Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620001369910
Ethics application status
Approved
Date submitted
26/10/2020
Date registered
21/12/2020
Date last updated
21/12/2020
Date data sharing statement initially provided
21/12/2020
Type of registration
Retrospectively registered

Titles & IDs
Public title
The IMPROVE trial: IMpact of PRObiotic interVEntion in Papua New Guinean newborns.
Scientific title
IMpact of PRObiotic interVEntion in Papua New Guinean newborns (IMPROVE): A double-blinded randomized-controlled clinical trial to determine the feasibility and safety, and possible beneficial impact on nasopharyngeal colonization and vaccine immunity, of probiotics supplementation in Papua New Guinean newborns.
Secondary ID [1] 302627 0
Bill & Melinda Gates Foundation Investment ID OPP1203918
Universal Trial Number (UTN)
Trial acronym
IMPROVE: IMpact of PRObiotic interVEntion in Papua New Guinean newborns.
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Clinical severe infection 319524 0
pneumococcal infection 319525 0
Condition category
Condition code
Infection 317475 317475 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Synbiotic 1, daily dose for 7 days (starting < 72 hours after birth):
Lactobacillus plantarum ATCC 202195 (1 billion CFU) combined with 150 mg fructo-oligosaccharide (FOS) with maltodextrin as excipient.

Synbiotic 2, daily dose for 7 days (starting < 72 hours after birth):
Bifidobacterium longum subspecies infantis (Bi-26) (4.2 billion CFU) combined with human oligosaccharide (HMO) (1.2 g) with maltodextrin as excipient.

Both supplements (investigational products) are supplied as lyophilized products in glass vials (one vial contains a single daily dose), and are reconstituted in 3 mL of breast milk expressed by the mother shortly before administration, or in 3 mL of sterile water if the mother cannot express.
The full dose (3 mL suspension) is administered orally in droplets (like the oral polio vaccine) using a sterile pipette by a research nurse. The volume administered (full dose, or volume if less than 3 mL) will be recorded. Infants will be monitored for 30 min and a repeat dose will be administered if an infant vomits within this observation period.
Intervention code [1] 318914 0
Prevention
Comparator / control treatment
Control group:
Potato maltodextrin, daily for 7 days (starting < 72 hours after birth)

To keep blinding, placebo is supplied as lyophilized product in the same glass vials as the investigational products (one vial contains a single daily dose), and is reconstituted and administered similar to the IPs.
Control group
Placebo

Outcomes
Primary outcome [1] 325510 0
Safety in terms of intolerance (diarrhoea, vomiting, abdominal distension, and weight gain) or probiotic sepsis during the supplementation period, leading to cessation of the study medication;

Children will be checked daily for:
- Vital signs including body temperature, pulse and respiratory rate
- Presence of of signs/symptoms of severe infection (incl. poor feeding; lethargy; fever; hypothermia; convulsions; severe chest wall in-drawing)
- Other clinical signs and symptoms of illness (incl. diarrhoea; vomiting; respiratory distress; infected umbilicus; jaundice; skin rashes/pustules; apnoea)
- Seeking medical attention (hospitalization; seeing a doctor)



Timepoint [1] 325510 0
24 hours after last day (day 7) of 7-day schedule of once-daily supplementation
Primary outcome [2] 325511 0
Feasibility of daily probiotic administration as measured by the proportion of children who successfully completed 7 days of the full daily supplementation (7 out of 7).

Research staff will administer the daily dose, record the volume administered (full 3 mL dose, or less), and monitor the infant for 30 min for vomiting.
Timepoint [2] 325511 0
Last day (day 7) of 7-day schedule of once-daily supplementation
Secondary outcome [1] 388248 0
Gut colonisation by probiotic species & strains as measured and quantified by rt-PCR in rectal swabs
Timepoint [1] 388248 0
Rectal swabs will be collected on the day of the 1st dosing (< 72 hours old) just before administration, on the day of the last dose (8-10 days old), and when the child is 2 weeks old.
Secondary outcome [2] 388249 0
Hospitalization rates

Study children admitted to Goroka Hospital Pediatric Ward (the only tertiary facility in the Province) will undergo clinical assessment and examination by the admitting pediatric team. Study staff will check the ward for study children at least once daily. Detailed study morbidity forms will be completed to record symptoms, diagnosis and treatments,


Timepoint [2] 388249 0
Children will be followed for the duration of the study until they are 6 months of age
Secondary outcome [3] 388250 0
Nasopharyngeal carriage of S. pneumoniae and other respiratory bacteria, as assessed by routine bacterial culture and rt-PCR of isolates obtained from routinely collected nasopharyngeal swabs
Timepoint [3] 388250 0
Nasopharyngeal swabs will be collected when children are 2 weeks and 1 month old (after completion of the intervention but before pneumococcal vaccination), and 4 months old (1 month after completion of 3 doses of pneumococcal conjugate vaccines).
Secondary outcome [4] 388251 0
Immunogenicity of childhood vaccines, including pneumococcal conjugate vaccine (PCV), Diphtheria, Tetanus and Pertussis (DTwP) vaccines, as assessed by IgG antibody concentrations against vaccine antigens measured by immuno-assays in serum samples.
Timepoint [4] 388251 0
Serum samples will be collected when children are 1 month old (before DTwP and PCV vaccination) and 4 months old (1 month after completion of 3 doses of DTwP and PCV).
Secondary outcome [5] 388252 0
Mucosal IgA and IgG antibody responses induced by pneumococcal conjugate vaccine (PCV) measured in saliva 1 month after the 3rd dose
Timepoint [5] 388252 0
Saliva samples will be collected when children are 1 month old (before PCV vaccination) and 4 months old (1 month after completion of 3 doses of PCV).
Secondary outcome [6] 388253 0
Kinetics of colonization with probiotics species & strains as measured and quantified by rt-PCR in rectal swabs for the duration of the study up to 6 months of age
Timepoint [6] 388253 0
In addition to rectal swabs collected for Secondary Outcome #1 to show gut colonization, additional samples will be collected when children are 1 month, 3 months, 4 months, and 6 months old to study kinetics of colonization
Secondary outcome [7] 388254 0
Rate of clinical severe infections

