<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/NCT03274375</url>
  </required_header>
  <id_info>
    <org_study_id>P150919</org_study_id>
    <secondary_id>2016-A00259-42</secondary_id>
    <nct_id>NCT03274375</nct_id>
  </id_info>
  <brief_title>Immunoadsorption Therapy in Managing NMDAR Antibodies Encephalitis</brief_title>
  <acronym>IANMDAR</acronym>
  <official_title>Prospective Assessment of Efficacy of Immunoadsorption Therapy in Managing Childhood NMDA-Receptor (NMDAR) Antibodies Encephalitis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Assistance Publique - Hôpitaux de Paris</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Assistance Publique - Hôpitaux de Paris</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of the study is to assess the efficacy of immunoadsorption therapy (IA) on&#xD;
      improving the neurological status of severe pediatric anti-NMDAR encephalitis patients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Anti-NMDA-Receptor (NMDAR) encephalitis, the most frequent autoimmune encephalitis after&#xD;
      Acute Demyelinating encephalomyelitis (ADEM), affects children with predominant movement&#xD;
      disorders, decline of consciousness, psychiatric symptoms, language dysfunction, seizures,&#xD;
      dysautonomic symptoms. The cerebrospinal fluid (CSF) is most often abnormal with lymphocytic&#xD;
      pleocytosis, CSF-specific oligoclonal bands with intrathecal synthesis of anti-NMDAR&#xD;
      antibodies. Antibody titres in CSF and serum seem correlated with clinical outcome. Early&#xD;
      start of immunotherapy has been reported to improve clinical outcome and associated with less&#xD;
      relapses. In a recent large series (211 children/577), 77% of the patients were admitted to&#xD;
      Intensive Care Unit (ICU) at the beginning. Within the group of children, first-line&#xD;
      immunotherapy (95%) consisted of corticosteroids (89%), and/or intravenous immunoglobulins&#xD;
      (IgIV) (83%), and/or plasma exchange (28%) with failure in 46%. The second-line immunotherapy&#xD;
      consisting in rituximab (24%) and/or cyclophosphamide (16%) was proposed in 32%, and tended&#xD;
      to be associated with good outcome (OR=3.35, CI: 0.86-12.98, p=0.081 for 53 children;&#xD;
      statistical significance was achieved for the entire population including adults (OR: 2.69,&#xD;
      CI: 1.24-5.80, p = 0.012) and less relapses.&#xD;
&#xD;
      In investigators' experience, the clinical benefit of rituximab is delayed over one month,&#xD;
      while children go on worsening (50% admitted in ICU) thus claiming for faster removal of the&#xD;
      antibodies. Plasma exchange is proposed in most of the series as alternative or combined&#xD;
      treatment in the acute stage (first-line immunotherapy); recently, another plasmatherapy,&#xD;
      immunoadsorption therapy (IA), has been reported as an efficient therapeutic approach in&#xD;
      11/13 patients. In this retrospective study, patients received a median of 6 IA sessions&#xD;
      within a median period of 8 days with relevant clinical improvement. However these&#xD;
      encouraging results and investigators' experience in few children need further prospective&#xD;
      and standardized evaluation.&#xD;
&#xD;
      In IANMDAR study, each patient will receive 10 IA sessions during 28 days maximum. Rituximab&#xD;
      will be given each week for 4 weeks (one injection by week +/- 3 days):&#xD;
&#xD;
        -  at least 1 day before each IA session&#xD;
&#xD;
        -  the 4 injections should be done before V2 (Day 28 after the inclusion)&#xD;
&#xD;
      To assess the efficacy of IA-therapy at short term, the neurological status of patients will&#xD;
      be evaluated before and after the 10 IA sessions using the Pediatric Cerebral Performance&#xD;
      Category Scale (PCPCS) and the modified Rankin Scale (mRS).&#xD;
&#xD;
      To assess the efficacy of IA-therapy at long term, patients will have a standardized&#xD;
      follow-up during two years including neuropsychological evaluation at 1 year and at 2 years&#xD;
      (see below for further details).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">June 23, 2021</start_date>
  <completion_date type="Anticipated">June 2026</completion_date>
  <primary_completion_date type="Anticipated">July 2024</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Neurological status evaluated with the Pediatric Cerebral Performance Category Scale (PCPCS)</measure>
    <time_frame>before and after the 10 IA sessions, 28 days maximum</time_frame>
    <description>at least reduction of 1 point in PCPCS between the two evaluations is expected</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in Neurological status evaluated with the modified Rankin Scale (mRS)</measure>
    <time_frame>before and after the 10 IA sessions, 28 days maximum</time_frame>
