Rituximab Drug: cyclosporine	Phase 3

Detailed Description

To date, the first-line immunosuppressive therapy of iMN includes corticosteroids combined with cyclophosphamide or Rituximab (RTX) which has been used more and more widely due to superior safety profiles. But the long term remission rate of RTX monotherapy is only 60% and it takes effect relatively slowly.

2 pilot studies reported that the combination therapy of cyclosporine (CsA) and RTX had better efficacy for inducing remission for iMN, with the long term remission rate up to 85%. CsA and RTX may have synergistic effect in the treatment of iMN because they have different time of action and different effects on the immune system and podocytes.

Based on the previous rationale, the investigators designed this trial to determine whether combination of CsA and RTX is more effective than RTX alone in the treatment of iMN.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

126 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Multicenter Randomized Controlled Trial of Rituximab Combined With Cyclosporine Versus Rituximab Alone in the Treatment of Idiopathic Membranous Nephropathy

Actual Study Start Date :

Apr 14, 2021

Anticipated Primary Completion Date :

Mar 1, 2023

Anticipated Study Completion Date :

Mar 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Rituximab monotherapy Rituximab 1000mg I.V. on Days 1 and 181, and will be retreated or not on Days 15 and 195 according to the CD19+ B cells count.	Drug: Rituximab Rituximab 1000mg, I.V. on Days 1 and 181, and will be retreated or not at Days 15 and 195 according to the CD19+ B cell count. Other Names: CD20 antibody
Experimental: Rituximab combined with cyclosporine Rituximab 1000mg I.V. on Days 1 and 181, and will be retreated or not on Days 15 and 195 according to CD19+ B cells count. cyclosporine (CsA) will be started at a dose of 3mg/kg/day p.o. divided into 2 equal doses given at 12 hour intervals. Doses of CsA will be adjusted according to the blood levels of CsA. CsA will be tapered after 6 months and discontinued over a 3 month period.	Drug: Rituximab Rituximab 1000mg, I.V. on Days 1 and 181, and will be retreated or not at Days 15 and 195 according to the CD19+ B cell count. Other Names: CD20 antibody Drug: cyclosporine cyclosporine (CsA) will be started at a dose of 3mg/kg/d and adjusted according to the blood levels of the CsA. CsA will be tapered after 6 months and discontinued over a three month period. Other Names: CsA

Arm

Intervention/Treatment

Active Comparator: Rituximab monotherapy

Rituximab 1000mg I.V. on Days 1 and 181, and will be retreated or not on Days 15 and 195 according to the CD19+ B cells count.

Drug: Rituximab

Rituximab 1000mg, I.V. on Days 1 and 181, and will be retreated or not at Days 15 and 195 according to the CD19+ B cell count.

Other Names:

CD20 antibody

Experimental: Rituximab combined with cyclosporine

Rituximab 1000mg I.V. on Days 1 and 181, and will be retreated or not on Days 15 and 195 according to CD19+ B cells count. cyclosporine (CsA) will be started at a dose of 3mg/kg/day p.o. divided into 2 equal doses given at 12 hour intervals. Doses of CsA will be adjusted according to the blood levels of CsA. CsA will be tapered after 6 months and discontinued over a 3 month period.

Drug: Rituximab

Rituximab 1000mg, I.V. on Days 1 and 181, and will be retreated or not at Days 15 and 195 according to the CD19+ B cell count.

Other Names:

CD20 antibody

Drug: cyclosporine

cyclosporine (CsA) will be started at a dose of 3mg/kg/d and adjusted according to the blood levels of the CsA. CsA will be tapered after 6 months and discontinued over a three month period.

Other Names:

CsA

Outcome Measures

Primary Outcome Measures

complete remission (CR) or partial remission (PR) at 24 month [24 months after randomization]
complete or partial remission at 24 month. complete remission is defined as urine protein≤0.5g/24h and serum albumin≥3.5g/dl. Partial remission is defined as reduction in baseline urine protein ≥50% plus urine protein≤3.5g/24h but >0.5g/24h

Secondary Outcome Measures

complete remission (CR) or partial remission (PR) on 6 month, 12 month, 18 month [6, 12, 18 months after randomization]
complete or partial remission on month 6, 12 and 18
complete remission (CR) on 6, 12, 18, 24 month [6, 12, 18, 24 months after randomization]
complete remission on month 6, 12, 18 and 24
Time to complete remission (CR) or partial remission (PR) [from date of randomization until the date of first remission, assessed up to 24 months]
Time to complete or partial remission
Change of estimated glomerular filtration rate (eGFR) [24 months]
Change of eGFR from baseline to 24 months
Serum creatinine increase≥50 percent from baseline [24 months]
proportion of patients with increase of serum creatinine ≥50 percent from baseline
Proportion of patients with relapse [12，18，24 months]
Rate of relapse. Relapse is defined as development of nephrotic range proportion of patients with relapse. Relapse is defined as development of proteinuria>3.5g/24h following CR or PR.
Anti-PLA2R titer [baseline and 3, 6, 9, 12, 18, 24 months]
Auto-antibodies to the M-type phospholipase A2 receptor(PLA2R)
The number of CD19+B cells [baseline and 3, 6, 9, 12, 18, 24 months]
CD19+ B cells
Quality of life measured by kidney disease and quality of life (KDQOL-36) [baseline, 12 and 24 month]
KDQOL-36 includes 36 questions which are scored positively (higher score indicating better quality of life) on a 0-100 scale using developer-recommended scoring.
Adverse events [through study completion until 24 months]
adverse events

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

idiopathic MN with or without diagnostic biopsy
Female, must be post-menopausal, sterile or have effective method of contraception
must be off steroid or mycophenolate mofetil for >1 month and alkylating agents for > 6 months
Angiotensin-converting-enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) for ≥3 months prior to randomization with controlled blood pressure or if patients is intolerant to ACEI/ARB
proteinuria ≥4g/24h using the average from two 24-hour urine samples collected within 2 weeks of each other, and decreased ≤50% from baseline.
estimated glomerular filtration rate (eGFR) ≥40ml/min/1.73m2

Exclusion Criteria:

presence of active infection or a secondary cause of MN
diabetes mellitus: to exclude proteinuria secondary to diabetic nephropathy.
pregnancy or breast feeding
history of resistance to CsA or other calcineurin inhibitors(CNI), RTX or alkylating agents.
Patients who previously achieved remission after treatment of CNI, RTX or alkylating agents but relapsed off CNI after 3 months, or relapsed off RTX or alkylating agents after 6 months, are eligible.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Fuwai Hospital, Chinese Academy of Medical Sciences	Beijing	Beijing	China	100037
2	Beijing Tongren Hospital， Capital Medical University	Beijing	Beijing	China	100730
3	Peking Union Medical College Hospital	Beijing	Beijing	China	100730
4	Beijing Luhe Hospital, Capital Medical University	Beijing	Beijing	China	101149
5	Nanyang Nanshi Hospital, Henan University	Nanyang	Henan	China	473065
6	The Seventh Affiliated Hospital, Sun Yat-sen University	Shenzhen	Shenzhen	China
7	The First Affiliated Hospital of Xinjiang Medical University	Urumqi	Xinjiang	China	830054