Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621001575820
Ethics application status
Approved
Date submitted
14/10/2021
Date registered
18/11/2021
Date last updated
27/06/2022
Date data sharing statement initially provided
18/11/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Combined human milk oligosaccharides (HMOs) and probiotics intervention for children with autism.
Scientific title
To investigate the effect of a combination of human milk oligosaccharides (HMOs) and probiotics on behavioural changes in children with autism spectrum disorder (ASD)
Secondary ID [1] 305430 0
NIL
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Dysfunctional behaviour 323017 0
Microbiome-gut-brain dysfunction 323018 0
Autism spectrum disorder 324238 0
Condition category
Condition code
Mental Health 320581 320581 0 0
Autistic spectrum disorders
Oral and Gastrointestinal 320582 320582 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Mental Health 321725 321725 0 0
Other mental health disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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) and receive the investigational product. Phase 1B will commence immediately following completion of Phase 1A.

The total duration of the trial (Phase 1A + Phase 1B) is 16 weeks.

Participants in the intervention group will receive the HMO product for a total of 16 weeks, while participants in the control group will receive a placebo for 8 weeks and the HMO product for 8 weeks.

Mode of administration: oral, powder. The investigational product has a very mild taste and is a colourless and odourless and completely dissolves in liquid or semi-solid food.

Dosing: two sachet/day (6g/day). Parents/guardians will be encouraged to administer one (1) sachet in the morning and one (1) sachet in the afternoon/evening.

The daily dose (2 sachets/day = 6g/day) of the investigational product contains:
1) 2.5g of a proprietary mix of four HMOs, combined with
2) 20 billion CFUs of probiotics (Lactobacillus rhamnosus; Lactobacillus plantarum; Bifidobacterium animalis spp. lactis; and Bifidobacterium longum).

Compliance: parents/guardian of participants will be provided with a "Participant Monitoring Sheet" to note dosing compliance which will be follow-up fortnightly by the research team (phone/email).
Intervention code [1] 321284 0
Treatment: Other
Comparator / control treatment
Phase 1A only.
Placebo: maltodextrin
Mode of administration: oral, powder. The placebo has a very mild taste and is a colourless and odourless and completely dissolves in liquid or semi-solid food.
Dosing: two sachet/per day (6g/day) for 8 weeks (Phase 1A only).
Control group
Placebo

Outcomes
Primary outcome [1] 328404 0
Change in behaviour as measured by the irritability sub-scale of the Aberrant Behaviour Checklist (I-ABC).
Timepoint [1] 328404 0
Baseline (week 0), mid-Phase 1A (week 4 post-intervention commencement), post-Phase 1A (week 8/9 post-intervention commencement), and post-Phase 1B (week 17/18 post-intervention commencement).


Primary outcome [2] 329484 0
Change in behaviour as measured by the Home Situational Questionnaire – ASD (HSQ-ASD).
Timepoint [2] 329484 0
Baseline (week 0), mid-Phase 1A (week 4 post-intervention commencement), post-Phase 1A (week 8/9 post-intervention commencement), and post-Phase 1B (week 17/18 post-intervention commencement).
Primary outcome [3] 329486 0
Change in behaviour as measured by Parent-Targeted Symptom Visual Analogue Scale (PTSVAS).
Timepoint [3] 329486 0
Baseline (week 0) and post-Phase 1A (week 8/9 post intervention commencement).
Secondary outcome [1] 398908 0
Change in gastrointestinal (GI) symptom severity as measured by the 6-item gastrointestinal severity index (6-GSI).
Timepoint [1] 398908 0
Baseline (week 0) and post-Phase 1A (week 8/9 post intervention commencement).
Secondary outcome [2] 398909 0
Stool consistency as measured by the Bristol Stool Chart (BSC, paediatric version)
Timepoint [2] 398909 0
Baseline (week 0), mid-Phase 1A (week 4 post-intervention commencement), post-Phase 1A (week 8/9 post-intervention commencement), and post-Phase 1B (week 17/18 post-intervention commencement).
Secondary outcome [3] 398910 0
Anxiety levels as measured by the Parent Reported Anxiety Scale – ASD (PRAS-ASD) questionnaire
Timepoint [3] 398910 0
Baseline (week 0) and post-Phase 1A (week 8/9 post intervention commencement).
Secondary outcome [4] 399209 0
Quality of Life (QoL) as measured by the Quality of Life in Autism (QoLA) questionnaire
Timepoint [4] 399209 0
Baseline (week 0) and post-Phase 1A (week 8/9 post intervention commencement).
Secondary outcome [5] 399210 0
Change or trends (diversity, bacterial species, metabolite potential) in the gut microbiome as analysed using stool shotgun metagenomic sequencing
Timepoint [5] 399210 0
Baseline (week 0) and post-Phase 1A (week 8/9 post intervention commencement).
Secondary outcome [6] 399211 0
Change in stool short chain fatty acids levels as measured using gas chromatography with flame ionisation detection (GC-FID)
Timepoint [6] 399211 0
Baseline (week 0) and post-Phase 1A (week 8/9 post intervention commencement).
Secondary outcome [7] 399212 0
Change in concentrations of the urinary serotonin metabolite, 5-Hydroxyindoleacetic acid as measured via double solvent front extraction, followed by reversed phase High Performance Liquid Chromatography (HPLC) with electrochemical detection (ECD).
Timepoint [7] 399212 0
Baseline (week 0) and post-Phase 1A (week 8/9 post intervention commencement).
Secondary outcome [8] 399213 0
Change to salivary cortisol levels as measured using the Elecsys® Cortisol II assay
Timepoint [8] 399213 0
Baseline (week 0) and post-Phase 1A (week 8/9 post intervention commencement).

