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Trial registered on ANZCTR


Registration number
ACTRN12621000029897
Ethics application status
Approved
Date submitted
29/10/2020
Date registered
14/01/2021
Date last updated
14/01/2021
Date data sharing statement initially provided
14/01/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Effect of Probiotic supplementation on gut bacteria in children with autism - a pilot randomized controlled trial
Scientific title
Effect of probiotic supplementation on composition of fecal microbiota in children with autism spectrum disorder-a pilot randomized controlled trial
Secondary ID [1] 302631 0
none
Universal Trial Number (UTN)
Trial acronym
PROACTIVE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Autism spectrum disorder 319530 0
Condition category
Condition code
Mental Health 317480 317480 0 0
Autistic spectrum disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The participants will receive 450 billion CFU of probiotics (or an equivalent volume of placebo) twice a day for one month followed by 450 billion CFU (or an equivalent volume of placebo) once a day for three months.The probiotic selected for this study is Vivomixx® Italy, with each sachet containing total 450 billion (450x10^9) lyophilized bacterial cells of eight probiotic strains: Streptococcus thermophilus DSM 24731, B. breve DSM 24732, B. longum DSM 24736, B. infantis DSM 24737), and L. acidophilus DSM 24735, L. plantarum DSM 24730, L. paracasei DSM 24733, L. delbrueckii subsp. bulgaricus DSM 24734). All strains in Vivomixx work in synergy (http://www.vivomixx.eu/en/2017/09/06/product-facts-why-so-many-different-strains/) Vivomixx® is currently being studied for various conditions in children (non-alcoholic steatohepatitis, infantile colic and ASD) and adults (HIV) , and pregnant women. It is available as water-soluble powder and administered orally. It can be dissolved directly in the mouth or mixed in a cold, but not carbonated drink.
During the study period to monitor adherence, we will check if there have been any changes in diet or medications. This will involve 2 phone calls a month apart. Any left over probiotics sachets with the parents will be asked to bring during there last visit to be returned to pharmacy.
Intervention code [1] 318918 0
Treatment: Other
Comparator / control treatment
Participants will be given,Equivalent volume of placebo, placebo sachets will contain 4.4 g of maltose and silicon dioxide.
Control group
Placebo

Outcomes
Primary outcome [1] 325515 0
composite primary outcome will be the “Compositional differences” in gut microbiome. The selected markers of ‘compositional differences’ will include alpha-diversity, richness, and abundance of particular species/pathways, or clusters based on unsupervised clustering of gut microbiome.
Fecal microbiota will be assessed using the 2 samples collected from each participant (before and after completing 4 months of study supplementation). Metagenomics studies will be performed by extracting the fecal DNA and creating an amplicon 16s rRNA library for analysis by high throughput 454 pyrosequencing to allow calculation of diversity indices and rarefaction curves
Timepoint [1] 325515 0
at baseline and after 4 months of study supplementation
Secondary outcome [1] 388257 0
Developmental outcomes: Participants will undergo developmental assessments and parenteral questionnaire
The Preschool Language Scale – 5


Timepoint [1] 388257 0
at baseline and after 4 months of study supplementation
Secondary outcome [2] 389478 0
2) Gastrointestinal outcomes: the Frequency of gastrointestinal symptoms including constipation, average stool consistency, stomach cramps, flatulence etc will be assessed by the Gastrointestinal severity index (GSI) .
Timepoint [2] 389478 0
at baseline and after 4 months of study supplementation
Secondary outcome [3] 389479 0
Fecal SCFA: Fecal acetate, propionate, and butyrate levels will be analysed using gas chromatography.
Timepoint [3] 389479 0
at baseline and after 4 months of study supplementation
Secondary outcome [4] 390302 0
Developmental outcomes: Participants will undergo developmental assessments and parenteral questionnaire
Repetitive Behaviour Scale – Revised (RBS-R),
Timepoint [4] 390302 0
at baseline and after four months of trial supplementation
Secondary outcome [5] 390303 0
Developmental outcomes: Participants will undergo developmental assessments and parenteral questionnaire
The Short Sensory Profile (SSP-2),
Timepoint [5] 390303 0
at baseline and after 4 months of trial supplementation
Secondary outcome [6] 390304 0
Developmental outcomes: Participants will undergo developmental assessments and parenteral questionnaire
Vineland Adaptive Behavioural Scales – 2nd edition (VABS-II),
Timepoint [6] 390304 0
at baseline and after 4 months of trial supplementation
Secondary outcome [7] 390305 0
Developmental outcomes: Participants will undergo developmental assessments and parenteral questionnaire
Mullen’s Scale of Early Learning (MSEL)
Timepoint [7] 390305 0
at baseline and after 4 months of trial supplementation

Eligibility
Key inclusion criteria
(1)Children Age: 2–5 years. (2) Confirmed diagnosis of ASD based on DSM-5 criteria.
Minimum age
2 Years
Maximum age
5 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
(1) Major congenital anomalies (2) Epilepsy syndromes, significant sensory impairment (e.g., blindness, deafness), neonatal hypoxic ischemic encephalopathy requiring therapeutic cooling (3) Coeliac disease, inflammatory bowel disease (4) Use of probiotics for 4 weeks in the 90 days before enrolment (5) Current or recent (within 4 weeks before enrolment) exposure to antibiotics, chemotherapy or immunosuppressant agents, or laxatives. (6) Prosthetic devices including heart valves (7) Confirmed HIV, Hepatitis B, and/or Hepatitis C. (8) Known allergy to probiotics (9) Special diets(10) Cows’ milk protein allergy, food allergy, or conditions such as atopic dermatitis, or eczema.

