<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/NCT03298698</url>
  </required_header>
  <id_info>
    <org_study_id>RSRNS17</org_study_id>
    <nct_id>NCT03298698</nct_id>
  </id_info>
  <brief_title>Efficacy of Rituximab in Comparison to Continued Corticosteroid Treatment in Idiopathic Nephrotic Syndrome</brief_title>
  <official_title>Efficacy of Rituximab in Comparison to Continued Corticosteroid Treatment in Idiopathic Nephrotic Syndrome Unresponsive to 8 Weeks of High Dose Prednisone</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Radboud University Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Radboud University Medical Center</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This will be an open-label, randomized controlled trial which compares continued treatment&#xD;
      with high dose prednisone (standard therapy) to treatment with rituximab in patients with&#xD;
      minimal change disease or focal segmental glomerulosclerosis unresponsive to 8 weeks of high&#xD;
      dose prednisone .&#xD;
&#xD;
      patients either receive 2 doses of Rituximab 375 mg/m2 iv at time 0 and 14 days with&#xD;
      termination of prednisone or standard therapy which consist of 8 additional weeks of high&#xD;
      dose prednisone treatment.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are important&#xD;
      causes of idiopathic nephrotic syndrome. First-line treatment with high dose prednisone up to&#xD;
      16 weeks is associated with serious side effects. Especially if treatment continues for more&#xD;
      than 8 weeks.&#xD;
&#xD;
      Retrospective studies suggested that Rituximab may be more effective in patients unresponsive&#xD;
      to 8 weeks of high dose prednisone. Treatment with rituximab was associated with a higher&#xD;
      proportion of patients attaining remission of proteinuria and with fewer side effects.&#xD;
&#xD;
      This will be an open-label, randomized controlled trial which compares continued treatment&#xD;
      with high dose prednisone (standard therapy) to treatment with rituximab in patients with an&#xD;
      idiopathic nephrotic syndrome due to biopsy proven MCD or FSGS age 18 years or older.&#xD;
&#xD;
      All patients will be treated with high dose prednisone (1 mg/kg/day) for 8 weeks.&#xD;
&#xD;
      Patients can be included in the trial in case of persistent persistent proteinuria ≥ 2 g/ 24&#xD;
      hours or a protein-to-creatinine ratio ≥ 2 g/10mmol (2 g/g) after 8 weeks of treatment with&#xD;
      high dose prednisone&#xD;
&#xD;
      Patients either receive 2 doses of Rituximab 375 mg/m2 iv at time 0 and 14 days with&#xD;
      termination of prednisone or standard therapy which consist of 8 additional weeks of high&#xD;
      dose prednisone treatment. In the Rituximab group, B-cells will be monitored weekly, and if&#xD;
      no complete depletion is achieved, additional dose(s) of Rituximab will be given at a weekly&#xD;
      interval (maximum of 2 additional doses) until complete B cell depletion.&#xD;
&#xD;
      Expected duration of the follow-up is 12 months, consisting of 9 visits.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">August 22, 2018</start_date>
  <completion_date type="Anticipated">January 22, 2022</completion_date>
  <primary_completion_date type="Anticipated">August 22, 2021</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>Complete remission</measure>
    <time_frame>8 weeks</time_frame>
    <description>The proportion of patients reaching complete remission defined as proteinuria &lt;0.3 g/day or &lt; 300 mg/g</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Partial remission</measure>
    <time_frame>8 weeks</time_frame>
    <description>The proportion of patients reaching partial remission defined as proteinuria &lt; 3.5 g/24 h or &lt; 3.5 g/g and 50% lower than baseline proteinuria</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Late complete or partial remission</measure>
    <time_frame>2-12 months</time_frame>
    <description>The proportion of patients reaching complete remission defined as proteinuria &lt;0.3 g/day or &lt; 300 mg/g or The proportion of patients reaching partial remission defined as proteinuria &lt; 3.5 g/24 h or &lt; 3500 mg/g and 50% lower than baseline proteinuria</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to remission</measure>
    <time_frame>12 months</time_frame>
    <description>Time between start of treatment and reaching partial or complete remission</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to relapse</measure>
    <time_frame>12 months</time_frame>
    <description>The time between partial or complete remission and relapse (defined as urinary protein excretion to ≥3.5 g/24 h or ≥3.5 g/g creatinine</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of patients with a relapse</measure>
