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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 : Recruiting
First Posted : March 15, 2016
Last Update Posted : October 13, 2017
Sponsor:
Collaborators:
Ministry of Health, Italy
Istituto di Fisiologia Clinica CNR
Information provided by (Responsible Party):
IRCCS Fondazione Stella Maris

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.

Condition or disease Intervention/treatment Phase
Autism Spectrum Disorder Dietary Supplement: Vivomixx® Dietary Supplement: Placebo Not Applicable

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 : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
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
Official Title: Gut to Brain Interaction in Autism. Role of Probiotics on Clinical, Biochemical and Neurophysiological Parameters
Study Start Date : November 2015
Estimated Primary Completion Date : September 2018
Estimated Study Completion Date : November 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: GI Vivomixx®
25 children with GI symptoms
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

Placebo Comparator: GI Placebo
25 children with GI symptoms
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

Active Comparator: NGI Vivomixx®
25 children without GI symptoms
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

Placebo Comparator: NGI placebo
25 children without GI symptoms
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




Primary Outcome Measures :
  1. Changes in severity level of ASD symptomatology [ Time Frame: 6 months ]
    Delta of scores at Autism Diagnostic Observation Schedule-2


Secondary Outcome Measures :
  1. Changes in GI symptomatology [ Time Frame: 3 months and 6 months ]
    Delta of scores at GI Severity Index

  2. Changes in Electroencephalogram (EEG) power [ Time Frame: 6 months ]
    Registration with a 128-channels digital EEG: power will be assessed within each frequency band

  3. Changes in EEG coherence [ Time Frame: 6 months ]
    Registration with a 128-channels digital EEG: coherence will be assessed within each frequency band

  4. Changes in EEG asymmetry [ Time Frame: 6 months ]
    Registration with a 128-channels digital EEG: asymmetry will be assessed within each frequency band

  5. Changes in levels of serum Lipopolysaccharide [ Time Frame: 6 months ]
    Delta of values of serum Lipopolysaccharide

  6. Changes in levels of serum Leptin [ Time Frame: 6 months ]
    Delta of values of serum Leptin

  7. Changes in levels of serum Resistin [ Time Frame: 6 months ]
    Delta of values of serum Resistin

  8. Changes in levels of serum Tumor Necrosis Factor - alfa [ Time Frame: 6 months ]
    Delta of values of serum Tumor Necrosis Factor - alfa

  9. Changes in levels of serum Interleukin-6 (IL-6) [ Time Frame: 6 months ]
    Delta of values of serum Interleukin-6 (IL-6)

  10. 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)

  11. Changes in levels of fecal calprotectin [ Time Frame: 3 months and 6 months ]
    Delta of values of fecal calprotectin

  12. Changes in global ASD symptomatology assessed by Childhood Autism Rating Scale [ Time Frame: 6 months ]
    Delta of scores at Childhood Autism Rating Scale

  13. Changes in ASD symptomatology: repetitive behaviors [ Time Frame: 3 months and 6 months ]
    Delta of scores at Repetitive Behavior Scale

  14. Changes in ASD symptomatology: sensory profiles [ Time Frame: 3 months and 6 months ]
    Delta of scores at Sensory Profile

  15. Changes in global ASD symptomatology assessed by Social Communication Questionnaire [ Time Frame: 3 months and 6 months ]
    Delta of scores at Social Communication Questionnaire

  16. Changes in Developmental Quotient [ Time Frame: 6 months ]
    Delta of score at Griffiths Mental Developmental Scale

  17. Changes in Adaptive Functioning [ Time Frame: 6 months ]
    Delta of scores at Vineland Adaptive Behavior Scale-II

  18. Changes in Behavioral Profiles [ Time Frame: 3 months and 6 months ]
    Delta of scores at Child Behavior Checklist 1.5-5

  19. Changes in Parental Stress [ Time Frame: 3 months and 6 months ]
    Delta of scores at Parenting Stress Index



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Ages Eligible for Study:   18 Months to 72 Months   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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)

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 ClinicalTrials.gov identifier (NCT number): NCT02708901


Contacts
Contact: Elisa Santocchi, MD, PhD +39 050 886111-313 e.santocchi@fsm.unipi.it
Contact: Letizia Guiducci, PhD +39 050 3153147 letizia.guiducci@ifc.cnr.it

Locations
Italy
IRCCS Stella Maris Foundation Recruiting
Calambrone, Pisa, Italy, 56128
Contact: Elisa Santocchi, MD, PhD    +39 050 886313-111    e.santocchi@fsm.unipi.it   
Contact: Letizia Guiducci, PhD    +39 050 3153147    letizia.guiducci@ifc.cnr.it   
Principal Investigator: Elisa Santocchi, Md, PhD         
Sub-Investigator: Letizia Guiducci, PhD         
Sponsors and Collaborators
IRCCS Fondazione Stella Maris
Ministry of Health, Italy
Istituto di Fisiologia Clinica CNR
Investigators
Principal Investigator: Elisa Santocchi, MD, PhD IRCCS Stella Maris Foundation

Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: IRCCS Fondazione Stella Maris
ClinicalTrials.gov Identifier: NCT02708901     History of Changes
Other Study ID Numbers: GR-2011-02348280
First Posted: March 15, 2016    Key Record Dates
Last Update Posted: October 13, 2017
Last Verified: August 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by IRCCS Fondazione Stella Maris:
Autism Spectrum Disorder
Probiotic Vivomixx®
Gastrointestinal Symptoms
Gut-Brain Axis
Endophenotypes

Additional relevant MeSH terms:
Autistic Disorder
Autism Spectrum Disorder
Child Development Disorders, Pervasive
Neurodevelopmental Disorders
Mental Disorders