<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04424862</url>
  </required_header>
  <id_info>
    <org_study_id>Version 3 20200607</org_study_id>
    <nct_id>NCT04424862</nct_id>
  </id_info>
  <brief_title>Multitarget Therapy for Idiopathic Membranous Nephropathy</brief_title>
  <acronym>MTIMN</acronym>
  <official_title>Multitarget Therapy for Idiopathic Membranous Nephropathy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Beijing Friendship Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Beijing Friendship Hospital</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Membranous nephropathy (MN) is one of the commonest causes of nephrotic syndrome in adults,&#xD;
      idiopathic membranous nephropathy (IMN) accounts for 70%-80% of all MN patients. There is no&#xD;
      standard specific treatment for IMN. Initial therapy should be supportive and involves&#xD;
      restricting dietary protein and sodium intake, controlling blood pressure, hyperlipidemia,&#xD;
      and edema. The best proven therapy for patients with IMN is combined use of corticosteroids&#xD;
      and cyclophosphamide. However, there are some potential risk of other serious side effects&#xD;
      associated with the use of cytotoxic agents, such as bone marrow toxicity, severe infections,&#xD;
      gonadal dysfunction, and the long-term risk of malignancy.&#xD;
&#xD;
      The ideal maintenance treatment scheme for patients with IMN requires not only a remission of&#xD;
      nephrotic syndrome but also, fewer adverse effects. Some retrospective study suggested that&#xD;
      multitarget therapy (prednisone+calcineurin inhibitors+mycophenolate mofetil) was effective&#xD;
      for refractory IMN. However, we cannot get confirmed conclusion from the previous study due&#xD;
      to the limitation of retrospective studies with small sample size.&#xD;
&#xD;
      In this prospective multicenter randomized trial, we compared the efficacy between&#xD;
      multitarget therapy and Ponticelli regimen.&#xD;
&#xD;
      Trial Aims and Hypothesis The specific aims of this trial are to test the hypothesis&#xD;
&#xD;
        1. that multitarget therapy is non-inferior to Ponticelli regimen in inducing long-term&#xD;
           remission (CR or PR) of proteinuria in patients with IMN.&#xD;
&#xD;
        2. that multitarget therapy reduces the number of relapses (efficacy in sustaining&#xD;
           remission) and increases the time to relapse when compared with treatment with&#xD;
           Ponticelli regimen.&#xD;
&#xD;
        3. that multitarget therapy has a better side-effect profile when compared with treatment&#xD;
           with Ponticelli regimen in patients with IMN.&#xD;
&#xD;
      Methods:&#xD;
&#xD;
      Patient Recruitment Inclusion and exclusion criteria are as follows.&#xD;
&#xD;
      Inclusion Criteria:&#xD;
&#xD;
        -  Age: 18-70 years.&#xD;
&#xD;
        -  Body weight: 50-90 kg.&#xD;
&#xD;
        -  Patients with membranous nephropathy were eligible if their diagnosis was confirmed by&#xD;
           renal biopsy, with the biopsy sample examined by light, immunofluorescence, and electron&#xD;
           microscopy. Renal biopsy samples were reviewed by the two principal investigators and&#xD;
           two renal pathologists.&#xD;
&#xD;
        -  IMN patients with moderate risk and have a decline of less than 50% in proteinuria&#xD;
           despite renin-angiotensin system blockade for at least 6 months before randomization.&#xD;
           OR, IMN patients with high risk or very high risk.&#xD;
&#xD;
        -  Serum albumin &lt; 30 g/L.&#xD;
&#xD;
        -  eGFR by MDRD formula had to be ≥ 60 ml/min per 1.73 m2.&#xD;
&#xD;
      Exclusion criteria:&#xD;
&#xD;
        -  Secondary MN, pregnancy, breastfeeding, immunosuppressive treatment in the 3 preceding&#xD;
           months, and active infectious disease.&#xD;
&#xD;
        -  Hepatitis B serology included Hbs antigen and Hbs and Hbc antibodies. Patients with&#xD;
           active hepatitis B and those with past hepatitis B infection without anti-Hbs antibodies&#xD;
           will be excluded.&#xD;
&#xD;
        -  Patients with reproductive demand will be excluded.&#xD;
&#xD;
      Randomization and Treatment Groups Once all entry criteria have been satisfied and confirmed,&#xD;
      patients will be randomized to treatment with multitarget therapy or Ponticelli regimen.&#xD;
&#xD;
