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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

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.

Condition or disease Intervention/treatment Phase
Tuberous Sclerosis Complex TSC Related Cognitive Disability TSC Related Autism TSC Related Learning Problems Drug: Everolimus Drug: Placebo Phase 2 Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Efficacy of RAD001/Everolimus in Autism and NeuroPsychological Deficits in Children With Tuberous Sclerosis Complex
Study Start Date : November 2012
Estimated Primary Completion Date : November 2015
Estimated Study Completion Date : November 2016

Arm Intervention/treatment
Experimental: Everolimus
Everolimus once daily for 1 year, titration to trough levels of 5-10 ng/ml
Drug: Everolimus
Everolimus once daily titrated to trough levels of 5-10 ng/ml.
Other Names:
  • RAD001
  • Votubia

Placebo Comparator: Placebo
Placebo treatment for 1 year. Tablets will be identical to everolimus tablets.
Drug: Placebo

Primary Outcome Measures :
  1. 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)

Secondary Outcome Measures :
  1. Autistic features [ Time Frame: 12 Months ]
    Assessed by Autism Diagnostic Observation Schedule (ADOS)

  2. Social and communicational skills [ Time Frame: 12 Months ]
    Assessed by social responsiveness scale (SRS) and Dutch Children's Communication Checklist (CCC-2-NL) questionnaires

  3. Working memory and attention, information processing [ Time Frame: 6 and 12 Months ]
    Assessed by Cambridge Neuropsychological Test Automated Battery (CANTAB)

  4. Visual-motor integration [ Time Frame: 12 Months ]
    Assessed by BEERY Visual-Motor Integration (BEERY VMI), grooved pegboard

  5. Child behavior [ Time Frame: 12 Months ]
    Assessed by Child Behavior Checklist (CBCL) and Teacher's Report Form (TRF) questionnaires

  6. Executive functioning [ Time Frame: 12 Months ]
    Assessed by Behavior Rating Inventory of Executive Functioning (BRIEF) questionnaire Dutch version

  7. Sleeping problems [ Time Frame: 12 Months ]
    Assessed by Sleep Disturbance Scale for Children (SDSC) questionnaire

  8. Child health [ Time Frame: 12 Months ]
    Assessed by Child Health Questionnaire Parent Form (CHQ-PF50) questionnaire

  9. Sensory related difficulties [ Time Frame: 12 Months ]
    Assessed by Short Sensory Profile (SSP) questionnaire

  10. Epilepsy [ Time Frame: 12 Months ]

    Comparison of epilepsy frequency during month previous to study start and last month of trial participation.

    EEG abnormalities

Other Outcome Measures:
  1. School level [ Time Frame: 12 Months ]
    Assessed by the school CITO (centraal instituut voor toetsontwikkeling) scores or reading and arithmetic scores

  2. Pharmacokinetics [ Time Frame: 12 Months ]
    Assessed by measuring trough levels of everolimus

  3. Safety [ Time Frame: 12 Months ]
    Levels of and abnormalities in blood control values

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   4 Years to 15 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01730209

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Contact: M.C.Y. de Wit, MD. PhD. +31 10 703 6956

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Erasmus Medical Center Recruiting
Rotterdam, Netherlands
Contact: M.C.Y. de Wit, MD. PhD.    +31 10 703 6956   
Principal Investigator: M.C.Y. de Wit, MD. PhD.         
Sub-Investigator: I.E. Overwater, MSc         
Sponsors and Collaborators
Erasmus Medical Center
Utrecht University
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Principal Investigator: M.C.Y. de Wit, MD. PhD. Erasmus Medical Center

Additional Information:
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: M.C.Y. de Wit, MD PhD, Pediatric Neurologist, Erasmus Medical Center Identifier: NCT01730209    
Other Study ID Numbers: NL38619.078.11
First Posted: November 21, 2012    Key Record Dates
Last Update Posted: May 5, 2015
Last Verified: May 2015
Keywords provided by M.C.Y. de Wit, MD PhD, Erasmus Medical Center:
Tuberous Sclerosis Complex
Learning problems
Intellectual disability
Additional relevant MeSH terms:
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Tuberous Sclerosis
Autistic Disorder
Pathologic Processes
Autism Spectrum Disorder
Child Development Disorders, Pervasive
Neurodevelopmental Disorders
Mental Disorders
Neoplasms, Multiple Primary
Neoplastic Syndromes, Hereditary
Malformations of Cortical Development, Group I
Malformations of Cortical Development
Nervous System Malformations
Nervous System Diseases
Neurocutaneous Syndromes
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Congenital Abnormalities
Genetic Diseases, Inborn
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic