Trial of RAD001 and Neurocognition in Tuberous Sclerosis Complex (TSC)
Condition: Tuberous Sclerosis Complex
MeSH terms: Tuberous Sclerosis; Sclerosis
Intervention: RAD001; Placebo
Intervention description: RAD001 is formulated as tablets of 5.0 mg strength, blister-packed under aluminum foil in units of 10 tablets and dosed on a regular basis. RAD001 tablets should be opened only at the time of administration as drug is both hygroscopic and light-sensitive.
Patients will be instructed to take 4.5 mg/m2 of RAD001 orally with a glass of water at regular intervals at the same time in the morning after a light, nonfat breakfast.; Matching placebo will be provided as a matching tablet and will also be blister packed under aluminum foil in units of 10. Matching placebo tablets should be opened only at the time of administration as drug is both hygroscopic and light-sensitive.
Patients will be instructed to take 4.5 mg/m2 of the matching placebo orally with a glass of water at regular intervals at the same time in the morning after a light, nonfat breakfast.
Intervention MeSH terms: Everolimus
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 52.0
Sex: All
Minimum age: 6 Years
Maximum age: 21 Years
Healthy volunteers: No
Keywords: Tuberous Sclerosis Complex; Autism; Neurocognition; RAD001; Everolimus; Afinitor; TSC

Summary:

      Tuberous Sclerosis Complex (TSC) is a multi-system disease, usually presenting with seizures,
      mental retardation and autism, and exhibiting a high variability in clinical findings both
      among and within families. Investigators are doing research in order to identify possible
      neurocognitive benefits from treatment with RAD001 or placebo for a six month period. There
      may also be potential for improvements in seizure frequency, sleep and autistic behaviors. We
      hope this trial will lead to a better understanding of TSC and to new forms of treatment, to
      benefit children and adults with TSC in the future.

      Individuals diagnosed with TSC will be asked to participate in this study if they are between
      the ages of 6 and 21 years of age and have an IQ of greater than or equal to 60. Both males
      and females will be asked to participate. Additionally, to be eligible for study
      participation, individuals must have been on the same seizure medication(s), if applicable,
      for at least 6 months. Individuals must also be able to participate in neuropsychological
      testing and meet certain medical criteria. They will need to sign an informed consent. If
      enrolled in the study, participants will have a number of screening tests to help determine
      if they are eligible for participation in the clinical trial. If eligible for the treatment
      phase of the trial, they will be asked to take either the study drug or a placebo (pill with
      no medicine), which is determined by chance.

      The study involves about 9 visits, 3 of which can be done locally, over a six month period,
      as well as follow-up calls with our research nurse. Study visits will vary in length.
      Screening, three month and six month visits may last up to 8 hours, while all other visits
      will be less than 2 hours. The study visits include blood draws, laboratory tests and
      neuropsychological assessments. There is no fee to participate in this study. The study drug
      will be provided at no charge during the study.

      After all study data has been analyzed, families will be informed of the overall results.
      Treatment on this study may or may not improve a child's learning skills (neurocognition).
      Future patients may benefit from what is learned.
    

Eligibility criteria:

        Inclusion criteria:

          1. Male or female patients ages 6 to 21 years of age.

          2. IQ ≥60.

          3. Ability to participate in direct neuropsychological and developmental testing.

          4. English as primary language.

          5. Diagnosis of tuberous sclerosis complex confirmed by genetic testing and/or clinically
             definite diagnosis of tuberous sclerosis complex according to the modified Gomez
             criteria and an IQ>60.

          6. Stable anti-epileptic drugs (no changes in medications except dose for >6 months).

          7. Adequate renal function. The GFR would be greater than 50 ml/min.m2 as determined by
             the Schwartz Formula for children and MDRD for adults:

             http://www.nkdep.nih.gov/professionals/gfr_calculators/index.htm

          8. If female and of child bearing potential, documentation of negative pregnancy test
             prior to enrollment. Sexually active pre-menopausal female patients (and female
             partners of male patients) must use adequate contraceptive measures, excluding
             estrogen containing contraceptives, while on study. Abstinence will be considered an
             adequate contraceptive measure.

          9. INR ≤1.5 (Anticoagulation is allowed if target INR ≤ 1.5 on a stable dose of warfarin
             or on a stable dose of LMW heparin for >2 weeks at time of randomization.)

         10. Adequate liver function as shown by:

               -  serum bilirubin ≤ 1.5 x ULN

               -  ALT and AST ≤ 2.5x ULN (≤ 5x ULN in patients with liver metastases)

         11. Written informed consent according to local guidelines.

        Exclusion criteria:

          1. Change of one or more antiepileptic medication in the past 6 months.

          2. Prior exposure to the systemic use of an mTOR inhibitor.

          3. Exposure to any investigational agent in the 30 days prior to randomization.

          4. Neurosurgery within 6 months.

          5. Known impaired lung function (e.g.FEV1 or DLCO <70% of predicted), if not resolved or
             if resolved within past 24 months.

          6. Significant hematological or hepatic abnormality (i.e. transaminase levels > 2.5 x ULN
             or serum bilirubin > 1.5 x ULN, hemoglobin < 9 g/dL, platelets < 80,000/ mm3, absolute
             neutrophil count < 1,000/mm3).

          7. Serum creatinine > 1.5 x ULN.

          8. Uncontrolled hyperlipidemia: Fasting serum cholesterol > 300 mg/dL OR > 7.75 mmol/L
             AND Fasting triglycerides > 2.5 x ULN.

          9. Uncontrolled diabetes mellitus as defined by fasting serum glucose > 1.5 x ULN.

         10. Patients with bleeding diathesis or on oral anti-vitamin K medication (except low dose
             warfarin).

         11. Patients with known history of HIV seropositivity.

         12. Pregnancy or breast feeding.

         13. Active infection at date of randomization.

         14. Prior history of organ transplant.

         15. Recent surgery (involving entry into a body cavity or requiring sutures) within the 4
             weeks prior to randomization.

         16. Inability to attend scheduled clinic visits.

         17. History of malignancy in the past two years, other than squamous or basal cell skin
             cancer.

         18. Patients should not receive immunization with attenuated live vaccines within one
             month of study entry or during study period. Close contact with those who have
             received attenuated live vaccines should be avoided during treatment with everolimus.
             Examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral
             polio, BCG, yellow fever, varicella and TY21a typhoid vaccines.

         19. Liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh class C).

             Note: A detailed assessment of Hepatitis B/C medical history and risk factors must be
             done at screening for all patients. HBV DNA and HCV RNA PCR testing are required at
             screening for all patients with a positive medical history based on risk factors
             and/or confirmation of prior HBV/HCV infection.

         20. Patients receiving chronic, systemic treatment with corticosteroids or another
             immunosuppressive agent. Topical or inhaled corticosteroids are allowed.

         21. Patients who have any severe and/or uncontrolled medical conditions or other
             conditions that could affect their participation in the study such as:

               -  symptomatic congestive heart failure of New York heart Association Class III or
                  IV

               -  unstable angina pectoris, symptomatic congestive heart failure, myocardial
                  infarction within 6 months of start of study drug, serious uncontrolled cardiac
                  arrhythmia or any other clinically significant cardiac disease

         22. Patients who have received an IQ score under 60 in the six months prior to the study
             screening visit will be deemed ineligible.