Multitarget Therapy for Idiopathic Membranous Nephropathy

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

1. that multitarget therapy is non-inferior to Ponticelli regimen in inducing long-term remission (CR or PR) of proteinuria in patients with IMN.
2. 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.
3. 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.

Conditions

• Efficacy

Interventions

DRUG

Prednisone, ciclosporin and mycophenolate mofetil

Multitarget Therapy

DRUG

Ponticelli Regimen

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

Sponsors & Collaborators

• Beijing Friendship Hospital

  lead OTHER

Principal Investigators

• Zongli Diao, MD · Beijing Frienship Hospital, Capital Medical University

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

70 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2020-06-09

Primary Completion

2021-02-03

Completion

2022-02-03

Countries

• China

Study Locations