Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12624001387516
Ethics application status
Approved
Date submitted
4/11/2024
Date registered
22/11/2024
Date last updated
22/11/2024
Date data sharing statement initially provided
22/11/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
The Pro-Kids Study: Probiotics to prevent acute respiratory infection in First Nations infants in the Northern Territory
Scientific title
Neonatal probiotics to prevent early-onset acute respiratory infections (ARIs) in high-risk children: a multisite, double-blinded, randomised controlled trial (RCT)
Secondary ID [1] 310414 0
None
Universal Trial Number (UTN)
U1111-1296-8365
Trial acronym
Pro-Kids
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute Respiratory Infection 331174 0
Condition category
Condition code
Respiratory 327949 327949 0 0
Other respiratory disorders / diseases
Inflammatory and Immune System 327950 327950 0 0
Normal development and function of the immune system
Infection 327951 327951 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm 1: Interventional Group
Study product - Powder of Lactiplantibacillus plantarum plus fructo oligosaccharide (LpFOS) - [L.. Plantarum ATCC 202195 1 x 1000000000 colony forming units (CFU) plus 150mg FOS with 100 mg corn maltodextrin as excipient].

Administration of the study product:
Participants will be allocated to 7-consecutive days supervised administration of the study product. Briefly, study eligible infants will be given a single daily oral dose, commencing <=3 days of birth (<=72 hours from birth) and continuing for 7 consecutive days total. The study staff mainly comprising midwives and child health nurses will be tasked with locating/recalling participants and administering the supervised dose of the study product . The product will be prepared fresh daily by mixing with 3 ml of sterile water or breast milk if it is available.
Intervention code [1] 327790 0
Prevention
Intervention code [2] 327791 0
Treatment: Other
Comparator / control treatment
Placebo (0.26 grams powder of corn maltodextrin).

Administration of the study product:
Participants will be allocated to 7-consecutive days supervised administration of the study placebo.. Briefly, study eligible infants will be given a single daily oral dose, commencing <=3 days of birth (<=72 hours from birth) and continuing for 7 consecutive days total. The study staff mainly comprising midwives and child health nurses will be tasked with locating/recalling participants and administering the supervised dose of the study product. The product will be prepared fresh daily by mixing with 3 ml of sterile water or breast milk if it is available.

The active and placebo study products are both tasteless and identical in appearance and packaging.
Control group
Placebo

Outcomes
Primary outcome [1] 337127 0
New Acute Respiratory Infection (ARI) episodes (hospital or primary-care) in the first year of life.

Assessment method: ARI presentations will be identified from medical records (electronic or otherwise). ARI will encompass both lower (LRI) and upper (URI) respiratory infections.
Timepoint [1] 337127 0
From birth until 12 months of age. Medical file records will be reviewed at brith, post intervention (defined as less than or equal to 3 days after day-7 dose) and at 1, 4, 7 and 12 months of infant age.

Secondary outcome [1] 430802 0
Intervention tolerance and safety. This is a composite outcome.

Assessment method: From day 1 of oral administration of the investigational product, infants will be monitored for any adverse events for at least 10 minutes immediately after oral administration and until 24 hours after the last dose which will be on day 7 since the start of the intervention. A 7-day daily dosing diary will be maintained and completed by the staff administering the investigational product and includes a tolerance and safety questionnaire-checklist as part of data collection tools.

An adverse event (AE) is assessed as any untoward, undesired, or unplanned event in the form of signs, symptoms, disease, or laboratory or physiologic observations occurring in a person given an investigational product or in a clinical study. The event does not need to be causally related to the investigational product or clinical study. An AE includes, but is not limited to, the following:
• Any clinically significant worsening of a preexisting condition
• An AE resulting from overdose of an investigational product, whether accidental or intentional. Overdose is defined as a dose of any magnitude above that specified in the protocol
• An AE resulting from abuse (eg, use for non-clinical reasons) of an investigational product,
• An AE that has been associated with the discontinuation of the use of an investigational product
Timepoint [1] 430802 0
Intervention tolerance and safety will be asssessed daily via a checklist included in the daily dosing diary during the 7-day study intervention period.
Secondary outcome [2] 430803 0
L. Plantarum colonisation.

Assessment method: The duration of colonisation will be determined using quantitative PCR on stool samples from baseline, post intervention, 1, 4 and 7 months.
Timepoint [2] 430803 0
Baseline, post intervention (defined as less than or equal to 3 days after day-7 dose), 1, 4 and 7 months of infant age..
Secondary outcome [3] 430804 0
Gut microbiome.

Assessment method: To determine if the intervention promotes a health-associated microbiome profile (dominated by Lactobacillus and Bifidobacterium species), shotgun metagenomic sequencing and/or full-length 16S rRNA gene sequencing will be performed on stool samples at baseline, post intervention, 1, 4 and 7 months.
Timepoint [3] 430804 0
Baseline, post intervention (defined as less than or equal to 3 days after day-7 dose), 1, 4 and 7 months of infant age.
Secondary outcome [4] 430805 0
Upper respiratory (nasal) microbiome.

