Impact of Improving GI Symptoms on Autism Symptoms and Oxidative Stress

• ClinicalTrials.gov Identifier: NCT02442115
• Recruitment Status: Unknown
• First Posted: May 13, 2015
• Last Update Posted: January 10, 2019
• Sponsor: Children's Hospital Los Angeles
• Information provided by (Responsible Party): Pat Levitt, PhD, Children's Hospital Los Angeles

Study Description

Brief Summary:

The clinical manifestation of autism spectrum disorder (ASD) is complex, with medical and mental health disruptions that occur with the three core behavioral criteria used for diagnosis (social behavior, communication, restricted interests/repetitive behavior). Co-occurring medical conditions, such as gastrointestinal dysfunction (GID), often are overlooked when designing research strategies to understand the mechanisms underlying the expression of ASD. This study was initially a collaboration between Children's Hospital Los Angeles (CHLA) and the Children's Hospital at Vanderbilt University. The current research project proposes to recruit subject at CHLA and the Center for Autism and Developmental Disorders (CAND), a Children's Hospital of Orange County and University of California Irvine (UCI) Health collaborative program. In Aim 1, the investigators will characterize GID in pediatric populations with ASD. Over a 12 month period, subjects will receive standard of care for their GID, typically functional constipation. The study population will be characterized with a standardized instrument for diagnosing functional GI disorders in children, the Questionnaire on Pediatric Gastrointestinal Symptoms, and with the clinical acumen of an experienced pediatric gastroenterologist. Nutritional information also will be collected to determine whether there are patterns of GIDs that correlate with dietary and nutritional status. The in-depth characterization and treatment of GIDs in children with ASD will provide a unique way of determining if ASD symptom and GID symptom improvement are related to each other. In Aim 2, the investigators will do in-depth assessment of each subjects functional status for social communication, emotional regulation, cognitive function, speech-language, sensory integration, and a biomarker of oxidative stress. The latter will be measured in urine samples over the course of one year. There are no direct interventions for autism symptoms in this study. Rather, subjects will receive standard of care for the GID diagnosis and secondary effects on ASD symptoms will be evaluated. Our power calculation shows that the investigators will be adequately powered with the proposed study design and recruitment targets. As part of the study, the investigators have developed a collaboration with investigators in the University of Southern California (USC) School of Engineering, in which the investigators will work with them to develop computational tools to assist in the characterization of videotaped Autism Diagnostic Observation Schedule (ADOS-2) assessments.

Condition or disease	Intervention/treatment
Autistic Disorder; Constipation; Gastrointestinal Diseases	Other: Treatment of Functional Constipation by

Detailed Description:

Children ages 7 years 0 months to 12 years 11 months will be recruited into 1 clinical group (ASD+/FC+), utilizing the following clinics in Southern California:

CHLA-affiliated Clinics

• Boone-Fetter Clinic, home of the CHLA Autism Treatment Network
• University Center of Excellence on Developmental Disabilities (UCEDD) Clinic at CHLA - UC Irvine/Orange County-affiliated clinics
• Center for Autism and Neurodevelopmental Disorders in Orange County
• Children's Hospital of Orange County Exclusion criteria include a diagnosed syndromic disorder, prematurity, failure to meet standard birth weight, not enrolled in any ASD treatment program. For each child, the Questionnaire on Pediatric Gastrointestinal Symptoms (QPGS)-Rome III is administered and the child is seen by a board-certified pediatric gastroenterologist. The child will be seen at baseline, 3, 6 and 12 months for their research visits. Treatment of FC in children with ASD is based on the Autism Treatment Network (ATN) modified protocol of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) and includes the following: 1) a thorough dietary history is reviewed and adjusted for introducing a diet rich in fiber (or supplements if able to be tolerated by the child; typically this will be in older children in the study); 2) assessment of abdominal pain, perianal skin tags, hemorrhoids, fissures, rectal exam if needed, frequency of stooling, quality of stool, rectal bleeding, other possible associated symptoms such as reflux/dyspepsia, vomiting, headaches, increase or decrease in appetite; 3) behavioral techniques, such as toileting after meal times, and other strategies are added; and 4) medicine and dietary adjustments are made. At each visit, the following instruments/questionnaires will be administered by a clinical psychologist: 1) social responsiveness scale; 2) Kaufman Brief Intelligence Test; 3) Child Behavior Checklist; 4) Aberrant Behavior Checklist; 5) Pediatric Quality of Life Inventory (Peds QL); 6) Repetitive Behavioral Scale-Revised; 7) Autism Impact Measure; 8) Pearson Short Sensory Profile. The Vineland will be administered at baseline and 12 months. The ADOS-2 will be used at baseline to ensure an ASD diagnosis.

At each visit, subject urine is collected and stored until an assay for the oxidative stress marker F2-isoprostane is measured.

A buccal swab is collected and DNA extracted for future genetic studies.

