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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01929642
Recruitment Status : Completed
First Posted : August 28, 2013
Last Update Posted : January 23, 2018
Information provided by (Responsible Party):
Tanjala Gipson, 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.

Condition or disease Intervention/treatment Phase
Tuberous Sclerosis Complex Self-injury Autism Drug: Sirolimus Drug: Everolimus 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.

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Study Type : Interventional  (Clinical Trial)
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 : July 2013
Actual Primary Completion Date : July 2016
Actual Study Completion Date : August 2016

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 Name: Rapamune, Rapamycin

Drug: Everolimus
Other Name: Afinitor

Primary Outcome Measures :
  1. Compliance [ Time Frame: 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.

  2. Caregiver Burden [ Time Frame: 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.

  3. Feasibility measurements of parental stress [ Time Frame: 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.

Secondary Outcome Measures :
  1. Direct, Structured Behavioral Observation [ Time Frame: 1 year ]
    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.

  2. Cognitive Function [ Time Frame: 1 year ]
    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.

  3. Repetitive behavior [ Time Frame: 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.

  4. Self-Injury Trauma Scale--SIT Scale [ Time Frame: 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%.

  5. Confirmation and Characterization of Autism Spectrum Disorder [ Time Frame: 1 year ]
    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.

  6. Safety [ Time Frame: 1 year ]
    Safety will be assessed by measured by number, type, and severity of adverse events as well as compliance and attrition associated with these events.

  7. Seizure Diary [ Time Frame: 1 year ]
    Parents will be asked to document the frequency of their child's seizures using a manual or electronic ( 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.

  8. MRI [ Time Frame: Baseline and every 6 months ]
    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.

  9. Seizure Characterization and monitoring [ Time Frame: Change from baseline and visit 6 week 27 ]

    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.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   2 Years to 30 Years   (Child, Adult)
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01929642

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United States, Maryland
Kennedy Krieger Institute
Baltimore, Maryland, United States, 21205
Sponsors and Collaborators
Hugo W. Moser Research Institute at Kennedy Krieger, Inc.
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Principal Investigator: Tanjala Gipson, MD Hugo W. Moser Research Institute at Kennedy Krieger, Inc.
Additional Information:
Gomez M, Sampson JR, Whittemore VH, editors. Tuberous sclerosis complex. 3rd ed. Oxford University Press; 1999.
Prescibing Information for Sirolimus. 1999).
Rapamune: U.S. Physician Prescribing Information. 1999).
Abidin R. Parental stress index - 4, short form. fourth edition ed. Odessa, FL: Psychological Assessment Resources, Inc.; 2009. [Internet].; 2012.
Roid G, Miller L. Leiter international performance scale, revised. Torrance, CA: Western Psychological Services; 1998.
Mullen E. Mullen scales of early learning. Circle Pines, MN: American Guidance Service, Inc.; 1995.
Constantino J. The social responsiveness scale. Los Angeles: Western Psychological Services; 2002.
Rutter M, Bailey A, Lord C. Social communication questionnaire. Western Psychological Services; 2003.

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Responsible Party: Tanjala Gipson, Assistant Professor, Hugo W. Moser Research Institute at Kennedy Krieger, Inc. Identifier: NCT01929642    
Other Study ID Numbers: AM00037881
First Posted: August 28, 2013    Key Record Dates
Last Update Posted: January 23, 2018
Last Verified: January 2018
Keywords provided by Tanjala Gipson, Hugo W. Moser Research Institute at Kennedy Krieger, Inc.:
Tuberous Sclerosis Complex (TSC)
Additional relevant MeSH terms:
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Tuberous Sclerosis
Autistic Disorder
Self-Injurious Behavior
Pathologic Processes
Autism Spectrum Disorder
Child Development Disorders, Pervasive
Neurodevelopmental Disorders
Mental Disorders
Neoplasms, Multiple Primary
Neoplastic Syndromes, Hereditary
Malformations of Cortical Development, Group I
Malformations of Cortical Development
Nervous System Malformations
Nervous System Diseases
Neurocutaneous Syndromes
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Congenital Abnormalities
Genetic Diseases, Inborn
Behavioral Symptoms
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents