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

Tracking Information
First Submitted Date	January 28, 2013
First Posted Date	January 31, 2013
Last Update Posted Date	February 7, 2018
Actual Study Start Date	January 2013
Estimated Primary Completion Date	February 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.
Change History	Complete list of historical versions of study NCT01780441 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures	Not Provided
Original Secondary Outcome Measures	Not Provided
Current Other Outcome Measures	Not Provided
Original Other 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; 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.; 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.; 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 Mar 23. pii: 10.1212/WNL.0000000000005352. doi: 10.1212/WNL.0000000000005352. [Epub ahead of print]
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status	Active, not recruiting
Actual Enrollment; (submitted: January 27, 2017)	166
Original Estimated Enrollment; (submitted: January 30, 2013)	150
Estimated Study Completion Date	December 2019
Estimated Primary Completion Date	February 2019 (Final data collection date for primary outcome measure)
Eligibility Criteria	Inclusion Criteria: 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.; 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: Prematurity, defined as gestational age < 36 weeks at time of delivery; Has taken an investigational drug as part of another research study, within 30 days prior to study enrollment; Is taking an mTOR inhibitor such as rapamycin, sirolimus, or everolimus (other than topical formulations) at the time of study enrollment; Subependymal Giant Cell Astrocytoma requiring medical or surgical treatment at the time of study enrollment; History of epilepsy surgery at the time of study enrollment; 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
Removed Location Countries
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 2018