    <time_frame>12 months</time_frame>
    <description>The proportion of patients with relapse (defined as urinary protein excretion to ≥3.5 g/24 h or ≥3.5 g/g creatinine in patients who had at least attained a partial remission and the time to relapse</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of patients treated with additional immunosuppressive drugs</measure>
    <time_frame>12 months</time_frame>
    <description>Proportion of patients treated with immunosuppressive drugs other than the assigned treatment with rituximab or prednisolone</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>General health assessment</measure>
    <time_frame>at 2, 6, 9 and 12 months</time_frame>
    <description>Difference in general health measured by RAND-36</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of life measured with TAAQOL</measure>
    <time_frame>at 2, 6, 9 and 12 months</time_frame>
    <description>Difference in quality of life measured with TNO-academisch Ziekenhuis Leiden Questionnaire for Adult's Health-Difference in Quality of Life</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of patients with adverse events</measure>
    <time_frame>at 2 and 12 months</time_frame>
    <description>The proportion of patients with adverse events. Adverse events graded according to Common Terminology Criteria For Adverse Events (NCI-CTCAE v4.03)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cost-effectiveness analysis</measure>
    <time_frame>at 2, 6, 9 and 12 months</time_frame>
    <description>Cost-effectiveness will be calculated by dividing the difference in costs by the difference in effectiveness (based on the number of patients in remission) derived from the two groups. The resulting cost-effectiveness ratio will be expressed as costs per one more patient in remission</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cost-utility analysis</measure>
    <time_frame>at 2, 6, 9 and 12 months</time_frame>
    <description>Cost-utility analysis will be calculated by dividing the difference in costs by the difference in Quality Adjusted Life Years (QALY's). QALY's will be derived from the EuroQol-5d-5L questionnaire.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Difference in kidney function</measure>
    <time_frame>at 2 and 12 months</time_frame>
    <description>Difference in creatinine clearance and estimated glomerular filtration rate</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of patients with an increase of baseline serum creatinine ≥ 50%</measure>
    <time_frame>at 2 and 12 months</time_frame>
    <description>The percentage of patients with an increase &gt; 50% of serum creatinine from baseline.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Benefit-risk ratio 1</measure>
    <time_frame>at 2 and 12 months</time_frame>
    <description>Difference in the percentage of remissions (benefit) divided by the difference in adverse events grade 3 or 4, including Serious Adverse Events and Suspected Unexpected Serious Adverse Reaction (risk)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Benefit-risk ratio 2</measure>
    <time_frame>at 2 and 12 months</time_frame>
    <description>Difference in the percentage of remissions (benefit) divided by the difference in the total number of adverse events (risk)</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">40</enrollment>
  <condition>Idiopathic Nephrotic Syndrome</condition>
  <condition>Minimal Change Disease</condition>
  <condition>Focal Segmental Glomerulosclerosis</condition>
  <arm_group>
    <arm_group_label>Rituximab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Rituximab: 375 mg/m2 intravenously on day 0 and day 14 B-cells will be monitored weekly, and if no complete depletion is achieved, additional dose(s) of Rituximab will be given at a weekly interval until complete B cell depletion (maximum of 2 additional doses).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Prednisone</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Prednisone 1 mg/kg/day (max 80 mg/day) for 8 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rituximab</intervention_name>
    <description>Rituximab: 375 mg/m2 intravenously on day 0 and day 14 B-cells will be monitored weekly, and if no complete depletion is achieved, additional dose(s) of Rituximab will be given at a weekly interval until complete B cell depletion (maximum of 2 additional doses).</description>
    <arm_group_label>Rituximab</arm_group_label>
    <other_name>Mabthera</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Prednisone</intervention_name>
    <description>Prednisone 1 mg/kg/day (max 80 mg/day) for 8 weeks</description>
    <arm_group_label>Prednisone</arm_group_label>
    <other_name>Prednisolone</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age ≥ 18 years&#xD;
&#xD;
          -  Persistent proteinuria ≥ 2 g/ 24 hours or a protein-to-creatinine ratio ≥ 2 g/10mmol&#xD;
             (2 g/g) after 8 weeks of treatment with high dose prednisone 1 mg/kg/day (max 80&#xD;
             mg/day)&#xD;
&#xD;
          -  Idiopathic nephrotic syndrome caused by biopsy proven minimal change disease or focal&#xD;
             segmental glomerulosclerosis&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Severe nephrotic syndrome with hypotension&#xD;
&#xD;
          -  Previous treatment with immunosuppressive medication other than prednisone&#xD;
&#xD;
          -  Treatment with prednisone &gt; 10 weeks in last six months&#xD;
&#xD;
          -  Secondary form of FSGS or minimal change disease&#xD;
&#xD;
          -  Patients who test positive for hepatitis B surface antigen (HBsAg) or hepatitis B core&#xD;
             antibody (anti-HBc).&#xD;
&#xD;
          -  Patients infected with HIV or suffering from other active infections&#xD;
&#xD;
          -  Patients inoculated with a vaccine within 4 weeks prior to inclusion&#xD;
&#xD;
          -  Pregnancy, breast feeding, women with inadequate contraception&#xD;
&#xD;
          -  Malignancy&#xD;
&#xD;
          -  Kidney transplantation&#xD;
&#xD;
          -  Previous treatment with monoclonal antibodies within 2 years prior to inclusion&#xD;
&#xD;
          -  Neutrophils &lt; 1.5 x 109/L and/or platelet counts &lt; 75 x 109/L&#xD;
&#xD;
          -  Severe heart failure (New York Heart Association Class IV) or severe, uncontrolled&#xD;
             cardiac disease&#xD;
&#xD;
          -  Active peptic ulcer&#xD;
&#xD;
          -  Known hypersensitivity to glucocorticoids&#xD;
&#xD;
          -  Insulin resistant diabetes mellitus&#xD;
&#xD;
          -  Treatment with carbamazepine, phenobarbital, phenytoin en rifampicin&#xD;
&#xD;
          -  Severe osteoporosis with vertebral fracture&#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>Jeroen K Deegens, MD,PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Radboud University Nijmegen Medical center</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Jack F Wetzels, MD, PhD</last_name>
    <role>Study Chair</role>
    <affiliation>Radboud University Nijmegen Medical Center</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Jeroen Deegens, MD,PhD</last_name>
    <phone>+31243614761</phone>
    <email>Jeroen.Deegens@radboudumc.nl</email>
  </overall_contact>
  <location>
    <facility>
      <name>Radboud University Medical Center</name>
      <address>
        <city>Nijmegen</city>
        <zip>6500HB</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jeroen K Deegens, MD, PhD</last_name>
      <phone>+31243614761</phone>
      <email>Jeroen.Deegens@radboudumc.nl</email>
    </contact>
    <contact_backup>
      <last_name>Jack F Wetzels, MD, PhD</last_name>
      <phone>+31243614761</phone>
      <email>Jack.Wetzels@radboudumc.nl</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <verification_date>August 2018</verification_date>
  <study_first_submitted>August 24, 2017</study_first_submitted>
  <study_first_submitted_qc>September 26, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">October 2, 2017</study_first_posted>
  <last_update_submitted>August 23, 2018</last_update_submitted>
  <last_update_submitted_qc>August 23, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">August 27, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Idiopathic nephrotic syndrome</keyword>
  <keyword>Minimal change disease</keyword>
  <keyword>Focal segmental glomerulosclerosis</keyword>
  <keyword>Rituximab</keyword>
  <keyword>Randomized clinical trial</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nephrotic Syndrome</mesh_term>
    <mesh_term>Nephrosis</mesh_term>
    <mesh_term>Glomerulosclerosis, Focal Segmental</mesh_term>
    <mesh_term>Nephrosis, Lipoid</mesh_term>
    <mesh_term>Syndrome</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Prednisone</mesh_term>
    <mesh_term>Prednisolone</mesh_term>
    <mesh_term>Rituximab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT03298698
org study id: RSRNS17
nct id: NCT03298698
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
This will be an open-label, randomized controlled trial which compares continued treatment
      with high dose prednisone (standard therapy) to treatment with rituximab in patients with
      minimal change disease or focal segmental glomerulosclerosis unresponsive to 8 weeks of high
      dose prednisone .