    <description>at least reduction of 1 point in mRS between the two evaluations is expected</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Need of hospitalization in ICU and pediatric neurology unit</measure>
    <time_frame>28 days</time_frame>
    <description>To assess immunoadsorption therapy at short term in pediatric severe anti-NMDAR encephalitis patients</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of hospitalization in ICU and pediatric neurology unit</measure>
    <time_frame>28 days</time_frame>
    <description>To assess immunoadsorption therapy at short term in pediatric severe anti-NMDAR encephalitis patients</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Need for mechanical ventilation</measure>
    <time_frame>28 days</time_frame>
    <description>To assess immunoadsorption therapy at short term in pediatric severe anti-NMDAR encephalitis patients</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Need for vasopressive treatment</measure>
    <time_frame>28 days</time_frame>
    <description>To assess immunoadsorption therapy at short term in pediatric severe anti-NMDAR encephalitis patients</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time of recovery of independent daily-life activities</measure>
    <time_frame>28 days</time_frame>
    <description>independent ambulation, enteral feeding, responsiveness to simple instructions and verbal communication (first word)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Name and duration of medication for behavioral disorders and sleep disorders</measure>
    <time_frame>28 days</time_frame>
    <description>To assess immunoadsorption therapy at short term in pediatric severe anti-NMDAR encephalitis patients</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evolution of movement disorders assessed by the Movement Disorder Childhood Scale with video-taping, performed before and after IA therapy</measure>
    <time_frame>28 days</time_frame>
    <description>To assess immunoadsorption therapy at short term in pediatric severe anti-NMDAR encephalitis patients</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Biological evolution of NMDAR antibodies tested in serum</measure>
    <time_frame>28 days</time_frame>
    <description>before and after IA sessions</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Biological evolution of NMDAR antibodies tested in CSF</measure>
    <time_frame>28 days</time_frame>
    <description>at diagnosis and after IA sessions</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Titration of NMDAR antibodies in serum before and after the first and the last (tenth) IA session</measure>
    <time_frame>28 days</time_frame>
    <description>To assess immunoadsorption therapy at short term in pediatric severe anti-NMDAR encephalitis patients</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of each immunoadsorption treatment</measure>
    <time_frame>28 days</time_frame>
    <description>To assess tolerance of IA therapy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of use of medication for sedation by pharmaceutical class</measure>
    <time_frame>28 days</time_frame>
    <description>to assess need of sedation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Occurrence of hypotension with need for vasopressive treatment</measure>
    <time_frame>28 days</time_frame>
    <description>To assess tolerance of IA therapy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Occurrence of dysautonomic events (linked to the pathology): cardiac arrhythmia and heart rate events, flush, apnea</measure>
    <time_frame>28 days</time_frame>
    <description>To assess tolerance of IA therapy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Occurrence of vascular access complications : Infections (number, duration of antibiotics used), inadvertent removal, inefficiency (duration of retention of each vascular access)</measure>
    <time_frame>28 days</time_frame>
    <description>To assess tolerance of IA therapy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total duration of the immunoadsorption therapy</measure>
    <time_frame>28 days</time_frame>
    <description>To assess tolerance of IA therapy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total number of sessions</measure>
    <time_frame>28 days</time_frame>
    <description>To assess tolerance of IA therapy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of adsorbers used for each patient</measure>
    <time_frame>28 days</time_frame>
    <description>To assess tolerance of IA therapy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse events of associated treatments</measure>
    <time_frame>28 days</time_frame>
    <description>To assess tolerance of IA therapy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PCPCS score</measure>
    <time_frame>3 months</time_frame>
    <description>To assess Immunoadsorption therapy at long term</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>mRS score</measure>
