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Trial registered on ANZCTR


Registration number
ACTRN12618000130268
Ethics application status
Approved
Date submitted
21/12/2017
Date registered
30/01/2018
Date last updated
29/01/2019
Date data sharing statement initially provided
29/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Effect of a probiotic on Otitis media (ear infections) and Upper Respiratory Tract Infections amongst 6-24 month old children.
Scientific title
A randomised placebo controlled trial of the effect of BLIS probiotic, S. salivarius (K12) on Otitis media (ear infections) and Upper Respiratory Tract Infections amongst 6-24 month old children, as measured by medical record events.
Secondary ID [1] 293481 0
None
Universal Trial Number (UTN)
U1111-1189-9184
Trial acronym
BLIS-OM
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Otitis media 305671 0
Upper Respiratory Tract Infections 305672 0
Condition category
Condition code
Infection 304892 304892 0 0
Other infectious diseases
Ear 305326 305326 0 0
Other ear disorders
Respiratory 305327 305327 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A probiotic powder containing Streptococcus salivarius K12 (at least 1.25 billion CFU/dose), isomalt, maltodextrin and natural flavour (strawberry) will be taken daily by participants in the active group from the age of 6 months to 24 months of age.

Parents/caregivers will provide a 1.25 cubic centimetre (CC ~ 1/4 teaspoon) spoonful of the powder to infants orally preferably after food by one of the following methods; mixing on a clean spoon with a small amount of water, breast milk or formula and administered to the child's mouth and gums by the parents, using either a clean finger or provided silicon finger brush to rub the paste on. Or emptied into a provided silicon mesh infant feeder (also known as a teething feeder). Or mixed with cooled food (when children start to receive solid food). The powder will be stored in opaque plastic containers which will be weighed before given to participants and when returned, as a measure of compliance.
Intervention code [1] 299724 0
Prevention
Comparator / control treatment
A placebo powder containing isomalt, maltodextrin and natural flavour (strawberry) will be taken by participants in the placebo group every day for 18 months, as per the methods described for the active group (outlined above).
Control group
Placebo

Outcomes
Primary outcome [1] 304083 0
The primary outcome will be rate of doctor recorded otitis media in the 18 months the child is taking part in the trial.
Timepoint [1] 304083 0
Medical record search when the child is 2 years of age, covering the study period (child is 6 months - 2 years of age).
Secondary outcome [1] 340891 0
Number of medical visits for Upper and Lower Respiratory Tract Infections (composite).
Timepoint [1] 340891 0
Medical record search when the child is 2 years of age, covering the study period (child is 6 months - 2 years of age).
Secondary outcome [2] 340892 0
Doctor prescriptions for antibiotics for respiratory conditions (otitis media, URTI, LRTI).
Timepoint [2] 340892 0
Medical record search when the child is 2 years of age, covering the study period (child is 6 months - 2 years of age).
Secondary outcome [3] 340893 0
Number of doctor diagnoses with croup.
Timepoint [3] 340893 0
Medical record search when the child is 2 years of age, covering the study period (child is 6 months - 2 years of age).
Secondary outcome [4] 341462 0
Severity of doctor diagnosed otitis media from BPAC guidelines for diagnosis and treatment.
Timepoint [4] 341462 0
Medical record search when the child is 2 years of age, covering the study period (child is 6 months - 2 years of age).
Secondary outcome [5] 341463 0
Frequency of doctor diagnosed URTI.
Timepoint [5] 341463 0
Medical record search when the child is 2 years of age, covering the study period (child is 6 months - 2 years of age).
Secondary outcome [6] 341464 0
Parental reported ear infections.
Timepoint [6] 341464 0
Study designed questionnaire asked of parents when the child is 2 years of age, covering the study period (child is 6 months - 2 years of age).
Secondary outcome [7] 341465 0
Parental reported URTI.
Timepoint [7] 341465 0
Study designed questionnaire asked of parents when the child is 2 years of age, covering the study period (child is 6 months - 2 years of age).
Secondary outcome [8] 341466 0
Evidence of dental decay using ICDAS.
Timepoint [8] 341466 0
Dental examination when the child is 2 years of age.
Secondary outcome [9] 341467 0
Parental reports of hospital admissions for respiratory conditions (otitis media, URTI, LRTI).
Timepoint [9] 341467 0
Study designed questionnaire asked of parents when the child is 2 years of age, covering the study period (child is 6 months - 2 years of age).
Secondary outcome [10] 341468 0
Parental reports of outpatient referrals to paediatrics or ENT for respiratory tract infections (otitis media, URTI, LRTI).
Timepoint [10] 341468 0
Study designed questionnaire asked of parents when the child is 2 years of age, covering the study period (child is 6 months - 2 years of age).
Secondary outcome [11] 341469 0
Parental report of course of antibiotics taken for respiratory conditions (otitis media, URTI, LRTI).
Timepoint [11] 341469 0
Study designed questionnaire asked of parents when the child is 2 years of age, covering the study period (child is 6 months - 2 years of age).

Eligibility
Key inclusion criteria
Infant must be enrolled in a medical practice, planning to live in the Hutt Valley, Wellington or Christchurch regions for the duration of the study,
Minimum age
6 Months
Maximum age
6 Months
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Infants with serious medical conditions such as congenital heart conditions, severe immunodeficiency, families who plan to permanently move from the Wellington/Christchurch regions during the 18 month study period. Infants already receiving regular BLIS probiotics or a parent planning to give them to their child, children with a severe dairy allergy.

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation concealment of bottles between placebo and active will occur by the manufacturer, off-site, who will use central randomisation by computer to allocate bottle codes. Researchers will use the next available bottle number, and are blinded to allocation throughout the study.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomisation by computer.
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
Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Acute otitis media in New Zealand children under 1 years of age and 1–2 year olds are estimated to occur with 499 and 377, respectively, episodes per 1,000 children per annum (Gribben et al 2012). Applying <1 year old rate for the period from age 6 months to a year, the rate from 6 months to 2 years of age is expected to be 586. Four hundred and twenty participants will have a 90% power for a 50% reduction in that rate for an unclustered analysis with a negative binomial regression, assuming the distribution of multiple episodes for children under 5 years of age in Gribben et al (2012), and that participants do not withdraw their consent for the medical record search. A 50% reduction was used as it seemed a level of reduction that might result in treatment being used. It is a smaller reduction than the 70% reduction found in the study by Di Pierro et al (2012) that was not randomised, not placebo-controlled, and also not blinded.

The analysis of counts of acute otitis media, upper respiratory tract infections, caries , antibiotic prescribing for URTIs , and croup will be intention-to-treat analyses, with treatments compared using negative binomial regressions adjusted for centre and clustering by general practice. For acute otitis media and upper respiratory tract infection each analysis will be adjusted for whether they had been diagnosed before baseline.

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 outside Australia
Country [1] 9398 0
New Zealand
State/province [1] 9398 0
Wellington
Country [2] 9399 0
New Zealand
State/province [2] 9399 0
Christchurch

Funding & Sponsors
Funding source category [1] 298100 0
Government body
Name [1] 298100 0
Health Research Council of New Zealand
Address [1] 298100 0
Level 3, ProCARE Building, Grafton Mews
110 Stanley Street
Auckland 1010
Country [1] 298100 0
New Zealand
Primary sponsor type
Individual
Name
Julian Crane
Address
University of Otago, Wellington
23a Mein Street
Newtown
Wellington 6021
Country
New Zealand
Secondary sponsor category [1] 297177 0
None
Name [1] 297177 0
Address [1] 297177 0
Country [1] 297177 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299120 0
Central Health and Disability Ethics Committee
Ethics committee address [1] 299120 0
Health and Disability Ethics Committees
Ministry of Health
133 Molesworth Street
Wellington 6011
Ethics committee country [1] 299120 0
New Zealand
Date submitted for ethics approval [1] 299120 0
16/11/2016
Approval date [1] 299120 0
30/01/2017
Ethics approval number [1] 299120 0
16/CEN/190

Summary
Brief summary
This study will investigate the effect of an oral probiotic (manufactured by BLIS technologies) on preventing very common infectious problems during early infancy, particularly ear infections (otitis media), upper respiratory tract infections and reducing dental caries. The probiotic is known to reduce the bacteria that cause these infections and this study will examine the potential of this probiotic to prevent them when taken daily by infants from 6 months to 24 months of age.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 79362 0
Prof Julian Crane
Address 79362 0
Department of Medicine
University of Otago Wellington
23a Mein Street
Newtown
Wellington 6021
Country 79362 0
New Zealand
Phone 79362 0
+64 4 918 5258
Fax 79362 0
Email 79362 0
julian.crane@otago.ac.nz
Contact person for public queries
Name 79363 0
Prof Julian Crane
Address 79363 0
Department of Medicine
University of Otago Wellington
23a Mein Street
Newtown
Wellington 6021
Country 79363 0
New Zealand
Phone 79363 0
+64 4 918 5258
Fax 79363 0
Email 79363 0
julian.crane@otago.ac.nz
Contact person for scientific queries
Name 79364 0
Prof Julian Crane
Address 79364 0
Department of Medicine
University of Otago Wellington
23a Mein Street
Newtown
Wellington 6021
Country 79364 0
New Zealand
Phone 79364 0
+64 4 918 5258
Fax 79364 0
Email 79364 0
julian.crane@otago.ac.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
permission was not sought from participants
What supporting documents are/will be available?
No other documents available
Summary results
Not applicable