      patients either receive 2 doses of Rituximab 375 mg/m2 iv at time 0 and 14 days with
      termination of prednisone or standard therapy which consist of 8 additional weeks of high
      dose prednisone treatment.
Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are important
      causes of idiopathic nephrotic syndrome. First-line treatment with high dose prednisone up to
      16 weeks is associated with serious side effects. Especially if treatment continues for more
      than 8 weeks.

      Retrospective studies suggested that Rituximab may be more effective in patients unresponsive
      to 8 weeks of high dose prednisone. Treatment with rituximab was associated with a higher
      proportion of patients attaining remission of proteinuria and with fewer side effects.

      This will be an open-label, randomized controlled trial which compares continued treatment
      with high dose prednisone (standard therapy) to treatment with rituximab in patients with an
      idiopathic nephrotic syndrome due to biopsy proven MCD or FSGS age 18 years or older.

      All patients will be treated with high dose prednisone (1 mg/kg/day) for 8 weeks.

      Patients can be included in the trial in case of persistent persistent proteinuria ≥ 2 g/ 24
      hours or a protein-to-creatinine ratio ≥ 2 g/10mmol (2 g/g) after 8 weeks of treatment with
      high dose prednisone

      Patients either receive 2 doses of Rituximab 375 mg/m2 iv at time 0 and 14 days with
      termination of prednisone or standard therapy which consist of 8 additional weeks of high
      dose prednisone treatment. In the Rituximab group, B-cells will be monitored weekly, and if
      no complete depletion is achieved, additional dose(s) of Rituximab will be given at a weekly
      interval (maximum of 2 additional doses) until complete B cell depletion.

      Expected duration of the follow-up is 12 months, consisting of 9 visits.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Complete remission
time frame: 8 weeks
description: The proportion of patients reaching complete remission defined as proteinuria <0.3 g/day or < 300 mg/g
measure: Partial remission
time frame: 8 weeks
description: The proportion of patients reaching partial remission defined as proteinuria < 3.5 g/24 h or < 3.5 g/g and 50% lower than baseline proteinuria
measure: Late complete or partial remission
time frame: 2-12 months
description: The proportion of patients reaching complete remission defined as proteinuria <0.3 g/day or < 300 mg/g or The proportion of patients reaching partial remission defined as proteinuria < 3.5 g/24 h or < 3500 mg/g and 50% lower than baseline proteinuria
measure: Time to remission
time frame: 12 months
description: Time between start of treatment and reaching partial or complete remission
measure: Time to relapse
time frame: 12 months
description: The time between partial or complete remission and relapse (defined as urinary protein excretion to ≥3.5 g/24 h or ≥3.5 g/g creatinine
measure: Proportion of patients with a relapse
time frame: 12 months
description: The proportion of patients with relapse (defined as urinary protein excretion to ≥3.5 g/24 h or ≥3.5 g/g creatinine in patients who had at least attained a partial remission and the time to relapse
measure: Proportion of patients treated with additional immunosuppressive drugs
time frame: 12 months
description: Proportion of patients treated with immunosuppressive drugs other than the assigned treatment with rituximab or prednisolone
measure: General health assessment
time frame: at 2, 6, 9 and 12 months
description: Difference in general health measured by RAND-36
