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Gut to Brain Interaction in Autism. Role of Probiotics on Clinical, Biochemical and Neurophysiological Parameters

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ClinicalTrials.gov Identifier: NCT02708901
Recruitment Status : Completed
First Posted : March 15, 2016
Last Update Posted : February 18, 2019
Sponsor:
Collaborators:
Ministry of Health, Italy
Istituto di Fisiologia Clinica CNR
Information provided by (Responsible Party):
IRCCS Fondazione Stella Maris

Tracking Information
First Submitted Date  ICMJE March 4, 2016
First Posted Date  ICMJE March 15, 2016
Last Update Posted Date February 18, 2019
Actual Study Start Date  ICMJE November 2015
Actual Primary Completion Date August 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 9, 2016)
Changes in severity level of ASD symptomatology [ Time Frame: 6 months ]
Delta of scores at Autism Diagnostic Observation Schedule-2
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02708901 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 15, 2016)
  • Changes in GI symptomatology [ Time Frame: 3 months and 6 months ]
    Delta of scores at GI Severity Index
  • Changes in Electroencephalogram (EEG) power [ Time Frame: 6 months ]
    Registration with a 128-channels digital EEG: power will be assessed within each frequency band
  • Changes in EEG coherence [ Time Frame: 6 months ]
    Registration with a 128-channels digital EEG: coherence will be assessed within each frequency band
  • Changes in EEG asymmetry [ Time Frame: 6 months ]
    Registration with a 128-channels digital EEG: asymmetry will be assessed within each frequency band
  • Changes in levels of serum Lipopolysaccharide [ Time Frame: 6 months ]
    Delta of values of serum Lipopolysaccharide
  • Changes in levels of serum Leptin [ Time Frame: 6 months ]
    Delta of values of serum Leptin
  • Changes in levels of serum Resistin [ Time Frame: 6 months ]
    Delta of values of serum Resistin
  • Changes in levels of serum Tumor Necrosis Factor - alfa [ Time Frame: 6 months ]
    Delta of values of serum Tumor Necrosis Factor - alfa
  • Changes in levels of serum Interleukin-6 (IL-6) [ Time Frame: 6 months ]
    Delta of values of serum Interleukin-6 (IL-6)
  • Changes in levels of serum Plasminogen Activator Inhibitor-1 (PAI-1) [ Time Frame: 6 months ]
    Delta of values of serum Plasminogen Activator Inhibitor-1 (PAI-1)
  • Changes in levels of fecal calprotectin [ Time Frame: 3 months and 6 months ]
    Delta of values of fecal calprotectin
  • Changes in global ASD symptomatology assessed by Childhood Autism Rating Scale [ Time Frame: 6 months ]
    Delta of scores at Childhood Autism Rating Scale
  • Changes in ASD symptomatology: repetitive behaviors [ Time Frame: 3 months and 6 months ]
    Delta of scores at Repetitive Behavior Scale
  • Changes in ASD symptomatology: sensory profiles [ Time Frame: 3 months and 6 months ]
    Delta of scores at Sensory Profile
  • Changes in global ASD symptomatology assessed by Social Communication Questionnaire [ Time Frame: 3 months and 6 months ]
    Delta of scores at Social Communication Questionnaire
  • Changes in Developmental Quotient [ Time Frame: 6 months ]
    Delta of score at Griffiths Mental Developmental Scale
  • Changes in Adaptive Functioning [ Time Frame: 6 months ]
    Delta of scores at Vineland Adaptive Behavior Scale-II
