<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/NCT03018535</url>
  </required_header>
  <id_info>
    <org_study_id>EudraCT 2011 006115-59</org_study_id>
    <nct_id>NCT03018535</nct_id>
  </id_info>
  <brief_title>Rituximab Versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy</brief_title>
  <acronym>RI-CYCLO</acronym>
  <official_title>A Randomized Controlled Trial of Rituximab Versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Bari</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Azienda Ospedaliera Brotzu</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Messina</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Milan</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Universita di Verona</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Chieti</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Bologna</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Azienda Sanitaria Locale Roma E</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>IRCCS Azienda Ospedaliero-Universitaria di Bologna</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Regione Piemonte</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Modena and Reggio Emilia</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Pisa</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Milano Bicocca</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Humanitas Hospital, Italy</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Azienda Ospedaliera Universitaria Policlinico</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Fondazione Salvatore Maugeri</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Bern</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Alberta</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Istituto Giannina Gaslini</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Idiopathic Membranous nephropathy (IMN) is an auto-immune glomerular disease. Recent studies&#xD;
      suggest that circulating auto-antibodies against the podocyte surface antigens phospholipase&#xD;
      A2 receptor1 (PLA2R1) and thrombospondin type 1 domain-containing 7A (THSD7A) cause the&#xD;
      disease in the majority of the patients. Additional autoantibodies, directed to podocyte&#xD;
      neo-expressed cytoplasm proteins have been described, including aldose reductase (AR),&#xD;
      Mn-superoxide dismutase (SOD2) and alpha-enolase (alpha-ENO).&#xD;
&#xD;
      The commonest presentation of IMN is nephrotic syndrome. Data from placebo arms of&#xD;
      interventional studies show that 30-40% of the untreated patients with persistent nephrotic&#xD;
      syndrome (NS) progress to end-stage renal disease (ESRD).&#xD;
&#xD;
      The best-validated treatment regimen of IMN is combination therapy with steroids and&#xD;
      cyclophosphamide, capable to induce remission of protenuria in two-third of the patients.&#xD;
&#xD;
      Despite this evidence of efficacy, there are concerns about the use of cyclophosphamide,&#xD;
      since it may be associated with adverse events, including bone marrow suppression, gonadal&#xD;
      toxicity, infections and oncogenic effects. Thus, the availability of alternative therapies&#xD;
      highly effective but with a greater safety profile is desirable.&#xD;
&#xD;
      Given the key role of IgG antibodies in IMN, B cell depletion may favourably impact the&#xD;
      glomerular disease. The anti-CD20 monoclonal antibody Rituximab is a selective B cell&#xD;
      depleting agent. There is evidence that Rituximab is effective in the treatment of other&#xD;
      diseases in which B cells play a key role, such as ANCA-related vasculitis. Observational&#xD;
      studies in IMN provided encouraging data; in addition, the drug seems well tolerated.&#xD;
&#xD;
      Head-to-head comparisons between Rituximab and steroid plus ciclophosphamide in randomized&#xD;
      clinical trials are missing.&#xD;
&#xD;
      The investigators propose this study in order to test, in a randomized controlled trial, the&#xD;
      hypothesis that Rituximab is more effective than cyclical steroid/alkylating-agent therapy in&#xD;
      inducing remission in patients with IMN and NS undergoing the initial treatment. In addition,&#xD;
      the levels of the above-mentioned pathogenetic autoantibodies will be measured at baseline&#xD;
      and during treatment. Finally, the study will compare the safety profile of steroid plus&#xD;
