Clinical trial NCT04293783: Randomized Double-blind Clinical Trial With L.Reuteri Supplementation in Children With Autism Spectrum Disorder
Official title: Efficacy of Lactobacillus Reuteri in Managing Social Deficits in Children With Autistic Spectrum Disorder: a Randomized Clinical Trial With Evaluation of Gut Microbiota and Metabolomics Profiles
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Autism Spectrum Disorder
Keywords: Probiotic
Gut-Brain axis
L. Reuteri
Social Behavior
Microbiome
Metabolome
Inflammatory Profile
Gastrointestinal Symptoms
Lead sponsor: University of Rome Tor Vergata
Sponsor class: OTHER
Collaborators: name: University of Bari
First posted: 2020-03-03
Enrollment: 43
Sex: ALL
Minimum age (years): 18
Maximum age (years): 8
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: double-blind randomized, parallel-group, placebo-controlled study
Primary purpose: TREATMENT

Brief summary: The aim of this study is to assess the effects of a 6-months probiotic supplementation on behavioral profiles, microbiota and metabolic profiles, inflammatory biomarkers, gastrointestinal disturbances, in children with Autism Spectrum Disorders (ASD) with or without GI symptoms.

Detailed description: Autism Spectrum Disorder (ASD) is a condition that includes social deficits, repetitive behaviors and language difficulties; its prevalence continues to increase worldwide, however, there are no medication for the core symptoms of this disorder. In addition to these core symptoms, children with ASD are 3.5 times more likely to suffer from gastrointestinal issues than children without developmental disorders. Moreover, GI problems have been associated with changes in the microbial communities inhabiting the gut of ASD individuals.

Studies in animal models have suggested that the gut microbes can modulate central nervous system-driven behaviors.

In 2019, a research group (Buffington et al.) found that a specific strain (L. Reuteri PTA) rescues the deficit in social interaction-induced VTA plasticity in ASD mouse, enhancing the salience and rewarding value of social stimuli.

These data support the idea that microbial therapies could ameliorate specific endophenotypes associates with ASD.

Aim of the study The aim of this pilot study is to determine the possible effects of supplementation with a specific probiotic strain (L. Reuteri ATCC PTA 6475) in ASD children on the core deficits of the disorder, the social behavior. A secondary aim is to evaluate the effects of probiotic supplementation on specific GI symptoms, and repetitive, dysfunctional behaviors, widely described in ASD children. Finally, the investigators will evaluate gut microbiota (fecal and salivary samples) and metabolomics (urinary samples) profiles differences before and after the supplementation.

Methods and participants Double blind randomized, placebo-controlled trial, with a nutritional supplement, with two parallel arms, an allocation ratio of 1:1, and a superiority framework.

The investigators aim to enroll 80 patients. A detailed informed consent will be given and and both parents will sign it before the start of the data collection.

The participants, after a first evaluation, will be divided into 2 groups; each arm will be blind randomized 1:1 to regular diet with a specific probiotic strain (L. Reuteri ATCC PTA 6475) or with placebo for 6 months.

After randomization the investigators will explain how to take the product and the first dose will be administered.

During the study the child is not allowed to take other probiotics. The type of neurologic/rehabilitation therapy ongoing at T0 cannot be changed until the study is finished.

Study Product Test product chewable tablets: 1x108 CFU Lactobacillus reuteri DSM 17938 + 1x108 CFU Lactobacillus reuteri ATCC PTA 6475 (together 2x108 CFU) Placebo chewable caps: identical in shape and taste to the test product without the Lactobacillus reuteri components Both study products are delivered in identical containers and labelled as XXX. Dosing: Two tablets/cps once a day.

Assessment

At the time of enrollment, each participant will undergo a comprehensive neuropsychological and biochemical evaluation, in order to establish the baseline of the primary and secondary outcome measures. A detailed Case Record Forms (CRF) containing all data pertinent to the study will be prepared.

At T0 the investigators will also collect blood, urinary salivary and fecal sample from each participant in order to perform biochemical, microbiological and metabolomics evaluation. The parents have to fill out questionnaire about dietary habits in a 5 day-diary.

After three months from the enrollment (T1), each child will undergo a second evaluation with some clinical and biological measures.