      Multitarget therapy:&#xD;
&#xD;
      Combination with prednisone, ciclosporin and mycophenolate mofetil.&#xD;
&#xD;
      Ponticelli regimen:&#xD;
&#xD;
      Cyclical corticosteroid/alkylating-agent therapy for IMN. Outcomes Primary outcome: The&#xD;
      primary clinical outcome was the composite of complete or partial remission at 12 months.&#xD;
&#xD;
      Secondary outcome: the composite of complete or partial remission at 6 months; complete&#xD;
      remission at 6 months; and adverse events, relapse.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Membranous nephropathy (MN) is one of the commonest causes of nephrotic syndrome in adults,&#xD;
      idiopathic membranous nephropathy (IMN) accounts for 70%-80% of all MN patients. There is no&#xD;
      standard specific treatment for IMN. Initial therapy should be supportive and involves&#xD;
      restricting dietary protein and sodium intake, controlling blood pressure, hyperlipidemia,&#xD;
      and edema. The best proven therapy for patients with IMN is combined use of corticosteroids&#xD;
      and cyclophosphamide. However, there are some potential risk of other serious side effects&#xD;
      associated with the use of cytotoxic agents, such as bone marrow toxicity, severe infections,&#xD;
      gonadal dysfunction, and the long-term risk of malignancy.&#xD;
&#xD;
      The ideal maintenance treatment scheme for patients with IMN requires not only a remission of&#xD;
      nephrotic syndrome but also, fewer adverse effects. Some retrospective study suggested that&#xD;
      multitarget therapy (prednisone+calcineurin inhibitors+mycophenolate mofetil) was effective&#xD;
      for refractory IMN. However, we cannot get confirmed conclusion from the previous study due&#xD;
      to the limitation of retrospective studies with small sample size.&#xD;
&#xD;
      In this prospective multicenter randomized trial, we compared the efficacy between&#xD;
      multitarget therapy and Ponticelli regimen.&#xD;
&#xD;
      Trial Aims and Hypothesis The specific aims of this trial are to test the hypothesis&#xD;
&#xD;
        1. that multitarget therapy is non-inferior to Ponticelli regimen in inducing long-term&#xD;
           remission (CR or PR) of proteinuria in patients with IMN.&#xD;
&#xD;
        2. that multitarget therapy reduces the number of relapses (efficacy in sustaining&#xD;
           remission) and increases the time to relapse when compared with treatment with&#xD;
           Ponticelli regimen.&#xD;
&#xD;
        3. that multitarget therapy has a better side-effect profile when compared with treatment&#xD;
           with Ponticelli regimen in patients with IMN.&#xD;
&#xD;
      Methods:&#xD;
&#xD;
      Patient Recruitment Inclusion and exclusion criteria are as follows.&#xD;
&#xD;
      Inclusion Criteria:&#xD;
&#xD;
        -  Age: 18-70 years.&#xD;
&#xD;
        -  Body weight: 50-90 kg.&#xD;
&#xD;
        -  Patients with membranous nephropathy were eligible if their diagnosis was confirmed by&#xD;
           renal biopsy, with the biopsy sample examined by light, immunofluorescence, and electron&#xD;
           microscopy. Renal biopsy samples were reviewed by the two principal investigators and&#xD;
           two renal pathologists.&#xD;
&#xD;
        -  IMN patients with moderate risk and have a decline of less than 50% in proteinuria&#xD;
           despite renin-angiotensin system blockade for at least 6 months before randomization.&#xD;
           OR, IMN patients with high risk or very high risk.&#xD;
&#xD;
        -  Serum albumin &lt; 30 g/L.&#xD;
&#xD;
        -  eGFR by MDRD formula had to be ≥ 60 ml/min per 1.73 m2.&#xD;
&#xD;
      Exclusion criteria:&#xD;
&#xD;
        -  Secondary MN, pregnancy, breastfeeding, immunosuppressive treatment in the 3 preceding&#xD;
           months, and active infectious disease.&#xD;
&#xD;
        -  Hepatitis B serology included Hbs antigen and Hbs and Hbc antibodies. Patients with&#xD;
           active hepatitis B and those with past hepatitis B infection without anti-Hbs antibodies&#xD;
           will be excluded.&#xD;
&#xD;
        -  Patients with reproductive demand will be excluded.&#xD;
&#xD;
      Randomization and Treatment Groups Once all entry criteria have been satisfied and confirmed,&#xD;
      patients will be randomized to treatment with multitarget therapy or Ponticelli regimen.&#xD;
&#xD;
      Multitarget therapy:&#xD;
&#xD;