      cyclophosphamide and Rituximab by evaluating the rate and severity of adverse events&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Idiopathic Membranous nephropathy (IMN) is an immune-mediated glomerular disease&#xD;
      characterized by deposition of IgG4 antibodies in the subepithelial area of the glomerular&#xD;
      basement membrane (GBM). Proteinuria is the hallmark of the disease. The commonest&#xD;
      presentation of IMN is nephrotic syndrome with preserved kidney function. The natural course&#xD;
      of the disease can be variable and may be punctuated with spontaneous remissions and&#xD;
      relapses. In about 20% of patients, there is spontaneous complete remission of the nephrotic&#xD;
      syndrome, and another 15-20% undergo partial remission; about 30% of patients may remain with&#xD;
      fluctuating proteinuria and about 30% may progress to end-stage renal disease (ESRD).&#xD;
      However, data from natural history studies and placebo arms of intervention studies with&#xD;
      follow-up lasting more than 10 years show that about 30-40% of the untreated patients with&#xD;
      persistent nephrotic syndrome progress to ESRD.&#xD;
&#xD;
      Complete remission of nephrotic syndrome predicts excellent long-term kidney and patient&#xD;
      survival, and partial remission also significantly reduces the risk of progression to ESRD.&#xD;
      Therefore, persisting remission of the nephrotic state is an acceptable surrogate end-point&#xD;
      to assess efficacy of treatment. The primary aims of treatment, therefore, are to induce a&#xD;
      lasting reduction in proteinuria. The best-validated regimen is combination therapy with&#xD;
      corticosteroids and cyclophosphamide (&quot;Ponticelli&quot; regimen). This treatment is superior to&#xD;
      supportive therapy alone in inducing remissions and preventing long-term decline of kidney&#xD;
      function in patients with idiopathic MN and persisting nephrotic syndrome. However, there are&#xD;
      concerns about the use of cyclophosphamide, since its use may be associated with adverse&#xD;
      events, leading to treatment interruption in about 9% of patients. These adverse events&#xD;
      include bone marrow suppression, gonadal toxicity, infections and oncogenic effects.&#xD;
&#xD;
      Thus, the availability of alternative therapies highly effective but with a greater safety&#xD;
      profile is desirable.&#xD;
&#xD;
      Recent human studies confirmed that MN is an autoimmune disease, suggesting that the disease&#xD;
      may be triggered by isotype specific autoantibodies directed against podocyte enzymes and&#xD;
      podocyte receptors that are recognized as antigens, including M-type phospholipase-2&#xD;
      receptors(PLA2R1) and thrombospondin type 1 domain-containing 7A (THSD7A). The podocyte&#xD;
      expression of these autoantigens can trigger the production of specific antibodies and in&#xD;
      situ deposits of immune complexes, with consequent activation of complement cascade, oxygen&#xD;
      radicals, and other inflammatory pathways leading to tissue injury and fibrosis. Additional&#xD;
      autoantibodies, directed to podocyte neo-expressed cytoplasm proteins have been described,&#xD;
      including aldose reductase (AR), Mn-superoxide dismutase (SOD2) and alpha-enolase&#xD;
      (alpha-ENO).&#xD;
&#xD;
      However, the mechanisms eliciting the expression of these neoantigens on podocytes and&#xD;
      regulating the deposition of the auto-antibodies on the subepithelial surface of the&#xD;
      glomerular basement membrane is not known.&#xD;
&#xD;
      Considering the potential role of IgG antibodies in the pathogenesis of IMN, B cell depletion&#xD;
      may favourably impact the glomerular disease as reflected by a reduction in proteinuria. The&#xD;
      anti-CD20 monoclonal antibody Rituximab is a selective B cell depleting agent, capable to&#xD;
      maintain B cells undetectable for 3-12 months. There is evidence that this strategy is&#xD;
      effective in the treatment of other diseases in which B cells play a key role, such as&#xD;
      ANCA-related vasculitis and humoral allograft rejection. Preliminary studies in IMN are&#xD;
      promising, with observational studies providing encouraging data; in addition, the drug seems&#xD;
      well tolerated with minimal adverse events.&#xD;
&#xD;
      Head-to-head comparisons between Rituximab and steroid plus ciclophosphamide in randomized&#xD;
      clinical trials are missing.&#xD;
&#xD;
      The investigators propose this study in order to test in a randomized controlled trial the&#xD;
      hypothesis that selective B lymphocyte depletion obtained with Rituximab is more effective&#xD;
      than cyclical corticosteroid/alkylating-agent therapy in inducing long-term remission of&#xD;
      proteinuria in patients undergoing the initial treatment of with IMN and nephrotic syndrome.&#xD;
      In addition, since specific assay for the above-mentioned autoantibodies are now available,&#xD;
      the levels of these pathogenetic autoantibodies will be measured at baseline and during&#xD;
      treatment. Finally, the study will compare the safety profile of steroid plus&#xD;
      cyclophosphamide and Rituximab by evaluating the rate and severity of adverse events.&#xD;
&#xD;
      Design and Power Considerations&#xD;
&#xD;
      The investigators hypothesized that the remission probability in the RTX arm will be greater&#xD;
      than in the active comparator group (superiority design). Available data (Ponticelli 1998)&#xD;
      suggest that the probability of complete remission with standard therapy is 15% at one year.&#xD;
&#xD;
      The investigators plan to enroll 70 patients in this pilot RCT. This sample size will be able&#xD;
      to detect with a power of 80% (and a two-sided P of 0.05) an odds ratio of 3, i.e. change in&#xD;
      probability from 0.15 to 0.45 - a very optimistic effect. Smaller (and likely more&#xD;
      reasonable) effects would require larger studies.&#xD;
&#xD;
      The study will provide an estimate of this true effect, if it exists.&#xD;
&#xD;
      Adverse effects:&#xD;
&#xD;
      Patients will be directly questioned every two weeks during the drug exposure and then at&#xD;
      monthly intervals during follow-up. In addition a contact number will be provided to the&#xD;
      subjects to call if they experience any adverse affect or if they suspect adverse effect at&#xD;
      any time between specific visits&#xD;
&#xD;
      Definition Of Proteinuric Status&#xD;
&#xD;
      UP = urinary protein (g/24h)&#xD;
&#xD;
      Complete remission (CR) UP ≤ 0.3 g&#xD;
&#xD;
      Partial remission (PR): Reduction in UP of &gt; 50% plus final UP ≤ 3.5 g but &gt;0.3g&#xD;
&#xD;
      Non-response (NR): Reduction in UP of &lt; 50% (includes increase in UP &lt;50%)&#xD;
&#xD;
      Neither CR nor PR&#xD;
&#xD;
      Progression: Proteinuria /S. creatinine increases by &gt; 50% over the baseline&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date>January 2012</start_date>
  <completion_date type="Anticipated">December 2019</completion_date>
  <primary_completion_date type="Anticipated">December 2019</primary_completion_date>
  <phase>Phase 3</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>change in probability of complete remission (proteinuria &lt; 0.3 g/day) Primary Outcome Measures The primary outcome measure is the change in probability of complete remission (proteinuria &lt; 0.3 g/day) at one year (see Design and power considerations).</measure>
    <time_frame>1 year</time_frame>
    <description>The primary outcome measure is the change in probability of complete remission (proteinuria &lt; 0.3 g/day) at one year</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change from baseline in proteinuria</measure>
    <time_frame>from randomization up to 36 months</time_frame>
    <description>Change from baseline in proteinuria at 6,12, 18, 24 and 36 months following treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CR (Complete Remission) or PR (Partial Remission: Reduction in UP of &gt; 50% plus final UP ≤ 3.5 g but &gt;0.3g )</measure>
    <time_frame>from randomization up to 36 months</time_frame>
    <description>CR (Complete Remission) or PR (Partial Remission) at 6, 12, 18, 24, and 36 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Estimated Glomerular filtration rate (MDRD formula)</measure>
    <time_frame>from randomization up to 36 months</time_frame>
    <description>Estimated Glomerular filtration rate (MDRD formula) at 6, 12, 18, 24, and 36 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum creatinine level (mg/dl)</measure>
    <time_frame>from randomization up to 36 months</time_frame>