  • Changes in Behavioral Profiles [ Time Frame: 3 months and 6 months ]
    Delta of scores at Child Behavior Checklist 1.5-5
  • Changes in Parental Stress [ Time Frame: 3 months and 6 months ]
    Delta of scores at Parenting Stress Index
Original Secondary Outcome Measures  ICMJE
 (submitted: March 9, 2016)
  • Changes in GI symptomatology [ Time Frame: 3 months and 6 months ]
    Delta of scores at GI Severity Index
  • Changes in EEG power [ Time Frame: 6 months ]
    Registration with a 128-channels digital EEG: power will be assessed within each frequency band
  • Changes in EEG coherence [ Time Frame: 6 months ]
    Registration with a 128-channels digital EEG: coherence will be assessed within each frequency band
  • Changes in EEG asymmetry [ Time Frame: 6 months ]
    Registration with a 128-channels digital EEG: asimmetry will be assessed within each frequency band
  • Changes in levels of serum Lipopolysaccharide [ Time Frame: 6 months ]
    Delta of values of serum Lipopolysaccharide
  • Changes in levels of serum Leptin [ Time Frame: 6 months ]
    Delta of values of serum Leptin
  • Changes in levels of serum Resistin [ Time Frame: 6 months ]
    Delta of values of serum Resistin
  • Changes in levels of serum Tumor Necrosis Factor - alfa [ Time Frame: 6 months ]
    Delta of values of serum Tumor Necrosis Factor - alfa
  • Changes in levels of serum IL-6 [ Time Frame: 6 months ]
    Delta of values of serum IL-6
  • Changes in levels of serum PAI-1 [ Time Frame: 6 months ]
    Delta of values of serum PAI-1
  • Changes in levels of fecal calprotectin [ Time Frame: 3 months and 6 months ]
    Delta of values of fecal calprotectin
  • Changes in global ASD symptomatology assessed by Childhood Autism Rating Scale [ Time Frame: 6 months ]
    Delta of scores at Childhood Autism Rating Scale
  • Changes in ASD symptomatology: repetitive behaviors [ Time Frame: 3 months and 6 months ]
    Delta of scores at Repetitive Behavior Scale
  • Changes in ASD symptomatology: sensory profiles [ Time Frame: 3 months and 6 months ]
    Delta of scores at Sensory Profile
  • Changes in global ASD symptomatology assessed by Social Communication Questionnaire [ Time Frame: 3 months and 6 months ]
    Delta of scores at Social Communication Questionnaire
  • Changes in Developmental Quotient [ Time Frame: 6 months ]
    Delta of score at Griffiths Mental Developmental Scale
  • Changes in Adaptive Functioning [ Time Frame: 6 months ]
    Delta of scores at Vineland Adaptive Behavior Scale-II
  • Changes in Behavioral Profiles [ Time Frame: 3 months and 6 months ]
    Delta of scores at Child Behavior Checklist 1.5-5
  • Changes in Parental Stress [ Time Frame: 3 months and 6 months ]
    Delta of scores at Parent Stress Index
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Gut to Brain Interaction in Autism. Role of Probiotics on Clinical, Biochemical and Neurophysiological Parameters
Official Title  ICMJE Gut to Brain Interaction in Autism. Role of Probiotics on Clinical, Biochemical and Neurophysiological Parameters
Brief Summary The purpose of this study is to assess the effects of a 6-months supplementation with probiotic Vivomixx® on inflammatory and gastrointestinal (GI) biomarkers, gastrointestinal disturbances, behavioral and developmental profiles, and neurophysiological features in preschoolers with Autism Spectrum Disorders (ASD) with or without GI symptoms.