Study Design

• Study Type: Observational
• Estimated Enrollment: 600 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: The MET Signaling System, Autism and Gastrointestinal Dysfunction
• Actual Study Start Date: September 2009
• Estimated Primary Completion Date: December 2019
• Estimated Study Completion Date: December 2019

Groups and Cohorts

Group/Cohort	Intervention/treatment
ASD with GID; Children with Autism Spectrum Disorder with Functional Constipation will be treated with standard of care defined by NASPGHAN by a pediatric gastroenterologist, and evaluated at 4 visits over 1 year for their medical condition. These children will be enrolled in some ASD treatment program by their parents. The treatment program is not part of the current study. Measures of ASD symptoms will be done at each visit to determine social communication, emotional and cognitive improvement due to the FC treatment. Measures of F2-isoprostane, a marker of oxidative stress, will be done at each visit to determine if FC treatment and ASD symptom improvement relates to improvement in a child's physiology.	Other: Treatment of Functional Constipation by; The NASPGHAN protocol is used by pediatric gastroenterologist to treat functional constipation. Status is monitored at 4 visits and adjustments to treatment are made based on clinical standards and judgment.; Other Name: NASPGHAN standard of care
ASD without GID; Children Autism Spectrum Disorder without Functional Constipation will be evaluated for their ASD symptoms at 4 times over 1 year. These children will be enrolled in some ASD treatment program by their parents. The treatment program is not part of the current study. Measures of F2-isoprostane, a marker of oxidative stress, will be done at each visit to determine if ASD symptom improvement relates to improvement in a child's physiology.

Outcome Measures

Primary Outcome Measures :

1. Reduction in F2-IsoProstanes (IsoPs) oxidative stress biomarker [ Time Frame: 1 year ]
2. Reduction in T-score from Social Responsiveness Scale (SRS-2) (Teacher questionnaire) [ Time Frame: 1 year ]

Biospecimen Retention:   Samples With DNA

Urine sample collection. Saliva sample collection for DNA extraction.

Eligibility Criteria

• Ages Eligible for Study: 5 Years to 17 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Probability Sample

Study Population

Children with Autism Spectrum Disorders with and without functional constipation

Criteria

Inclusion Criteria:

• English or Spanish-speaking of any ethnicity

• Boys or girls aged 5 years 0 months to 17 years 11 months

  • A clinical diagnosis of functional constipation (FC) for the ASD+/FC+ group, with or without encopresis
  • Clinical assessment of ASD using Diagnostic and Statistical Manual of Mental Disorders (DSM IV or V criteria)
  • ADOS-validated diagnosis of ASD
• Gestational age between 36 and 42 weeks

• Birth weight of at least 2500 grams

  • Children with suspected or an existing clinical diagnosis of ASD and FC will be recruited and consented for the study. Assessments and clinical diagnosis may be completed and confirmed through the Baseline study visit for subjects to be eligible.

    • Teacher participation is not required for child participation. However, teacher participation will be requested around the time of child enrollment.

Exclusion Criteria:

• severe sensory or motor impairments (deafness, blindness;
• identified inherited metabolic, syndromic, or progressive neurological disorders (including epilepsy, Down Syndrome, Rett Syndrome, Tuberous Sclerosis, Neurofibromatosis, Fragile X Syndrome);
• a non-functional GID, such as ulcerative colitis, Celiac disease or Hirschsprung's disease;
• failure to meet birth weight/gestational age as noted above
• participation in another ASD research study at the same time
• not enrolled in an ASD intervention program

Contacts and Locations

Contacts

Contact: Pat Levitt, PhD; TummyTroubles@chla.usc.edu

Contact: Sandra Figueroa, BS; 323-361-5284; sfigueroa@chla.usc.edu

Locations

United States, California

Children's Hospital Los Angeles; Recruiting

Los Angeles, California, United States, 90027

Contact: Pat Levitt, PhD Tummytroubles@chla.usc.edu

Contact: Sandra Figueroa 323-361-5284 sfigueroa@chla.usc.edu

The Center for Autism & Neurodevelopmental Disorders; Recruiting

Santa Ana, California, United States, 92705

Contact: John Donnelly, MD

Contact: Jennifer Phan 949- 267-0454 phanjt@uci.edu

Sponsors and Collaborators

Children's Hospital Los Angeles

Investigators

• Principal Investigator: Pat Levitt, PhD; Children's Hospital Los Angeles

More Information

• Responsible Party: Pat Levitt, PhD, Simms/Mann Chair in Developmental Neurogenetics, Institute for the Developing Mind, Children's Hospital Los Angeles
• ClinicalTrials.gov Identifier: NCT02442115
• Other Study ID Numbers: 09-00212
• First Posted: May 13, 2015
• Last Update Posted: January 10, 2019
• Last Verified: January 2019

Keywords provided by Pat Levitt, PhD, Children's Hospital Los Angeles:

Autism; Autism Spectrum Disorder (ASD); Tummy Troubles; Constipation; GI Disorders; Gastrointestinal Disorders; Gastrointestinal; Oxidative Stress; Stomach problems; Behaviors; Autistic; ASD; MET gene; GID; Pediatric; Pediatric GI disorders; Children with Autism; functional constipation

Additional relevant MeSH terms:

Gastrointestinal Diseases; Digestive System Diseases; Constipation; Autistic Disorder; Autism Spectrum Disorder; Child Development Disorders, Pervasive; Neurodevelopmental Disorders; Mental Disorders; Signs and Symptoms, Digestive