<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/NCT01730209</url>
  </required_header>
  <id_info>
    <org_study_id>NL38619.078.11</org_study_id>
    <nct_id>NCT01730209</nct_id>
  </id_info>
  <brief_title>Efficacy of RAD001/Everolimus in Autism and NeuroPsychological Deficits in Children With Tuberous Sclerosis Complex</brief_title>
  <acronym>RAPIT</acronym>
  <official_title>Efficacy of RAD001/Everolimus in Autism and NeuroPsychological Deficits in Children With Tuberous Sclerosis Complex</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Erasmus Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Utrecht University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Erasmus Medical Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Tuberous sclerosis complex (TSC) is a genetic disease that leads to mental retardation in&#xD;
      over 50% of patients, and to learning problems, behavioral problems, autism and epilepsy in&#xD;
      up to 90% of patients. The underlying deficit of TSC, loss of inhibition of the mammalian&#xD;
      target of rapamycin (mTOR) protein due to dysfunction of the tuberin/hamartin protein&#xD;
      complex, can be rescued by everolimus. Everolimus has been registered as treatment for renal&#xD;
      cell carcinoma and giant cell astrocytoma (SEGA). Evidence in human and animal studies&#xD;
      suggests that mTOR inhibitors improve learning and development in patients with TSC.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Randomized double-blind placebo controlled intervention study in children with TSC between&#xD;
      age 4 and 15 years with an intelligence quotient (IQ) estimated &lt;80 and/or special schooling&#xD;
      and/or autism spectrum disorder and/or learning disability requiring remedial teaching.&#xD;
&#xD;
      Patients are randomised to receive everolimus or placebo during a period of 12 months.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>November 2012</start_date>
  <completion_date type="Anticipated">November 2016</completion_date>
  <primary_completion_date type="Anticipated">November 2015</primary_completion_date>
  <phase>Phase 2/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>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Cognitive ability measured by IQ</measure>
    <time_frame>12 months</time_frame>
    <description>Assessed by Wechsler scales: Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III NL) and Wechsler Intelligence Scale for Children (WISC-III-NL)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Autistic features</measure>
    <time_frame>12 Months</time_frame>
    <description>Assessed by Autism Diagnostic Observation Schedule (ADOS)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Social and communicational skills</measure>
    <time_frame>12 Months</time_frame>
    <description>Assessed by social responsiveness scale (SRS) and Dutch Children's Communication Checklist (CCC-2-NL) questionnaires</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Working memory and attention, information processing</measure>
    <time_frame>6 and 12 Months</time_frame>
    <description>Assessed by Cambridge Neuropsychological Test Automated Battery (CANTAB)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Visual-motor integration</measure>
    <time_frame>12 Months</time_frame>
    <description>Assessed by BEERY Visual-Motor Integration (BEERY VMI), grooved pegboard</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Child behavior</measure>
    <time_frame>12 Months</time_frame>
    <description>Assessed by Child Behavior Checklist (CBCL) and Teacher's Report Form (TRF) questionnaires</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Executive functioning</measure>
    <time_frame>12 Months</time_frame>
    <description>Assessed by Behavior Rating Inventory of Executive Functioning (BRIEF) questionnaire Dutch version</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Sleeping problems</measure>
    <time_frame>12 Months</time_frame>
    <description>Assessed by Sleep Disturbance Scale for Children (SDSC) questionnaire</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Child health</measure>
    <time_frame>12 Months</time_frame>
    <description>Assessed by Child Health Questionnaire Parent Form (CHQ-PF50) questionnaire</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Sensory related difficulties</measure>
    <time_frame>12 Months</time_frame>
    <description>Assessed by Short Sensory Profile (SSP) questionnaire</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Epilepsy</measure>
    <time_frame>12 Months</time_frame>
    <description>Comparison of epilepsy frequency during month previous to study start and last month of trial participation.&#xD;
EEG abnormalities</description>
  </secondary_outcome>
  <other_outcome>
    <measure>School level</measure>
    <time_frame>12 Months</time_frame>
    <description>Assessed by the school CITO (centraal instituut voor toetsontwikkeling) scores or reading and arithmetic scores</description>
  </other_outcome>
  <other_outcome>
    <measure>Pharmacokinetics</measure>
    <time_frame>12 Months</time_frame>
    <description>Assessed by measuring trough levels of everolimus</description>
  </other_outcome>
  <other_outcome>
    <measure>Safety</measure>
    <time_frame>12 Months</time_frame>
    <description>Levels of and abnormalities in blood control values</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">60</enrollment>
  <condition>Tuberous Sclerosis Complex</condition>
  <condition>TSC Related Cognitive Disability</condition>
  <condition>TSC Related Autism</condition>
  <condition>TSC Related Learning Problems</condition>
  <arm_group>
    <arm_group_label>Everolimus</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Everolimus once daily for 1 year, titration to trough levels of 5-10 ng/ml</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo treatment for 1 year. Tablets will be identical to everolimus tablets.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Everolimus</intervention_name>