At the end of the study, six months from baseline, the investigators will perform another complete assessment through the same clinical, biochemical and neuropsychological evaluation performed at T0, to evaluate the possible changes in (1) autism symptoms severity; (2) affective and behavioral comorbid symptoms; (3) GI symptoms; (4) plasmatic, urinary and fecal biomarkers related to abnormal intestinal/inflammatory function. At T2, urinary salivary, and fecal sample will be also collected from each participant in order to perform microbiological and metabolomics evaluation.

All children recruited will undergo the evaluation at Child Neurology and Psychiatry unit, Policlinico Tor Vergata, Rome, Italy.

Eligibility criteria: Inclusion Criteria:

- Autism Spectrum Disorder (DSM-5 criteria diagnosis)

Exclusion Criteria:

* neurological syndromes (that explain autism symptoms)
* coeliac disease
* other organic GI disorder
* special diet.

Primary outcomes:
measure: Changes in severity level of ASD symptomatology
timeFrame: 6 months
measure: Changes in Microbiome Profile
timeFrame: 3 months and 6 months
Secondary outcomes:
measure: Changes in GI symptoms
timeFrame: 3 months and 6 months
measure: Changes in ASD symptomatology: problematic behaviors
timeFrame: 3 months and 6 months
measure: Changes in ASD symptomatology: repetitive behaviors
timeFrame: 3 months and 6 months
measure: Changes in Adaptive Functioning
timeFrame: 6 months
measure: Changes in global ASD symptomatology
timeFrame: 3 months and 6 months
measure: Changes in Behavioral Profiles
timeFrame: 3 months and 6 months
measure: Changes in Parental Stress
timeFrame: 3 months and 6 months
measure: Changes in Metabolomic Profile
timeFrame: 6 months
measure: Changes in Inflammatory Profile
timeFrame: 6 months
Other outcomes:
Locations:
city: Bari
country: Italy
facility: University of Bari
state: BA
city: Rome
country: Italy
facility: University of Rome Tor Vergata
state: RM
Study officials:
affiliation: University of Rome Tor Vergata
name: Mazzone Luigi, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Bari
name: Francavilla Ruggiero, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Sgritta M, Dooling SW, Buffington SA, Momin EN, Francis MB, Britton RA, Costa-Mattioli M. Mechanisms Underlying Microbial-Mediated Changes in Social Behavior in Mouse Models of Autism Spectrum Disorder. Neuron. 2019 Jan 16;101(2):246-259.e6. doi: 10.1016/j.neuron.2018.11.018. Epub 2018 Dec 3.
citation: Vuong HE, Yano JM, Fung TC, Hsiao EY. The Microbiome and Host Behavior. Annu Rev Neurosci. 2017 Jul 25;40:21-49. doi: 10.1146/annurev-neuro-072116-031347. Epub 2017 Mar 8.
citation: Schieve LA, Gonzalez V, Boulet SL, Visser SN, Rice CE, Van Naarden Braun K, Boyle CA. Concurrent medical conditions and health care use and needs among children with learning and behavioral developmental disabilities, National Health Interview Survey, 2006-2010. Res Dev Disabil. 2012 Mar-Apr;33(2):467-76. doi: 10.1016/j.ridd.2011.10.008. Epub 2011 Nov 24.
citation: Lussu M, Noto A, Masili A, Rinaldi AC, Dessi A, De Angelis M, De Giacomo A, Fanos V, Atzori L, Francavilla R. The urinary 1 H-NMR metabolomics profile of an italian autistic children population and their unaffected siblings. Autism Res. 2017 Jun;10(6):1058-1066. doi: 10.1002/aur.1748. Epub 2017 Mar 11.
citation: Indrio F, Di Mauro A, Riezzo G, Civardi E, Intini C, Corvaglia L, Ballardini E, Bisceglia M, Cinquetti M, Brazzoduro E, Del Vecchio A, Tafuri S, Francavilla R. Prophylactic use of a probiotic in the prevention of colic, regurgitation, and functional constipation: a randomized clinical trial. JAMA Pediatr. 2014 Mar;168(3):228-33. doi: 10.1001/jamapediatrics.2013.4367.