<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/NCT03763643</url>
  </required_header>
  <id_info>
    <org_study_id>PEDS-2018-25868</org_study_id>
    <nct_id>NCT03763643</nct_id>
  </id_info>
  <brief_title>PRI-VENT FSGS: Preemptive Rituximab to Prevent Recurrent Focal Segmental Glomerulosclerosis Post-Transplant</brief_title>
  <official_title>PRI-VENT FSGS: Preemptive Rituximab to Prevent Recurrent Focal Segmental Glomerulosclerosis Post-Transplant</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Minnesota</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>United States Department of Defense</agency>
      <agency_class>U.S. Fed</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Minnesota</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a pilot/feasibility, multicenter, randomized, open label, clinical trial to test that&#xD;
      hypothesis that plasmapheresis plus rituximab prior to or at the time of kidney&#xD;
      transplantation can prevent recurrent FSGS in children and adults.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Recurrent FSGS is a risk factor for graft lost: Recurrence of FSGS can occur rapidly, within&#xD;
      minutes of transplantation, and can lead to immediate onset of proteinuria and graft&#xD;
      dysfunction. Recurrent FSGS is definitively diagnosed with a kidney biopsy. Early kidney&#xD;
      biopsies in recurrent FSGS often demonstrate only extensive foot process effacement with the&#xD;
      classic focal sclerosis appearing only after months of proteinuria. Recurrent FSGS is the&#xD;
      single most important cause of graft failure in patients with FSGS. Patients with recurrent&#xD;
      FSGS have significantly decreased graft survival compared to patients without recurrence and&#xD;
      often require multiple kidney transplants in their lifetime. A number of clinical risk&#xD;
      factors for recurrent FSGS have been identified including prior recurrence, Caucasian race,&#xD;
      rapid progression of primary FSGS to ESRD within 3 years, mesangial hypercellularity on&#xD;
      primary biopsy and living donor transplant, however these findings are inconsistent among&#xD;
      various small studies. 3 A recent study from Europe identified late steroid resistant FSGS&#xD;
      (nephrotic syndrome that is initially responsive to steroids, then later resistant) as a&#xD;
      strong risk factor for recurrence. These findings have been replicated in our recent&#xD;
      retrospective study of a North American cohort from the Midwest Pediatric Nephrology&#xD;
      Consortium (N=116) that showed risk of recurrent FSGS was 70.6% in children with late steroid&#xD;
      resistant FSGS compared to 35.8% risk in children with initial steroid resistant FSGS&#xD;
      (manuscript in preparation). Genetic risk factors for late steroid resistant FSGS are&#xD;
      unknown. In the same study Investigators identified native kidney biopsy findings that may&#xD;
      predict risk of recurrence. Unfortunately, an individual's risk of recurrent disease cannot&#xD;
      be predicted accurately prior to transplant. Thus, patients with FSGS have a high risk of&#xD;
      recurrent disease post-transplant that is difficult to predict and patients have poor kidney&#xD;
      transplant outcomes.&#xD;
&#xD;
      Plasmapheresis is utilized as a treatment for recurrent FSGS once it occurs: Several&#xD;
      therapies for recurrent FSGS have been attempted with varying degrees of success but there&#xD;
      remains no proven treatment for recurrent FSGS post-transplant. 7-10 The demonstration of a&#xD;
      possible causative circulating factor by Savin et. al. 11 galvanized the field to attempt&#xD;
      plasmapheresis to remove 'the permeability factor' as a therapy for recurrent FSGS.&#xD;
      Therefore, recurrent FSGS is most often treated with plasmapheresis to remove the circulating&#xD;
      factor and this is effective in a subset of patients. The results of uncontrolled single&#xD;
      center case reports and series suggest a benefit from plasmapheresis 12-14 although graft&#xD;
      loss from recurrent disease remains unacceptably high. Patients who do not respond to&#xD;
      plasmapheresis have rapidly progressive chronic kidney disease. These patients have been&#xD;
      treated with alternate agents such as rituximab, abatacept, or high dose cyclosporine with&#xD;
      variable responses.15-17 Ideally, therapies will be identified to prevent recurrent FSGS&#xD;
      before it occurs. Prevention of recurrent FSGS will lead to longer kidney transplant survival&#xD;
      and reduced health care costs.&#xD;
&#xD;
      No treatments are available to prevent the recurrence of FSGS after transplant: Since 2005,&#xD;
      there have been 3 published studies that have utilized a variety of protocols of&#xD;
      plasmapheresis for the prevention of recurrent FSGS with inconsistent results. 18-20 The&#xD;
      University of Minnesota pediatric transplant program has utilized pre-emptive plasmapheresis&#xD;
      in children at risk for recurrent FSGS since 2006. In a recent review of our data, the&#xD;
      incidence of recurrent FSGS post-transplant was not significantly different in patients who&#xD;
      had undergone pre-emptive prophylactic plasmapheresis versus historic controls who had not&#xD;
      (31% vs. 23%, p 0.5) (manuscript in press). Although this is a retrospective study, the data&#xD;
