Combined Human Milk Oligosaccharides (HMOs) and Probiotics Intervention for Children With Autism

Study Overview
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Brief Summary
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This research project will investigate if a supplement containing a unique combination of prebiotics and probiotics can influence behaviour in children diagnosed with autism spectrum disorder. The study will use a combination of human milk oligosaccharides (HMOs, prebiotics) and probiotics as an oral powder.This clinical trial will have two consecutive phases. Phase 1A is an 8-week randomised, double-blinded, placebo-controlled trial. Participants will be recruited and randomised (1:1) to receive either the investigational product (treatment group, n=30) or the placebo (control group, n=30). Phase 1B is an 8-week open-label study. All participants that complete Phase 1A will move into Phase 1B (n=60). This allows all participants to receive the investigational product and will provide additional information on increased duration of treatment.

Official Title
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The Effect of a Combination of Human Milk Oligosaccharides (HMOs) and Probiotics on Behavioural Change in Children With Autism Spectrum Disorder (ASD).

Conditions
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Autism Spectrum Disorder, Neurodevelopmental Disorders, Anxiety

Intervention / Treatment
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* Dietary Supplement: Experimental
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 5.00 years to 12.99 years. A confirmed diagnosis of ASD or Pervasive Developmental Disorders (PDD) including autistic disorder, Asperger's disorder (AS); PDD not otherwise specified (PDD-NOS); and atypical autism. Exclusion Criteria: Organic GI disorders such as inflammatory bowel disease, coeliac disease, eosinophilic disorders, or current infection of the GI tract. Bowel surgery or short bowel syndrome Participants who have a diagnosed cow milk protein allergy. Participants who suffer from the conditions listed below or who are taking any of the following medications or supplements: antibiotics or antifungals in the last two months probiotic supplements in the last two months immunocompromised or severely ill genetic disorders (e.g. Fragile X Syndrome) chronic health conditions such as diabetes, heart disease or an eating disorder.

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be recruited into a two-phase project. Phase 1A: an 8-week double-blinded, placebo-controlled, randomised trial. Participants child will be randomised to one of groups 1) treatment (HMOs/Probiotic group) or 2) control group (placebo product). Phase 1B: is an 8-week open-label trial. All children who successfully complete phase 1A will be recruited into phase 1B. All participants in phase 1B will receive the treatment product (HMOs/probiotics). Follow up will occur at week 8 and week 17.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HMOs + Probiotics<br>Dosing: A total daily dose of 2 x sachets (6g/day) Product Comprised of: 2.5g of a proprietary blend of human milk oligosaccharides combined with 20 billion CFUs of a mixture of Lactobacillus rhamnosus, Lactobacillus plantarum, Bifidobacterium animalis spp. lactis, and Bifidobacterium longum. Mode of administration: oral. | Dietary Supplement: Experimental<br>* 2 x sachets per day<br>|
| Placebo Comparator: Placebo<br>Dosing: A total daily dose of 2 x sachets (6g/day)u (8 weeks of phase 1A). Product: powdered maltodextrin. Mode of administration: oral. | Other: Placebo<br>* 2 x sachets per day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Behaviour change | Changes in behavioural symptoms as measured by the Irritability sub-scale of the Aberrant Behavior Checklist - Community (Version 2) (I-ABC). The ABC 58-item parent-rated questionnaire and consists of five subscales, including: 1) irritability (15 items); 2) lethargy/social withdrawal (16 items); 3) stereotypic behaviour (7 items); 4) hyperactivity/noncompliance (16 items); and 5) inappropriate speech (4 items). Each item is scored as 0=never a problem, 1=slight problem, 2=moderately serious problem, or 3=severe problem. The score range is 0-174, with a higher score indicating greater severity or difficulties. | Baseline, Phase IA midpoint (week 4) and post-Phase 1A(week 8/9), post-Phase 1B (week 17/18) | 
| Behaviour Change | Changes in behavioural symptoms as measured by the Home Situations Questionnaire - Autism Spectrum Disorder (HSQ-ASD). The HSQ-ASD is a 24-item, parent-rated measure of non compliant behaviour in children with ASD. The scale yields per-item mean scores of 0 to 9, with higher scores indicating greater noncompliance. | Baseline, Phase 1A midpoint (week 4) and post-Phase 1A (week 8/9) | 
| Behaviour Change | Changes in parent/guardian targeted behaviours as measured by the Parent Targeted Symptom Visual Analogue Scale (PTSVAS). The PTSVAS tool requests parents/guardians report their top three (3) target behaviours (behaviours of concern) on a Visual Analogue Scale (VAS). The VAS is a horizontal line of 100mm in length, with each end defined as the extreme limits of the behaviour of concern (best to worst), to be measured from left to right. The parents will score the behaviour by placing a mark on the VAS at baseline and post-intervention. Each mark will be measured on the scale of 0-100mm and the change from baseline to post-intervention noted. | Baseline and post-Phase 1A (week 8/9) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in GI Symptom Severity | Change in GI symptom severity as measured by the 6-item gastrointestinal severity index (6-GSI). The 6-GSI assesses each GI symptom using a Likert scale of 0-2 (0 = nil/mild/infrequent; 1 = moderate/occasional; 2 = severe/frequent). Score range 0-12. Mild GI issues are defined as a score of under three and moderate or severe GI issues defined as a score of three or above. | Baseline and post-Phase 1A (week 8/9) | 
| Change in the Gut Microbiome | This is an explorative outcome to compare and characterise changes in gut (stool) micorbiome between treatment groups. Change or trends (diversity, bacterial species, metabolite potential) in the gut microbiome as analysed using stool shotgun metagenomic sequencing. | Baseline and post-Phase 1A (week 8/9) | 
| Change in Anxiety Levels | Change in anxiety levels as measured by the Parent Rated Anxiety Scale - Autism Spectrum Disorder (PRAS-ASD) questionnaire. This is a 25-item tool using a Likert scale of 0-3 (0=none; 1=mild; 2=moderate; 3=severe). Score range 0-75, with higher scores indicating greater levels of anxiety. | Baseline and post-Phase 1A (week 8/9) | 
| Change in Quality of Life | Quality of life (QoL) measured by the Quality of life Autism (QoLA) questionnaire. The QoLA is a 48-item questionnaire divided into 2 subsets (Part A and Part B). The QoLA utilises a 5-point scale (0-4). Possible scores range from 48-240, with higher scores equating to higher perceived QoL. | Baseline and post-Phase 1A (week 8/9) | 
| Change in Stool Consistency | Change in Stool consistency as measured by the Bristol Stool Chart (BSC, paediatric version) | Baseline, Phase A1 midpoint (week 4), and post-Phase 1A (week 8/9), post-Phase 1B (week 17/18) . | 
| Change in stool short chain fatty acids levels | Change in stool short chain fatty acids levels as measured using gas chromatography with flame ionisation detection (GC-FID) | Baseline and post-Phase 1A (weeks 8/9) | 
| Change in urinary serotonin concentration | Change in concentrations of the urinary serotonin metabolite, 5-Hydroxyindoleacetic acid as measured using a double solvent front extraction, followed by reversed phase High Performance Liquid Chromatography (HPLC) with electrochemical detection (ECD) | Baseline and post-Phase 1A (weeks 8/9) | 
| Change in salivary cortisol levels | Change to salivary cortisol levels as measured using the Elecsys® Cortisol II assay | Baseline and post-Phase 1A (weeks 8/9) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gut microbiome, Behaviour