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Trial registered on ANZCTR


Registration number
ACTRN12619000369123p
Ethics application status
Submitted, not yet approved
Date submitted
28/02/2019
Date registered
8/03/2019
Date last updated
8/03/2019
Date data sharing statement initially provided
8/03/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Use of probiotics to improve gut health and vaccine response in newborn babies
Scientific title
A Randomised Controlled Trial: Effect Of Probiotics On Gut Microbiome And Vaccine Responses In Newborns With Antibiotic-Induced Dysbiosis (ADAPTS: Antibiotic Dysbiosis and Probiotics Trial in infantS)
Secondary ID [1] 294676 0
Nil known
Universal Trial Number (UTN)
U1111-1212-6059
Trial acronym
ADAPTS (Antibiotic Dysbiosis And Probiotics Trial in for infantS)
Linked study record
N/A

Health condition
Health condition(s) or problem(s) studied:
Gastrointestinal microbiome 307532 0
Gastroesophageal reflux 311830 0
Infantile colic 311831 0
Vaccine response to childhood vaccinations 311832 0
Condition category
Condition code
Oral and Gastrointestinal 306610 306610 0 0
Normal oral and gastrointestinal development and function
Oral and Gastrointestinal 306611 306611 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Inflammatory and Immune System 306613 306613 0 0
Normal development and function of the immune system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Probiotic (Lactobacillus acidophilus, Bifidobacterium bifidum (breve) and Bifidobacterium infantis): liquid formulation; suspension is medium chain oils
Dosage: 4 drops once daily (1 drop=0.38x10^9 colony forming units)
Duration: 28 days
Mode: oral
Adherence and adverse outcomes: questionnaire completed by parent; review of bottles of trial intervention
Timing: Intervention will be administered after antibiotics have been completed. The course will be completed after 1 month (i.e. prior to the routine immunisation schedule). Routine immunisations commence at 2 months of age.
Intervention code [1] 300976 0
Treatment: Drugs
Comparator / control treatment
Placebo: liquid formulation of medium chain oils
Dosage: 4 drops once daily
Duration: 28 days
Mode: oral
Adherence and adverse outcomes: questionnaire completed by parent; review of bottles of trial intervention
Control group
Placebo

Outcomes
Primary outcome [1] 305617 0
Gastrointestinal Microbiome (stool sample):
- Proportion of potentially pathogenic bacteria (such as Enterobacteriaceae family)
Timepoint [1] 305617 0
4-6 week post enrolment
Primary outcome [2] 319334 0
Gastrointestinal Microbiome (stool sample):
- Diversity and composition of Operational Taxonomic Units (OTU) of the stool
Timepoint [2] 319334 0
4-6 week post enrolment
Primary outcome [3] 319335 0
Gastrointestinal Microbiome (stool sample):
- Bacterial 16S ribosomal RNA
Timepoint [3] 319335 0
4-6 week post enrolment
Secondary outcome [1] 345917 0
Gastrointestinal Microbiome (stool sample):
- Diversity and composition of Operational Taxonomic Units (OTU) of the stool
Timepoint [1] 345917 0
Baseline (prior to commencement of intervention)
8 months post enrolment - to compare gastrointestinal microbiome to vaccine response
12 months post enrolment - to compare the long-term change in gastrointestinal microbiome
Secondary outcome [2] 345918 0
Gastrointestinal reflux will be assessed using a gastrointestinal questionnaire (Infant Gastroesophageal Reflux Questionnaire)
Timepoint [2] 345918 0
4-6 weeks post enrolment
3 months post enrolment
Secondary outcome [3] 345919 0
Infantile colic - this will be assessed using a daily cry and behavioural chart
Timepoint [3] 345919 0
4-6 weeks post enrolment
3 months post enrolment
Secondary outcome [4] 367623 0
Vaccine response to PCV13 serotypes ((serum assay):
- Antigen-specific IgG will be measured in duplicate using a multiplex fluorescent bead assay for PCV13 serotypes, and diphtheria, tetanus, Hib, and pertussis antigens
Timepoint [4] 367623 0
8 Months post enrolment
Secondary outcome [5] 367819 0
Gastrointestinal Microbiome (stool sample):
- Bacterial 16S ribosomal RNA
Timepoint [5] 367819 0
Baseline (prior to commencement of intervention)
8 months post enrolment - to compare gastrointestinal microbiome to vaccine response
12 months post enrolment - to compare the long-term change in gastrointestinal microbiome
Secondary outcome [6] 367820 0
Gastrointestinal Microbiome (stool sample):
- Proportion of potentially pathogenic bacteria (such as Enterobacteriaceae family)
Timepoint [6] 367820 0
Baseline (prior to commencement of intervention)
8 months post enrolment - to compare gastrointestinal microbiome to vaccine response
12 months post enrolment - to compare the long-term change in gastrointestinal microbiome
Secondary outcome [7] 367821 0
Vaccine response to diphtheria (serum assay):
- Antigen-specific IgG will be measured in duplicate using a multiplex fluorescent bead assay for PCV13 serotypes, and diphtheria, tetanus, Hib, and pertussis antigens
Timepoint [7] 367821 0
8 Months post enrolment
Secondary outcome [8] 367822 0
Vaccine response to Tetanus (serum assay):
- Antigen-specific IgG will be measured in duplicate using a multiplex fluorescent bead assay for PCV13 serotypes, and diphtheria, tetanus, Hib, and pertussis antigens
Timepoint [8] 367822 0
8 Months post enrolment
Secondary outcome [9] 367823 0
Vaccine response to Haemophilus Influenzae B (serum assay):
- Antigen-specific IgG will be measured in duplicate using a multiplex fluorescent bead assay for PCV13 serotypes, and diphtheria, tetanus, Hib, and pertussis antigens
Timepoint [9] 367823 0
8 Months post enrolment
Secondary outcome [10] 367824 0
Vaccine response to Pertussis (serum assay):
- Antigen-specific IgG will be measured in duplicate using a multiplex fluorescent bead assay for PCV13 serotypes, and diphtheria, tetanus, Hib, and pertussis antigens
Timepoint [10] 367824 0
8 Months post enrolment

