Clinical trial NCT02708901: Gut to Brain Interaction in Autism. Role of Probiotics on Clinical, Biochemical and Neurophysiological Parameters
Official title: Gut to Brain Interaction in Autism. Role of Probiotics on Clinical, Biochemical and Neurophysiological Parameters
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Autism Spectrum Disorder
Keywords: Autism Spectrum Disorder
Probiotic Vivomixx®
Gastrointestinal Symptoms
Gut-Brain Axis
Endophenotypes
Lead sponsor: IRCCS Fondazione Stella Maris
Sponsor class: OTHER
Collaborators: name: Ministry of Health, Italy
name: Istituto di Fisiologia Clinica CNR
First posted: 2016-03-15
Enrollment: 85
Sex: ALL
Minimum age (years): 18
Maximum age (years): 72
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized double blind study of dietary supplement compared to placebo
Primary purpose: TREATMENT

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.

Eligibility 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)

Primary outcomes:
measure: Changes in severity level of ASD symptomatology
timeFrame: 6 months
Secondary outcomes:
measure: Changes in GI symptomatology
timeFrame: 3 months and 6 months
measure: Changes in Electroencephalogram (EEG) power
timeFrame: 6 months
measure: Changes in EEG coherence
timeFrame: 6 months
measure: Changes in EEG asymmetry
timeFrame: 6 months
measure: Changes in levels of serum Lipopolysaccharide
timeFrame: 6 months
measure: Changes in levels of serum Leptin
timeFrame: 6 months
measure: Changes in levels of serum Resistin
timeFrame: 6 months
measure: Changes in levels of serum Tumor Necrosis Factor - alfa
timeFrame: 6 months
measure: Changes in levels of serum Interleukin-6 (IL-6)
timeFrame: 6 months
measure: Changes in levels of serum Plasminogen Activator Inhibitor-1 (PAI-1)
timeFrame: 6 months
measure: Changes in levels of fecal calprotectin
timeFrame: 3 months and 6 months
measure: Changes in global ASD symptomatology assessed by Childhood Autism Rating Scale
timeFrame: 6 months
measure: Changes in ASD symptomatology: repetitive behaviors
timeFrame: 3 months and 6 months
measure: Changes in ASD symptomatology: sensory profiles
timeFrame: 3 months and 6 months
measure: Changes in global ASD symptomatology assessed by Social Communication Questionnaire
timeFrame: 3 months and 6 months
measure: Changes in Developmental Quotient
timeFrame: 6 months
measure: Changes in Adaptive Functioning
timeFrame: 6 months
measure: Changes in Behavioral Profiles
timeFrame: 3 months and 6 months
measure: Changes in Parental Stress
timeFrame: 3 months and 6 months
Other outcomes:
Locations:
city: Calambrone
country: Italy
facility: IRCCS Stella Maris Foundation
state: Pisa
Study officials:
affiliation: IRCCS Stella Maris Foundation
name: Elisa Santocchi, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Fulceri F, Morelli M, Santocchi E, Cena H, Del Bianco T, Narzisi A, Calderoni S, Muratori F. Gastrointestinal symptoms and behavioral problems in preschoolers with Autism Spectrum Disorder. Dig Liver Dis. 2016 Mar;48(3):248-54. doi: 10.1016/j.dld.2015.11.026. Epub 2015 Dec 11.
citation: Santocchi E, Guiducci L, Fulceri F, Billeci L, Buzzigoli E, Apicella F, Calderoni S, Grossi E, Morales MA, Muratori F. Gut to brain interaction in Autism Spectrum Disorders: a randomized controlled trial on the role of probiotics on clinical, biochemical and neurophysiological parameters. BMC Psychiatry. 2016 Jun 4;16:183. doi: 10.1186/s12888-016-0887-5.
citation: Calderoni S, Santocchi E, Del Bianco T, Brunori E, Caponi L, Paolicchi A, Fulceri F, Prosperi M, Narzisi A, Cosenza A, Tancredi R, Muratori F. Serological screening for Celiac Disease in 382 pre-schoolers with Autism Spectrum Disorder. Ital J Pediatr. 2016 Nov 16;42(1):98. doi: 10.1186/s13052-016-0308-x.
citation: Prosperi M, Santocchi E, Balboni G, Narzisi A, Bozza M, Fulceri F, Apicella F, Igliozzi R, Cosenza A, Tancredi R, Calderoni S, Muratori F. Behavioral Phenotype of ASD Preschoolers with Gastrointestinal Symptoms or Food Selectivity. J Autism Dev Disord. 2017 Nov;47(11):3574-3588. doi: 10.1007/s10803-017-3271-5.
citation: Santocchi E, Guiducci L, Prosperi M, Calderoni S, Gaggini M, Apicella F, Tancredi R, Billeci L, Mastromarino P, Grossi E, Gastaldelli A, Morales MA, Muratori F. Effects of Probiotic Supplementation on Gastrointestinal, Sensory and Core Symptoms in Autism Spectrum Disorders: A Randomized Controlled Trial. Front Psychiatry. 2020 Sep 25;11:550593. doi: 10.3389/fpsyt.2020.550593. eCollection 2020.