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Trial record 1 of 6 for:    rapamycin autism
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Efficacy of RAD001/Everolimus in Autism and NeuroPsychological Deficits in Children With Tuberous Sclerosis Complex (RAPIT)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01730209
Recruitment Status : Unknown
Verified May 2015 by M.C.Y. de Wit, MD PhD, Erasmus Medical Center.
Recruitment status was:  Recruiting
First Posted : November 21, 2012
Last Update Posted : May 5, 2015
Utrecht University
Information provided by (Responsible Party):
M.C.Y. de Wit, MD PhD, Erasmus Medical Center

Tracking Information
First Submitted Date  ICMJE October 26, 2012
First Posted Date  ICMJE November 21, 2012
Last Update Posted Date May 5, 2015
Study Start Date  ICMJE November 2012
Estimated Primary Completion Date November 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 20, 2012)
Cognitive ability measured by IQ [ Time Frame: 12 months ]
Assessed by Wechsler scales: Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III NL) and Wechsler Intelligence Scale for Children (WISC-III-NL)
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT01730209 on Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: November 20, 2012)
  • Autistic features [ Time Frame: 12 Months ]
    Assessed by Autism Diagnostic Observation Schedule (ADOS)
  • Social and communicational skills [ Time Frame: 12 Months ]
    Assessed by social responsiveness scale (SRS) and Dutch Children's Communication Checklist (CCC-2-NL) questionnaires
  • Working memory and attention, information processing [ Time Frame: 6 and 12 Months ]
    Assessed by Cambridge Neuropsychological Test Automated Battery (CANTAB)
  • Visual-motor integration [ Time Frame: 12 Months ]
    Assessed by BEERY Visual-Motor Integration (BEERY VMI), grooved pegboard
  • Child behavior [ Time Frame: 12 Months ]
    Assessed by Child Behavior Checklist (CBCL) and Teacher's Report Form (TRF) questionnaires
  • Executive functioning [ Time Frame: 12 Months ]
    Assessed by Behavior Rating Inventory of Executive Functioning (BRIEF) questionnaire Dutch version
  • Sleeping problems [ Time Frame: 12 Months ]
    Assessed by Sleep Disturbance Scale for Children (SDSC) questionnaire
  • Child health [ Time Frame: 12 Months ]
    Assessed by Child Health Questionnaire Parent Form (CHQ-PF50) questionnaire
  • Sensory related difficulties [ Time Frame: 12 Months ]
    Assessed by Short Sensory Profile (SSP) questionnaire
  • Epilepsy [ Time Frame: 12 Months ]
    Comparison of epilepsy frequency during month previous to study start and last month of trial participation. EEG abnormalities
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: November 20, 2012)
  • School level [ Time Frame: 12 Months ]
    Assessed by the school CITO (centraal instituut voor toetsontwikkeling) scores or reading and arithmetic scores
  • Pharmacokinetics [ Time Frame: 12 Months ]
    Assessed by measuring trough levels of everolimus
  • Safety [ Time Frame: 12 Months ]
    Levels of and abnormalities in blood control values
Original Other Pre-specified Outcome Measures Same as current
Descriptive Information
Brief Title  ICMJE Efficacy of RAD001/Everolimus in Autism and NeuroPsychological Deficits in Children With Tuberous Sclerosis Complex
Official Title  ICMJE Efficacy of RAD001/Everolimus in Autism and NeuroPsychological Deficits in Children With Tuberous Sclerosis Complex
Brief Summary 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.
Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Tuberous Sclerosis Complex
  • TSC Related Cognitive Disability
  • TSC Related Autism
  • TSC Related Learning Problems
Intervention  ICMJE
  • Drug: Everolimus
    Everolimus once daily titrated to trough levels of 5-10 ng/ml.
    Other Names:
    • RAD001
    • Votubia
  • Drug: Placebo
Study Arms  ICMJE
  • Experimental: Everolimus
    Everolimus once daily for 1 year, titration to trough levels of 5-10 ng/ml
    Intervention: Drug: Everolimus
  • Placebo Comparator: Placebo
    Placebo treatment for 1 year. Tablets will be identical to everolimus tablets.
    Intervention: Drug: Placebo
Publications * Overwater IE, Rietman AB, Mous SE, Bindels-de Heus K, Rizopoulos D, Ten Hoopen LW, van der Vaart T, Jansen FE, Elgersma Y, Moll HA, de Wit MY; ENCORE Expertise Centre for Neurodevelopmental Disorders. A randomized controlled trial with everolimus for IQ and autism in tuberous sclerosis complex. Neurology. 2019 Jul 9;93(2):e200-e209. doi: 10.1212/WNL.0000000000007749. Epub 2019 Jun 19.

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Unknown status
Estimated Enrollment  ICMJE
 (submitted: November 20, 2012)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE November 2016
Estimated Primary Completion Date November 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Children with a definite diagnosis of TSC between 4 and 15 years.
  • With an IQ estimated <80 and/or special schooling and/or autism spectrum disorder and/or learning disability requiring remedial teaching.
  • Written informed consent by parents/care-takers, and the patient if he or she is 12 years or older and cognitively able to consent.
  • In girls after menarche, appropriate contraception must be used or abstinence practiced.

Exclusion Criteria:

  • Hepatic dysfunction
  • Surgery <6wk
  • Current infection at time of inclusion
  • Developmental age estimated below 3.5 years
  • Intractable epilepsy with more than 1 seizure/week
  • Inability to comply with the treatment protocol
  • Additional diseases or disorders that may influence the endpoints, including:

    • SEGA requiring treatment
    • Uncontrolled diabetes mellitus
    • Known impaired lung function
  • Allergy for any of the components of the study medication
  • Prior treatment with mTOR inhibitors
  • HIV seropositivity
  • Bleeding diathesis or oral anti-vitamin K medication
  • Serum creatinine > 1.5 x ULN
  • Uncontrolled hyperlipidemia (fasting serum cholesterol > 7.75 mmol/L, fasting serum triglycerides > 2.5 x ULN)
  • Use of investigational drug within 30 days prior to inclusion
  • History of myocardial infarction, angina or stroke related to atherosclerosis, organ transplantation, malignancy in the past 2 years
  • Pregnancy or breastfeeding
  • Children at risk for Hepatitis B (HB), unless hepatitis B serology is normal. Risk groups are children who have lived in Asia, Africa, Central and South America, Eastern Europe, Spain, Portugal, and Greece, children with known or suspected past or current hepatitis B infection, current or prior IV illicit drug use, current or prior dialysis, household contact with hepatitis B infected patient(s), current or prior high-risk sexual activity, body piercing or tattoos, mother known to have hepatitis B history. If vaccinated, presence of HBs Ab is normal.
  • Known or suspected hepatitis C infection, unless hepatitis C serology is normal.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 4 Years to 15 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Netherlands
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT01730209
Other Study ID Numbers  ICMJE NL38619.078.11
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party M.C.Y. de Wit, MD PhD, Erasmus Medical Center
Study Sponsor  ICMJE Erasmus Medical Center
Collaborators  ICMJE Utrecht University
Investigators  ICMJE
Principal Investigator: M.C.Y. de Wit, MD. PhD. Erasmus Medical Center
PRS Account Erasmus Medical Center
Verification Date May 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP