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Trial registered on ANZCTR


Registration number
ACTRN12617000856314
Ethics application status
Approved
Date submitted
2/06/2017
Date registered
9/06/2017
Date last updated
5/11/2018
Date data sharing statement initially provided
5/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Antibiotics and Immune Responses in infants
Scientific title
A clinical study to determine whether antibiotic-driven dysbiosis is associated with impaired vaccine responses in infants.
Secondary ID [1] 292113 0
None
Universal Trial Number (UTN)
U1111-1197-3921
Trial acronym
AIR
Linked study record
None

Health condition
Health condition(s) or problem(s) studied:
Neonatal intestinal dysbiosis 303539 0
Condition category
Condition code
Inflammatory and Immune System 302947 302947 0 0
Normal development and function of the immune system
Reproductive Health and Childbirth 302958 302958 0 0
Complications of newborn

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
This is an observational trial which will examine and compare immune responses to vaccines in infants in three groups classified by exposure to antibiotics.
Group 1 –Infant with direct antibiotic exposure within 28 days of birth
Group 2 - Infant born to mother who received intrapartam maternal antibiotics within 28 days prior to delivery
Group 3 – Infant with no direct or maternal antibiotic exposure
Participants will be followed up from birth until 18 months of age.
Intervention code [1] 298260 0
Not applicable
Comparator / control treatment
Observational study - immune responses in group 3 (no antibiotic exposure group) will be compared with Group 1 (direct antibiotic exposure) and Group 2 (maternal antibiotic exposure) to assess any effect of antibiotic exposure on infant immune responses to routine vaccines.
Control group
Active

Outcomes
Primary outcome [1] 302344 0
Percentage of enrolled participants achieving a seroprotective antibody response (greater than or equal to 0.35 micrograms/mL) as measured by serum assay,
Timepoint [1] 302344 0
4-6 weeks post the third dose of 13-valent pneumococcal conjugate vaccine PCV13 (approximately 7 months of age)
Primary outcome [2] 302345 0
Geometric mean concentrations in micrograms/ml of anticapsular antibodies for serotypes included in the 13-valent pneumococcal conjugate vaccine ( PCV13) as measured by serum assay.
Timepoint [2] 302345 0
4-6 weeks post the third dose of PCV13
Secondary outcome [1] 335602 0
Percentage of enrolled participants achieving a seroprotective antibody response (greater than or equal to 0.35 micrograms/mL) as measured by serum assay,
Timepoint [1] 335602 0
12 months (+/- 2 weeks) post the third dose of 13-valent pneumococcal conjugate vaccine PCV13 (approximately 18 months of age)
Secondary outcome [2] 335603 0
Geometric mean concentrations in micrograms/ml of anticapsular antibodies for serotypes included in the 13-valent pneumococcal conjugate vaccine ( PCV13) as measured by serum assay.
Timepoint [2] 335603 0
12 months (+/- 2 weeks) post the third dose of 13-valent pneumococcal conjugate vaccine PCV13 (approximately 18 months of age)
Secondary outcome [3] 335604 0
Percentage of enrolled participants achieving seroprotective antibody responses to diphtheria ( greater than 0.1 international unit/mL) as measured by serum assay,
Timepoint [3] 335604 0
4-6 weeks post the third dose of routine infant vaccines (approximately 7 months of age)
Secondary outcome [4] 335654 0
Percentage of enrolled participants achieving seroprotective antibody responses to tetanus (greater than or equal to 0.1 international unit/mL) as measured by serum assay,
Timepoint [4] 335654 0
4-6 weeks post the third dose of routine infant vaccines (approximately 7 months of age)
Secondary outcome [5] 335655 0
Percentage of enrolled participants achieving seroprotective antibody responses to hepatitis B (greater than or equal to 10 mIU/mL) as measured by serum assay,
Timepoint [5] 335655 0
4-6 weeks post the third dose of routine infant vaccines (approximately 7 months of age)
Secondary outcome [6] 335656 0
Percentage of enrolled participants achieving seroprotective antibody responses to Hib PRP (greater than or equal to 0.15 micrograms/ml) as measured by serum assay,
Timepoint [6] 335656 0
4-6 weeks post the third dose of routine infant vaccines (approximately 7 months of age)
Secondary outcome [7] 335657 0
Characterisation of the gut microbiome in each group of infants from stool sample using DNA extraction and metagenomics
Timepoint [7] 335657 0
Stool samples collected in the first week of life and again at 6 weeks of age
Secondary outcome [8] 335786 0
An additional exploratory outcome will be to identify gene expression modules and compare antibiotic exposed groups with the unexposed infant group. To do this, RNA sequencing will be performed on cells isolated from blood samples collected from infants at baseline and 1 week post vaccination. RNA sequencing data will be compared using EdgeR analysis software.
Timepoint [8] 335786 0
immediately prior to vaccination schedule for 6 weeks of age and one week following vaccination.

Eligibility
Key inclusion criteria
1. Healthy term infant (at least 37 weeks gestation)
2. Infant expected to have routine immunisation according to the National Immunisation Program (NIP)
3. Infant delivered vaginally
Minimum age
No limit
Maximum age
7 Days
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1, Infant delivered by caesarean section
2. Infant has a confirmed sepsis (defined by laboratory confirmed bacterial infection in blood cultures or CSF)
3. Mother or infant has a known or suspected disorder of the immune system that would prevent an immune response to the vaccines, such as participant with congenital or acquired immunodeficiency or those receiving systemic immunosuppressive therapy.
4. Infant has suspected or confirmed HIV, major congenital abnormality or serious illness.
5. Mother or infant is participating in a clinical study that may interfere with participation in, or outcomes of this study
6.Mother of infant had a recorded Body Mass Index >30kg/m2 at a first trimester antenatal visit



Study design
Purpose
Natural history
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
We have designed and powered the study to describe the impact of antibiotic exposure on two primary outcomes: PCV13-specific IgG GMC and proportions achieving seroprotective antibody levels at 7 months (following 3 doses of PCV13 vaccination at 2, 4 and 6 months).
Descriptive statistics including mean (95% CI) GMC (continuous) and proportion seroprotected/seroresponsive (categorical) will be reported by antibiotic exposure group. To assess the relationship between antibiotic exposure and vaccine response, univariate and multivariable linear regression models will be used to compare continuous outcome variables (ie mean GMC between antibiotic exposure groups and control group) whilst adjusting for potential confounders such as maternal age, maternal BMI, gestation age etc. Similarly, logistic regression models will be used to compare categorical outcomes (likelihood of reaching relevant antibiotic thresholds for exposed groups compared to the non-exposed control group) whilst adjusting for relevant confounders.
Based on animal data and published data from a randomised, double-blind, multicentre trial of 1,709 PCV13-vaccinated, healthy infants in the US, we conservatively estimated the effect size for our study to be a 25% reduction in mean GMC in the antibiotic exposed groups, with a coefficient of variation of 1.23. Using these parameters, we require 180/group to detect effects at greater than 85% power (alpha 0.05). For the categorical analysis of differences in proportions achieving PCV13 seroprotective antibody responses (greater than or equal to 0.35 microgram/mL), using a conservative assumption that the proportion would be at least 88% in the control group, we require 140/group to detect a 15% difference (alpha 0.05) with 90% power.

We have therefore designed the study to enrol 200 infants/group to allow for withdrawals and/or insufficient blood collections for approximately 10%.

Recruitment
Recruitment status
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)
SA
Recruitment hospital [1] 8242 0
Womens and Childrens Hospital - North Adelaide
Recruitment postcode(s) [1] 16301 0
5006 - North Adelaide

Funding & Sponsors
Funding source category [1] 296652 0
Hospital
Name [1] 296652 0
Vaccinology and Immunology Research Trials Unity, Women's and Children's Hospital
Address [1] 296652 0
72 King William Road, North Adelaide, SA 5006
Country [1] 296652 0
Australia
Primary sponsor type
Government body
Name
Women's and Children's Health Network
Address
72 King William Road, North Adelaide, SA 5006
Country
Australia
Secondary sponsor category [1] 295606 0
None
Name [1] 295606 0
Address [1] 295606 0
Country [1] 295606 0
Other collaborator category [1] 279595 0
Other Collaborative groups
Name [1] 279595 0
South Australian Health and Medical Research Institute
Address [1] 279595 0
North Terrace, Adelaide SA 5000
Country [1] 279595 0
Australia
Other collaborator category [2] 279596 0
Other Collaborative groups
Name [2] 279596 0
Telethon Kids Institute
Address [2] 279596 0
Telethon Kids Institute
100 Roberts Road,
Subiaco Western Australia 6008
Country [2] 279596 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297876 0
Women's and Children's Health Network Human Research Ethics Committee
Ethics committee address [1] 297876 0
72 King William Road
North Adelaide, SA 5006
Ethics committee country [1] 297876 0
Australia
Date submitted for ethics approval [1] 297876 0
07/02/2017
Approval date [1] 297876 0
20/04/2017
Ethics approval number [1] 297876 0
HREC/17/WCHN/19

Summary
Brief summary
A multicentre clinical observational study to determine whether dysbiosis of the neonatal gut microbiome, driven by antibiotic exposure in the perinatal period, leads to impairment of subsequent antigen-specific responses to routine infant immunisations. This study will enrol vaginally born, term infants, with and without perinatal antibiotic exposure (maternal intrapartum antibiotics administered within 28 days of delivery or direct infant antibiotic exposure in the first 28 days of life. Infants will be vaccinated according to the National Immunisation Program and will have stool and blood samples collected to assess gut microbiome, gene expression responses and antigen specific vaccine responses. Proportions achieving seroprotective antibody titres at approximately 7 months and 18 months of age will be compared between exposed and unexposed groups to assess impact of early antibiotic exposure on subsequent vaccine responses.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 75342 0
Prof Helen Marshall
Address 75342 0
Vaccinology and Immunology Research Trials Unit
Women's and Children's Hospital
72 King William Road,
North Adelaide, SA 5006
Country 75342 0
Australia
Phone 75342 0
+61 8 8161 8115
Fax 75342 0
+61 8 8161 7031
Email 75342 0
helen.marshall@adelaide.edu.au
Contact person for public queries
Name 75343 0
Prof Helen Marshall
Address 75343 0
Vaccinology and Immunology Research Trials Unit
Women's and Children's Hospital
72 King William Road,
North Adelaide, SA 5006
Country 75343 0
Australia
Phone 75343 0
+61 8 8161 8115
Fax 75343 0
+61 8 8161 7031
Email 75343 0
helen.marshall@adelaide.edu.au
Contact person for scientific queries
Name 75344 0
Prof Helen Marshall
Address 75344 0
Vaccinology and Immunology Research Trials Unit
Women's and Children's Hospital
72 King William Road,
North Adelaide, SA 5006
Country 75344 0
Australia
Phone 75344 0
+61 8 8161 8115
Fax 75344 0
+61 8 8161 7031
Email 75344 0
helen.marshall@adelaide.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Undecided
No/undecided IPD sharing reason/comment
to be decided and approved by in investigators and collaborators and with WCHN HREC approval
What supporting documents are/will be available?
Study protocol
Informed consent form
Ethical approval
Summary results
Not applicable