Rapalogues for Autism Phenotype in TSC: A Feasibility Study

This is a feasibility and safety study primarily designed to assess the feasibility and
safety of conducting a larger clinical trial with sirolimus in individuals with TSC. The
present study will employ an ABA design in which three pediatric participants will be
selected to receive baseline medical, developmental, behavioral, and cognitive evaluations,
followed by a 26 week administration of sirolimus, repeated baseline assessments at the end
of the 26 week treatment phase, and a 4 week titrated withdrawal followed by a 22 week period
in which no rapalogue is administered. All participants will again be administered baseline
medical, behavioral, and cognitive evaluations at the end of the study in order to compare
all evaluations done at baseline, the end of the 26 week treatment, and completion of the
study. These comparisons will be done to assess secondary outcomes that include reductions in
autistic symptoms, self-injury, and aggression, as well as improvements in cognitive function
across multiple domains. Furthermore, administration of the secondary outcome measures will
also allow us to better understand the sensitivity of these measures in patients with TSC
during the course of a clinical trial.

Families of potentially eligible children who express interest in the study and meet
prescreening criteria will be invited to attend a screening visit to determine eligibility,
inclusion/exclusion criteria, and availability for eight additional study visits. Prior to
enrollment, informed consent will be obtained from the parent or legal guardian.

Investigators will use the methods of analysis of single-subject research (ABA design, where
first A represents baseline, B represents treatment, and A represents reversal of treatment.
The analysis will focus on each of the 3 subjects separately. Data on feasibility and safety
(primary outcome) and on frequency of disruptive behavior (secondary outcome) will be plotted
and visually inspected to detect any temporal changes by phase: 1. Baseline, 2. Treatment, 3.
After treatment. Data in each phase will be summarized as mean +/- standard deviation (SD).
We will use the summary data to assess the potential effect of the intervention. Consistency
of the effect will be examined across the 3 study participants.

Inclusion Criteria:

1. Diagnosed with Tuberous Sclerosis Complex as defined by the revised NIH consensus
criteria

2. Possible autism or autism spectrum disorder and/or possible intellectual disability
and/or global developmental delay

3. Currently displaying disruptive behaviors, such as self-injury and aggression

4. Seizures or epilepsy with at least one seizure within six months prior to enrollment

5. 2-30 years of age

6. English-speaking caregiver if participant is non-verbal.

7. If individuals are currently being treated with everolimus, they must have been taking
it for less than or equal to 6 months.

Exclusion Criteria:

1. Participants who require live vaccines that are contraindicated with sirolimus will be
excluded - bacille Calmette Guerin(BCG), measles-mumps-rubella vaccine(MMR),
poliovirus, rotavirus, smallpox, typhoid, varicella, or yellow fever.

2. Participants who have a history of multiple or severe infections, or reside in a
household with anyone who has a chronic, contagious condition will be excluded.
Multiple infections will be defined as eight or more lifetime episodes of otitis media
or two or more lifetime episodes of bacterial pneumonia. Severe infections will be
defined as infections requiring more than one hospital admission for treatment.

3. Participants with any of the following laboratory abnormalities will be excluded:
hematocrit < 27%, absolute neutrophil count(ANC) < 1,500, platelet count < 100,000,
serum glutamate oxaloacetate transaminase(SGOT) or serum glutamate pyruvate
transaminase (SGPT) > two times normal for age, bilirubin > two times normal for age,
alkaline phosphatase > two times normal for age, epidermal growth factor receptor
(eGFR) < 30, or evidence of renal failure, hypercholesterolemia.

4. Participants who have medical contraindications to undergoing an MRI will be excluded.

5. Participants with devices implanted in the brain will be excluded.

6. Pregnant participants will be excluded. All young ladies of child bearing potential
will have a blood test for pregnancy prior to the start of the study and every study
visit for the duration of the study.

7. Participants who have a history of herpes simplex virus, cytomegalovirus, and/or HIV
infection will be excluded