Detailed Description Autism Spectrum Disorders (ASD) are most likely multifactorial diseases in which the combination of genetic and environmental factors might have a role in the expression of the phenotype. A high incidence of gastrointestinal (GI) symptoms is reported in ASD. GI disturbances and altered gut microflora could make a child with a genetic predisposition for ASD more prone to express the ASD phenotype or increase the severity of his behavioral symptoms. The exploitation of strategies which can reduce the gut production and absorption of toxins or restore normal gut microbiota, such as probiotics may represent a non-pharmacological option in the treatment of GI disturbances in ASD. The aim of this study is to determine effects of probiotics supplementation with Vivomixx® in ASD children on specific GI symptoms, ASD core deficits, cognitive and language development, on inflammatory and gastrointestinal (GI) biomarkers and on Quantitative Electroencephalographic measures (QEEG). Vivomixx® is a probiotic mixture of 8 probiotic strains (Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus paracasei, Lactobacillus bulgaricus and Streptococcus thermophilus). An additional aim of the study is to determine the environmental exposure to phthalates (chemical pollutant) in ASD children, and the possible effects of probiotic supplementation on their urinary concentrations. A group of 100 unselected preschoolers with ASD will be classified as belonging to the Gastro Intestinal (GI) group or to the Not Gastro Intestinal (NGI) group on the basis of the presence of significant GI symptoms at GI severity Index. Subjects belonging to the two groups (GI and NGI) will be blind randomized 1:1 to regular diet with probiotic Vivomixx® or with placebo for 6 months. All the participants will be assessed at the baseline, after three months and after six months from the baseline in order to evaluate the possible changes in GI symptoms, in ASD symptomatology, in other affective and behavioral comorbid symptoms, in plasmatic, urinary and fecal biomarkers related to abnormal intestinal function and in the electrophysiological patterns. The effects of treatments with probiotics on children with ASD need to be confirmed by rigorous controlled trials. Aiming to examine the impact of this treatment not only on clinical but also on neurophysiological patterns this trial sets out to provide new insights into the gut-brain connection in autism. Moreover, this study's results could add new data on the relationship between the presence of phthalates, clinical features and neurophysiological patterns in ASD.
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Randomized double blind study of dietary supplement compared to placebo
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Autism Spectrum Disorder
Intervention  ICMJE
  • Dietary Supplement: Vivomixx®
    Two packets (900 billions bacteria) per os (P.O.) daily x 1 month and one packet (450 billions bacteria) P.O. daily x 5 months
  • Dietary Supplement: Placebo
    Two packets (4,4 grams of maltose and silicon dioxide x 2) P.O. daily x 1 month and one packet (4,4 grams of maltose and silicon dioxide) P.O. daily x 5 months
Study Arms  ICMJE
  • Active Comparator: GI Vivomixx®
    25 children with GI symptoms
    Intervention: Dietary Supplement: Vivomixx®
  • Placebo Comparator: GI Placebo
    25 children with GI symptoms
    Intervention: Dietary Supplement: Placebo
  • Active Comparator: NGI Vivomixx®
    25 children without GI symptoms
    Intervention: Dietary Supplement: Vivomixx®
  • Placebo Comparator: NGI placebo
    25 children without GI symptoms
    Intervention: Dietary Supplement: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: February 15, 2019)
85
Original Estimated Enrollment  ICMJE
 (submitted: March 9, 2016)
100
Actual Study Completion Date  ICMJE September 2018
Actual Primary Completion Date August 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • age-range: 18-72 months
  • ASD diagnosis according to Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) criteria

Exclusion Criteria:

  • brain anomalies detected by Magnetic Resonance Imaging (MRI)
  • neurological syndromes or focal neurological signs
  • anamnesis of birth asphyxia, severe premature birth (≤ 28 gestational weeks) or perinatal injuries
  • epilepsy
  • significant sensory impairment
  • diagnosis of organic GI Disorder (i.e. gastroesophageal reflux, food allergies, Inflammatory Bowel Disease)
  • diagnosis of Coeliac Disease
  • special diet (i.e. gluten-free diet, casein-free diet, high-protein diet, ketogenic diet)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Months to 72 Months   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Italy
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02708901
Other Study ID Numbers  ICMJE GR-2011-02348280
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party IRCCS Fondazione Stella Maris
Study Sponsor  ICMJE IRCCS Fondazione Stella Maris
Collaborators  ICMJE
  • Ministry of Health, Italy
  • Istituto di Fisiologia Clinica CNR
Investigators  ICMJE
Principal Investigator: Elisa Santocchi, MD, PhD IRCCS Stella Maris Foundation
PRS Account IRCCS Fondazione Stella Maris
Verification Date August 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP