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Trial registered on ANZCTR


Registration number
ACTRN12618000265279p
Ethics application status
Not yet submitted
Date submitted
14/02/2018
Date registered
21/02/2018
Date last updated
21/02/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Restoring gut health of newborns- a clinical trial of probiotics
Scientific title
Restoring neonatal gut biodiversity and mucosal immunity after postnatal antibiotics exposure (Restore trial)
Secondary ID [1] 293210 0
None
Universal Trial Number (UTN)
U1111-1204-2229
Trial acronym
RESTORE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Neonatal gut microbial biodiversity 305218 0
Immune development 306603 0
Condition category
Condition code
Reproductive Health and Childbirth 304526 304526 0 0
Complications of newborn
Oral and Gastrointestinal 305697 305697 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
multi-strain probiotic powder (multiple strains of lactobacilli and bifidobacterium, 7 billion cfu per gram- supplied in 3x60gm bottles) - two grams (two scoops) dissolved in expressed breast milk every day for 12 weeks orally
Adherence/compliance to intervention will be monitored by parental diary and by measuring left over powder on return of bottles at the end of intervention
Intervention code [1] 299468 0
Treatment: Drugs
Comparator / control treatment
similar looking powder of placebo containing maltodextrin (supplied in 3x60gm bottles) - two grams (two scoops) every day for 12 weeks orally
The reference group (40 infants of matched gestation without antibiotic exposure) will not receive any treatment.
Control group
Placebo

Outcomes
Primary outcome [1] 303766 0
Stool microbial diversity - by 16S rRNA sequencing
Timepoint [1] 303766 0
4 weeks of age
Secondary outcome [1] 340109 0
stool microbial diversity - by 16S rRNA sequencing
This analysis will show whether the effect of probiotics on diversity is sustained beyond post-cessation.
Timepoint [1] 340109 0
12 weeks of age (at treatment completion), 6 months of age (3 months post-treatment completion) and 12 months of age (9 months post-treatment completion)
Secondary outcome [2] 343170 0
Secretory IgA stool
Timepoint [2] 343170 0
4 weeks of age (4 weeks post-treatment commencement), 12 weeks of age (at treatment completion), 6 months of age (3 months post-treatment completion) and 12 months of age (9 months post-treatment completion)
Secondary outcome [3] 343171 0
medically diagnosed allergy/eczema/atopy - assessed by parents questionnaire designed for this study
Timepoint [3] 343171 0
12 months of age (9 months post-treatment completion)
Secondary outcome [4] 343276 0
Secretory IgA in saliva
Timepoint [4] 343276 0
4 weeks of age (4 weeks post-treatment commencement), 12 weeks of age (at treatment completion), 6 months of age (3 months post-treatment completion) and 12 months of age (9 months post-treatment completion)

Eligibility
Key inclusion criteria
Newborns (gestation > or equal to 37+0 weeks) who have been given antibiotics for clinical indications (at least two doses) within 48 hours of birth
Age and gestation matched newborns without antibiotic exposure will be included as the 'reference group'
Minimum age
0 Days
Maximum age
3 Days
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
-gestational age <37 weeks
-anticipated exposure of antibiotics more than 5 days post birth
-major congenital anomalies (e.g. gastroschisis)
-bilious vomiting
-probiotic intake other than study drug by mum or baby

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)
Centrally computer-generated randomisation will be used and the trial pharmacist (unblinded) will allocate participants to probiotic or placebo group. Participants, clinicians and the investigators will be blinded to the group allocation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
block randomization
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
40 probiotic group, 40 placebo and 40 babies not exposed to antibiotics used as reference group
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Intention to treat 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
Recruitment hospital [1] 9249 0
Fiona Stanley Hospital - Murdoch
Recruitment postcode(s) [1] 17911 0
6150 - Murdoch

Funding & Sponsors
Funding source category [1] 297840 0
Hospital
Name [1] 297840 0
Fiona Stanley Hospital
Address [1] 297840 0
11 Robin warren drive, Murdoch WA 6150
Country [1] 297840 0
Australia
Primary sponsor type
Hospital
Name
Fiona Stanley Hospital
Address
11 Robin warren drive, Murdoch WA 6150
Country
Australia
Secondary sponsor category [1] 296878 0
None
Name [1] 296878 0
NA
Address [1] 296878 0
NA
Country [1] 296878 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 298887 0
South Metro Area Health Service Ethics Committee
Ethics committee address [1] 298887 0
Fiona Stanley Hospital, Education Building, 11 Robin Warren Drive, Murdoch WA 6150
Ethics committee country [1] 298887 0
Australia
Date submitted for ethics approval [1] 298887 0
30/05/2018
Approval date [1] 298887 0
Ethics approval number [1] 298887 0

Summary
Brief summary
Due to high susceptibility to infections, antibiotics are the most widely used drugs for newborns. Recent evidence suggests that antibiotics exposure in newborn period (first 4 weeks of life) predisposes to an imbalance in the gut, which may have long lasting consequences. Imbalances in the infants’ gut bacteria (microbiome) caused by antibiotics has been shown to alter the development of the neonate’s immune response. This altered immune development caused by a poorly balanced microbiome during this crucial phase of early life has been associated with the development of atopy, asthma, eczema, allergy, type 1 diabetes and inflammatory bowel disease. Mucosal immunity development in the gut has been shown to be aberrant as early as one month of age in children who go on to develop allergy symptoms in future. RESTORE is a clinical trial of a multi-strain probiotic for antibiotics exposed term newborn infants with aims to restore biodiversity and reduce dysbiosis (imbalance of bacteria) in the newborn gut in early months after birth. This is the first study of its kind to examine effects of probiotics on these high-risk infants’ gut biodiversity and mucosal immune development.
Research Questions
1. Can the gut microbial diversity of infants exposed to postnatal antibiotics be restored earlier (within neonatal period after birth) by daily use of multi-strain probiotic supplementation?
2. Is this effect sustained at 3 months and 12 months?
3. Can probiotics in antibiotic exposed infants improve the production of salivary and secretory IgA to that seen in infants without antibiotics exposure?
Methodology
This randomised control trial will be conducted at Fiona Stanley Hospital. A total of 120 term neonates will be recruited, 80 of whom would have received antibiotics at birth for clinical reasons. Forty of the antibiotic exposed neonates will receive daily probiotics for 3 months and forty infants will receive a placebo. Forty infants without antibiotic exposure will serve as a reference group. Stool, saliva and blood will collected for microbiome and/or immunological tests at five time-points in the first 12 months of life.
Predicted Benefits and Relevance:
Neonatal infections, antibiotic use and allergy in later life are highly relevant health issues for infants, with gut microbiome as the potential denominator. In Australia, the economic cost of allergic diseases is estimated to be >$30 billion annually. Probiotics have been extensively used to restore microbiome balance in adults and hold potential to be useful for newborns for this indication. Although some promising data exists from animal studies, No human studies have yet determined whether probiotics are effective in rapidly restoring the balance of bacteria in term neonates’ gut following exposure to antibiotics. We are proposing a randomised control trial to determine if multi-strain probiotics can rapidly normalize the infants’ microbiome following neonatal antibiotic exposure during the crucial time of immune development and improve mucosal immunity. This study will provide insights for conducting larger multicentre trial to confirm clinical benefits; which will potentially change the practice to routinely supplement these high-risk babies with probiotics in the newborn period.

Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 78566 0
Dr Shailender Mehta
Address 78566 0
Fiona Stanley Hospital, 11 Robin Warren Drive, Murdoch WA 6150
Country 78566 0
Australia
Phone 78566 0
+61861522222
Fax 78566 0
Email 78566 0
shailender.mehta@health.wa.gov.au
Contact person for public queries
Name 78567 0
Dr Shailender Mehta
Address 78567 0
Fiona Stanley Hospital, 11 Robin Warren Drive, Murdoch WA 6150
Country 78567 0
Australia
Phone 78567 0
+61861522222
Fax 78567 0
Email 78567 0
shailender.mehta@health.wa.gov.au
Contact person for scientific queries
Name 78568 0
Dr Shailender Mehta
Address 78568 0
Fiona Stanley Hospital, 11 Robin Warren Drive, Murdoch WA 6150
Country 78568 0
Australia
Phone 78568 0
+61861522222
Fax 78568 0
Email 78568 0
shailender.mehta@health.wa.gov.au

No information has been provided regarding IPD availability
Summary results
No Results