      seems to suggest that plasmapheresis alone is not effective for preventing recurrence of&#xD;
      FSGS. In addition, as stated above, the benefit of plasmapheresis in the treatment of&#xD;
      recurrence is reported. 12-14 Thus, plasmapheresis with additional preemptive strategies to&#xD;
      prevent recurrent FSGS are needed.&#xD;
&#xD;
      Rituximab has been used to treat recurrent FSGS and is a promising novel therapy to prevent&#xD;
      recurrent disease. Rituximab is a chimeric monoclonal antibody against CD20 on B cells that&#xD;
      leads to B cell depletion that has been used successfully for the treatment of primary&#xD;
      steroid sensitive nephrotic syndrome as well as steroid sensitive and resistant FSGS. 21,22&#xD;
      Rituximab may act in FSGS via alterations in B-cell/T-cell interactions leading to changes in&#xD;
      cytokine secretion or co-stimulation. Alternately, rituximab may have a direct effect on&#xD;
      podocyte structure and function as it has been found to bind directly to the sphingomyelin&#xD;
      phosphodiesterase acid-like 3b protein on the surface of podocytes. 23 Recent systematic&#xD;
      reviews on the use of rituximab in the treatment of post-transplant FSGS (either with or&#xD;
      without plasmapheresis) demonstrate partial or complete remission in ~60% of treated&#xD;
      patients.15,24 The use of preemptive rituximab has been reported to be effective in&#xD;
      preventing recurrent FSGS in 4 patients at very high risk due to prior graft loss from&#xD;
      recurrent disease, however randomized controlled trials have not been performed. 25 Given the&#xD;
      effectiveness of rituximab in the treatment of some patients with both primary and recurrent&#xD;
      FSGS and the report of successful preemptive use of rituximab in high risk transplant&#xD;
      patients, treatment with Rituximab in patients with FSGS prior to kidney transplant is a&#xD;
      promising novel therapy to prevent recurrent disease. Preventing recurrent FSGS, rather than&#xD;
      treating it once it has already occurred, is likely to minimize graft injury and prolong&#xD;
      graft life, therefore preemptive strategies are needed.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">July 1, 2019</start_date>
  <completion_date type="Anticipated">December 31, 2024</completion_date>
  <primary_completion_date type="Anticipated">August 31, 2023</primary_completion_date>
  <phase>Early Phase 1</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>
    <intervention_model_description>Control group and treatment/intervention group</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Feasibility assessment</measure>
    <time_frame>through study completion, an average of 1 year</time_frame>
    <description>quantifying the number and proportion of patients who can undergo the steps of recruitment, informed consent, enrollment, randomization, and follow-ups within the time frame of interest.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Patient and graft survival at 1 year post-transplant</measure>
    <time_frame>through study completion, an average of 1 year</time_frame>
    <description>Outcome is reported as the number of participants who survive with a functional graft one year post-transplant.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Graft function at 1 year post-transplant</measure>
    <time_frame>through study completion, an average of 1 year</time_frame>
    <description>Graft function will be assessed using the glomerular filtration rate (GFR) and Schwartz equation (for age ≤17 years) or the CKD-EPI (for age ≥18 years).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion with acute rejection at 1 year post-transplant</measure>
    <time_frame>through study completion, an average of 1 year</time_frame>
    <description>Outcome is reported as the percentage of participants who experience an acute graft rejection at one ear post-transplant.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion with CD19+ &lt;1%</measure>
    <time_frame>1 month, 6 months, and 12 months</time_frame>
    <description>Outcome is reported as the percentage with participants with a reconstitution of CD19+ B cells at one year post-transplant.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Recurrent FSGS free survival</measure>
    <time_frame>after 1 year post-transplant</time_frame>
    <description>To determine the difference in rate of recurrent FSGS after 1 year post-transplant in patients receiving plasmapheresis and rituximab prior to or at the time of kidney transplantation compared to those receiving plasmapheresis alone.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">60</enrollment>
  <condition>Focal Segmental Glomerulosclerosis</condition>
  <arm_group>
    <arm_group_label>Rituximab + plasmapharesis</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>This is a phase III, multicenter, randomized, open-label clinical trial. Participants with FSGS will be randomized 1:1 to receive rituximab or placebo on day -1, 0 and +1 prior to or after kidney transplantation in addition to standard plasmapheresis.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo + plasmapharesis</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>This is a phase III, multicenter, randomized, open-label clinical trial. Participants with FSGS will be randomized 1:1 to receive rituximab or placebo on day -1, 0 and +1 prior to or after kidney transplantation in addition to standard plasmapheresis.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rituximab</intervention_name>
    <description>Rituximab 375mg/m2 intravenous on day 0 or -1 prior to kidney transplant</description>
    <arm_group_label>Rituximab + plasmapharesis</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Plasmapheresis</intervention_name>
    <description>1.5 volume exchange plasmapheresis with fresh frozen plasma replacement</description>
    <arm_group_label>Placebo + plasmapharesis</arm_group_label>
    <arm_group_label>Rituximab + plasmapharesis</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        In order to be eligible to participate in this study, an individual must meet all of the&#xD;
        following criteria:&#xD;
&#xD;
          1. Age 1-65 years at the time of kidney transplant&#xD;
&#xD;
          2. Biopsy proven diagnosis of primary FSGS or minimal change disease&#xD;
&#xD;
          3. History of nephrotic syndrome (proteinuria, edema, hypoalbuminemia)&#xD;
&#xD;
          4. First kidney transplant or second or third transplant with a history of recurrent FSGS&#xD;
             in the first or second kidney transplant.&#xD;
&#xD;
          5. The patient (if ≥18 years old) or the child's parent or guardian must be able and&#xD;
             willing to give written informed consent and comply with the requirements of the study&#xD;
             protocol. Patient assent if &lt;18 years old will be required per local IRB requirements.&#xD;
&#xD;
          6. Negative urine pregnancy test prior to randomization (for females who are&#xD;
             post-menarche).&#xD;
&#xD;
          7. Males and females of reproductive potential (sexually active in boys or post-menarche&#xD;
             in girls) must agree to use an acceptable method of birth control during treatment and&#xD;
             for twelve months (1 year) after completion of treatment with rituximab.&#xD;
&#xD;
        An individual who meets any of the following criteria will be excluded from participation&#xD;
        in this study:&#xD;
&#xD;
        1. Known genetic cause of FSGS 2. Patients with FSGS secondary to another condition&#xD;
        (obesity, viral infection, medications, etc.) 3. 4. Received rituximab within 1 year prior&#xD;
        to transplant 5. Known hypersensitivity to rituximab, to any of its excipients, or to&#xD;
        murine proteins 6. History of severe allergic or anaphylactic reactions to humanized or&#xD;
        murine monoclonal antibodies 7. Known active bacterial, viral (e.g. HIV, hepatitis B,&#xD;
        hepatitis C), fungal, mycobacterial, or other infection (including tuberculosis or atypical&#xD;
        mycobacterial disease, but excluding fungal infections of nail beds) or any major episode&#xD;
        of infection requiring hospitalization or treatment with iv antibiotics within 4 weeks of&#xD;
        screening or oral antibiotics within 2 weeks prior to screening visit.&#xD;
&#xD;
        8. Participation in another therapeutic trial within 30 days of enrollment or 5 half-lives&#xD;
        of the investigational drug (whichever is longer) 9. ANC &lt; 1.5 x 103 10. Hemoglobin: &lt; 8.0&#xD;
        gm/dL 11. Platelets: &lt; 100,000/mm 12. AST or ALT &gt;2.5 x Upper Limit of Normal at the local&#xD;
        institution's laboratory 13. History of drug, alcohol, or chemical abuse within 6 months&#xD;
        prior to screening visit.&#xD;
&#xD;
        14. Pregnant, lactating, or refusal of birth control in an adolescent of child-bearing&#xD;
        potential 15. Concomitant malignancies or previous malignancies 16. History of psychiatric&#xD;
        disorder that would interfere with normal participation in this protocol 17. History of&#xD;
        significant cardiac (including arrhythmias) or pulmonary disease (including obstructive&#xD;
        pulmonary disease) 18. Any other disease, metabolic dysfunction, physical examination&#xD;
        finding, or clinical laboratory finding giving reasonable suspicion of a disease or&#xD;
        condition that contraindicates the use of an investigational drug or that may affect the&#xD;
        interpretation of the results or render the patient at high risk from treatment&#xD;
        complications 19. Inability to comply with study and follow-up procedures&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>1 Year</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Michelle Rheault, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Minnesota</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Amy Hanson</last_name>
    <phone>612-626-4424</phone>
    <email>amhanson@umn.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Kayla Arndt</last_name>
    <email>arndt374@umn.edu</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>University of Alabama</name>
      <address>
        <city>Tuscaloosa</city>
        <state>Alabama</state>
        <zip>35487</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Michael Siefert, MD</last_name>
      <email>mseifert@uabmc.edu</email>
    </contact>
    <investigator>
      <last_name>Michael Siefert, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of California at Davis</name>
      <address>
        <city>Davis</city>
        <state>California</state>
