Rapalogues for Autism Phenotype in TSC: A Feasibility Study

Phase 2

Completed

Conditions: Self-injury
Tuberous Sclerosis Complex
Autism

Interventions: Drug: Sirolimus
Drug: Everolimus

Registration Number: NCT01929642

Lead Sponsor: Hugo W. Moser Research Institute at Kennedy Krieger, Inc.

Brief Summary: 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.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 3

Inclusion Criteria

Diagnosed with Tuberous Sclerosis Complex as defined by the revised NIH consensus criteria
Possible autism or autism spectrum disorder and/or possible intellectual disability and/or global developmental delay
Currently displaying disruptive behaviors, such as self-injury and aggression
Seizures or epilepsy with at least one seizure within six months prior to enrollment
2-30 years of age
English-speaking caregiver if participant is non-verbal.
If individuals are currently being treated with everolimus, they must have been taking it for less than or equal to 6 months.

Exclusion Criteria

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.
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.
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.
Participants who have medical contraindications to undergoing an MRI will be excluded.
Participants with devices implanted in the brain will be excluded.
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.
Participants who have a history of herpes simplex virus, cytomegalovirus, and/or HIV infection will be excluded

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Sirolimus or Everolimus	Everolimus	Oral solution or tablet,titrated to therapeutic serum trough range (sirolimus); Oral tablet, titrated to therapeutic serum trough range (everolimus)
Sirolimus or Everolimus	Sirolimus	Oral solution or tablet,titrated to therapeutic serum trough range (sirolimus); Oral tablet, titrated to therapeutic serum trough range (everolimus)

Primary Outcome Measures

Name	Time	Method
Number of Participants With Compliance to the Treatment Protocol.	Change from baseline to EOT visit 12 week 53	One outcome measurement of feasibility will include family/patient compliance with the treatment protocol, which will be assessed and documented at every study visit and telephone follow-up call, by the physician and/or study team member. This was calculated by calculating dividing the total number of study visits and study assessments completed by the total number of study visits and study assessments indicated by the treatment protocol.
Caregiver Burden	Change from baseline to EOT visit 12 week 53	The Caregiver Burden Scale is a standard set of questions which will be used to measure the non-medical impact of TSC on caregivers and how it affects the feasibility of study completion. The Caregiver's Burden Scale (CBS) is a 22-item scale that assess subjectively experienced burden by caregiver's to chronically disabled persons. maximum scores: 88 \& Minumum scores: 22 High values represent a worse outcome
Feasibility Measurements of Parental Stress	Change from baseline to EOT visit 12 week 53	Measurements of stress will be administered. Specifically, we will use the Parental Stress Index. Quantifying stress, as well as compliance with the study protocol, will allow investigators to objectively assess the feasibility of a larger clinical trial of sirolimus in patients with TSC. Parental stress index maximum score: 180 Parental stress index minimum score: 36 higher raw scores indicate higher levels of stress.

Secondary Outcome Measures

Name	Time	Method
Cognitive Function as Assessed by the Capute Scale	1 year	Score range maximum: 100 Score range minimum: 0 High values represent a high cognitive function Below 70 is abnormal. 70-100 is the normal range.
Total Number of Aggressions or Self-injuries	1 year	This is the total number of aggressions or self-injuries for all participants.
Repetitive Behavior	1 year	Repetitive behavior will be assessed using the Repetitive Behavior Scale - revised, a questionnaire to characterize several domains of repetitive behavior including ritualistic behavior, stereotypic behavior, self-injurious behavior, compulsive behavior, and restricted interests. There are 36 items on the scale. Behaviors are rated on a 4-point scale: 0-Behavior does not occur, 1-Behavior occurs and is a mild problem, 2-Behavior occurs and is a moderate problem, 3-Behavior occurs and is a severe problem. Maximum score: 108 \& minimum score: 0 A high score represents the worse outcome
Self-Injury Trauma Scale--SIT Scale	1 year	The SIT Scale is a 3-part clinician-completed scale used to quantify visible injuries caused by self-injurious behavior(SIB). Part 1 includes sections to indicate SIB topographies and any evidence of healed injury. In Part 2 evaluators document the location and severity of injury (on a 3-point scale). In Part 3, respective scores from Parts 1 and 2 are summed to obtain a Number Index, a Severity Index, and Estimate of Current Risk. This Scale has been used in research with adults with SIB with inter-rater reliability averaging 85%. Maximum score: 100 Minimum score: 0 High score represent worse outcome.
Frequency of Seizures Assessed by Total Number of Seizures	at baseline	Parents will be asked to document the frequency of their child's seizures using a manual or electronic (seizuretracker.com) seizure diary. The total number of seizures at baseline for all participants.