Trial of RAD001 and Neurocognition in Tuberous Sclerosis Complex (TSC)

Randomized Double-Blind Phase 2 Trial Of RAD001 For Neurocognition In Individuals With Tuberous Sclerosis Complex

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.

This is a signal-seeking Phase II randomized, placebo-controlled trial of RAD001 in children and young adults with TSC with neurocognition as the primary outcome and autism spectrum disorder as a secondary outcome.

Specific Aims /Objectives Primary objective

• To evaluate the efficacy of RAD001 on neurocognition in patients with TSC compared to placebo as measured by well-validated, standardized, direct and indirect neurocognitive tools.
• To evaluate the safety of RAD001 compared with placebo in patients with TSC focusing on NCI CTCAE Grade 3 and 4 adverse events, serious adverse events, and Grade 3 and 4 laboratory toxicities.

Secondary objectives

• Comparison of absolute change from baseline in frequency of epileptiform events as recorded on seizure diaries between patients taking RAD001 vs. placebo
• Comparison of sleep disturbances between patients taking RAD001 vs. placebo, measured by the Pediatric Sleep Questionnaire (PSQ) and sleep logs
• Comparison of autism spectrum disorders features between patients taking RAD001 vs. placebo, measured by ADOS and SRS
• Comparison of academic skills between patients taking RAD001 vs. placebo, measured by WRAT4
• Comparison of behavioral problems between patients taking RAD001 vs placebo, measured by behavioral rating scales (BRIEF, BASC, SDQ, CHQ and SRS)

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.