        <zip>95616</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Junichuro Sageshima, MD</last_name>
      <email>jsageshima@ucdavis.edu</email>
    </contact>
    <investigator>
      <last_name>Junichuro Sageshima, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Lurie Children's Hospital</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60611</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Priya Verghese, MD, MPH</last_name>
      <email>pverghese@luriechildren.org</email>
    </contact>
    <investigator>
      <last_name>Priya Verghese, MD, MPH</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Iowa</name>
      <address>
        <city>Iowa City</city>
        <state>Iowa</state>
        <zip>52242</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Christie Thomas, MD</last_name>
      <email>Christie-thomas@uiowa.edu</email>
    </contact>
    <investigator>
      <last_name>Christie Thomas, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Lyndsay Harshman, MD, MS</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Children's Hospital of Colorado</name>
      <address>
        <city>Aurora</city>
        <state>Minnesota</state>
        <zip>80045</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Margret Bock, MD, MS</last_name>
      <email>Margret.bock@childrenscolorado.org</email>
    </contact>
    <investigator>
      <last_name>Margret Bock, MD, MS</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Hennepin Health</name>
      <address>
        <city>Minneapolis</city>
        <state>Minnesota</state>
        <zip>55415</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ajay Israni, MD, MS</last_name>
      <email>Isran001@umn.edu</email>
    </contact>
    <investigator>
      <last_name>Ajay Israni, MD, MS</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Minnesota</name>
      <address>
        <city>Minneapolis</city>
        <state>Minnesota</state>
        <zip>55455</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Michelle Rheault, MD</last_name>
      <phone>612-626-2922</phone>
      <email>rheau002@umn.edu</email>
    </contact>
    <investigator>
      <last_name>Michelle Rheault, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Mayo Clinic</name>
      <address>
        <city>Rochester</city>
        <state>Minnesota</state>
        <zip>55905</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Amer Hatem, MD</last_name>
      <email>Amer.hatem@mayo.edu</email>
    </contact>
    <investigator>
      <last_name>Amer Hatem, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Mireille El Ters, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Carl Cramer, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Duke University</name>
      <address>
        <city>Durham</city>
        <state>North Carolina</state>
        <zip>27708</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Rasheed Gbadegesin, MD, MBBS</last_name>
      <email>Rasheed.gbadegesin@duke.edu</email>
    </contact>
    <investigator>
      <last_name>Rasheed Rasheed.gbadegesin@duke.edu, MD, MBBS</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Eileen Tsai Chambers, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Cincinnati</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <zip>45221</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Amit Govil, MD</last_name>
      <email>govilat@ucmail.uc.edu</email>
    </contact>
    <investigator>
      <last_name>Amit Govil, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Cincinnati Children's Hospital</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <zip>45229</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>David Hooper, MD, MS</last_name>
      <email>David.Hooper@cchmc.org</email>
    </contact>
    <investigator>
      <last_name>David Hooper, MD, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Children's Hospital of Philadelphia</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Sandra Amaral, MD, MHS</last_name>
      <email>AmaralS@email.chop.edu</email>
    </contact>
    <investigator>
      <last_name>Sandra Amaral, MD, MHS</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Seattle Children's Hospital</name>
      <address>
        <city>Seattle</city>
        <state>Washington</state>
        <zip>98105</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jodi Smith, MD, MPH</last_name>
      <email>Jodi.smith@seattlechildrens.org</email>
    </contact>
    <investigator>
      <last_name>Jodi Smith, MD, MPH</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>August 7, 2018</study_first_submitted>
  <study_first_submitted_qc>December 3, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 4, 2018</study_first_posted>
  <last_update_submitted>June 21, 2023</last_update_submitted>
  <last_update_submitted_qc>June 21, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 22, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Glomerulosclerosis, Focal Segmental</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Rituximab</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/NCT03763643
org study id: PEDS-2018-25868
nct id: NCT03763643
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This is a pilot/feasibility, multicenter, randomized, open label, clinical trial to test that
      hypothesis that plasmapheresis plus rituximab prior to or at the time of kidney
      transplantation can prevent recurrent FSGS in children and adults.