    <description>Serum creatinine level (mg/dl) at 6, 12, 18, 24, and 36 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Frequency of and time to relapse of nephrotic syndrome</measure>
    <time_frame>up to 36 months</time_frame>
    <description>Frequency of and time to relapse of nephrotic syndrome</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Frequency of auto-antibodies and its relation to therapy and proteinuria response in a subgroup of patients</measure>
    <time_frame>baseline and after treatment (day 3, month 1, 3, 6 , 6 and 12)</time_frame>
    <description>Frequency of auto-antibodies and its relation to therapy and proteinuria response in a subgroup of patients at baseline and 3 days, 1 month, 3 months, 6 months and 12 months after treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>serious side effects: Death, Life-threatening event, Hospitalization, Disability in the patient's body function/structure or physical activity or quality of life, Congenital anomaly, Intervention to prevent permanent impairment or damage)</measure>
    <time_frame>up to 36 months</time_frame>
    <description>serious side effects: Death, Life-threatening event, Hospitalization, Disability in the patient's body function/structure or physical activity or quality of life, Congenital anomaly, Intervention to prevent permanent impairment or damage.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">76</enrollment>
  <condition>Glomerulonephritis, Membranous</condition>
  <arm_group>
    <arm_group_label>RITUXIMAB</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>1 g. IV of Rituximab on days 1 and 15</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Corticosteroids and Cyclophosphamide</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Month 1, 3 and 5: 1g IV methylprednisolone daily for 3 doses; oral methylprednisolone (0.4mg/kg/day) or prednisone (0.5/mg/kg/day); Month 2, 4 and 6: Oral Cyclophosphamide (2.0 mg/kg/day)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rituximab</intervention_name>
    <description>Rituximab,1 g IV, day 1 and day 15</description>
    <arm_group_label>RITUXIMAB</arm_group_label>
    <other_name>Mabthera</other_name>
    <other_name>Rituxan</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Methylprednisolone</intervention_name>
    <description>Methylprednisolone 1 g IV daily for 3 doses, then oral methylprednisolone (0.4 mg/kg/day) or oral prednisone (0.5mg/kg/day) for 27 days during Month 1, 3, 5.</description>
    <arm_group_label>Corticosteroids and Cyclophosphamide</arm_group_label>
    <other_name>URBASON</other_name>
    <other_name>SOLUMEDROL</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cyclophosphamide</intervention_name>
    <description>Month 2, 4 and 6: Oral Cyclophosphamide (2.0 mg/kg/day) for 30 days</description>
    <arm_group_label>Corticosteroids and Cyclophosphamide</arm_group_label>
    <other_name>Cytoxan</other_name>
    <other_name>Endoxan</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Biopsy-proven diagnosis of idiopathic MN performed within the past 24 months&#xD;
&#xD;
          2. Proteinuria &gt; 3.5 g/24h on three 24-hour urine collection (once a week for 3 weeks)&#xD;
&#xD;
          3. Estimated GFR (MDRD formula) ≥ 30ml/min/1.73m2 under ACEI/ARB therapy&#xD;
&#xD;
          4. Post-menopausal females, or females surgically sterile or practicing a medically&#xD;
             approved method of contraception (no birth-control pill)&#xD;
&#xD;
          5. Three months of ACEI and/or ARB therapy before treatment&#xD;
&#xD;
          6. Blood Pressure &lt;130/80 mm Hg&#xD;
&#xD;
          7. HMG-CoA reductase inhibitor therapy&#xD;
&#xD;
          8. Patients remaining with proteinuria &gt;3.5g/24h after 3 months of ACEI and/or ARB&#xD;
             therapy and Blood Pressure &lt;130/80 mm Hg may be randomized to RTX / cyclical&#xD;
             corticosteroid/alkylating-agent therapy without the need of the run-in/conservative&#xD;
             phase of the study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. serum creatinine &gt;2.5 mg/dl; Estimated GFR &lt; 30 ml/min/1.73m2&#xD;
&#xD;
          2. previous treatment with Rituximab, Steroids, Alkylating Agents, Calcineurin&#xD;
             Inhibitors, Synthetic ACTH, MMF, Azathioprine&#xD;
&#xD;
          3. Presence of active infection&#xD;
&#xD;
          4. Secondary cause of MN (e.g. hepatitis B, SLE, medications, malignancies). Testing for&#xD;
             HIV, Hepatitis B and C should have occurred &lt; 6 months prior to enrollment into the&#xD;
             study&#xD;
&#xD;
          5. Type 1 or 2 diabetes mellitus&#xD;
&#xD;
          6. Pregnancy or nursing for safety reasons&#xD;
&#xD;
          7. Renal vein thrombosis documented prior to entry by renal US or CT scan&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>FRANCESCO SCOLARI, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Division of Nephrology, Montichiari Hospital, ASST Spedali Civili di Brescia</name>
      <address>
        <city>Montichiari</city>
        <state>Brescia</state>
        <zip>25018</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <reference>
    <citation>Glassock RJ. The pathogenesis of membranous nephropathy: evolution and revolution. Curr Opin Nephrol Hypertens. 2012 May;21(3):235-42. doi: 10.1097/MNH.0b013e3283522ea8.</citation>
    <PMID>22388552</PMID>
  </reference>
  <reference>
    <citation>Cravedi P, Remuzzi G, Ruggenenti P. Rituximab in primary membranous nephropathy: first-line therapy, why not? Nephron Clin Pract. 2014;128(3-4):261-9. doi: 10.1159/000368589. Epub 2014 Nov 22.</citation>
    <PMID>25427622</PMID>
  </reference>
  <reference>
    <citation>Murtas C, Bruschi M, Candiano G, Moroni G, Magistroni R, Magnano A, Bruno F, Radice A, Furci L, Argentiero L, Carnevali ML, Messa P, Scolari F, Sinico RA, Gesualdo L, Fervenza FC, Allegri L, Ravani P, Ghiggeri GM. Coexistence of different circulating anti-podocyte antibodies in membranous nephropathy. Clin J Am Soc Nephrol. 2012 Sep;7(9):1394-400. doi: 10.2215/CJN.02170312. Epub 2012 Jul 5.</citation>
    <PMID>22773590</PMID>
  </reference>
  <reference>
    <citation>Ponticelli C, Zucchelli P, Passerini P, Cesana B, Locatelli F, Pasquali S, Sasdelli M, Redaelli B, Grassi C, Pozzi C, et al. A 10-year follow-up of a randomized study with methylprednisolone and chlorambucil in membranous nephropathy. Kidney Int. 1995 Nov;48(5):1600-4. doi: 10.1038/ki.1995.453.</citation>
    <PMID>8544420</PMID>
  </reference>
  <reference>
    <citation>Jha V, Ganguli A, Saha TK, Kohli HS, Sud K, Gupta KL, Joshi K, Sakhuja V. A randomized, controlled trial of steroids and cyclophosphamide in adults with nephrotic syndrome caused by idiopathic membranous nephropathy. J Am Soc Nephrol. 2007 Jun;18(6):1899-904. doi: 10.1681/ASN.2007020166. Epub 2007 May 9.</citation>
    <PMID>17494881</PMID>
  </reference>
  <verification_date>May 2019</verification_date>
  <study_first_submitted>January 9, 2017</study_first_submitted>
  <study_first_submitted_qc>January 10, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 12, 2017</study_first_posted>
  <last_update_submitted>May 16, 2019</last_update_submitted>
  <last_update_submitted_qc>May 16, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">May 20, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia</investigator_affiliation>
    <investigator_full_name>Francesco Scolari</investigator_full_name>
    <investigator_title>DIRECTOR OF THE DIVISION OF NEPHROLOGY, MONTICHIARI HOSPITAL</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Glomerulonephritis</mesh_term>
    <mesh_term>Glomerulonephritis, Membranous</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Methylprednisolone</mesh_term>
    <mesh_term>Methylprednisolone Acetate</mesh_term>
    <mesh_term>Methylprednisolone Hemisuccinate</mesh_term>
    <mesh_term>Prednisolone</mesh_term>
    <mesh_term>Prednisolone acetate</mesh_term>
    <mesh_term>Cyclophosphamide</mesh_term>
    <mesh_term>Rituximab</mesh_term>
    <mesh_term>Prednisolone hemisuccinate</mesh_term>
    <mesh_term>Prednisolone phosphate</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03018535
org study id: EudraCT 2011 006115-59
nct id: NCT03018535
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has dmc: No
Idiopathic Membranous nephropathy (IMN) is an auto-immune glomerular disease. Recent studies
      suggest that circulating auto-antibodies against the podocyte surface antigens phospholipase
      A2 receptor1 (PLA2R1) and thrombospondin type 1 domain-containing 7A (THSD7A) cause the
      disease in the majority of the patients. Additional autoantibodies, directed to podocyte
      neo-expressed cytoplasm proteins have been described, including aldose reductase (AR),
      Mn-superoxide dismutase (SOD2) and alpha-enolase (alpha-ENO).

