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Multitarget Therapy for Idiopathic Membranous Nephropathy (MTIMN)

Primary Purpose

Efficacy

Status
Completed
Phase
Phase 4
Locations
China
Study Type
Interventional
Intervention
Prednisone, ciclosporin and mycophenolate mofetil
Ponticelli Regimen
Sponsored by
Beijing Friendship Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Efficacy

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Age: 18-70 years.
  • Body weight: 50-90 kg.
  • Patients with membranous nephropathy were eligible if their diagnosis was confirmed by renal biopsy, with the biopsy sample examined by light, immunofluorescence, and electron microscopy. Renal biopsy samples were reviewed by the two principal investigators and two renal pathologists.
  • IMN patients with moderate risk and have a decline of less than 50% in proteinuria despite renin-angiotensin system blockade for at least 6 months before randomization. OR, IMN patients with high risk or very high risk.
  • Serum albumin < 30 g/L.
  • eGFR by MDRD formula had to be ≥ 60 ml/min per 1.73 m2.

Exclusion criteria:

  • Secondary MN, pregnancy, breastfeeding, immunosuppressive treatment in the 3 preceding months, and active infectious disease.
  • Hepatitis B serology included Hbs antigen and Hbs and Hbc antibodies. Patients with active hepatitis B and those with past hepatitis B infection without anti-Hbs antibodies will be excluded.
  • Patients with reproductive demand will be excluded.

Sites / Locations

  • Beijing Friendship Hospital, Capital Medical University
  • Beijing Frienship Hospital, Capital Medical University

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Multitarget Therapy

Control

Arm Description

The combined therapy with prednisone, ciclosporin and mycophenolate mofetil.

Ponticelli Regimen

Outcomes

Primary Outcome Measures

The composite of complete or partial remission at 12 months
complete remission: proteinuria of no more than 0.3 g per 24 hours and a serum albumin level of at least 35 g per milliliter. Partial remission: a reduction in proteinuria of at least 50% from baseline plus final proteinuria between 0.3 g and 3.5 g per 24 hours regardless of creatinine clearance or the serum albumin level.

Secondary Outcome Measures

Composite of complete or partial remission at 6 months
complete remission: proteinuria of no more than 0.3 g per 24 hours and a serum albumin level of at least 35 g per milliliter. Partial remission: a reduction in proteinuria of at least 50% from baseline plus final proteinuria between 0.3 g and 3.5 g per 24 hours regardless of creatinine clearance or the serum albumin level.
Treatment failure
proteinuria decreased no more than 25% of baseline at month
adverse events
Advers events happened during study period
Relapse
Relapse during study period

Full Information

First Posted
June 7, 2020
Last Updated
February 2, 2022
Sponsor
Beijing Friendship Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT04424862
Brief Title
Multitarget Therapy for Idiopathic Membranous Nephropathy
Acronym
MTIMN
Official Title
Multitarget Therapy for Idiopathic Membranous Nephropathy
Study Type
Interventional