Recurrent FSGS is a risk factor for graft lost: Recurrence of FSGS can occur rapidly, within
      minutes of transplantation, and can lead to immediate onset of proteinuria and graft
      dysfunction. Recurrent FSGS is definitively diagnosed with a kidney biopsy. Early kidney
      biopsies in recurrent FSGS often demonstrate only extensive foot process effacement with the
      classic focal sclerosis appearing only after months of proteinuria. Recurrent FSGS is the
      single most important cause of graft failure in patients with FSGS. Patients with recurrent
      FSGS have significantly decreased graft survival compared to patients without recurrence and
      often require multiple kidney transplants in their lifetime. A number of clinical risk
      factors for recurrent FSGS have been identified including prior recurrence, Caucasian race,
      rapid progression of primary FSGS to ESRD within 3 years, mesangial hypercellularity on
      primary biopsy and living donor transplant, however these findings are inconsistent among
      various small studies. 3 A recent study from Europe identified late steroid resistant FSGS
      (nephrotic syndrome that is initially responsive to steroids, then later resistant) as a
      strong risk factor for recurrence. These findings have been replicated in our recent
      retrospective study of a North American cohort from the Midwest Pediatric Nephrology
      Consortium (N=116) that showed risk of recurrent FSGS was 70.6% in children with late steroid
      resistant FSGS compared to 35.8% risk in children with initial steroid resistant FSGS
      (manuscript in preparation). Genetic risk factors for late steroid resistant FSGS are
      unknown. In the same study Investigators identified native kidney biopsy findings that may
      predict risk of recurrence. Unfortunately, an individual's risk of recurrent disease cannot
      be predicted accurately prior to transplant. Thus, patients with FSGS have a high risk of
      recurrent disease post-transplant that is difficult to predict and patients have poor kidney
      transplant outcomes.

      Plasmapheresis is utilized as a treatment for recurrent FSGS once it occurs: Several
      therapies for recurrent FSGS have been attempted with varying degrees of success but there
      remains no proven treatment for recurrent FSGS post-transplant. 7-10 The demonstration of a
      possible causative circulating factor by Savin et. al. 11 galvanized the field to attempt
      plasmapheresis to remove 'the permeability factor' as a therapy for recurrent FSGS.
      Therefore, recurrent FSGS is most often treated with plasmapheresis to remove the circulating
      factor and this is effective in a subset of patients. The results of uncontrolled single
      center case reports and series suggest a benefit from plasmapheresis 12-14 although graft
      loss from recurrent disease remains unacceptably high. Patients who do not respond to
      plasmapheresis have rapidly progressive chronic kidney disease. These patients have been
      treated with alternate agents such as rituximab, abatacept, or high dose cyclosporine with
      variable responses.15-17 Ideally, therapies will be identified to prevent recurrent FSGS
      before it occurs. Prevention of recurrent FSGS will lead to longer kidney transplant survival
      and reduced health care costs.

      No treatments are available to prevent the recurrence of FSGS after transplant: Since 2005,
      there have been 3 published studies that have utilized a variety of protocols of
      plasmapheresis for the prevention of recurrent FSGS with inconsistent results. 18-20 The
      University of Minnesota pediatric transplant program has utilized pre-emptive plasmapheresis
      in children at risk for recurrent FSGS since 2006. In a recent review of our data, the
      incidence of recurrent FSGS post-transplant was not significantly different in patients who
      had undergone pre-emptive prophylactic plasmapheresis versus historic controls who had not
      (31% vs. 23%, p 0.5) (manuscript in press). Although this is a retrospective study, the data
      seems to suggest that plasmapheresis alone is not effective for preventing recurrence of
      FSGS. In addition, as stated above, the benefit of plasmapheresis in the treatment of
      recurrence is reported. 12-14 Thus, plasmapheresis with additional preemptive strategies to
      prevent recurrent FSGS are needed.