    <time_frame>3 months</time_frame>
    <description>To assess Immunoadsorption therapy at long term</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PCPCS score</measure>
    <time_frame>6 months</time_frame>
    <description>To assess Immunoadsorption therapy at long term</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>mRS score</measure>
    <time_frame>6 months</time_frame>
    <description>To assess Immunoadsorption therapy at long term</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PCPCS score</measure>
    <time_frame>1 year</time_frame>
    <description>To assess Immunoadsorption therapy at long term</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PCPCS score</measure>
    <time_frame>at 2 years</time_frame>
    <description>To assess Immunoadsorption therapy at long term</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>mRS score</measure>
    <time_frame>1 year</time_frame>
    <description>To assess Immunoadsorption therapy at long term</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>mRS score</measure>
    <time_frame>at 2 years</time_frame>
    <description>To assess Immunoadsorption therapy at long term</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Need of hospitalization in functional rehabilitation unit</measure>
    <time_frame>2 years</time_frame>
    <description>To assess Immunoadsorption therapy at long term</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of hospitalization in functional rehabilitation unit</measure>
    <time_frame>2 years</time_frame>
    <description>To assess Immunoadsorption therapy at long term</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>School attendance (special school or not) and rehabilitation attendance</measure>
    <time_frame>2 years</time_frame>
    <description>To assess Immunoadsorption therapy at long term</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neuropsychological assessment for cognitive and behavioral status with Wechsler scales</measure>
    <time_frame>1 year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neuropsychological assessment for cognitive and behavioral status with Wechsler scales</measure>
    <time_frame>at 2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neuropsychological assessment for cognitive and behavioral status with Child Behavior Checklist (CBCL)</measure>
    <time_frame>1 year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neuropsychological assessment for cognitive and behavioral status with Child Behavior Checklist (CBCL)</measure>
    <time_frame>at 2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neuropsychological assessment for cognitive and behavioral status with Brief Inventory of Executive Functions (BRIEF)</measure>
    <time_frame>1 year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neuropsychological assessment for cognitive and behavioral status with Brief Inventory of Executive Functions (BRIEF)</measure>
    <time_frame>at 2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neuropsychological assessment for cognitive and behavioral status with Pediatric Quality of Life questionnaire (PedsQL)</measure>
    <time_frame>1 year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neuropsychological assessment for cognitive and behavioral status with Pediatric Quality of Life questionnaire (PedsQL)</measure>
    <time_frame>at 2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Visual attention evaluated with NEPSY scale</measure>
    <time_frame>1 year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Visual attention evaluated with NEPSY scale</measure>
    <time_frame>at 2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rey's figure test to evaluate visuospatial abilities and memory</measure>
    <time_frame>1 year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rey's figure test to evaluate visuospatial abilities and memory</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CMS to assess memory</measure>
    <time_frame>1 year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CMS to assess memory</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Digit span to assess memory</measure>
    <time_frame>1 year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Digit span to assess memory</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Movement disorders assessment with the Movement Disorder Childhood Scale</measure>
    <time_frame>3 months</time_frame>
    <description>To assess Immunoadsorption therapy at long term</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Movement disorders assessment with video-taping</measure>
    <time_frame>3 months</time_frame>
    <description>To assess Immunoadsorption therapy at long term</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Movement disorders assessment with the Movement Disorder Childhood Scale</measure>
    <time_frame>6 months</time_frame>
    <description>To assess Immunoadsorption therapy at long term</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Movement disorders assessment with video taping</measure>
    <time_frame>6 months</time_frame>
    <description>To assess Immunoadsorption therapy at long term</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Movement disorders assessment with the Movement Disorder Childhood Scale</measure>
    <time_frame>1 year</time_frame>
    <description>To assess Immunoadsorption therapy at long term</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Movement disorders assessment with the Movement Disorder Childhood Scale</measure>
    <time_frame>2 years</time_frame>
    <description>To assess Immunoadsorption therapy at long term</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Movement disorders assessment with video-taping</measure>
    <time_frame>1 year</time_frame>
    <description>To assess Immunoadsorption therapy at long term</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Movement disorders assessment with video-taping</measure>
    <time_frame>at 2 years</time_frame>
    <description>To assess Immunoadsorption therapy at long term</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Occurrence and date of relapses</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Presence of NMDAR antibodies in CSF</measure>
    <time_frame>6 months</time_frame>
    <description>titration at 6 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Presence of NMDAR antibodies in CSF</measure>
    <time_frame>1 year</time_frame>
    <description>titration at 1 year</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Presence of NMDAR antibodies in serum</measure>
    <time_frame>3 months</time_frame>
    <description>titration at 3 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Presence of NMDAR antibodies in serum</measure>
    <time_frame>6 months</time_frame>
    <description>titration at 6 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Presence of NMDAR antibodies in serum</measure>
    <time_frame>1 year</time_frame>
    <description>titration at 1 year</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proteinorachia</measure>
    <time_frame>6 months</time_frame>
    <description>titration at 6 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proteinorachia</measure>
    <time_frame>1 year</time_frame>
    <description>titration at 1 year</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Presence of oligoclonal bands in serum</measure>
    <time_frame>1 year</time_frame>
    <description>checked at 1 year</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Presence of oligoclonal bands in serum</measure>
    <time_frame>3 months</time_frame>
    <description>checked at 3 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Presence of oligoclonal bands in serum</measure>
    <time_frame>6 months</time_frame>
    <description>checked at 6 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Presence of oligoclonal bands in CSF</measure>
    <time_frame>6 months</time_frame>
    <description>checked at 6 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Presence of oligoclonal bands in CSF</measure>
    <time_frame>1 year</time_frame>
    <description>checked at 1 year</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of lymphocytes in serum</measure>
    <time_frame>3 months</time_frame>
    <description>checked at 3 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of lymphocytes in serum</measure>
    <time_frame>6 months</time_frame>
    <description>checked at 6 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of lymphocytes in serum</measure>
    <time_frame>1 year</time_frame>
    <description>checked at 1 year</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of lymphocytes in CSF</measure>
    <time_frame>6 months</time_frame>
    <description>checked at 6 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of lymphocytes in CSF</measure>
    <time_frame>1 year</time_frame>
    <description>checked at 1 year</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">20</enrollment>
  <condition>Anti-NMDAR Encephalitis</condition>
  <arm_group>
    <arm_group_label>IA session</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>4 Rituximab injections&#xD;
10 IA sessions</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>IA session</intervention_name>
    <description>10 IA sessions performed in 28 days maximum, using TherasorbTM adsorbers which contain sheep derived polyvalent antihuman-immunoglobulin coupled to SepharoseTM CL-4B.</description>
    <arm_group_label>IA session</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rituximab</intervention_name>
    <description>Concomitantly, Rituximab will be given each week for 4 weeks (one injection by week +/- 3 days):&#xD;
at least 1 day before each IA session&#xD;
the last injection will occur after the last session IA (minimum one day after)</description>
    <arm_group_label>IA session</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age: 0-18 years inclusive&#xD;
&#xD;
          -  Autoimmune encephalitis with positive anti-NMDAR antibodies in CSF (definite&#xD;
             anti-NMDAR encephalitis according to Graus's criteria (Graus et al., 2016).&#xD;
&#xD;
          -  PCPCS and mRS at 4 or over at the inclusion after first line therapy (steroids and/or&#xD;
             IgIV) when Rituximab therapy is warranted&#xD;
&#xD;
          -  Parents or legal guardians signed the Informed consent form&#xD;
&#xD;
          -  Social insurance affiliation&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Autoimmune encephalitis without NMDAR antibodies&#xD;
&#xD;
          -  PCPCS and mRS scores under 4 after first-line therapy&#xD;
&#xD;
          -  Contraindication to perform central vascular access&#xD;
&#xD;
          -  Pregnancy, breastfeeding or absence of effective contraception (including abstinence)&#xD;
             in a pubertal patient.&#xD;
&#xD;
          -  Contraindication to perform IA therapy :&#xD;
&#xD;
               -  Clinical conditions that prohibit transitory volume changes&#xD;
&#xD;
               -  Indications that prohibit anticoagulation using Heparin and/or ACD-A solutions&#xD;
&#xD;
               -  History of hypercoagulability&#xD;
&#xD;
               -  Generalized viral, bacterial and/or mycotic infections&#xD;
&#xD;
               -  Severe immune deficiencies (e.g. AIDS)&#xD;
&#xD;
               -  Suspected allergies against sheep antibodies or agarose&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>18 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Rémi SALOMON, Md, PhD</last_name>
    <role>Study Chair</role>
    <affiliation>Assistance Publique - Hôpitaux de Paris</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Isabelle DESGUERRE, MD, PhD</last_name>
    <phone>+33 1.44.49.41.42</phone>
    <email>isabelle.desguerre@aphp.fr</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Aminata TRAORE</last_name>
    <phone>+33 1 48 19 27 34</phone>
    <email>aminata.traore6@aphp.fr</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Hôpital Necker Enfants-Malades</name>
      <address>
        <city>Paris</city>
        <zip>75015</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Isabelle DESGUERRE, MD, PhD</last_name>
      <phone>+33 1 44 49 41 42</phone>
      <email>isabelle.desguerre@aphp.fr</email>
    </contact>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>July 24, 2017</study_first_submitted>
  <study_first_submitted_qc>September 4, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 6, 2017</study_first_posted>
  <last_update_submitted>July 12, 2023</last_update_submitted>
  <last_update_submitted_qc>July 12, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 13, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Anti-NMDAR encephalitis</keyword>
  <keyword>IA adsorption</keyword>
  <keyword>Paediatric</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Anti-N-Methyl-D-Aspartate Receptor Encephalitis</mesh_term>
    <mesh_term>Encephalitis</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/NCT03274375
org study id: P150919
secondary id: 2016-A00259-42
nct id: NCT03274375
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The purpose of the study is to assess the efficacy of immunoadsorption therapy (IA) on
      improving the neurological status of severe pediatric anti-NMDAR encephalitis patients.
Anti-NMDA-Receptor (NMDAR) encephalitis, the most frequent autoimmune encephalitis after
      Acute Demyelinating encephalomyelitis (ADEM), affects children with predominant movement
      disorders, decline of consciousness, psychiatric symptoms, language dysfunction, seizures,
      dysautonomic symptoms. The cerebrospinal fluid (CSF) is most often abnormal with lymphocytic
      pleocytosis, CSF-specific oligoclonal bands with intrathecal synthesis of anti-NMDAR
      antibodies. Antibody titres in CSF and serum seem correlated with clinical outcome. Early
      start of immunotherapy has been reported to improve clinical outcome and associated with less
      relapses. In a recent large series (211 children/577), 77% of the patients were admitted to
      Intensive Care Unit (ICU) at the beginning. Within the group of children, first-line
      immunotherapy (95%) consisted of corticosteroids (89%), and/or intravenous immunoglobulins
      (IgIV) (83%), and/or plasma exchange (28%) with failure in 46%. The second-line immunotherapy
      consisting in rituximab (24%) and/or cyclophosphamide (16%) was proposed in 32%, and tended
      to be associated with good outcome (OR=3.35, CI: 0.86-12.98, p=0.081 for 53 children;
      statistical significance was achieved for the entire population including adults (OR: 2.69,
      CI: 1.24-5.80, p = 0.012) and less relapses.