Eligibility
Key inclusion criteria
1. Newborn infant born at > 37 week post menstrual age
2. Infant less than 72 hours of age
3. Admitted with suspected sepsis and commenced on intravenous antibiotics
4. Parents have intention to give childhood immunisations
5. Parents agree to use trial intervention and not provide other forms of probiotics
Minimum age
0 Days
Maximum age
72 Hours
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Anticipated antibiotic exposure for more than 5 days
2. Major congenital anomaly
3. Caesarean section

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)
Numbered intervention boxes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be performed by trials pharmacist using block randomisation with block size of 4.
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
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Statistical methods / analysis
Sample Size Calculation
A study by Fouhy (Fouhy F., et al., High-Throughput sequencing reveals the incomplete, short-term recovery of infant gut microbiota following parenteral antibiotic treatment with ampicillin and gentamicin. Antim. Ag. Chem, 2012. 56(11): p. 5811-20), found that infants treated with ampicillin and gentamicin had significantly higher enterobacteriaceae at the genus level measured using 16S RNA. They found members of the enterobacteriaceae family (predominantly pathogenic organisms such as E. Coli, Salmonella, Klebsiella, Shigella, Enterobacter and Serratia) made up 75% of the gut microbiota compared with 38% of controls at 4 weeks post antibiotic treatment. A total sample size of 62 (n=31 in each group) would be required to demonstrate a reduction of these pathogenic bacteria from 70% to 35% (50% reduction) after 4 weeks of supplementation in the probiotic group with an alpha error of 0.05 and power of 80%. To allow for 15% attrition we would require n=35 in each arm with a total study sample size of 70. These results will then inform us of the effect of probiotics on gastrointestinal microbiota and vaccine uptake and allow us to complete a sample size calculation to plan for further research.

General Analysis
Descriptive statistics will be used report the study sample characteristics. Chi-square test for statistical significance between groups will be used and Student’s t-test for continuous data will be used to detect differences. The level of statistical significance will be p<0.05. Logistic regression will be used to determine correlations between variables and independent predictors associated with dysbiosis.

Microbiome Analyses
Microbiome analysis involves complex methodology and will be performed by a statistician that has expert experience in this area. Sequence data will be processed, filtered to remove chimeric amplicons then candidate operation taxonomic units (OTUs) assigned and validated using an appropriate processing pipeline such as QIIME, RDPipeline, mothur or MG-RAST. The output will then be analysed using MicrobiomeAnalyst (a web-based tool for statistical and visual analysis of microbiome data; https://www.microbiomeanalyst.ca/) to calculate the alpha and beta diversity, richness, Shannon index and hierarchical/phylogenetic profiling. Phylogenetic sequence homologies of 97% and 99% will be used for genus and species identification, respectively. Taxonomic composition and diversity will be visualised using heat maps, clustering analysis and principal component analysis. Weighted/unweighted and generalised UniFrac distances will be compared using multivariate analysis (e.g. PCA) with jackknifing to determine the relationships/differences between microbial communities and the effects of antibiotic treatment and time.

