Efficacy of RAD001/Everolimus in Autism and NeuroPsychological Deficits in Children With Tuberous Sclerosis Complex (RAPIT)

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2013 by Erasmus Medical Center
Sponsor:
Collaborator:
University Hospital Utrecht
Information provided by (Responsible Party):
M.C.Y. de Wit, MD PhD, Erasmus Medical Center
ClinicalTrials.gov Identifier:
NCT01730209
First received: October 26, 2012
Last updated: March 25, 2013
Last verified: March 2013
  Purpose

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 Intervention Phase
Tuberous Sclerosis Complex
TSC Related Cognitive Disability
TSC Related Autism
TSC Related Learning Problems
Drug: Everolimus
Drug: Placebo
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Efficacy of RAD001/Everolimus in Autism and NeuroPsychological Deficits in Children With Tuberous Sclerosis Complex

Resource links provided by NLM:


Further study details as provided by Erasmus Medical Center:

Primary Outcome Measures:
  • Cognitive ability measured by IQ [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    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:
  • Autistic features [ Time Frame: 12 Months ] [ Designated as safety issue: No ]
    Assessed by Autism Diagnostic Observation Schedule (ADOS)

  • Social and communicational skills [ Time Frame: 12 Months ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    Assessed by Cambridge Neuropsychological Test Automated Battery (CANTAB)

  • Visual-motor integration [ Time Frame: 12 Months ] [ Designated as safety issue: No ]
    Assessed by BEERY Visual-Motor Integration (BEERY VMI), grooved pegboard

  • Child behavior [ Time Frame: 12 Months ] [ Designated as safety issue: No ]
    Assessed by Child Behavior Checklist (CBCL) and Teacher's Report Form (TRF) questionnaires

  • Executive functioning [ Time Frame: 12 Months ] [ Designated as safety issue: No ]
    Assessed by Behavior Rating Inventory of Executive Functioning (BRIEF) questionnaire Dutch version

  • Sleeping problems [ Time Frame: 12 Months ] [ Designated as safety issue: No ]
    Assessed by Sleep Disturbance Scale for Children (SDSC) questionnaire

  • Child health [ Time Frame: 12 Months ] [ Designated as safety issue: No ]
    Assessed by Child Health Questionnaire Parent Form (CHQ-PF50) questionnaire

  • Sensory related difficulties [ Time Frame: 12 Months ] [ Designated as safety issue: No ]
    Assessed by Short Sensory Profile (SSP) questionnaire

  • Epilepsy [ Time Frame: 12 Months ] [ Designated as safety issue: No ]

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

    EEG abnormalities



Other Outcome Measures:
  • School level [ Time Frame: 12 Months ] [ Designated as safety issue: No ]
    Assessed by the school CITO (centraal instituut voor toetsontwikkeling) scores or reading and arithmetic scores

  • Pharmacokinetics [ Time Frame: 12 Months ] [ Designated as safety issue: Yes ]
    Assessed by measuring trough levels of everolimus

  • Safety [ Time Frame: 12 Months ] [ Designated as safety issue: Yes ]
    Levels of and abnormalities in blood control values


Estimated Enrollment: 60
Study Start Date: November 2012
Estimated Study Completion Date: November 2016
Estimated Primary Completion Date: November 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.

  Eligibility

Ages Eligible for Study:   4 Years to 15 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01730209

Contacts
Contact: M.C.Y. de Wit, MD. PhD. +31 10 703 6956 tubereuzesclerose@erasmusmc.nl

Locations
Netherlands
Erasmus Medical Center Recruiting
Rotterdam, Netherlands
Contact: M.C.Y. de Wit, MD. PhD.    +31 10 703 6956    tubereuzesclerose@erasmusmc.nl   
Principal Investigator: M.C.Y. de Wit, MD. PhD.         
Sub-Investigator: I.E. Overwater, MSc         
Sponsors and Collaborators
Erasmus Medical Center
University Hospital Utrecht
Investigators
Principal Investigator: M.C.Y. de Wit, MD. PhD. Erasmus Medical Center Rotterdam
  More Information

Additional Information:
No publications provided

Responsible Party: M.C.Y. de Wit, MD PhD, Pediatric Neurologist, Erasmus Medical Center
ClinicalTrials.gov Identifier: NCT01730209     History of Changes
Other Study ID Numbers: NL38619.078.11
Study First Received: October 26, 2012
Last Updated: March 25, 2013
Health Authority: Netherlands: Medical Ethics Review Committee (METC)

Keywords provided by Erasmus Medical Center:
Tuberous Sclerosis Complex
TSC
Autism
Learning problems
Everolimus
RAD001
Treatment
Cognition
Intellectual disability

Additional relevant MeSH terms:
Tuberous Sclerosis
Sclerosis
Autistic Disorder
Pathologic Processes
Child Development Disorders, Pervasive
Mental Disorders Diagnosed in Childhood
Mental Disorders
Hamartoma
Neoplasms
Neoplasms, Multiple Primary
Neoplastic Syndromes, Hereditary
Malformations of Cortical Development
Nervous System Malformations
Nervous System Diseases
Neurocutaneous Syndromes
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Congenital Abnormalities
Genetic Diseases, Inborn
Everolimus
Sirolimus
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Antibiotics, Antineoplastic
Antineoplastic Agents

ClinicalTrials.gov processed this record on September 18, 2014