      In investigators' experience, the clinical benefit of rituximab is delayed over one month,
      while children go on worsening (50% admitted in ICU) thus claiming for faster removal of the
      antibodies. Plasma exchange is proposed in most of the series as alternative or combined
      treatment in the acute stage (first-line immunotherapy); recently, another plasmatherapy,
      immunoadsorption therapy (IA), has been reported as an efficient therapeutic approach in
      11/13 patients. In this retrospective study, patients received a median of 6 IA sessions
      within a median period of 8 days with relevant clinical improvement. However these
      encouraging results and investigators' experience in few children need further prospective
      and standardized evaluation.

      In IANMDAR study, each patient will receive 10 IA sessions during 28 days maximum. Rituximab
      will be given each week for 4 weeks (one injection by week +/- 3 days):

        -  at least 1 day before each IA session

        -  the 4 injections should be done before V2 (Day 28 after the inclusion)

      To assess the efficacy of IA-therapy at short term, the neurological status of patients will
      be evaluated before and after the 10 IA sessions using the Pediatric Cerebral Performance
      Category Scale (PCPCS) and the modified Rankin Scale (mRS).

      To assess the efficacy of IA-therapy at long term, patients will have a standardized
      follow-up during two years including neuropsychological evaluation at 1 year and at 2 years
      (see below for further details).
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Change in Neurological status evaluated with the Pediatric Cerebral Performance Category Scale (PCPCS)
time frame: before and after the 10 IA sessions, 28 days maximum
description: at least reduction of 1 point in PCPCS between the two evaluations is expected
measure: Change in Neurological status evaluated with the modified Rankin Scale (mRS)
time frame: before and after the 10 IA sessions, 28 days maximum
description: at least reduction of 1 point in mRS between the two evaluations is expected
measure: Need of hospitalization in ICU and pediatric neurology unit
time frame: 28 days
description: To assess immunoadsorption therapy at short term in pediatric severe anti-NMDAR encephalitis patients
measure: Duration of hospitalization in ICU and pediatric neurology unit
time frame: 28 days
description: To assess immunoadsorption therapy at short term in pediatric severe anti-NMDAR encephalitis patients
measure: Need for mechanical ventilation
time frame: 28 days
description: To assess immunoadsorption therapy at short term in pediatric severe anti-NMDAR encephalitis patients
measure: Need for vasopressive treatment
time frame: 28 days
description: To assess immunoadsorption therapy at short term in pediatric severe anti-NMDAR encephalitis patients
measure: Time of recovery of independent daily-life activities
time frame: 28 days
description: independent ambulation, enteral feeding, responsiveness to simple instructions and verbal communication (first word)
measure: Name and duration of medication for behavioral disorders and sleep disorders
time frame: 28 days
description: To assess immunoadsorption therapy at short term in pediatric severe anti-NMDAR encephalitis patients
measure: Evolution of movement disorders assessed by the Movement Disorder Childhood Scale with video-taping, performed before and after IA therapy
time frame: 28 days
description: To assess immunoadsorption therapy at short term in pediatric severe anti-NMDAR encephalitis patients
measure: Biological evolution of NMDAR antibodies tested in serum
time frame: 28 days
description: before and after IA sessions
measure: Biological evolution of NMDAR antibodies tested in CSF
time frame: 28 days
description: at diagnosis and after IA sessions
measure: Titration of NMDAR antibodies in serum before and after the first and the last (tenth) IA session
time frame: 28 days
description: To assess immunoadsorption therapy at short term in pediatric severe anti-NMDAR encephalitis patients
measure: Duration of each immunoadsorption treatment
time frame: 28 days
description: To assess tolerance of IA therapy
measure: Duration of use of medication for sedation by pharmaceutical class
time frame: 28 days
description: to assess need of sedation
measure: Occurrence of hypotension with need for vasopressive treatment
time frame: 28 days
description: To assess tolerance of IA therapy
measure: Occurrence of dysautonomic events (linked to the pathology): cardiac arrhythmia and heart rate events, flush, apnea
time frame: 28 days
description: To assess tolerance of IA therapy
measure: Occurrence of vascular access complications : Infections (number, duration of antibiotics used), inadvertent removal, inefficiency (duration of retention of each vascular access)
time frame: 28 days
description: To assess tolerance of IA therapy
measure: Total duration of the immunoadsorption therapy
time frame: 28 days
description: To assess tolerance of IA therapy
measure: Total number of sessions
time frame: 28 days
description: To assess tolerance of IA therapy
measure: Number of adsorbers used for each patient
time frame: 28 days
description: To assess tolerance of IA therapy
measure: Adverse events of associated treatments
time frame: 28 days
description: To assess tolerance of IA therapy
measure: PCPCS score
time frame: 3 months
description: To assess Immunoadsorption therapy at long term
measure: mRS score
time frame: 3 months
description: To assess Immunoadsorption therapy at long term
measure: PCPCS score
time frame: 6 months
description: To assess Immunoadsorption therapy at long term
measure: mRS score
time frame: 6 months
description: To assess Immunoadsorption therapy at long term
measure: PCPCS score
time frame: 1 year
description: To assess Immunoadsorption therapy at long term
measure: PCPCS score
time frame: at 2 years
description: To assess Immunoadsorption therapy at long term
measure: mRS score
time frame: 1 year
description: To assess Immunoadsorption therapy at long term
measure: mRS score
time frame: at 2 years
description: To assess Immunoadsorption therapy at long term
measure: Need of hospitalization in functional rehabilitation unit
time frame: 2 years
description: To assess Immunoadsorption therapy at long term
measure: Duration of hospitalization in functional rehabilitation unit
time frame: 2 years
description: To assess Immunoadsorption therapy at long term
measure: School attendance (special school or not) and rehabilitation attendance
time frame: 2 years
description: To assess Immunoadsorption therapy at long term
measure: Neuropsychological assessment for cognitive and behavioral status with Wechsler scales
time frame: 1 year
measure: Neuropsychological assessment for cognitive and behavioral status with Wechsler scales
time frame: at 2 years
measure: Neuropsychological assessment for cognitive and behavioral status with Child Behavior Checklist (CBCL)
time frame: 1 year
measure: Neuropsychological assessment for cognitive and behavioral status with Child Behavior Checklist (CBCL)
time frame: at 2 years
measure: Neuropsychological assessment for cognitive and behavioral status with Brief Inventory of Executive Functions (BRIEF)
time frame: 1 year
measure: Neuropsychological assessment for cognitive and behavioral status with Brief Inventory of Executive Functions (BRIEF)
time frame: at 2 years
measure: Neuropsychological assessment for cognitive and behavioral status with Pediatric Quality of Life questionnaire (PedsQL)
time frame: 1 year
measure: Neuropsychological assessment for cognitive and behavioral status with Pediatric Quality of Life questionnaire (PedsQL)
time frame: at 2 years
measure: Visual attention evaluated with NEPSY scale
time frame: 1 year
measure: Visual attention evaluated with NEPSY scale
time frame: at 2 years
measure: Rey's figure test to evaluate visuospatial abilities and memory
time frame: 1 year
measure: Rey's figure test to evaluate visuospatial abilities and memory
time frame: 2 years
measure: CMS to assess memory
time frame: 1 year
measure: CMS to assess memory
time frame: 2 years
measure: Digit span to assess memory
time frame: 1 year
measure: Digit span to assess memory
