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

Primary Purpose

Idiopathic Membranous Nephropathy

Status
Recruiting
Phase
Phase 3
Locations
China
Study Type
Interventional
Intervention
Rituximab
cyclosporine
Sponsored by
Peking Union Medical College Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Idiopathic Membranous Nephropathy focused on measuring Rituximab, cyclosporine, idiopathic membranous nephropathy

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept 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.

Sites / Locations

  • Fuwai Hospital, Chinese Academy of Medical Sciences
  • Beijing Tongren Hospital， Capital Medical University
  • Peking Union Medical College HospitalRecruiting
  • Beijing Luhe Hospital, Capital Medical University
  • Nanyang Nanshi Hospital, Henan University
  • The Seventh Affiliated Hospital, Sun Yat-sen University
  • The First Affiliated Hospital of Xinjiang Medical University

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Rituximab monotherapy

Rituximab combined with cyclosporine

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

complete remission (CR) or partial remission (PR) at 24 month
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
complete or partial remission on month 6, 12 and 18
complete remission (CR) on 6, 12, 18, 24 month
complete remission on month 6, 12, 18 and 24
Time to complete remission (CR) or partial remission (PR)
Time to complete or partial remission
Change of estimated glomerular filtration rate (eGFR)
Change of eGFR from baseline to 24 months
Serum creatinine increase≥50 percent from baseline
proportion of patients with increase of serum creatinine ≥50 percent from baseline
Proportion of patients with relapse
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
Auto-antibodies to the M-type phospholipase A2 receptor(PLA2R)
The number of CD19+B cells
CD19+ B cells
Quality of life measured by kidney disease and quality of life (KDQOL-36)
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
adverse events

Full Information

First Posted
January 30, 2021
Last Updated
May 16, 2021
Sponsor
Peking Union Medical College Hospital
Collaborators
Beijing Tongren Hospital, Chinese Academy of Medical Sciences, Fuwai Hospital, The Luhe Teaching Hospital of the Capital Medical University, The Seventh Affiliated Hospital of Sun Yat-sen University, First Affiliated Hospital of Xinjiang Medical University, Nanyang Nanshi Hospital of Henan University, Shanghai Fosun Pharmaceutical Industrial Development Co. Ltd.
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1. Study Identification

Unique Protocol Identification Number
NCT04743739
Brief Title
Rituximab Combined With Cyclosporine Versus Rituximab Alone in the Treatment of iMN
Official Title
A Multicenter Randomized Controlled Trial of Rituximab Combined With Cyclosporine Versus Rituximab Alone in the Treatment of Idiopathic Membranous Nephropathy
Study Type
Interventional

2. Study Status

Record Verification Date
May 2021
Overall Recruitment Status
Recruiting
Study Start Date
April 14, 2021 (Actual)
Primary Completion Date
March 2023 (Anticipated)
Study Completion Date
March 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Peking Union Medical College Hospital
Collaborators
Beijing Tongren Hospital, Chinese Academy of Medical Sciences, Fuwai Hospital, The Luhe Teaching Hospital of the Capital Medical University, The Seventh Affiliated Hospital of Sun Yat-sen University, First Affiliated Hospital of Xinjiang Medical University, Nanyang Nanshi Hospital of Henan University, Shanghai Fosun Pharmaceutical Industrial Development Co. Ltd.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No

5. 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).
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Idiopathic Membranous Nephropathy
Keywords
Rituximab, cyclosporine, idiopathic membranous nephropathy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
126 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Rituximab monotherapy
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Rituximab combined with cyclosporine
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Rituximab
Other Intervention Name(s)
CD20 antibody
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
cyclosporine
Other Intervention Name(s)
CsA
Intervention Description
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.
Primary Outcome Measure Information:
Title
complete remission (CR) or partial remission (PR) at 24 month
Description
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
Time Frame
24 months after randomization
Secondary Outcome Measure Information:
Title
complete remission (CR) or partial remission (PR) on 6 month, 12 month, 18 month
Description
complete or partial remission on month 6, 12 and 18
Time Frame
6, 12, 18 months after randomization
Title
complete remission (CR) on 6, 12, 18, 24 month
Description
complete remission on month 6, 12, 18 and 24
Time Frame
6, 12, 18, 24 months after randomization
Title
Time to complete remission (CR) or partial remission (PR)
Description
Time to complete or partial remission
Time Frame
from date of randomization until the date of first remission, assessed up to 24 months
Title
Change of estimated glomerular filtration rate (eGFR)
Description
Change of eGFR from baseline to 24 months
Time Frame
24 months
Title
Serum creatinine increase≥50 percent from baseline
Description
proportion of patients with increase of serum creatinine ≥50 percent from baseline
Time Frame
24 months
Title
Proportion of patients with relapse
Description
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.
Time Frame
12，18，24 months
Title
Anti-PLA2R titer
Description
Auto-antibodies to the M-type phospholipase A2 receptor(PLA2R)
Time Frame
baseline and 3, 6, 9, 12, 18, 24 months
Title
The number of CD19+B cells
Description
CD19+ B cells
Time Frame
baseline and 3, 6, 9, 12, 18, 24 months
Title
Quality of life measured by kidney disease and quality of life (KDQOL-36)
Description
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.
Time Frame
baseline, 12 and 24 month
Title
Adverse events
Description
adverse events
Time Frame
through study completion until 24 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Sanxi Ai, Doctor
Phone
18811054896
Email
sanxiai@163.com
First Name & Middle Initial & Last Name or Official Title & Degree
Yan Qin, Doctor
Email
qinyanbeijing@126.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Yan Qin, Doctor
Organizational Affiliation
Peking Union Medical College Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Fuwai Hospital, Chinese Academy of Medical Sciences
City
Beijing
State/Province
Beijing
ZIP/Postal Code
100037
Country
China
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jianfang Cai
Facility Name
Beijing Tongren Hospital， Capital Medical University
City
Beijing
State/Province
Beijing
ZIP/Postal Code
100730
Country
China
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Guojuan Zhang
Facility Name
Peking Union Medical College Hospital
City
Beijing
State/Province
Beijing
ZIP/Postal Code
100730
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sanxi Ai
Phone
18811054896
Email
sanxiai@163.com
First Name & Middle Initial & Last Name & Degree
Yan Qin
Facility Name
Beijing Luhe Hospital, Capital Medical University
City
Beijing
State/Province
Beijing
ZIP/Postal Code
101149
Country
China
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Zhongxin Li
Facility Name
Nanyang Nanshi Hospital, Henan University
City
Nanyang
State/Province
Henan
ZIP/Postal Code
473065
Country
China
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Mingwei Zhu
Facility Name
The Seventh Affiliated Hospital, Sun Yat-sen University
City
Shenzhen
State/Province
Shenzhen
Country
China
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Zhihua Zheng
Facility Name
The First Affiliated Hospital of Xinjiang Medical University
City
Urumqi
State/Province
Xinjiang
ZIP/Postal Code
830054
Country
China
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Suhua Li

12. IPD Sharing Statement

Plan to Share IPD
No
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Rituximab Combined With Cyclosporine Versus Rituximab Alone in the Treatment of iMN

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