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Multitarget Therapy for Idiopathic Membranous Nephropathy (MTIMN)

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ClinicalTrials.gov Identifier: NCT04424862
Recruitment Status : Not yet recruiting
First Posted : June 11, 2020
Last Update Posted : June 11, 2020
Sponsor:
Information provided by (Responsible Party):
Wenhu Liu, Beijing Friendship Hospital

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

  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.


Condition or disease Intervention/treatment Phase
Efficacy Drug: Prednisone, ciclosporin and mycophenolate mofetil Drug: Ponticelli Regimen Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 78 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Multitarget Therapy for Idiopathic Membranous Nephropathy
Estimated Study Start Date : June 2020
Estimated Primary Completion Date : December 2022
Estimated Study Completion Date : December 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Multitarget Therapy
The combined therapy with prednisone, ciclosporin and mycophenolate mofetil.
Drug: Prednisone, ciclosporin and mycophenolate mofetil
Multitarget Therapy

Active Comparator: Control
Ponticelli Regimen
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




Primary Outcome Measures :
  1. The composite of complete or partial remission at 12 months [ Time Frame: Month 12 ]
    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 :
  1. Composite of complete or partial remission at 6 months [ Time Frame: at momth 6 ]
    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.

  2. Treatment failure [ Time Frame: at momth 6 ]
    proteinuria decreased no more than 25% of baseline at month

  3. adverse events [ Time Frame: within 12 months ]
    Advers events happened during study period

  4. Relapse [ Time Frame: within 12 months ]
    Relapse during study period



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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04424862


Contacts
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Contact: Zongli Diao, Dr. 86-1063138579 diaoted@163.com

Locations
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China, Beijing
Beijing Frienship Hospital, Capital Medical University
Beijing, Beijing, China, 100050
Contact: Zongli Diao, MD    86-01063138679    diaoted@163.com   
Sponsors and Collaborators
Beijing Friendship Hospital
Investigators
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Principal Investigator: Zongli Diao, MD Beijing Frienship Hospital, Capital Medical University
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Responsible Party: Wenhu Liu, Doctor, Beijing Friendship Hospital
ClinicalTrials.gov Identifier: NCT04424862    
Other Study ID Numbers: Version 3 20200607
First Posted: June 11, 2020    Key Record Dates
Last Update Posted: June 11, 2020
Last Verified: June 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Glomerulonephritis, Membranous
Kidney Diseases
Urologic Diseases
Glomerulonephritis
Nephritis
Autoimmune Diseases
Immune System Diseases
Cyclosporine
Mycophenolic Acid
Prednisone
Cyclosporins
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Antifungal Agents
Anti-Infective Agents
Dermatologic Agents
Antirheumatic Agents
Calcineurin Inhibitors
Antibiotics, Antineoplastic
Antibiotics, Antitubercular
Antitubercular Agents