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
Recruitment hospital [1] 10775 0
Joondalup Health Campus - Joondalup
Recruitment postcode(s) [1] 22513 0
6027 - Joondalup

Funding & Sponsors
Funding source category [1] 299288 0
Charities/Societies/Foundations
Name [1] 299288 0
Ramsay Hospital Research Foundation
Address [1] 299288 0
Level 8, 154 Pacific Hwy, St Leonards NSW 2065, Australia
Country [1] 299288 0
Australia
Primary sponsor type
Hospital
Name
Joondalup Health Campus
Address
Grand Blvd &, Shenton Ave, Joondalup WA 6027
Country
Australia
Secondary sponsor category [1] 298556 0
None
Name [1] 298556 0
Address [1] 298556 0
Country [1] 298556 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 300197 0
Joondalup Health Campus Human Research Ethics Committee
Ethics committee address [1] 300197 0
Grand Blvd and Shenton Ave, Joondalup WA 6027
Ethics committee country [1] 300197 0
Australia
Date submitted for ethics approval [1] 300197 0
05/02/2018
Approval date [1] 300197 0
Ethics approval number [1] 300197 0

Summary
Brief summary
Background
Early life exposure to antibiotics causes significant imbalance to the healthy intestinal flora (dysbiosis), and increases the risk of non-communicable childhood conditions such as allergic disease, asthma, immune function as well as vaccine responses. Probiotics have been shown to be useful in reducing dysbiosis and having a positive effect on health.

Aims
This novel study aims to: 1) Study the effect of antibiotic exposure in early life and subsequent imbalances to the gut flora, 2) Study the efficacy of probiotic administration on improvement in gut flora 3) Study the effect of probiotic administration on vaccine responses and gastrointestinal symptoms.

Methods
This will be a double blinded, randomised controlled trial that will recruit 70 term infants that have received antibiotics from the neonatal unit at Joondalup Health Campus. Thirty-five of the infants will receive a placebo and 35 will receive a probiotic (containing lactobacillus acidophilus, bifidobacterium bifidum and bifidobacterium infantis) for a total of 4 weeks. Infant stool will be collected for microbiome analysis, blood will be collected for vaccine response and a gastro-oesophageal reflux questionnaire and a behavioural chart will be completed to review gastrointestinal and colic symptoms.

Outcomes
The two main analyses are: 1) Microbiome diversity and composition of operation taxonomic units of the stool will be compared between the two groups at baseline, 1 week, 2 weeks, 1 month and 8 months; and 2) antigen-specific antibody levels to vaccines will be compared between the two groups at baseline and 8 months.

Benefits
This study will address a major child health issue, which is to explore the negative effects of antibiotic exposure in newborn infants and provide an affordable but effective intervention (probiotics) to modulate these effects. The findings from this study will have direct benefits to infants as well as provide further evidence that early life antibiotics may have long-standing consequences. The findings will be easily translated into clinical practice and will have a significant national and international impact.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 82882 0
Dr Jason K Tan
Address 82882 0
Joondalup Health Campus, Grand Blvd &, Shenton Ave, Joondalup WA 6027
Country 82882 0
Australia
Phone 82882 0
+61 894009889
Fax 82882 0
Email 82882 0
jason.tan@health.wa.gov.au
Contact person for public queries
Name 82883 0
Dr Jason K Tan
Address 82883 0
Joondalup Health Campus, Grand Blvd &, Shenton Ave, Joondalup WA 6027
Country 82883 0
Australia
Phone 82883 0
+61 894009889
Fax 82883 0
Email 82883 0
jason.tan@health.wa.gov.au
Contact person for scientific queries
Name 82884 0
Dr Jason K Tan
Address 82884 0
Joondalup Health Campus, Grand Blvd &, Shenton Ave, Joondalup WA 6027
Country 82884 0
Australia
Phone 82884 0
+61 894009889
Fax 82884 0
Email 82884 0
jason.tan@health.wa.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Can be requested but will be subject to Joondalup health campus human research and ethics committee approval
What supporting documents are/will be available?
Ethical approval
Summary results
No Results