      Rituximab has been used to treat recurrent FSGS and is a promising novel therapy to prevent
      recurrent disease. Rituximab is a chimeric monoclonal antibody against CD20 on B cells that
      leads to B cell depletion that has been used successfully for the treatment of primary
      steroid sensitive nephrotic syndrome as well as steroid sensitive and resistant FSGS. 21,22
      Rituximab may act in FSGS via alterations in B-cell/T-cell interactions leading to changes in
      cytokine secretion or co-stimulation. Alternately, rituximab may have a direct effect on
      podocyte structure and function as it has been found to bind directly to the sphingomyelin
      phosphodiesterase acid-like 3b protein on the surface of podocytes. 23 Recent systematic
      reviews on the use of rituximab in the treatment of post-transplant FSGS (either with or
      without plasmapheresis) demonstrate partial or complete remission in ~60% of treated
      patients.15,24 The use of preemptive rituximab has been reported to be effective in
      preventing recurrent FSGS in 4 patients at very high risk due to prior graft loss from
      recurrent disease, however randomized controlled trials have not been performed. 25 Given the
      effectiveness of rituximab in the treatment of some patients with both primary and recurrent
      FSGS and the report of successful preemptive use of rituximab in high risk transplant
      patients, treatment with Rituximab in patients with FSGS prior to kidney transplant is a
      promising novel therapy to prevent recurrent disease. Preventing recurrent FSGS, rather than
      treating it once it has already occurred, is likely to minimize graft injury and prolong
      graft life, therefore preemptive strategies are needed.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Control group and treatment/intervention group
primary purpose: Prevention
masking: None (Open Label)
measure: Feasibility assessment
time frame: through study completion, an average of 1 year
description: quantifying the number and proportion of patients who can undergo the steps of recruitment, informed consent, enrollment, randomization, and follow-ups within the time frame of interest.
measure: Patient and graft survival at 1 year post-transplant
time frame: through study completion, an average of 1 year
description: Outcome is reported as the number of participants who survive with a functional graft one year post-transplant.
measure: Graft function at 1 year post-transplant
time frame: through study completion, an average of 1 year
description: Graft function will be assessed using the glomerular filtration rate (GFR) and Schwartz equation (for age ≤17 years) or the CKD-EPI (for age ≥18 years).
measure: Proportion with acute rejection at 1 year post-transplant
time frame: through study completion, an average of 1 year
description: Outcome is reported as the percentage of participants who experience an acute graft rejection at one ear post-transplant.
measure: Proportion with CD19+ <1%
time frame: 1 month, 6 months, and 12 months
description: Outcome is reported as the percentage with participants with a reconstitution of CD19+ B cells at one year post-transplant.
measure: Recurrent FSGS free survival
time frame: after 1 year post-transplant
description: To determine the difference in rate of recurrent FSGS after 1 year post-transplant in patients receiving plasmapheresis and rituximab prior to or at the time of kidney transplantation compared to those receiving plasmapheresis alone.
arm group label: Rituximab + plasmapharesis
arm group type: Experimental
description: This is a phase III, multicenter, randomized, open-label clinical trial. Participants with FSGS will be randomized 1:1 to receive rituximab or placebo on day -1, 0 and +1 prior to or after kidney transplantation in addition to standard plasmapheresis.
arm group label: Placebo + plasmapharesis
arm group type: Placebo Comparator
description: This is a phase III, multicenter, randomized, open-label clinical trial. Participants with FSGS will be randomized 1:1 to receive rituximab or placebo on day -1, 0 and +1 prior to or after kidney transplantation in addition to standard plasmapheresis.
intervention type: Drug
intervention name: Rituximab
description: Rituximab 375mg/m2 intravenous on day 0 or -1 prior to kidney transplant
arm group label: Rituximab + plasmapharesis
intervention type: Procedure
intervention name: Plasmapheresis
description: 1.5 volume exchange plasmapheresis with fresh frozen plasma replacement
arm group label: Placebo + plasmapharesis
arm group label: Rituximab + plasmapharesis
criteria: 
gender: All
minimum age: 1 Year
maximum age: 65 Years
healthy volunteers: No
last name: Michelle Rheault, MD
role: Principal Investigator
affiliation: University of Minnesota
last name: Amy Hanson
phone: 612-626-4424
email: amhanson@umn.edu
last name: Kayla Arndt
email: arndt374@umn.edu
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status: Recruiting
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country: United States
responsible party type: Sponsor
mesh term: Glomerulosclerosis, Focal Segmental
mesh term: Rituximab
sharing ipd: No