    <description>Everolimus once daily titrated to trough levels of 5-10 ng/ml.</description>
    <arm_group_label>Everolimus</arm_group_label>
    <other_name>RAD001</other_name>
    <other_name>Votubia</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Children with a definite diagnosis of TSC between 4 and 15 years.&#xD;
&#xD;
          -  With an IQ estimated &lt;80 and/or special schooling and/or autism spectrum disorder&#xD;
             and/or learning disability requiring remedial teaching.&#xD;
&#xD;
          -  Written informed consent by parents/care-takers, and the patient if he or she is 12&#xD;
             years or older and cognitively able to consent.&#xD;
&#xD;
          -  In girls after menarche, appropriate contraception must be used or abstinence&#xD;
             practiced.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Hepatic dysfunction&#xD;
&#xD;
          -  Surgery &lt;6wk&#xD;
&#xD;
          -  Current infection at time of inclusion&#xD;
&#xD;
          -  Developmental age estimated below 3.5 years&#xD;
&#xD;
          -  Intractable epilepsy with more than 1 seizure/week&#xD;
&#xD;
          -  Inability to comply with the treatment protocol&#xD;
&#xD;
          -  Additional diseases or disorders that may influence the endpoints, including:&#xD;
&#xD;
               -  SEGA requiring treatment&#xD;
&#xD;
               -  Uncontrolled diabetes mellitus&#xD;
&#xD;
               -  Known impaired lung function&#xD;
&#xD;
          -  Allergy for any of the components of the study medication&#xD;
&#xD;
          -  Prior treatment with mTOR inhibitors&#xD;
&#xD;
          -  HIV seropositivity&#xD;
&#xD;
          -  Bleeding diathesis or oral anti-vitamin K medication&#xD;
&#xD;
          -  Serum creatinine &gt; 1.5 x ULN&#xD;
&#xD;
          -  Uncontrolled hyperlipidemia (fasting serum cholesterol &gt; 7.75 mmol/L, fasting serum&#xD;
             triglycerides &gt; 2.5 x ULN)&#xD;
&#xD;
          -  Use of investigational drug within 30 days prior to inclusion&#xD;
&#xD;
          -  History of myocardial infarction, angina or stroke related to atherosclerosis, organ&#xD;
             transplantation, malignancy in the past 2 years&#xD;
&#xD;
          -  Pregnancy or breastfeeding&#xD;
&#xD;
          -  Children at risk for Hepatitis B (HB), unless hepatitis B serology is normal. Risk&#xD;
             groups are children who have lived in Asia, Africa, Central and South America, Eastern&#xD;
             Europe, Spain, Portugal, and Greece, children with known or suspected past or current&#xD;
             hepatitis B infection, current or prior IV illicit drug use, current or prior&#xD;
             dialysis, household contact with hepatitis B infected patient(s), current or prior&#xD;
             high-risk sexual activity, body piercing or tattoos, mother known to have hepatitis B&#xD;
             history. If vaccinated, presence of HBs Ab is normal.&#xD;
&#xD;
          -  Known or suspected hepatitis C infection, unless hepatitis C serology is normal.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>4 Years</minimum_age>
    <maximum_age>15 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>M.C.Y. de Wit, MD. PhD.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Erasmus Medical Center</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>M.C.Y. de Wit, MD. PhD.</last_name>
    <phone>+31 10 703 6956</phone>
    <email>tubereuzesclerose@erasmusmc.nl</email>
  </overall_contact>
  <location>
    <facility>
      <name>Erasmus Medical Center</name>
      <address>
        <city>Rotterdam</city>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>M.C.Y. de Wit, MD. PhD.</last_name>
      <phone>+31 10 703 6956</phone>
      <email>tubereuzesclerose@erasmusmc.nl</email>
    </contact>
    <investigator>
      <last_name>M.C.Y. de Wit, MD. PhD.</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>I.E. Overwater, MSc</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <verification_date>May 2015</verification_date>
  <study_first_submitted>October 26, 2012</study_first_submitted>
  <study_first_submitted_qc>November 20, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 21, 2012</study_first_posted>
  <last_update_submitted>May 4, 2015</last_update_submitted>
  <last_update_submitted_qc>May 4, 2015</last_update_submitted_qc>
  <last_update_posted type="Estimate">May 5, 2015</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Erasmus Medical Center</investigator_affiliation>
    <investigator_full_name>M.C.Y. de Wit, MD PhD</investigator_full_name>
    <investigator_title>Pediatric Neurologist</investigator_title>
  </responsible_party>
  <keyword>Tuberous Sclerosis Complex</keyword>
  <keyword>TSC</keyword>
  <keyword>Autism</keyword>
  <keyword>Learning problems</keyword>
  <keyword>Everolimus</keyword>
  <keyword>RAD001</keyword>
  <keyword>Treatment</keyword>
  <keyword>Cognition</keyword>
  <keyword>Intellectual disability</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tuberous Sclerosis</mesh_term>
    <mesh_term>Sclerosis</mesh_term>
    <mesh_term>Autistic Disorder</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Everolimus</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01730209
org study id: NL38619.078.11
nct id: NCT01730209
lead sponsor: 
collaborator: 
has dmc: Yes
Tuberous sclerosis complex (TSC) is a genetic disease that leads to mental retardation in
      over 50% of patients, and to learning problems, behavioral problems, autism and epilepsy in
      up to 90% of patients. The underlying deficit of TSC, loss of inhibition of the mammalian
      target of rapamycin (mTOR) protein due to dysfunction of the tuberin/hamartin protein
      complex, can be rescued by everolimus. Everolimus has been registered as treatment for renal
      cell carcinoma and giant cell astrocytoma (SEGA). Evidence in human and animal studies
      suggests that mTOR inhibitors improve learning and development in patients with TSC.