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)
Randomisation (using computer generated random numbers) will be stratified based on Mullen’s Early learning composite score as less them or equal to 85. This approach is selected because consideration of the intellectual/developmental ability is important as it reflects severity of ASD, and influences the ability for proper neurodevelopmental assessment. Allocation concealment will be optimised by using serially numbered, sealed, coded, opaque envelopes .
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA

Funding & Sponsors
Funding source category [1] 307062 0
Other
Name [1] 307062 0
Telethon Kids institute
Address [1] 307062 0
Northern Entrance, Perth Children's Hospital, 15 Hospital Ave, Nedlands WA 6009
Country [1] 307062 0
Australia
Primary sponsor type
Hospital
Name
Perth children hospital, Child and Adolescent health services
Address
15 Hospital Ave, Nedlands, WA 6009
Country
Australia
Secondary sponsor category [1] 307631 0
None
Name [1] 307631 0
Address [1] 307631 0
Country [1] 307631 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307186 0
Child and Adolescent health services,Human Research Ethics Committee (HREC
Ethics committee address [1] 307186 0
Perth children hospital, 15 Hospital avenue, Nedlands, WA Perth 6009
Ethics committee country [1] 307186 0
Australia
Date submitted for ethics approval [1] 307186 0
01/07/2019
Approval date [1] 307186 0
12/08/2020
Ethics approval number [1] 307186 0
RGS0000003318

Summary
Brief summary
Autism is a condition with early-onset difficulties in social communication and unusually restricted, repetitive behaviors. It is being increasingly diagnosed in the last 10 years and is currently diagnosed in 1 in 59 children. Children with Autism need lifelong support for their symptoms and associated conditions. Current options for improving their behavioral issues are limited or only partially effective.

Beneficial bacteria that commonly live in the gut promote health by suppressing the growth of harmful bacteria, and improving immune function of the gut. Humans have been consuming probiotics (beneficial bacteria) for hundreds of years in the form of various foods. . Research suggests that the proportion of beneficial bacteria in the gut is reduced (called as ‘dysbiosis’) in children with autism, and may explain their symptoms.
We plan to study whether probiotic supplementation will improve the proportion of beneficial bacteria in the gut of children with autism. Such an effect may improve their behavioral symptoms
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 106326 0
Dr Sachin agrawal
Address 106326 0
King Edward Memorial Hospital for women,
374 Bagot Road, Subiaco, Perth 6008
Country 106326 0
Australia
Phone 106326 0
+61 864582222
Fax 106326 0
+61864581266
Email 106326 0
sachin.agrawal@health.wa.gov.au
Contact person for public queries
Name 106327 0
Dr Sachin agrawal
Address 106327 0
King Edward Memorial hospital for women,
374 Bagot Road, Subiaco,Perth 6008
Country 106327 0
Australia
Phone 106327 0
+61 864582222
Fax 106327 0
Email 106327 0
sachin.agrawal@health.wa.gov.au
Contact person for scientific queries
Name 106328 0
Prof Sanjay Patole
Address 106328 0
King Edward Memorial hospital for women,
374 Bagot Road, Subiaco,Perth 6008
Country 106328 0
Australia
Phone 106328 0
+618 64582222
Fax 106328 0
+61864581266
Email 106328 0
sanjay.patole@health.wa.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
all of the individual participant data collected during the trial, after de-identification; individual participant data underlying published results only
When will data be available (start and end dates)?
Available for 5 years after publication
Available to whom?
Only to those who request for systematic review and meta-analysis of IPD data
Available for what types of analyses?
IPD meta-analysis
How or where can data be obtained?
From the principle investigator and only after ethics approval.
Sachin.agrawal@health.wa.gov.au
What supporting documents are/will be available?
Study protocol
Informed consent form
Ethical approval
How or where can supporting documents be obtained?
Type [1] 9539 0
Study protocol
Citation [1] 9539 0
Link [1] 9539 0
Email [1] 9539 0
Other [1] 9539 0
Type [2] 9541 0
Informed consent form
Citation [2] 9541 0
Link [2] 9541 0
Email [2] 9541 0
Other [2] 9541 0
Type [3] 9542 0
Ethical approval
Citation [3] 9542 0
Link [3] 9542 0
Email [3] 9542 0
Other [3] 9542 0
Summary results
No Results