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

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.