      The commonest presentation of IMN is nephrotic syndrome. Data from placebo arms of
      interventional studies show that 30-40% of the untreated patients with persistent nephrotic
      syndrome (NS) progress to end-stage renal disease (ESRD).

      The best-validated treatment regimen of IMN is combination therapy with steroids and
      cyclophosphamide, capable to induce remission of protenuria in two-third of the patients.

      Despite this evidence of efficacy, there are concerns about the use of cyclophosphamide,
      since it may be associated with adverse events, including bone marrow suppression, gonadal
      toxicity, infections and oncogenic effects. Thus, the availability of alternative therapies
      highly effective but with a greater safety profile is desirable.

      Given the key role of IgG antibodies in IMN, B cell depletion may favourably impact the
      glomerular disease. The anti-CD20 monoclonal antibody Rituximab is a selective B cell
      depleting agent. There is evidence that Rituximab is effective in the treatment of other
      diseases in which B cells play a key role, such as ANCA-related vasculitis. Observational
      studies in IMN provided encouraging data; in addition, the drug seems well tolerated.

      Head-to-head comparisons between Rituximab and steroid plus ciclophosphamide in randomized
      clinical trials are missing.

      The investigators propose this study in order to test, in a randomized controlled trial, the
      hypothesis that Rituximab is more effective than cyclical steroid/alkylating-agent therapy in
      inducing remission in patients with IMN and NS undergoing the initial treatment. In addition,
      the levels of the above-mentioned pathogenetic autoantibodies will be measured at baseline
      and during treatment. Finally, the study will compare the safety profile of steroid plus
      cyclophosphamide and Rituximab by evaluating the rate and severity of adverse events
Idiopathic Membranous nephropathy (IMN) is an immune-mediated glomerular disease
      characterized by deposition of IgG4 antibodies in the subepithelial area of the glomerular
      basement membrane (GBM). Proteinuria is the hallmark of the disease. The commonest
      presentation of IMN is nephrotic syndrome with preserved kidney function. The natural course
      of the disease can be variable and may be punctuated with spontaneous remissions and
      relapses. In about 20% of patients, there is spontaneous complete remission of the nephrotic
      syndrome, and another 15-20% undergo partial remission; about 30% of patients may remain with
      fluctuating proteinuria and about 30% may progress to end-stage renal disease (ESRD).
      However, data from natural history studies and placebo arms of intervention studies with
      follow-up lasting more than 10 years show that about 30-40% of the untreated patients with
      persistent nephrotic syndrome progress to ESRD.

      Complete remission of nephrotic syndrome predicts excellent long-term kidney and patient
      survival, and partial remission also significantly reduces the risk of progression to ESRD.
      Therefore, persisting remission of the nephrotic state is an acceptable surrogate end-point
      to assess efficacy of treatment. The primary aims of treatment, therefore, are to induce a
      lasting reduction in proteinuria. The best-validated regimen is combination therapy with
      corticosteroids and cyclophosphamide ("Ponticelli" regimen). This treatment is superior to
      supportive therapy alone in inducing remissions and preventing long-term decline of kidney
      function in patients with idiopathic MN and persisting nephrotic syndrome. However, there are
      concerns about the use of cyclophosphamide, since its use may be associated with adverse
      events, leading to treatment interruption in about 9% of patients. These adverse events
      include bone marrow suppression, gonadal toxicity, infections and oncogenic effects.

      Thus, the availability of alternative therapies highly effective but with a greater safety
      profile is desirable.

      Recent human studies confirmed that MN is an autoimmune disease, suggesting that the disease
      may be triggered by isotype specific autoantibodies directed against podocyte enzymes and
      podocyte receptors that are recognized as antigens, including M-type phospholipase-2
      receptors(PLA2R1) and thrombospondin type 1 domain-containing 7A (THSD7A). The podocyte
      expression of these autoantigens can trigger the production of specific antibodies and in
      situ deposits of immune complexes, with consequent activation of complement cascade, oxygen
      radicals, and other inflammatory pathways leading to tissue injury and fibrosis. Additional
      autoantibodies, directed to podocyte neo-expressed cytoplasm proteins have been described,
      including aldose reductase (AR), Mn-superoxide dismutase (SOD2) and alpha-enolase
      (alpha-ENO).

      However, the mechanisms eliciting the expression of these neoantigens on podocytes and
      regulating the deposition of the auto-antibodies on the subepithelial surface of the
      glomerular basement membrane is not known.

      Considering the potential role of IgG antibodies in the pathogenesis of IMN, B cell depletion
      may favourably impact the glomerular disease as reflected by a reduction in proteinuria. The
      anti-CD20 monoclonal antibody Rituximab is a selective B cell depleting agent, capable to
      maintain B cells undetectable for 3-12 months. There is evidence that this strategy is
      effective in the treatment of other diseases in which B cells play a key role, such as
      ANCA-related vasculitis and humoral allograft rejection. Preliminary studies in IMN are
      promising, with observational studies providing encouraging data; in addition, the drug seems
      well tolerated with minimal adverse events.