2. Study Status

Record Verification Date
February 2022
Overall Recruitment Status
Completed
Study Start Date
June 9, 2020 (Actual)
Primary Completion Date
February 3, 2021 (Actual)
Study Completion Date
February 3, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Beijing Friendship Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
Membranous nephropathy (MN) is one of the commonest causes of nephrotic syndrome in adults, idiopathic membranous nephropathy (IMN) accounts for 70%-80% of all MN patients. There is no standard specific treatment for IMN. Initial therapy should be supportive and involves restricting dietary protein and sodium intake, controlling blood pressure, hyperlipidemia, and edema. The best proven therapy for patients with IMN is combined use of corticosteroids and cyclophosphamide. However, there are some potential risk of other serious side effects associated with the use of cytotoxic agents, such as bone marrow toxicity, severe infections, gonadal dysfunction, and the long-term risk of malignancy. The ideal maintenance treatment scheme for patients with IMN requires not only a remission of nephrotic syndrome but also, fewer adverse effects. Some retrospective study suggested that multitarget therapy (prednisone+calcineurin inhibitors+mycophenolate mofetil) was effective for refractory IMN. However, we cannot get confirmed conclusion from the previous study due to the limitation of retrospective studies with small sample size. In this prospective multicenter randomized trial, we compared the efficacy between multitarget therapy and Ponticelli regimen. Trial Aims and Hypothesis The specific aims of this trial are to test the hypothesis that multitarget therapy is non-inferior to Ponticelli regimen in inducing long-term remission (CR or PR) of proteinuria in patients with IMN. that multitarget therapy reduces the number of relapses (efficacy in sustaining remission) and increases the time to relapse when compared with treatment with Ponticelli regimen. that multitarget therapy has a better side-effect profile when compared with treatment with Ponticelli regimen in patients with IMN. Methods: Patient Recruitment Inclusion and exclusion criteria are as follows. Inclusion Criteria: Age: 18-70 years. Body weight: 50-90 kg. Patients with membranous nephropathy were eligible if their diagnosis was confirmed by renal biopsy, with the biopsy sample examined by light, immunofluorescence, and electron microscopy. Renal biopsy samples were reviewed by the two principal investigators and two renal pathologists. IMN patients with moderate risk and have a decline of less than 50% in proteinuria despite renin-angiotensin system blockade for at least 6 months before randomization. OR, IMN patients with high risk or very high risk. Serum albumin < 30 g/L. eGFR by MDRD formula had to be ≥ 60 ml/min per 1.73 m2. Exclusion criteria: Secondary MN, pregnancy, breastfeeding, immunosuppressive treatment in the 3 preceding months, and active infectious disease. Hepatitis B serology included Hbs antigen and Hbs and Hbc antibodies. Patients with active hepatitis B and those with past hepatitis B infection without anti-Hbs antibodies will be excluded. Patients with reproductive demand will be excluded. Randomization and Treatment Groups Once all entry criteria have been satisfied and confirmed, patients will be randomized to treatment with multitarget therapy or Ponticelli regimen. Multitarget therapy: Combination with prednisone, ciclosporin and mycophenolate mofetil. Ponticelli regimen: Cyclical corticosteroid/alkylating-agent therapy for IMN. Outcomes Primary outcome: The primary clinical outcome was the composite of complete or partial remission at 12 months. Secondary outcome: the composite of complete or partial remission at 6 months; complete remission at 6 months; and adverse events, relapse.
Detailed Description
Membranous nephropathy (MN) is one of the commonest causes of nephrotic syndrome in adults, idiopathic membranous nephropathy (IMN) accounts for 70%-80% of all MN patients. There is no standard specific treatment for IMN. Initial therapy should be supportive and involves restricting dietary protein and sodium intake, controlling blood pressure, hyperlipidemia, and edema. The best proven therapy for patients with IMN is combined use of corticosteroids and cyclophosphamide. However, there are some potential risk of other serious side effects associated with the use of cytotoxic agents, such as bone marrow toxicity, severe infections, gonadal dysfunction, and the long-term risk of malignancy. The ideal maintenance treatment scheme for patients with IMN requires not only a remission of nephrotic syndrome but also, fewer adverse effects. Some retrospective study suggested that multitarget therapy (prednisone+calcineurin inhibitors+mycophenolate mofetil) was effective for refractory IMN. However, we cannot get confirmed conclusion from the previous study due to the limitation of retrospective studies with small sample size. In this prospective multicenter randomized trial, we compared the efficacy between multitarget therapy and Ponticelli regimen. Trial Aims and Hypothesis The specific aims of this trial are to test the hypothesis that multitarget therapy is non-inferior to Ponticelli regimen in inducing long-term remission (CR or PR) of proteinuria in patients with IMN. that multitarget therapy reduces the number of relapses (efficacy in sustaining remission) and increases the time to relapse when compared with treatment with Ponticelli regimen. that multitarget therapy has a better side-effect profile when compared with treatment with Ponticelli regimen in patients with IMN. Methods: Patient Recruitment Inclusion and exclusion criteria are as follows. Inclusion Criteria: Age: 18-70 years. Body weight: 50-90 kg. Patients with membranous nephropathy were eligible if their diagnosis was confirmed by renal biopsy, with the biopsy sample examined by light, immunofluorescence, and electron microscopy. Renal biopsy samples were reviewed by the two principal investigators and two renal pathologists. IMN patients with moderate risk and have a decline of less than 50% in proteinuria despite renin-angiotensin system blockade for at least 6 months before randomization. OR, IMN