Rapalogues for Autism Phenotype in TSC: A Feasibility Study

The purpose of this study is to assess the feasibility and safety of administering rapalogues, sirolimus or everolimus, in participants with Tuberous Sclerosis Complex (TSC) and self-injury and to measure cognitive and behavioral changes, including reduction in autistic symptoms, self-injurious and aggressive behaviors, as well as improvements in cognition across multiple domains of cognitive function.

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.

Eligibility Criteria:
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