Assessment method: To understand the impact of the intervention on the nasal microbiome, 16S rRNA-gene amplicons will be sequenced
Timepoint [4] 430805 0
At post-intervention (defined as less than or equal to 3 days after day-7 dose), 1,4 and 7 months follow-up.
Secondary outcome [5] 434318 0
Immunology (cord blood and infant blood)
Timepoint [5] 434318 0
Determine systemic immune response (these include cellular immune response to challenge with respiratory pathogens, cytokines, vaccine antibodies) in infants at 1, 4 and 7 months of infant age
Secondary outcome [6] 441992 0
Incidence of gastroenteritis hospitalisations assessed via review of patient medical records with documented diagnosis of gastroenteritis,
Timepoint [6] 441992 0
From baseline to 12 months of infant age.
Secondary outcome [7] 441993 0
Incidence of sepsis assessed through medical file review with documented diagnosis of sepsis.
Timepoint [7] 441993 0
From baseline to 12 months of infant age.

Eligibility
Key inclusion criteria
Eligibility Criteria
1. Mother is aged >=18 years
2. Infant is of First Nations descent
3. Infant is a resident in urban Darwin or one of the approved participating communities

Inclusion Criteria
1. Mother/guardian must be able to provide written informed consent in English (with or without an interpreter)
2. Infant is born >=35 weeks gestation
3. Infant is <=3 days (or <=72 hours) post-partum
4. Infant birth weight is >2.0 kilograms (kgs)
5. Infant is feeding orally




Minimum age
1 Days
Maximum age
3 Days
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Exclusion Criteria
1. Infant has major congenital anomalies
2. Infant has known infection or signs of active infection (fever >38°C)
3. Infant is requiring respiratory support (except O2)
4. Infant is being given antibiotics <=3 days post-partum and is not suitable to enter the study in the opinion of their attending clinician
5. Infant is admitted in special care nursery <=3 days post-partum and is not suitable to enter the study in the opinion of their attending clinician
6. Infant is admitted in the paediatric ward <=3 days post-partum and is not suitable to enter the study in the opinion of their attending clinician
7. Infant is enrolled in other concurrent intervention trials deemed to conflict the outcome of this trial
8. Infant is on oral probiotics

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 is concealed. Allocation of study product will occur using pre-randomised and sequentially labelled study product sachets. Permuted block size of four will be used and stratified by community (urban/remote) and antibiotic exposure (maternal antepartum, intrapartum, postpartum and/or infant) <=7 days before the intervention (yes/no). Study product will be received allocation concealed (sequentially numbered) at the study site.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomisation
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 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Primary analysis will compare the ARI rate (episodes/child-month) between study groups (active intervention versus placebo). Briefly, we will compare the ARI rate (episodes/child/12 months) between LpFOS and placebo treated infants. Primary analysis will be intention to treat. This will be done with a negative binomial regression model producing an estimate of the incidence rate ratio (IRR; with 95% CI). Supplementation efficacy will be defined as (1-IRR) x 100. A per protocol analysis, excluding those who missed >3 consecutive doses will also be conducted. Moreover, we will assess the proportion of children having any ARI episode <12 months (effects will be presented as risk ratios) using generalised linear model and the time to first ARI presentation using Cox regression (effects presented as hazard ratios).

Secondary analyses will evaluate tolerance and adverse event episodes (intervention period); incidence of sepsis and gastroenteritis hospitalisations; L. plantarum colonisation prevalence in the gut at baseline, post-intervention (<=3 days after day-7 dose), 1, 4 and 7 months; gut and nasal microbiome compositions and immune profiles at post-intervention, 1, 4 and 7 months between the two groups.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
2/12/2024
Actual
Date of last participant enrolment
Anticipated
15/11/2027
Actual
Date of last data collection
Anticipated
15/11/2028
Actual
Sample size
Target
148
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NT
Recruitment hospital [1] 26042 0
Royal Darwin Hospital - Tiwi
Recruitment postcode(s) [1] 41889 0
0810 - Tiwi

Funding & Sponsors
Funding source category [1] 314623 0
Government body
Name [1] 314623 0
National Health and Medical Research Council: MRFF ICTC Grant #2023834
Country [1] 314623 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Menzies School of Health Research
Address
PO Box 41096, Casuarina NT 0811
Country
Australia
Secondary sponsor category [1] 316585 0
None
Name [1] 316585 0
Address [1] 316585 0
Country [1] 316585 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313646 0
Human Research Ethics Committee of the Northern Territory Department of Health and Menzies School of Health Research
Ethics committee address [1] 313646 0
Ethics committee country [1] 313646 0
Australia
Date submitted for ethics approval [1] 313646 0
08/11/2023
Approval date [1] 313646 0
21/03/2024
Ethics approval number [1] 313646 0
HREC 23-4759

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 128862 0
A/Prof Michael Binks
Address 128862 0
John Mathews Building (Bldg 58), Royal Darwin Hospital Campus, Rocklands Drive, Casuarina NT 0810
Country 128862 0
Australia
Phone 128862 0
+61 8 8946 8444
Fax 128862 0
Email 128862 0
michael.binks@menzies.edu.au
Contact person for public queries
Name 128863 0
Michael Binks
Address 128863 0
John Mathews Building (Bldg 58), Royal Darwin Hospital Campus, Rocklands Drive, Casuarina NT 0810
Country 128863 0
Australia
Phone 128863 0
+61 8 8946 8444
Fax 128863 0
Email 128863 0
michael.binks@menzies.edu.au
Contact person for scientific queries
Name 128864 0
Michael Binks
Address 128864 0
John Mathews Building (Bldg 58), Royal Darwin Hospital Campus, Rocklands Drive, Casuarina NT 0810
Country 128864 0
Australia
Phone 128864 0
+61 8 8946 8444
Fax 128864 0
Email 128864 0
michael.binks@menzies.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Our current ethics approval does not support this.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.