      The patients in the multitarget group continued to receive prednisone 1 mg/kg/d (maximum&#xD;
      dosage 60mg/d) for 2 weeks and then tapered by 5mg per week. When reduced to 30mg/d,&#xD;
      maintained for 1 month, and then tapered by 5 mg per month. When reduced to 20mg/d,&#xD;
      maintained for 2 months, and then tapered by 2.5 mg per two-month. When reduced to 5 mg/d,&#xD;
      maintained for 4 months.&#xD;
&#xD;
      Mycophenolate mofetil (1 g/d for 6 months and then tapered to 0.75 g/d for another 12 months,&#xD;
      and tapered 0.5g for another 12 months) Ciclosporin (initial dosage 100 mg/d, and adjusted&#xD;
      the dosage to maintain trough concentration at 80-120 ng/mL. If the patients get complete&#xD;
      remission during dosage adjustment period, then maintain the dosage, don't need to get to the&#xD;
      target trough concentration. (1) When the patients get complete remission, maintain the&#xD;
      dosage for 2 weeks, then tapered by 25mg/d per 3 months. When reduced to 50 mg/d, maintain&#xD;
      for 12 months, then tapered to 25mg/d for another 12 months. (2) When the patients only get&#xD;
      partial remission, maintain the target dosage for 12 months, and then adjust the dosage&#xD;
      followed &quot;(1)&quot;. (3) When the patients no response, maintain the target dosage for 6 months,&#xD;
      if the decreased UTP &lt; 25%, suggested change the therapy regimen. If the decreased UTP ≥ 25%,&#xD;
      maintain the dosage for another 6 months, then follow &quot;(2)&quot;.&#xD;
&#xD;
      Ponticelli regimen:&#xD;
&#xD;
      Cyclical corticosteroid/alkylating-agent therapy for IMN. Outcomes Primary outcome: The&#xD;
      primary clinical outcome was the composite of complete or partial remission at 12 months.&#xD;
&#xD;
      Secondary outcome: the composite of complete or partial remission at 6 months; complete&#xD;
      remission at 6 months; and adverse events, relapse.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 9, 2020</start_date>
  <completion_date type="Actual">February 3, 2022</completion_date>
  <primary_completion_date type="Actual">February 3, 2021</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>The composite of complete or partial remission at 12 months</measure>
    <time_frame>Month 12</time_frame>
    <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.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Composite of complete or partial remission at 6 months</measure>
    <time_frame>at momth 6</time_frame>
    <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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Treatment failure</measure>
    <time_frame>at momth 6</time_frame>
    <description>proteinuria decreased no more than 25% of baseline at month</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>adverse events</measure>
    <time_frame>within 12 months</time_frame>
    <description>Advers events happened during study period</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Relapse</measure>
    <time_frame>within 12 months</time_frame>
    <description>Relapse during study period</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">82</enrollment>
  <condition>Efficacy</condition>
  <arm_group>
    <arm_group_label>Multitarget Therapy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The combined therapy with prednisone, ciclosporin and mycophenolate mofetil.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Ponticelli Regimen</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Prednisone, ciclosporin and mycophenolate mofetil</intervention_name>
    <description>Multitarget Therapy</description>
    <arm_group_label>Multitarget Therapy</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ponticelli Regimen</intervention_name>
    <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</description>
    <arm_group_label>Control</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age: 18-70 years.&#xD;
&#xD;
          -  Body weight: 50-90 kg.&#xD;
&#xD;
          -  Patients with membranous nephropathy were eligible if their diagnosis was confirmed by&#xD;
             renal biopsy, with the biopsy sample examined by light, immunofluorescence, and&#xD;
             electron microscopy. Renal biopsy samples were reviewed by the two principal&#xD;
             investigators and two renal pathologists.&#xD;
&#xD;