time frame: 2 years
measure: Movement disorders assessment with the Movement Disorder Childhood Scale
time frame: 3 months
description: To assess Immunoadsorption therapy at long term
measure: Movement disorders assessment with video-taping
time frame: 3 months
description: To assess Immunoadsorption therapy at long term
measure: Movement disorders assessment with the Movement Disorder Childhood Scale
time frame: 6 months
description: To assess Immunoadsorption therapy at long term
measure: Movement disorders assessment with video taping
time frame: 6 months
description: To assess Immunoadsorption therapy at long term
measure: Movement disorders assessment with the Movement Disorder Childhood Scale
time frame: 1 year
description: To assess Immunoadsorption therapy at long term
measure: Movement disorders assessment with the Movement Disorder Childhood Scale
time frame: 2 years
description: To assess Immunoadsorption therapy at long term
measure: Movement disorders assessment with video-taping
time frame: 1 year
description: To assess Immunoadsorption therapy at long term
measure: Movement disorders assessment with video-taping
time frame: at 2 years
description: To assess Immunoadsorption therapy at long term
measure: Occurrence and date of relapses
time frame: 2 years
measure: Presence of NMDAR antibodies in CSF
time frame: 6 months
description: titration at 6 months
measure: Presence of NMDAR antibodies in CSF
time frame: 1 year
description: titration at 1 year
measure: Presence of NMDAR antibodies in serum
time frame: 3 months
description: titration at 3 months
measure: Presence of NMDAR antibodies in serum
time frame: 6 months
description: titration at 6 months
measure: Presence of NMDAR antibodies in serum
time frame: 1 year
description: titration at 1 year
measure: Proteinorachia
time frame: 6 months
description: titration at 6 months
measure: Proteinorachia
time frame: 1 year
description: titration at 1 year
measure: Presence of oligoclonal bands in serum
time frame: 1 year
description: checked at 1 year
measure: Presence of oligoclonal bands in serum
time frame: 3 months
description: checked at 3 months
measure: Presence of oligoclonal bands in serum
time frame: 6 months
description: checked at 6 months
measure: Presence of oligoclonal bands in CSF
time frame: 6 months
description: checked at 6 months
measure: Presence of oligoclonal bands in CSF
time frame: 1 year
description: checked at 1 year
measure: Number of lymphocytes in serum
time frame: 3 months
description: checked at 3 months
measure: Number of lymphocytes in serum
time frame: 6 months
description: checked at 6 months
measure: Number of lymphocytes in serum
time frame: 1 year
description: checked at 1 year
measure: Number of lymphocytes in CSF
time frame: 6 months
description: checked at 6 months
measure: Number of lymphocytes in CSF
time frame: 1 year
description: checked at 1 year
arm group label: IA session
arm group type: Experimental
description: 4 Rituximab injections
10 IA sessions
intervention type: Drug
intervention name: IA session
description: 10 IA sessions performed in 28 days maximum, using TherasorbTM adsorbers which contain sheep derived polyvalent antihuman-immunoglobulin coupled to SepharoseTM CL-4B.
arm group label: IA session
intervention type: Drug
intervention name: Rituximab
description: Concomitantly, Rituximab will be given each week for 4 weeks (one injection by week +/- 3 days):
at least 1 day before each IA session
the last injection will occur after the last session IA (minimum one day after)
arm group label: IA session
criteria: 
gender: All
minimum age: N/A
maximum age: 18 Years
healthy volunteers: No
last name: Rémi SALOMON, Md, PhD
role: Study Chair
affiliation: Assistance Publique - Hôpitaux de Paris
last name: Isabelle DESGUERRE, MD, PhD
phone: +33 1.44.49.41.42
email: isabelle.desguerre@aphp.fr
last name: Aminata TRAORE
phone: +33 1 48 19 27 34
email: aminata.traore6@aphp.fr
facility: 
status: Recruiting
contact: 
country: France
responsible party type: Sponsor
mesh term: Anti-N-Methyl-D-Aspartate Receptor Encephalitis
mesh term: Encephalitis
mesh term: Rituximab
sharing ipd: No