Eligibility
Key inclusion criteria
1. Aged 5.00 years to 12.99 years
2. 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.
Minimum age
5 Years
Maximum age
12 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Organic GI disorders such as inflammatory bowel disease, coeliac disease, eosinophilic disorders, or current infection of the GI tract.
2. Bowel surgery or short bowel syndrome.
3. Participants with a diagnosed cow milk protein allergy.
4. Participants who suffer from the conditions listed below or who are taking any of the following medications or supplements:
a. antibiotics or antifungals in the last two months
b. Probiotic supplements in the last two months
c. Immunocompromised or severely ill
d. Genetic disorders (e.g. Fragile X Syndrome)
e. Chronic health conditions such as diabetes, heart disease or an eating disorder.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
The industry partner, who is not directly involved in the recruitment of study participants or the analysis of trial results, will prepare the randomisation schedule. The schedule will be provided to the PI/AI and sealed opaque envelopes containing the treatment allocation of each randomisation code in case of emergency.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomisation schedule will be produced using computer-generated, block randomisation to maintain balance between treatment arms.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Power calculations are based on previous data and allow for drop-outs and missing data. Results will be considered statistically significant with P values less than or equal to 0.05. Statistical analysis will be performed using the Statistical Package for Social Sciences (SPSS) program.
Basic demographic and anthropometric data will be described using means and standard deviations (unless non normally distributed then median and range will be used). Success of the randomisation process will be determined by ANOVA assessment of key parameters such as 6-GSI scores at baseline. Potential differences in longitudinal changes in primary and secondary outcome variables will be assessed using repeated measures ANOVA at the time-points: baseline, mid point post-intervention. Associations between variables may be assessed using correlation analysis.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
18/04/2022
Actual
16/05/2022
Date of last participant enrolment
Anticipated
31/10/2022
Actual
Date of last data collection
Anticipated
20/02/2023
Actual
Sample size
Target
60
Accrual to date
17
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,WA,VIC

Funding & Sponsors
Funding source category [1] 309263 0
Commercial sector/Industry
Name [1] 309263 0
DSM Nutritional Products AG
Country [1] 309263 0
Switzerland
Primary sponsor type
University
Name
University of Queensland
Address
62 Graham Street
South Brisbane
Queensland 4101
Country
Australia
Secondary sponsor category [1] 310237 0
None
Name [1] 310237 0
Address [1] 310237 0
Country [1] 310237 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309104 0
University of Queensland Human Research Ethics Committee B
Ethics committee address [1] 309104 0
The University of Queensland
Cumbrae-Stewart Building
72 Research Road
St Lucia QLD 4072
Ethics committee country [1] 309104 0
Australia
Date submitted for ethics approval [1] 309104 0
19/10/2021
Approval date [1] 309104 0
08/03/2022
Ethics approval number [1] 309104 0
2021/HE001678

Summary
Brief summary
The primary aim of the trial is to investigate if a combination of HMOs and probiotics can improve behavioural outcomes for children with autism spectrum disorder (ASD). This aim will be tested in a two-phase clinical trial. 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. The primary outcome will be measured by the irritability subscale of the Aberrant Behaviour Checklist (I-ABC), Other behavioural measurement tools to support the primary end-point include behavioural changes as measured by the Home Situational Questionnaire – ASD (HSQ-ASD) and the Parent-Targeted Symptom Visual Analogue Scale (PTSVAS), Secondary measures include change in: gastrointestinal symptom severity; stool consistency, quality of life; anxiety; gut (stool) microbial composition; stool short chain fatty acids levels; urinary serotonin concentration; and saliva cortisol levels. It is hypothesised that a combined supplement of HMOs and probiotics will improve behavioural outcomes for children with ASD via mechanisms of the microbiome-gut-brain axis. Evidence of efficacy will support additional research to investigate the gut micorbiome as a therapeutic target for this cohort.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 112990 0
Prof Peter Davies
Address 112990 0
Child Health Research Centre, Faculty of Medicine
University of Queensland
62 Graham Street
South Brisbane QLD 4101
Country 112990 0
Australia
Phone 112990 0
+61 7 3069 7597
Fax 112990 0
Email 112990 0
[email protected]
Contact person for public queries
Name 112991 0
Mrs Leanne Mitchell
Address 112991 0
Child Health Research Centre, Faculty of Medicine
University of Queensland
62 Graham Street
South Brisbane QLD 4101
Country 112991 0
Australia
Phone 112991 0
+61 4146 89850
Fax 112991 0
Email 112991 0
[email protected]
Contact person for scientific queries
Name 112992 0
Mrs Leanne Mitchell
Address 112992 0
Child Health Research Centre, Faculty of Medicine
University of Queensland
62 Graham Street
South Brisbane QLD 4101
Country 112992 0
Australia
Phone 112992 0
+61 4146 89850
Fax 112992 0
Email 112992 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
IPD is the intellectual property of the funding industry partner.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
Current Study Results
No documents have been uploaded by study researchers.

Update to Study Results
Doc. No.TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
4167Plain language summaryNo N/A

Documents added automatically
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