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RAPT: Rapalogues for Autism Phenotype in TSC: A Feasibility Study

Sponsor
Hugo W. Moser Research Institute at Kennedy Krieger, Inc. (Other)
Overall Status
Completed
CT.gov ID
NCT01929642
Collaborator
(none)
3
Enrollment
1
Location
1
Arm
37
Duration (Months)
0.1
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 2

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.

Study Design

Study Type:
Interventional
Actual Enrollment :
3 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Rapalogues for Autism Phenotype in TSC: A Feasibility Study
Study Start Date :
Jul 1, 2013
Actual Primary Completion Date :
Jul 1, 2016
Actual Study Completion Date :
Aug 1, 2016

Arms and Interventions

Arm Intervention/Treatment
Experimental: Sirolimus or Everolimus

Oral solution or tablet,titrated to therapeutic serum trough range (sirolimus); Oral tablet, titrated to therapeutic serum trough range (everolimus)

Drug: Sirolimus
Other Names:
  • Rapamune, Rapamycin

    • Drug: Everolimus
    Other Names:
  • Afinitor

    		•

    Outcome Measures

    Primary Outcome Measures

    1. 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.

    2. 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

    3. 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

    1. Total Number of Aggressions or Self-injuries [1 year]

      This is the total number of aggressions or self-injuries for all participants.

    2. 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.

    3. 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

    4. 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.

    5. 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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    2 Years to 30 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Kennedy Krieger Institute Baltimore Maryland United States 21205

    Sponsors and Collaborators

    • Hugo W. Moser Research Institute at Kennedy Krieger, Inc.

    Investigators

    • Principal Investigator: Tanjala Gipson, MD, Hugo W. Moser Research Institute at Kennedy Krieger, Inc.

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    Responsible Party:
    Hugo W. Moser Research Institute at Kennedy Krieger, Inc.
    ClinicalTrials.gov Identifier:
    NCT01929642
    Other Study ID Numbers:
    • AM00037881
    First Posted:
    Aug 28, 2013
    Last Update Posted:
    Mar 29, 2021
    Last Verified:
    Mar 1, 2021
    Keywords provided by Hugo W. Moser Research Institute at Kennedy Krieger, Inc.
    Tuberous Sclerosis Complex (TSC)
    self-injury
    Autism
    Additional relevant MeSH terms:
    Tuberous Sclerosis
    Sclerosis
    Autistic Disorder
    Self-Injurious Behavior
    Sirolimus
    Everolimus

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Sirolimus or Everolimus
    Arm/Group Description Oral solution or tablet,titrated to therapeutic serum trough range (sirolimus); Oral tablet, titrated to therapeutic serum trough range (everolimus) Sirolimus Everolimus
    Period Title: Overall Study
    STARTED 3
    COMPLETED 1
    NOT COMPLETED 2

    Baseline Characteristics

    Arm/Group Title Everolimus or Sirolimus
    Arm/Group Description Medication choice
    Overall Participants 3
    Age (years) [Mean (Full Range) ]
    Mean (Full Range) [years]
    7
    Sex: Female, Male (Count of Participants)
    Female
    2
    66.7%
    Male
    1
    33.3%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    Asian
    1
    33.3%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    0
    0%
    White
    2
    66.7%
    More than one race
    0
    0%
    Unknown or Not Reported
    0
    0%
    Region of Enrollment (Count of Participants)
    United States
    3
    100%

    Outcome Measures

    1. Primary Outcome
    Title Number of Participants With Compliance to the Treatment Protocol.
    Description 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.
    Time Frame Change from baseline to EOT visit 12 week 53

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Everolimus or Sirolimus
    Arm/Group Description Medication
    Measure Participants 3
    Participant 002
    100
    Participant 003
    58
    Participant 001
    58
    2. Primary Outcome
    Title Caregiver Burden
    Description 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
    Time Frame Change from baseline to EOT visit 12 week 53

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Everolimus or Sirolimus
    Arm/Group Description Medication choice
    Measure Participants 3
    Mean (Full Range) [units on a scale]
    61
    3. Primary Outcome
    Title Feasibility Measurements of Parental Stress
    Description 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.
    Time Frame Change from baseline to EOT visit 12 week 53

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Everolimus or Sirolimus
    Arm/Group Description
    Measure Participants 3
    Mean (Full Range) [units on a scale]
    111
    4. Secondary Outcome
    Title Total Number of Aggressions or Self-injuries
    Description This is the total number of aggressions or self-injuries for all participants.
    Time Frame 1 year

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Everolimus or Sirolimus
    Arm/Group Description Medication choice
    Measure Participants 3
    Number [Number of aggressions or self-injuries]
    82
    5. Secondary Outcome
    Title Cognitive Function as Assessed by the Capute Scale
    Description 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.
    Time Frame 1 year

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Everolimus or Sirolimus
    Arm/Group Description Medication choice
    Measure Participants 3
    Mean (Full Range) [score on a scale]
    15
    6. Secondary Outcome
    Title Repetitive Behavior
    Description 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
    Time Frame 1 year

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Everolimus or Sirolimus
    Arm/Group Description Medication choice
    Measure Participants 3
    Mean (Full Range) [score on a scale]
    69
    7. Secondary Outcome
    Title Self-Injury Trauma Scale--SIT Scale
    Description 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.
    Time Frame 1 year

    Outcome Measure Data

    Analysis Population Description
    Self-injury was not severe enough to use the scale. Therefore analysis was not done.
    Arm/Group Title Everolimus or Sirolimus
    Arm/Group Description
    Measure Participants 0
    8. Secondary Outcome
    Title Frequency of Seizures Assessed by Total Number of Seizures
    Description 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.
    Time Frame at baseline

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Everolimus or Sirolimus
    Arm/Group Description Medication choice
    Measure Participants 3
    Number [seizures]
    0

    Adverse Events

    Time Frame
    Adverse Event Reporting Description
    Arm/Group Title Everolimus
    Arm/Group Description
    All Cause Mortality
    Everolimus
    Affected / at Risk (%) # Events
    Total / (NaN)
    Serious Adverse Events
    Everolimus
    Affected / at Risk (%) # Events
    Total 0/3 (0%)
    Other (Not Including Serious) Adverse Events
    Everolimus
    Affected / at Risk (%) # Events
    Total 1/3 (33.3%)
    Skin and subcutaneous tissue disorders
    aphthous ulcer 1/3 (33.3%) 1

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Dr. Tanjala Gipson
    Organization Boling Center for Developmental Disabilities
    Phone 901-448-6512
    Email sbarden@uthsc.edu
    Responsible Party:
    Hugo W. Moser Research Institute at Kennedy Krieger, Inc.
    ClinicalTrials.gov Identifier:
    NCT01929642
    Other Study ID Numbers:
    • AM00037881
    First Posted:
    Aug 28, 2013
    Last Update Posted:
    Mar 29, 2021
    Last Verified:
    Mar 1, 2021