      Head-to-head comparisons between Rituximab and steroid plus ciclophosphamide in randomized
      clinical trials are missing.

      The investigators propose this study in order to test in a randomized controlled trial the
      hypothesis that selective B lymphocyte depletion obtained with Rituximab is more effective
      than cyclical corticosteroid/alkylating-agent therapy in inducing long-term remission of
      proteinuria in patients undergoing the initial treatment of with IMN and nephrotic syndrome.
      In addition, since specific assay for the above-mentioned autoantibodies are now available,
      the levels of these pathogenetic autoantibodies will be measured at baseline and during
      treatment. Finally, the study will compare the safety profile of steroid plus
      cyclophosphamide and Rituximab by evaluating the rate and severity of adverse events.

      Design and Power Considerations

      The investigators hypothesized that the remission probability in the RTX arm will be greater
      than in the active comparator group (superiority design). Available data (Ponticelli 1998)
      suggest that the probability of complete remission with standard therapy is 15% at one year.

      The investigators plan to enroll 70 patients in this pilot RCT. This sample size will be able
      to detect with a power of 80% (and a two-sided P of 0.05) an odds ratio of 3, i.e. change in
      probability from 0.15 to 0.45 - a very optimistic effect. Smaller (and likely more
      reasonable) effects would require larger studies.

      The study will provide an estimate of this true effect, if it exists.

      Adverse effects:

      Patients will be directly questioned every two weeks during the drug exposure and then at
      monthly intervals during follow-up. In addition a contact number will be provided to the
      subjects to call if they experience any adverse affect or if they suspect adverse effect at
      any time between specific visits

      Definition Of Proteinuric Status

      UP = urinary protein (g/24h)

      Complete remission (CR) UP ≤ 0.3 g

      Partial remission (PR): Reduction in UP of > 50% plus final UP ≤ 3.5 g but >0.3g

      Non-response (NR): Reduction in UP of < 50% (includes increase in UP <50%)