measure: Quality of life measured with TAAQOL
time frame: at 2, 6, 9 and 12 months
description: Difference in quality of life measured with TNO-academisch Ziekenhuis Leiden Questionnaire for Adult's Health-Difference in Quality of Life
measure: Proportion of patients with adverse events
time frame: at 2 and 12 months
description: The proportion of patients with adverse events. Adverse events graded according to Common Terminology Criteria For Adverse Events (NCI-CTCAE v4.03)
measure: Cost-effectiveness analysis
time frame: at 2, 6, 9 and 12 months
description: Cost-effectiveness will be calculated by dividing the difference in costs by the difference in effectiveness (based on the number of patients in remission) derived from the two groups. The resulting cost-effectiveness ratio will be expressed as costs per one more patient in remission
measure: Cost-utility analysis
time frame: at 2, 6, 9 and 12 months
description: Cost-utility analysis will be calculated by dividing the difference in costs by the difference in Quality Adjusted Life Years (QALY's). QALY's will be derived from the EuroQol-5d-5L questionnaire.
measure: Difference in kidney function
time frame: at 2 and 12 months
description: Difference in creatinine clearance and estimated glomerular filtration rate
measure: Proportion of patients with an increase of baseline serum creatinine ≥ 50%
time frame: at 2 and 12 months
description: The percentage of patients with an increase > 50% of serum creatinine from baseline.
measure: Benefit-risk ratio 1
time frame: at 2 and 12 months
description: Difference in the percentage of remissions (benefit) divided by the difference in adverse events grade 3 or 4, including Serious Adverse Events and Suspected Unexpected Serious Adverse Reaction (risk)
measure: Benefit-risk ratio 2
time frame: at 2 and 12 months
description: Difference in the percentage of remissions (benefit) divided by the difference in the total number of adverse events (risk)
arm group label: Rituximab
arm group type: Experimental
description: Rituximab: 375 mg/m2 intravenously on day 0 and day 14 B-cells will be monitored weekly, and if no complete depletion is achieved, additional dose(s) of Rituximab will be given at a weekly interval until complete B cell depletion (maximum of 2 additional doses).
arm group label: Prednisone
arm group type: Active Comparator
description: Prednisone 1 mg/kg/day (max 80 mg/day) for 8 weeks
intervention type: Drug
intervention name: Rituximab
description: Rituximab: 375 mg/m2 intravenously on day 0 and day 14 B-cells will be monitored weekly, and if no complete depletion is achieved, additional dose(s) of Rituximab will be given at a weekly interval until complete B cell depletion (maximum of 2 additional doses).
arm group label: Rituximab
other name: Mabthera
intervention type: Drug
intervention name: Prednisone
description: Prednisone 1 mg/kg/day (max 80 mg/day) for 8 weeks
arm group label: Prednisone
other name: Prednisolone
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Jeroen K Deegens, MD,PhD
role: Principal Investigator
affiliation: Radboud University Nijmegen Medical center
last name: Jack F Wetzels, MD, PhD
role: Study Chair
affiliation: Radboud University Nijmegen Medical Center
last name: Jeroen Deegens, MD,PhD
phone: +31243614761
email: Jeroen.Deegens@radboudumc.nl
facility: 
status: Recruiting
contact: 
contact backup: 
country: Netherlands
responsible party type: Sponsor
mesh term: Nephrotic Syndrome
mesh term: Nephrosis
mesh term: Glomerulosclerosis, Focal Segmental
mesh term: Nephrosis, Lipoid
mesh term: Syndrome
mesh term: Prednisone
mesh term: Prednisolone
mesh term: Rituximab
sharing ipd: Undecided