patients with high risk or very high risk. Serum albumin < 30 g/L. eGFR by MDRD formula had to be ≥ 60 ml/min per 1.73 m2. Exclusion criteria: Secondary MN, pregnancy, breastfeeding, immunosuppressive treatment in the 3 preceding months, and active infectious disease. Hepatitis B serology included Hbs antigen and Hbs and Hbc antibodies. Patients with active hepatitis B and those with past hepatitis B infection without anti-Hbs antibodies will be excluded. Patients with reproductive demand will be excluded. Randomization and Treatment Groups Once all entry criteria have been satisfied and confirmed, patients will be randomized to treatment with multitarget therapy or Ponticelli regimen. Multitarget therapy: The patients in the multitarget group continued to receive prednisone 1 mg/kg/d (maximum dosage 60mg/d) for 2 weeks and then tapered by 5mg per week. When reduced to 30mg/d, maintained for 1 month, and then tapered by 5 mg per month. When reduced to 20mg/d, maintained for 2 months, and then tapered by 2.5 mg per two-month. When reduced to 5 mg/d, maintained for 4 months. Mycophenolate mofetil (1 g/d for 6 months and then tapered to 0.75 g/d for another 12 months, and tapered 0.5g for another 12 months) Ciclosporin (initial dosage 100 mg/d, and adjusted the dosage to maintain trough concentration at 80-120 ng/mL. If the patients get complete remission during dosage adjustment period, then maintain the dosage, don't need to get to the target trough concentration. (1) When the patients get complete remission, maintain the dosage for 2 weeks, then tapered by 25mg/d per 3 months. When reduced to 50 mg/d, maintain for 12 months, then tapered to 25mg/d for another 12 months. (2) When the patients only get partial remission, maintain the target dosage for 12 months, and then adjust the dosage followed "(1)". (3) When the patients no response, maintain the target dosage for 6 months, if the decreased UTP < 25%, suggested change the therapy regimen. If the decreased UTP ≥ 25%, maintain the dosage for another 6 months, then follow "(2)". Ponticelli regimen: Cyclical corticosteroid/alkylating-agent therapy for IMN. Outcomes Primary outcome: The primary clinical outcome was the composite of complete or partial remission at 12 months. Secondary outcome: the composite of complete or partial remission at 6 months; complete remission at 6 months; and adverse events, relapse.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Efficacy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
82 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Multitarget Therapy
Arm Type
Experimental
Arm Description
The combined therapy with prednisone, ciclosporin and mycophenolate mofetil.
Arm Title
Control
Arm Type
Active Comparator
Arm Description
Ponticelli Regimen
Intervention Type
Drug
Intervention Name(s)
Prednisone, ciclosporin and mycophenolate mofetil
Intervention Description
Multitarget Therapy
Intervention Type
Drug
Intervention Name(s)
Ponticelli Regimen
Intervention Description
Month 1: i.v. methylprednisolone (0.5 g) daily for three doses, then oral prednison (0.5 mg/kg/d, maximum dose 30mg/d) for 27 days Month 2: Oral cyclophosphamide (2.0 mg/kg/d, maximum dose 100mg/d) for 30 days Month 3: Repeat Month 1 Month 4: Repeat Month 2 Month 5: Repeat Month 1 Month 6: Repeat Month 2
Primary Outcome Measure Information:
Title
The composite of complete or partial remission at 12 months
Description
complete remission: proteinuria of no more than 0.3 g per 24 hours and a serum albumin level of at least 35 g per milliliter. Partial remission: a reduction in proteinuria of at least 50% from baseline plus final proteinuria between 0.3 g and 3.5 g per 24 hours regardless of creatinine clearance or the serum albumin level.
Time Frame
Month 12
Secondary Outcome Measure Information:
Title
Composite of complete or partial remission at 6 months
Description
complete remission: proteinuria of no more than 0.3 g per 24 hours and a serum albumin level of at least 35 g per milliliter. Partial remission: a reduction in proteinuria of at least 50% from baseline plus final proteinuria between 0.3 g and 3.5 g per 24 hours regardless of creatinine clearance or the serum albumin level.
Time Frame
at momth 6
Title
Treatment failure
Description
proteinuria decreased no more than 25% of baseline at month
Time Frame
at momth 6
Title
adverse events
Description
Advers events happened during study period
Time Frame
within 12 months
Title
Relapse
Description
Relapse during study period
Time Frame
within 12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age: 18-70 years. Body weight: 50-90 kg. Patients with membranous nephropathy were eligible if their diagnosis was confirmed by renal biopsy, with the biopsy sample examined by light, immunofluorescence, and electron microscopy. Renal biopsy samples were reviewed by the two principal investigators and two renal pathologists. IMN patients with moderate risk and have a decline of less than 50% in proteinuria despite renin-angiotensin system blockade for at least 6 months before randomization. OR, IMN patients with high risk or very high risk. Serum albumin < 30 g/L. eGFR by MDRD formula had to be ≥ 60 ml/min per 1.73 m2. Exclusion criteria: Secondary MN, pregnancy, breastfeeding, immunosuppressive treatment in the 3 preceding months, and active infectious disease. Hepatitis B serology included Hbs antigen and Hbs and Hbc antibodies. Patients with active hepatitis B and those with past hepatitis B infection without anti-Hbs antibodies will be excluded. Patients with reproductive demand will be excluded.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Zongli Diao, MD
Organizational Affiliation
Beijing Frienship Hospital, Capital Medical University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Beijing Friendship Hospital, Capital Medical University
City
Beijing
State/Province
Beijing
ZIP/Postal Code
100050
Country
China
Facility Name
Beijing Frienship Hospital, Capital Medical University
City
Beijing
State/Province
Beijing
ZIP/Postal Code
100050
Country
China

12. IPD Sharing Statement

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Multitarget Therapy for Idiopathic Membranous Nephropathy

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