Randomized double-blind placebo controlled intervention study in children with TSC between
      age 4 and 15 years with an intelligence quotient (IQ) estimated <80 and/or special schooling
      and/or autism spectrum disorder and/or learning disability requiring remedial teaching.

      Patients are randomised to receive everolimus or placebo during a period of 12 months.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Cognitive ability measured by IQ
time frame: 12 months
description: Assessed by Wechsler scales: Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III NL) and Wechsler Intelligence Scale for Children (WISC-III-NL)
measure: Autistic features
time frame: 12 Months
description: Assessed by Autism Diagnostic Observation Schedule (ADOS)
measure: Social and communicational skills
time frame: 12 Months
description: Assessed by social responsiveness scale (SRS) and Dutch Children's Communication Checklist (CCC-2-NL) questionnaires
measure: Working memory and attention, information processing
time frame: 6 and 12 Months
description: Assessed by Cambridge Neuropsychological Test Automated Battery (CANTAB)
measure: Visual-motor integration
time frame: 12 Months
description: Assessed by BEERY Visual-Motor Integration (BEERY VMI), grooved pegboard
measure: Child behavior
time frame: 12 Months
description: Assessed by Child Behavior Checklist (CBCL) and Teacher's Report Form (TRF) questionnaires
measure: Executive functioning
time frame: 12 Months
description: Assessed by Behavior Rating Inventory of Executive Functioning (BRIEF) questionnaire Dutch version
measure: Sleeping problems
time frame: 12 Months
description: Assessed by Sleep Disturbance Scale for Children (SDSC) questionnaire
measure: Child health
time frame: 12 Months
description: Assessed by Child Health Questionnaire Parent Form (CHQ-PF50) questionnaire
measure: Sensory related difficulties
time frame: 12 Months
description: Assessed by Short Sensory Profile (SSP) questionnaire
measure: Epilepsy
time frame: 12 Months
description: Comparison of epilepsy frequency during month previous to study start and last month of trial participation.
EEG abnormalities
measure: School level
time frame: 12 Months
description: Assessed by the school CITO (centraal instituut voor toetsontwikkeling) scores or reading and arithmetic scores
measure: Pharmacokinetics
time frame: 12 Months
description: Assessed by measuring trough levels of everolimus
measure: Safety
time frame: 12 Months
description: Levels of and abnormalities in blood control values
arm group label: Everolimus
arm group type: Experimental
description: Everolimus once daily for 1 year, titration to trough levels of 5-10 ng/ml
arm group label: Placebo
arm group type: Placebo Comparator
description: Placebo treatment for 1 year. Tablets will be identical to everolimus tablets.
intervention type: Drug
intervention name: Everolimus
description: Everolimus once daily titrated to trough levels of 5-10 ng/ml.
arm group label: Everolimus
other name: RAD001
other name: Votubia
intervention type: Drug
intervention name: Placebo
arm group label: Placebo
criteria: 
gender: All
minimum age: 4 Years
maximum age: 15 Years
healthy volunteers: No
last name: M.C.Y. de Wit, MD. PhD.
role: Principal Investigator
affiliation: Erasmus Medical Center
last name: M.C.Y. de Wit, MD. PhD.
phone: +31 10 703 6956
email: tubereuzesclerose@erasmusmc.nl
facility: 
status: Recruiting
contact: 
investigator: 
investigator: 
country: Netherlands
responsible party type: Principal Investigator
investigator affiliation: Erasmus Medical Center
investigator full name: M.C.Y. de Wit, MD PhD
investigator title: Pediatric Neurologist
mesh term: Tuberous Sclerosis
mesh term: Sclerosis
mesh term: Autistic Disorder
mesh term: Everolimus