Early Biomarkers of Autism in Infants With Tuberous Sclerosis Complex (TSC)

• ClinicalTrials.gov Identifier: NCT01780441
• Recruitment Status: Completed
• First Posted: January 31, 2013
• Last Update Posted: February 4, 2021
• Sponsor: Boston Children's Hospital
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS); Tuberous Sclerosis Alliance
• Information provided by (Responsible Party): Mustafa Sahin, Boston Children's Hospital

Tracking Information

• First Submitted Date: January 28, 2013
• First Posted Date: January 31, 2013
• Last Update Posted Date: February 4, 2021
• Actual Study Start Date: January 2013
• Actual Primary Completion Date: December 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 23, 2013)

• ADOS evaluation score at the 36 month visit [ Time Frame: 36 months ]
  The ADOS performed at 24 and 36 months will be used as a preliminary diagnosis for data analysis. The primary outcome is the possible clinical diagnosis of autism spectrum disorder per the DSM 5 guidelines (Autistic Disorder, Asperger's and PDD-NOS).
• MRI biomarkers [ Time Frame: 36 months ]
  MRI biomarkers obtained at baseline, 12, 24, 36 months will be applied to characterize individual patients in terms of brain tissue, white matter structure and connectivity, functional networks, and pathology. Brain tissue segmentation will be based on structural images derived from T1- and T2-weighted and FLAIR sequences using automated software tools designed for these tasks. White matter integrity and organization will be inferred from DTI imaging sequences. Structural connectivity networks will be delineated by DTI tractography assessment.
• EEG biomarkers [ Time Frame: 36 months ]
  One-hour video-EEG containing both wakefulness and sleep (minimum of 20 minutes of each) will be obtained at baseline, 3, 6, 9, 12, 18, 24 and 36 months. Functional connectivity and pathological activity will be determined by measurement of EEG coherence and gamma frequency/high frequency oscillations.

Original Primary Outcome Measures (submitted: January 30, 2013)

• ADOS evaluation score at the 36 month visit [ Time Frame: 36 months ]
  The primary outcome is the possible clinical diagnosis of autism spectrum disorder per the DSM 5 guidelines (Autistic Disorder, Asperger's and PDD-NOS).
• MRI biomarkers [ Time Frame: 36 months ]
  MRI biomarkers obtained at baseline, 12, 24, 36 months will be applied to characterize individual patients in terms of brain tissue, white matter structure and connectivity, functional networks, and pathology. Brain tissue segmentation will be based on structural images derived from T1- and T2-weighted and FLAIR sequences using automated software tools designed for these tasks. White matter integrity and organization will be inferred from DTI imaging sequences. Structural connectivity networks will be delineated by DTI tractography assessment.
• EEG biomarkers [ Time Frame: 36 months ]
  One-hour video-EEG containing both wakefulness and sleep (minimum of 20 minutes of each) will be obtained at baseline, 3, 6, 9, 12, 18, 24 and 36 months. Functional connectivity and pathological activity will be determined by measurement of EEG coherence and gamma frequency/high frequency oscillations.

• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Early Biomarkers of Autism in Infants With Tuberous Sclerosis Complex (TSC)
• Official Title: Longitudinal Study to Identify Early Biomarkers of Autism Spectrum Disorder (ASD) in Infants With Tuberous Sclerosis Complex (TSC)
• Brief Summary: The investigators are enrolling 3-12 month old infants with a diagnosis of tuberous sclerosis complex (TSC) for a new study on early markers of autism. The study is looking for early signs for autism in a population (TSC) where autism is common. The goal of this project is to use behavioral testing, MRI and EEG techniques to identify children at risk for developing autism starting at 3 months of age and continuing until 36 months of age. Throughout the study, the investigators will recommend Early Intervention services for any child who shows early signs of autism.

Detailed Description

This is a five-year multi-site study using MRI and EEG technologies to identify developmental precursors of Autism Spectrum Disorder in patients with Tuberous Sclerosis Complex (TSC). The study will be enrolling infants at five TSC centers throughout the country, including Boston Children's Hospital, Cincinnati Children's Hospital Medical Center, University of Alabama at Birmingham, University of Texas at Houston and University of California Los Angeles. The main goal of this study is to identify early signs of autism in children with TSC looking at the brain through MRI/diffusion tensor imaging, EEG and behavioral/neuropsychological methods. Eligible infants between the ages of 3-12 months will be evaluated longitudinally at regular visit intervals up to 3 years of age.

Study Objectives

1. To characterize the developmental precursors of ASD in a large number of TSC infants using a prospective multi-center design: Infants with TSC will be evaluated longitudinally at ages 3, 6, 9, 12, 18, 24 and 36 months. At each age, children will undergo standardized evaluations, using cognitive and adaptive measures. At age 24 and 36 months, formal assessment for autism will be performed. Clinical data including medication use, seizure history, EEG activity, genotypic variation, and co-morbidities will be recorded to determine if specific clinical factors modify the course of development.
2. To identify biomarkers with advanced diffusion tensor imaging (DTI) that help predict development of ASD in TSC infants: The investigators hypothesize that decreased white matter integrity performed annually for each of the first 3 years of life, including DTI sequences with tractography. Radial, axial, and mean diffusivity and fractional anisometry will be calculated for each time point and change over time correlated with development of ASD to determine relative risk. Individual measures at each time point will be compared between ASD and non-spectrum groups to assess the individual impact of each measure and timing.
3. To identify biomarkers with quantitative EEG that help predict development of ASD in TSC infants: The investigators hypothesize that altered functional connectivity, as measured by qEEG coherence and high frequency oscillations, will correlate with development of ASD in TSC. Quantitative EEG (qEEG), EEG coherence/gamma frequency (30-50Hz), and high frequency oscillations encompassing both ripples (80-250H) and fast ripples (250-500 Hz) will be measured at each time point. Changes over time will be correlated with development of ASD to determine relative risk, as will comparison of individual measures between the two groups. EEG findings will also be correlated with MR results obtained to further couple functional connectivity as measured by EEG with structural connectivity measured by DTI.

• Study Type: Observational
• Study Design: Observational Model: Cohort; Time Perspective: Prospective
• Target Follow-Up Duration: Not Provided

Biospecimen

Retention:   Samples With DNA

Description:

Blood

• Sampling Method: Non-Probability Sample
• Study Population: A total of 150 evaluable infants with TSC will be recruited. Diagnosis of TSC will be based on established clinical criteria and will not require genetic testing prior to participation. The target age of entry into study is 3-6 months, but infants up to age 12 months (less than or equal to 13.5 months) will be included.
• Condition: Tuberous Sclerosis Complex
• Intervention: Not Provided

Study Groups/Cohorts

Tuberous Sclerosis Complex (TSC)

Tuberous Sclerosis Complex

• Publications *: Srivastava S, Prohl AK, Scherrer B, Kapur K, Krueger DA, Warfield SK, Sahin M; TACERN Study Group. Cerebellar volume as an imaging marker of development in infants with tuberous sclerosis complex. Neurology. 2018 Apr 24;90(17):e1493-e1500. doi: 10.1212/WNL.0000000000005352. Epub 2018 Mar 23.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 27, 2017): 166
• Original Estimated Enrollment (submitted: January 30, 2013): 150
• Actual Study Completion Date: December 2020
• Actual Primary Completion Date: December 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Meets genetic or clinical diagnostic criteria for TSC (Tuberous Sclerosis), the latter based on current recommendations for diagnostic evaluation, such as physical exam, neuroimaging, echocardiogram.
2. Age criteria: 3 months- 12 months of age at time of enrollment. For study purposes, 3 months is defined as ≥ 9 weeks, 1 day and 12 months is defined as ≤ 13.5 months.

Exclusion Criteria:

1. Prematurity, defined as gestational age < 36 weeks at time of delivery
2. Has taken an investigational drug as part of another research study, within 30 days prior to study enrollment
3. Is taking an mTOR inhibitor such as rapamycin, sirolimus, or everolimus (other than topical formulations) at the time of study enrollment
4. Subependymal Giant Cell Astrocytoma requiring medical or surgical treatment at the time of study enrollment
5. History of epilepsy surgery at the time of study enrollment
6. Contraindications to MRI scanning, such as metal implants/non-compatible medical devices or medical conditions

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 3 Months to 12 Months (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01780441
• Other Study ID Numbers: IRB-P00005074; 1U01NS082320-01 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Mustafa Sahin, Boston Children's Hospital
• Study Sponsor: Boston Children's Hospital

Collaborators

• National Institute of Neurological Disorders and Stroke (NINDS)
• Tuberous Sclerosis Alliance

Investigators

• Principal Investigator: Mustafa Sahin, MD, PhD; Boston Children's Hospital
• Principal Investigator: Darcy Krueger, MD, PhD; Children's Hospital Medical Center, Cincinnati

• PRS Account: Boston Children's Hospital
• Verification Date: February 2021