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Trial registered on ANZCTR


Registration number
ACTRN12622000015741
Ethics application status
Approved
Date submitted
8/09/2021
Date registered
11/01/2022
Date last updated
8/03/2023
Date data sharing statement initially provided
11/01/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
The impact of faecal microbiome transfer on gut health in autistic adolescents and young adults
Scientific title
Faecal microbiome transfer for the treatment of gastrointestinal symptoms in autistic adolescents and young adults: A double-blinded randomised placebo-controlled trial
Secondary ID [1] 306015 0
Nil known
Universal Trial Number (UTN)
U1111-1261-0104
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Autism 323504 0
Functional gastrointestinal disorders 323505 0
Condition category
Condition code
Mental Health 321065 321065 0 0
Autistic spectrum disorders
Oral and Gastrointestinal 321308 321308 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
All participants will undergo bowel cleansing on the day before treatment using an oral solution containing 70 g of Glycoprep-O (active ingredient macrogol 3350) (Fresenius Kabi Australia, Mount Kuring-gai, Australia). After bowel cleansing, participants will fast overnight for at least 8 hours; in the morning at clinic, participants will take the first dose of either encapsulated faecal microbiome transfer (FMT) or placebo (saline), 10 capsules each swallowed with water or diluted juice. Following another 8-hour overnight fast, in the next morning, participants will receive a second dose of 10 capsules of the same treatment. After each dose, participants will need to remain fasted for another 2 hours.

The FMT treatment will be extracted from donor stools and be doubly encapsulated using delayed release hydroxypropyl methylcellulose capsules (DRCaps, Capsugel Inc, Sydney, Australia). The DRCaps mask taste, odour, and visual appearance; importantly, they are designed to remain intact during passage from the stomach to the intestine, ensuring FMT delivery to the proximal bowel. Thus, the use of invasive techniques (i.e. endoscopy) for FMT will not be required.

Methods for faecal microbiome isolation, preparation, and double encapsulation will be carried out as detailed in the Gut Bugs Trial study protocol (Leong et al. BMJ Open 2019). Briefly, immediately after donation, stools are placed in normal saline, blended, and sieved to remove particulate matter. Samples are then differentially centrifuged to isolate the microbiota pellet. The use of low-speed centrifugation to pellet the microbiota cells is a feature of this methodology that reduces the risk of having free viruses included into the treatment capsules. The pellet is suspended in normal saline (containing 15% glycerol – a cryoprotectant) at 1 g wet weight/ml before being dispensed into size 0 DRcaps capsules. These capsules are closed and secondarily sealed within size 00 DRcaps capsules. Each capsule will contain 0.5 ml of faecal suspension corresponding to approximately 0.5 g of microbiota, so that our treatment dose of 20 capsules will administer approximately 10 g of microbiota. Capsules will be stored frozen at -80°C and will remain viable for at least 6 months.
Intervention code [1] 321624 0
Treatment: Other
Comparator / control treatment
The control treatment are the placebo capsules containing only saline.
Control group
Placebo