Children presenting sick to the study clinic or hospital will checked for signs/symptoms of clinical severe infection, including: poor feeding; lethargy; convulsions; severe chest in-drawing; fever; and/or hypothermia.
When having any of the signs/symptoms, samples for septic work-up will be collected and processed for clinical microbiology, including blood for culture; urine; nasopharyngeal swab; rectal swab; and based on clinical indication optionally CSF; umbilical swab; skin swab; ear discharge; and/or eye swab.

Severe clinical infection is defined by having at least one of the listed symptoms/signs, and a positive sterile site culture or hospitalization with the intention to treat with parental antibiotics for at least 5 days.
Timepoint [7] 388254 0
Children will be followed for the duration of the study until they are 6 months of age

Eligibility
Key inclusion criteria
- Birth weight of at least 1.5 kg
- Postnatal age of less than 72 hours
- Feeding orally
- Resident within 60-minute driving distance from Institute of Medical Research, Goroka
- Intention to stay in the study area for at least 6 months
- Parental written informed consent
Minimum age
0 Hours
Maximum age
72 Hours
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
- Mother has foul smelling amniotic fluid
- Heavy meconium staining of amniotic fluid (thick with dark green particulate matter)
- Mother has fever (more than 38°C) within 2 days before delivery
- Infant received antibiotics
- Infant shows any feature of suspected infection at the time of screening
- Infant has major congenital abnormality
- Mother known to be HIV positive, or unknown status

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)
An allocation list has been prepared by the supplier that allocates numbered boxes (containing vials for 7 days of intervention) to consecutively enrolled participants.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Sample sizes of n=50 per group are estimated to achieve ~90% power to detect the colonisation rate of 30% in the intervention versus 5% in the placebo groups when using a two-sided test of proportions with continuity correction at 5% significance level. The final sample size of 65 per group takes into account 10% loss of follow-up and difficulties in collecting timely biosamples.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
29/10/2020
Date of last participant enrolment
Anticipated
31/10/2021
Actual
Date of last data collection
Anticipated
30/04/2022
Actual
Sample size
Target
195
Accrual to date
4
Final
Recruitment outside Australia
Country [1] 23076 0
Papua New Guinea
State/province [1] 23076 0
Goroka, Eastern Highland Province

Funding & Sponsors
Funding source category [1] 307058 0
Charities/Societies/Foundations
Name [1] 307058 0
Bill & Melinda Gates Foundation
Country [1] 307058 0
United States of America
Funding source category [2] 307061 0
Other Collaborative groups
Name [2] 307061 0
Immunising pregnant women and infants (IMPRINT) Network
Country [2] 307061 0
United Kingdom
Primary sponsor type
Other Collaborative groups
Name
Telethon Kids Institute
Address
15 Hospital Avenue
Nedlands WA 6009
Country
Australia
Secondary sponsor category [1] 307626 0
None
Name [1] 307626 0
Address [1] 307626 0
Country [1] 307626 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307182 0
Papua New Guinea Institute of Medical Research Institute Review Board
Ethics committee address [1] 307182 0
Ethics committee country [1] 307182 0
Papua New Guinea
Date submitted for ethics approval [1] 307182 0
08/11/2018
Approval date [1] 307182 0
07/12/2018
Ethics approval number [1] 307182 0
1809
Ethics committee name [2] 307185 0
Papua New Guinean Medical Research Advisory Committee (MRAC)
Ethics committee address [2] 307185 0
Ethics committee country [2] 307185 0
Papua New Guinea
Date submitted for ethics approval [2] 307185 0
11/12/2018
Approval date [2] 307185 0
07/01/2019
Ethics approval number [2] 307185 0
18.20

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

Contacts
Principal investigator
Name 106314 0
Dr Anita H.J. van den Biggelaar
Address 106314 0
Telethon Kids Institute
15 Hospital Avenue
Nedlands, WA 6009
Country 106314 0
Australia
Phone 106314 0
+61 8 6319 1281
Fax 106314 0
Email 106314 0
[email protected]
Contact person for public queries
Name 106315 0
Anita H.J. van den Biggelaar
Address 106315 0
Telethon Kids Institute
15 Hospital Avenue
Nedlands, WA 6009
Country 106315 0
Australia
Phone 106315 0
+61 8 6319 1281
Fax 106315 0
Email 106315 0
[email protected]
Contact person for scientific queries
Name 106316 0
Anita H.J. van den Biggelaar
Address 106316 0
Telethon Kids Institute
15 Hospital Avenue
Nedlands, WA 6009
Country 106316 0
Australia
Phone 106316 0
+61 8 6319 1281
Fax 106316 0
Email 106316 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


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.