          -  IMN patients with moderate risk and have a decline of less than 50% in proteinuria&#xD;
             despite renin-angiotensin system blockade for at least 6 months before randomization.&#xD;
             OR, IMN patients with high risk or very high risk.&#xD;
&#xD;
          -  Serum albumin &lt; 30 g/L.&#xD;
&#xD;
          -  eGFR by MDRD formula had to be ≥ 60 ml/min per 1.73 m2.&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
          -  Secondary MN, pregnancy, breastfeeding, immunosuppressive treatment in the 3 preceding&#xD;
             months, and active infectious disease.&#xD;
&#xD;
          -  Hepatitis B serology included Hbs antigen and Hbs and Hbc antibodies. Patients with&#xD;
             active hepatitis B and those with past hepatitis B infection without anti-Hbs&#xD;
             antibodies will be excluded.&#xD;
&#xD;
          -  Patients with reproductive demand will be excluded.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Zongli Diao, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Beijing Frienship Hospital, Capital Medical University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Beijing Friendship Hospital, Capital Medical University</name>
      <address>
        <city>Beijing</city>
        <state>Beijing</state>
        <zip>100050</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Beijing Frienship Hospital, Capital Medical University</name>
      <address>
        <city>Beijing</city>
        <state>Beijing</state>
        <zip>100050</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>February 2022</verification_date>
  <study_first_submitted>June 7, 2020</study_first_submitted>
  <study_first_submitted_qc>June 9, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 11, 2020</study_first_posted>
  <last_update_submitted>February 2, 2022</last_update_submitted>
  <last_update_submitted_qc>February 2, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">February 17, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Beijing Friendship Hospital</investigator_affiliation>
    <investigator_full_name>Wenhu Liu</investigator_full_name>
    <investigator_title>Director</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Glomerulonephritis, Membranous</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cyclosporine</mesh_term>
    <mesh_term>Mycophenolic Acid</mesh_term>
    <mesh_term>Prednisone</mesh_term>
    <mesh_term>Cyclosporins</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04424862
org study id: Version 3 20200607
nct id: NCT04424862
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
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.
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:

      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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: The composite of complete or partial remission at 12 months
time frame: Month 12
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.
measure: Composite of complete or partial remission at 6 months
time frame: at momth 6
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.
measure: Treatment failure
time frame: at momth 6
description: proteinuria decreased no more than 25% of baseline at month
measure: adverse events
time frame: within 12 months
description: Advers events happened during study period
measure: Relapse
time frame: within 12 months
description: Relapse during study period
arm group label: Multitarget Therapy
arm group type: Experimental
description: The combined therapy with prednisone, ciclosporin and mycophenolate mofetil.
arm group label: Control
arm group type: Active Comparator
description: Ponticelli Regimen
intervention type: Drug
intervention name: Prednisone, ciclosporin and mycophenolate mofetil
description: Multitarget Therapy
arm group label: Multitarget Therapy
intervention type: Drug
intervention name: Ponticelli Regimen
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
arm group label: Control
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Zongli Diao, MD
role: Principal Investigator
affiliation: Beijing Frienship Hospital, Capital Medical University
facility: 
facility: 
country: China
responsible party type: Principal Investigator
investigator affiliation: Beijing Friendship Hospital
investigator full name: Wenhu Liu
investigator title: Director
mesh term: Glomerulonephritis, Membranous
mesh term: Cyclosporine
mesh term: Mycophenolic Acid
mesh term: Prednisone
mesh term: Cyclosporins