Outcomes
Primary outcome [1] 328840 0
Gastrointestinal symptoms using the Gastrointestinal Symptoms Rating Scale (GSRS) overall score
Timepoint [1] 328840 0
6 weeks post-intervention
Secondary outcome [1] 400601 0
Gastrointestinal symptoms using the GSRS overall score
Timepoint [1] 400601 0
12, 20, and 26 weeks post-intervention
Secondary outcome [2] 400603 0
Total score from the Patient Health Questionnaire-9 (PHQ-9)
Timepoint [2] 400603 0
6, 12, and 26 weeks post-intervention
Secondary outcome [3] 400604 0
Total score from the Generalised Anxiety Disorder Assessment (GAD-7)
Timepoint [3] 400604 0
6, 12, and 26 weeks post-intervention
Secondary outcome [4] 400605 0
Total score from the Short Warwick-Edinburgh Mental Well-being Scale (SWEMWBS)
Timepoint [4] 400605 0
6, 12, and 26 weeks post-intervention
Secondary outcome [5] 400606 0
Total score from the the 10-item Perceived Stress Scale (PSS-10)
Timepoint [5] 400606 0
6, 12, and 26 weeks post-intervention
Secondary outcome [6] 400607 0
Total score from the Sleep Quality Scale (SQS)
Timepoint [6] 400607 0
6, 12, and 26 weeks post-intervention
Secondary outcome [7] 400608 0
Diet quality score assessed with the short food-frequency questionnaire (FFQ)
Timepoint [7] 400608 0
6, 12, and 26 weeks post-intervention
Secondary outcome [8] 400610 0
BMI standard deviation score (BMI SDS) (height determined by stadiometer, and weight determined using weighing scale)
Timepoint [8] 400610 0
6, 12, and 26 weeks post-intervention
Secondary outcome [9] 400612 0
Waist-to-hip ratio (waist and hip circumference determined using a tape measure)
Timepoint [9] 400612 0
6, 12, and 26 weeks post-intervention
Secondary outcome [10] 400613 0
Waist-to-height ratio (waist circumference determined using a tape measure, height determined using a stadiometer)
Timepoint [10] 400613 0
6, 12, and 26 weeks post-intervention
Secondary outcome [11] 400614 0
Percentage of fat mass from bioelectrical impedance analysis
Timepoint [11] 400614 0
26 weeks post-intervention
Secondary outcome [12] 400615 0
Percentage of fat-free mass from bioelectrical impedance analysis
Timepoint [12] 400615 0
26 weeks post-intervention
Secondary outcome [13] 400616 0
Hair cortisol levels
Timepoint [13] 400616 0
6, 12 and 26 weeks post-intervention
Secondary outcome [14] 400617 0
Gastrointestinal inflammation and permeability by measuring faecal markers including calprotectin, lactoferrin, M2-pyruvate kinase, S100A12, and zonulin (composite outcome)
Timepoint [14] 400617 0
6, 12, and 26 weeks post-intervention
Secondary outcome [15] 403999 0
Recipient gut microbiome diversity (assessed with faecal samples using taxonomic profiling methods)
Timepoint [15] 403999 0
6, 12 and 26 weeks post-intervention
Secondary outcome [16] 404000 0
Recipient gut microbiome composition (assessed with faecal samples using taxonomic profiling methods)
Timepoint [16] 404000 0
6, 12 and 26 weeks post-intervention
Secondary outcome [17] 404001 0
Donor strain engraftment (assessed with faecal samples using strain profiling methods)
Timepoint [17] 404001 0
6, 12 and 26 weeks post-intervention
Secondary outcome [18] 404002 0
Bacteriophage diversity (assessed with faecal samples using shotgun metagenomic sequencing)
Timepoint [18] 404002 0
6, 12 and 26 weeks post-intervention
Secondary outcome [19] 419338 0
Changes in gut metabolites detectable in serum/urine using LC-MS/MS
Timepoint [19] 419338 0
6, 12 and 26 weeks post-intervention

Eligibility
Key inclusion criteria
Aged 16-30 years inclusive at time of enrolment recruitment
Previous formal diagnosis of autism (including ASD, Asperger's Syndrome, Autistic Disorder, and PDD-NOS) as characterised in DSM-4, DSM-5, or ICD-10-AM
Moderate to severe gastrointestinal symptoms with mean overall GSRS score =2.0
Believe they are able to swallow treatment capsules
Willing to comply with the clinical assessments at baseline and follow-up visits
Minimum age
16 Years
Maximum age
30 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Systemic antibiotic use within the preceding month
Intake of probiotic supplements within the preceding month
Regular steroid treatment
Dependence upon tube feeding
Serious medical problems that require specific treatment
Moderate to severe depression and/or suicidal ideation as per PHQ-9
Pregnancy
Known allergy to any medications or foods and/or to macrogol

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)
Allocation concealment will be done using the REDCap electronic database based on a computer-generated randomisation list.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomised in a 1:1 ratio to either FMT or placebo, stratified by sex,
using block randomisation with variable block sizes of 2 and 4, based on a computer-generated randomisation sequence.
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
The power calculation was based on a mean and standard deviation of 2.44 and 0.47, respectively, for GSRS overall scores at baseline among 18 children and adolescents (aged 7-16 years) diagnosed with ASD (Kang et al. 2017). We aim to recruit 50 participants per group, which will allow us to detect a statistically significance difference in GSRS overall scores of 0.31 (approximately 12.7%) between groups, based on a two-tailed t-test with 90% power and a=0.05. In the event of a 20% loss to follow-up, with 40 participants per group our study would still be powered to detect a statistically significance difference in GSRS overall scores of 0.35 (approximately 14%) between groups.

The primary outcome analysis will be based on intention-to-treat with multiple imputations on missing data. For all continuous outcomes, linear mixed models with repeated measures will be used to control for correlated data collected from the same participants. Binary outcomes will be assessed using generalized linear models with a logit link. Models will be adjusted for the baseline outcome value and sex (stratification factor). Model-adjusted estimates and differences between groups will be calculated with 95% confidence intervals. Planned subgroup analyses by sex will be conducted on primary and secondary outcomes to evaluate the consistency of main treatment effects among male and female participants.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
13/02/2023
Actual
Date of last participant enrolment
Anticipated
31/12/2024
Actual
Date of last data collection
Anticipated
30/06/2025
Actual
Sample size
Target
100
Accrual to date
0
Final
Recruitment outside Australia
Country [1] 24097 0
New Zealand
State/province [1] 24097 0
Auckland
Country [2] 24098 0
New Zealand
State/province [2] 24098 0
Wellington
Country [3] 24452 0
New Zealand
State/province [3] 24452 0
Hamilton

Funding & Sponsors
Funding source category [1] 309602 0
Charities/Societies/Foundations
Name [1] 309602 0
Rockfield Trust
Country [1] 309602 0
New Zealand
Primary sponsor type
University
Name
University of Auckland
Address
Liggins Institute
University of Auckland
85 Park Road
Grafton 1023
Auckland
New Zealand
Country
New Zealand
Secondary sponsor category [1] 310615 0
None
Name [1] 310615 0
None
Address [1] 310615 0
None
Country [1] 310615 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309377 0
Central Health and Disability Ethics Committee
Ethics committee address [1] 309377 0
Health and Disability Ethics Committees
Ministry of Health
133 Molesworth Street
PO Box 5013
Wellington
6011
Ethics committee country [1] 309377 0
New Zealand
Date submitted for ethics approval [1] 309377 0
04/08/2021
Approval date [1] 309377 0
24/08/2021
Ethics approval number [1] 309377 0
21/CEN/211

Summary
Brief summary
Background
Many autistic children and adults have chronic gastrointestinal symptoms that adversely affect their quality of life. These symptoms have been associated with a disordered gut microbiome.

Aims
To evaluate the efficacy of oral encapsulated faecal microbiome transfer (FMT) in improving gastrointestinal symptoms and well-being among autistic adolescents and young adults.

Study design
Randomised double-blind placebo-controlled trial.

Participants
100 autistic adolescents and young adults aged 16-30 years with moderate to severe gastrointestinal symptoms.

Intervention
Participants will be randomised to either FMT or placebo (saline). FMT treatment will be extracted from stools of healthy donors, and will be doubly encapsulated. Treatment consists of 20 capsules taken over two days (10 per day).

Assessments
Questionnaires to assess gastrointestinal symptoms, well-being, sleep quality, and food selectivity will be administered. Stool and hair samples will be collected to monitor changes to the gut microbiome profile, gut inflammation and permeability, and stress hormone levels (cortisol). We will also take anthropometric measurements and assess body composition using bioelectrical impedance analysis.

Significance
The findings could lead to novel therapies for improving gastrointestinal health among autistic individuals.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 113942 0
Prof Wayne Cutfield
Address 113942 0
Liggins Institute,
Building 505,
Level 2, 85 Park Road,
Auckland, 1023
New Zealand
Country 113942 0
New Zealand
Phone 113942 0
+64 9 923 4476
Fax 113942 0
Email 113942 0
w.cutfield@auckland.ac.nz
Contact person for public queries
Name 113943 0
Prof Wayne Cutfield
Address 113943 0
Liggins Institute,
Building 505,
Level 2, 85 Park Road,
Auckland, 1023
New Zealand
Country 113943 0
New Zealand
Phone 113943 0
+64 9 923 4476
Fax 113943 0
Email 113943 0
w.cutfield@auckland.ac.nz
Contact person for scientific queries
Name 113944 0
Prof Wayne Cutfield
Address 113944 0
Liggins Institute,
Building 505,
Level 2, 85 Park Road,
Auckland, 1023
New Zealand
Country 113944 0
New Zealand
Phone 113944 0
+64 9 923 4476
Fax 113944 0
Email 113944 0
w.cutfield@auckland.ac.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Coded and anonymised health information may be shared with researchers outside of this study for future research deemed appropriate by the Data Access Committee from the Liggins Institute's Clinical Data Research Hub. Anonymised gut microbiome data will be deposited in an international sequence database where it may be used for future microbiome research outside of this study.
When will data be available (start and end dates)?
Immediately following publication; beginning 3 months to 5 years
Available to whom?
Researchers outside of this study for future research deemed appropriate by the Data Access Committee from the Liggins Institute's Clinical Data Research Hub.
Available for what types of analyses?
Any purpose deemed appropriate by the Data Access Committee from the Liggins Institute's Clinical Data Research Hub, except that no clinical data collected in this trial will be used in any studies seeking a cure for autism.
How or where can data be obtained?
For queries, contact Professor Wayne Cutfield (w.cutfield@auckland.ac.nz) or Professor Justin O'Sullivan (justin.osullivan@auckland.ac.nz). Requests to access clinical data will be forwarded to the Data Access Committee from the Liggins Institute's Clinical Data Research Hub.

Metagenomic sequencing data will be shared on NCBI's Sequence Read Archive (SRA)


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
13100Study protocol  w.cutfield@auckland.ac.nz The study protocol will be made available once it ... [More Details]
14461Statistical analysis planThe statistical analysis plan will be made available once the study protocol has been published. w.cutfield@auckland.ac.nz



Results publications and other study-related documents

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No documents have been uploaded by study researchers.

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