Rapalogues for Autism Phenotype in TSC: A Feasibility Study (RAPT)
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.
Tuberous Sclerosis Complex
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Rapalogues for Autism Phenotype in TSC: A Feasibility Study|
- Compliance [ Time Frame: Change from baseline to EOT visit 12 week 53 ] [ Designated as safety issue: No ]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.
- Caregiver Burden [ Time Frame: Change from baseline to EOT visit 12 week 53 ] [ Designated as safety issue: No ]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.
- Feasibility measurements of parental stress [ Time Frame: Change from baseline to EOT visit 12 week 53 ] [ Designated as safety issue: No ]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.
- Direct, Structured Behavioral Observation [ Time Frame: 1 year ] [ Designated as safety issue: No ]The secondary outcome measures will include frequency, severity, and characterization of disruptive behaviors, including repetitive, self-injurious, and aggressive behavior as measured by direct and structured behavioral observation by behavioral psychologists from the Neurobehavioral Unit of Kennedy Krieger Institute. These disruptive behaviors are associated with TSC, and no effective treatment has been developed. These behaviors are associated with morbidity, poor quality of life, and decreased opportunities for full participation in society. In this study, our goal will be to assess the feasibility in order to plan for the logistics of determining if treatment with sirolimus reduces the frequency, severity, or duration of repetitive, self-injurious, and aggressive behavior.
- Cognitive Function [ Time Frame: 1 year ] [ Designated as safety issue: No ]Participants will be evaluated using the Leiter, Revised edition.Participants unable to complete the Leiter-R will be evaluated using the Mullen Scales of Early Learning by a neuropsychologist. Participants with a cognitive level less than thirty six months will also undergo a developmental evaluation using the Capute scales. Vineland Adaptive Behavior Scales will be completed to measure participants' ability to function in activities of daily living. An experimental developmental paradigm designed to assess visual spatial memory and visual spatial working memory, designed by the investigators, will be administered. This paradigm will involve hiding a toy in the exam room while the participant observes through a two-way mirror. The participant will then be brought into the exam room via a door that is on the adjacent wall to the right of the two-way mirror and will be asked to find the hidden toy. Reaction time and search errors will be recorded.
- Repetitive behavior [ Time Frame: 1 year ] [ Designated as safety issue: No ]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.
- Self-Injury Trauma Scale--SIT Scale [ Time Frame: 1 year ] [ Designated as safety issue: No ]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%.
- Confirmation and Characterization of Autism Spectrum Disorder [ Time Frame: 1 year ] [ Designated as safety issue: No ]The Autism Diagnostic Observation Scale and Autism Diagnostic Interview- revised edition, will be completed by a certified speech/language pathologist. These two well validated diagnostic measures of autism and autism spectrum disorders (ASD) will be used in conjunction with clinical history, the Social Responsiveness Scale, the Social Communication Questionnaire, and the Repetitive Behavior Scale - revised edition to confirm a diagnosis of autism or ASD, as well as characterize the participants' specific autistic symptoms. The clinical history and aforementioned questionnaires will be completed with one of the participants' parents or caregivers in an interview format.
- Safety [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]Safety will be assessed by measured by number, type, and severity of adverse events as well as compliance and attrition associated with these events.
- Seizure Diary [ Time Frame: 1 year ] [ Designated as safety issue: No ]Parents will be asked to document the frequency of their child's seizures using a manual or electronic (seizuretracker.com) seizure diary. Seizures affect up to 90% of patients with TSC. Although not a primary or secondary outcome measure in the case series of patients treated with sirolimus or the experimental study of participants treated with everolimus, the investigators noted reduction in seizure frequency in all of the sirolimus-treated patients and nine of the sixteen everolimus-treated participants.
- MRI [ Time Frame: Baseline and every 6 months ] [ Designated as safety issue: No ]For participants who have not had brain Magnetic Resonance Imaging (MRI) in the 6 months preceding study entry, this will be obtained at study visits 3 and 12. Participants who have had a brain MRI in the 6 months preceding study entry, will be scheduled every 6 months starting with the date of their most recent brain MRI.
- Seizure Characterization and monitoring [ Time Frame: Change from baseline and visit 6 week 27 ] [ Designated as safety issue: No ]
A routine Electroencephalography (EEG) with video will be obtained to identify and characterize neurophysiologic signs of seizures or epileptiform activity. Routine EEGs are clinically indicated for patients with TSC because they are at risk for the development of epilepsy,including seizures without motor manifestation.
In addition to the routine EEG, parents will be given the choice of completion of a manual or electronic seizure diary to monitor the frequency and characteristics of seizures.
|Study Start Date:||July 2013|
|Estimated Study Completion Date:||December 2016|
|Estimated Primary Completion Date:||July 2016 (Final data collection date for primary outcome measure)|
Experimental: Sirolimus or Everolimus
Oral solution or tablet,titrated to therapeutic serum trough range (sirolimus); Oral tablet, titrated to therapeutic serum trough range (everolimus)
Other Name: Rapamune, RapamycinDrug: Everolimus
Other Name: Afinitor
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01929642
|United States, Maryland|
|Kennedy Krieger Institute|
|Baltimore, Maryland, United States, 21205|
|Principal Investigator:||Tanjala Gipson, MD||Hugo W. Moser Research Institute at Kennedy Krieger, Inc.|