      Neither CR nor PR

      Progression: Proteinuria /S. creatinine increases by > 50% over the baseline
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: change in probability of complete remission (proteinuria < 0.3 g/day) Primary Outcome Measures The primary outcome measure is the change in probability of complete remission (proteinuria < 0.3 g/day) at one year (see Design and power considerations).
time frame: 1 year
description: The primary outcome measure is the change in probability of complete remission (proteinuria < 0.3 g/day) at one year
measure: Change from baseline in proteinuria
time frame: from randomization up to 36 months
description: Change from baseline in proteinuria at 6,12, 18, 24 and 36 months following treatment
measure: CR (Complete Remission) or PR (Partial Remission: Reduction in UP of > 50% plus final UP ≤ 3.5 g but >0.3g )
time frame: from randomization up to 36 months
description: CR (Complete Remission) or PR (Partial Remission) at 6, 12, 18, 24, and 36 months
measure: Estimated Glomerular filtration rate (MDRD formula)
time frame: from randomization up to 36 months
description: Estimated Glomerular filtration rate (MDRD formula) at 6, 12, 18, 24, and 36 months
measure: Serum creatinine level (mg/dl)
time frame: from randomization up to 36 months
description: Serum creatinine level (mg/dl) at 6, 12, 18, 24, and 36 months
measure: Frequency of and time to relapse of nephrotic syndrome
time frame: up to 36 months
description: Frequency of and time to relapse of nephrotic syndrome
measure: Frequency of auto-antibodies and its relation to therapy and proteinuria response in a subgroup of patients
time frame: baseline and after treatment (day 3, month 1, 3, 6 , 6 and 12)
description: Frequency of auto-antibodies and its relation to therapy and proteinuria response in a subgroup of patients at baseline and 3 days, 1 month, 3 months, 6 months and 12 months after treatment
measure: serious side effects: Death, Life-threatening event, Hospitalization, Disability in the patient's body function/structure or physical activity or quality of life, Congenital anomaly, Intervention to prevent permanent impairment or damage)
time frame: up to 36 months
description: serious side effects: Death, Life-threatening event, Hospitalization, Disability in the patient's body function/structure or physical activity or quality of life, Congenital anomaly, Intervention to prevent permanent impairment or damage.
arm group label: RITUXIMAB
arm group type: Experimental
description: 1 g. IV of Rituximab on days 1 and 15
arm group label: Corticosteroids and Cyclophosphamide
arm group type: Active Comparator
description: Month 1, 3 and 5: 1g IV methylprednisolone daily for 3 doses; oral methylprednisolone (0.4mg/kg/day) or prednisone (0.5/mg/kg/day); Month 2, 4 and 6: Oral Cyclophosphamide (2.0 mg/kg/day)
intervention type: Drug
intervention name: Rituximab
description: Rituximab,1 g IV, day 1 and day 15
arm group label: RITUXIMAB
other name: Mabthera
other name: Rituxan
intervention type: Drug
intervention name: Methylprednisolone
description: Methylprednisolone 1 g IV daily for 3 doses, then oral methylprednisolone (0.4 mg/kg/day) or oral prednisone (0.5mg/kg/day) for 27 days during Month 1, 3, 5.
arm group label: Corticosteroids and Cyclophosphamide
other name: URBASON
other name: SOLUMEDROL
intervention type: Drug
intervention name: Cyclophosphamide
description: Month 2, 4 and 6: Oral Cyclophosphamide (2.0 mg/kg/day) for 30 days
arm group label: Corticosteroids and Cyclophosphamide
other name: Cytoxan
other name: Endoxan
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: FRANCESCO SCOLARI, MD
role: Principal Investigator
affiliation: Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia
facility: 
country: Italy
citation: Glassock RJ. The pathogenesis of membranous nephropathy: evolution and revolution. Curr Opin Nephrol Hypertens. 2012 May;21(3):235-42. doi: 10.1097/MNH.0b013e3283522ea8.
PMID: 22388552
citation: Cravedi P, Remuzzi G, Ruggenenti P. Rituximab in primary membranous nephropathy: first-line therapy, why not? Nephron Clin Pract. 2014;128(3-4):261-9. doi: 10.1159/000368589. Epub 2014 Nov 22.
PMID: 25427622
citation: Murtas C, Bruschi M, Candiano G, Moroni G, Magistroni R, Magnano A, Bruno F, Radice A, Furci L, Argentiero L, Carnevali ML, Messa P, Scolari F, Sinico RA, Gesualdo L, Fervenza FC, Allegri L, Ravani P, Ghiggeri GM. Coexistence of different circulating anti-podocyte antibodies in membranous nephropathy. Clin J Am Soc Nephrol. 2012 Sep;7(9):1394-400. doi: 10.2215/CJN.02170312. Epub 2012 Jul 5.
PMID: 22773590
citation: Ponticelli C, Zucchelli P, Passerini P, Cesana B, Locatelli F, Pasquali S, Sasdelli M, Redaelli B, Grassi C, Pozzi C, et al. A 10-year follow-up of a randomized study with methylprednisolone and chlorambucil in membranous nephropathy. Kidney Int. 1995 Nov;48(5):1600-4. doi: 10.1038/ki.1995.453.
PMID: 8544420
citation: Jha V, Ganguli A, Saha TK, Kohli HS, Sud K, Gupta KL, Joshi K, Sakhuja V. A randomized, controlled trial of steroids and cyclophosphamide in adults with nephrotic syndrome caused by idiopathic membranous nephropathy. J Am Soc Nephrol. 2007 Jun;18(6):1899-904. doi: 10.1681/ASN.2007020166. Epub 2007 May 9.
PMID: 17494881
responsible party type: Principal Investigator
investigator affiliation: Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia
investigator full name: Francesco Scolari
investigator title: DIRECTOR OF THE DIVISION OF NEPHROLOGY, MONTICHIARI HOSPITAL
mesh term: Glomerulonephritis
mesh term: Glomerulonephritis, Membranous
mesh term: Methylprednisolone
mesh term: Methylprednisolone Acetate
mesh term: Methylprednisolone Hemisuccinate
mesh term: Prednisolone
mesh term: Prednisolone acetate
mesh term: Cyclophosphamide
mesh term: Rituximab
mesh term: Prednisolone hemisuccinate
mesh term: Prednisolone phosphate
sharing ipd: No