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Trial registered on ANZCTR
Registration number
ACTRN12624001428550
Ethics application status
Approved
Date submitted
15/11/2024
Date registered
6/12/2024
Date last updated
6/12/2024
Date data sharing statement initially provided
6/12/2024
Type of registration
Prospectively registered
Titles & IDs
Public title
Dose-response study of probiotics in sick term and late preterm infants:
the PRINS-2 trial
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Scientific title
Dose-response study of probiotics in sick term and late preterm infants:
the PRINS-2 trial
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Secondary ID [1]
313386
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none
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Universal Trial Number (UTN)
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Trial acronym
PRINS 2
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
feed intolerance
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persistent pulmonary hypertension of newborn
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congenital diaphragmatic hernia
335909
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critical illness
335753
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hypoxic ischaemic encephalopathy
335754
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sepsis
335907
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gastroschisis
335908
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meconium aspiration syndrome
335905
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tracheoesophageal fistula
335910
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Condition category
Condition code
Diet and Nutrition
332309
332309
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0
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Other diet and nutrition disorders
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Reproductive Health and Childbirth
332310
332310
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0
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Complications of newborn
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Surgery
332311
332311
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0
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Other surgery
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Probiotic mixture containing B. breve M-16V, B. longum subsp. infantis M-63, and B. longum subsp. longum BB536 (3x109 CFU per sachet), manufactured and supplied by Morinaga Milk Industries, Japan)
Study infants will receive different dosage regimen of probiotic supplement as described below:
3 billion Colony-Forming Unit (CFU) daily (ONE sachet once a day)
6 billion CFU daily (ONE sachet twice a day)
9 billion CFU daily (ONE sachet three times a day)
Duration: until discharge from NICU
Route: oral or via feeding tube. Each Sachet (3x109 CFU per sachet) will be reconstituted with 1.5mL of water or breast milk or formula milk and then given once or twice or three times a day. The oral route of administration will be achieved by drawing the reconstituted trial supplement in a two ml syringe and administered immediately into the infant's mouth.
we will assess adherence to the intervention by filling out an accountability record in addition to the review of medical records.
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Intervention code [1]
329963
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Treatment: Drugs
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Comparator / control treatment
No probiotic group
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Control group
Active
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Outcomes
Primary outcome [1]
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the sum of relative abundance of potentially pathogenic families Enterococcaceae, Enterobacteriaceae, Pseudomonaceae, Yersiniaceae, Staphylococcaceae and Clostridiaceae
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Assessment method [1]
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Short read whole genome sequencing of stool samples
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Timepoint [1]
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after one week of supplementation
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Secondary outcome [1]
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The sum of relative abundance of potentially pathogenic families Enterococcaceae, Enterobacteriaceae, Pseudomonaceae, Yersiniaceae, Staphylococcaceae and Clostridiaceae
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Assessment method [1]
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Short read whole genome sequencing of stool samples.
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Timepoint [1]
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2, 3 and 4 weeks of supplementation.
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Secondary outcome [2]
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Time to full feeds of 120 ml/kg/day (tolerating for three consecutive days),
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Assessment method [2]
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medical records
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Timepoint [2]
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This is a number of days to reach full feeds during the Neonatal Intensive care Unit (NICU) stay. Assessed daily until full feeds have been reached during the Neonatal Intensive care Unit (NICU) stay
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Secondary outcome [3]
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Relative abundance of Bifidobacteriaceae
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Assessment method [3]
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Short read whole genome sequencing of stool samples
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Timepoint [3]
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1, 2, 3 and 4 weeks after the supplementation
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Secondary outcome [4]
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duration of parenteral nutrition
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Assessment method [4]
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medical records
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Timepoint [4]
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Number of days of parenteral nutrition during the duration of NICU stay
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Secondary outcome [5]
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Sepsis due to the administered bifidobacterial strains
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Assessment method [5]
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medical records
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Timepoint [5]
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Incidence of sepsis due to the administered bifidobacterial strain during the duration of NICU stay
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Secondary outcome [6]
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Faecal short chain fatty acid (SCFA) levels of stool samples
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Assessment method [6]
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modified gas chromatography–mass spectrometry
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Timepoint [6]
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1, 2, 3 and 4 weeks of supplementation
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Secondary outcome [7]
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all-cause mortality
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Assessment method [7]
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Medical records
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Timepoint [7]
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Incidence of death during the duration NICU stay
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Secondary outcome [8]
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anthropometry at discharge
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Assessment method [8]
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medical records
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Timepoint [8]
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at discharge
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Secondary outcome [9]
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The relative abundance of gamma-proteobacteria (known to contain many pathogenic gram-negative bacteria) in stool samples.
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Assessment method [9]
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Short read whole genome sequencing
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Timepoint [9]
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1, 2, 3 and 4 weeks of supplementation
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Secondary outcome [10]
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healthcare associated infections. This will be assessed as a composite outcome.
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Assessment method [10]
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Medical records
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Timepoint [10]
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Incidence of healthcare associated infections during the duration of NICU stay
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Secondary outcome [11]
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Postnatal growth restriction
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Assessment method [11]
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a difference worse than -0.8 in z scores between discharge and at one-week anthropometry. using medical records
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Timepoint [11]
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At discharge
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Secondary outcome [12]
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Healthcare associated blood stream infections. This will be assessed as a composite outcome.
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Assessment method [12]
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medical records
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Timepoint [12]
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Incidence of health care associated blood stream infections during the duration of NICU stay
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Eligibility
Key inclusion criteria
Infants will be eligible for study inclusion it they meet both the following inclusion criteria: >=35 weeks of gestational age with critical illness AND informed parental consent.
The infant should meet at least one of the following criteria to be deemed having critical illness:
• Need for mechanical ventilation
• Use of inotropic agents
• Persistent pulmonary hypertension of the newborn (PPHN), requiring inhaled nitric oxide or other pulmonary vasodilators
• Moderate to severe hypoxic-ischaemic encephalopathy (HIE) based on modified Sarnat or Thompson classification, requiring therapeutic hypothermia
• Neonatal sepsis (early or late): early-onset sepsis to be defined as sepsis within the first 72 hours of birth, and late-onset sepsis as sepsis after 72 hours of birth.
• Surgery under general anaesthesia for gastrointestinal or other anomalies: Oesophageal atresia, gastroschisis, exomphalos, congenital diaphragmatic hernia, malrotation, congenital duodenal obstruction, small intestinal atresia, colon atresia, Hirschsprung Disease, microcolon, anorectal anomalies. Other surgical conditions such as thoracic and renal will be included if their expected duration of hospital stay is more than two weeks. Infants with cardiac surgical conditions will be excluded since they are a critically high-risk group and will be moving between NICU, Paediatric Intensive Care Unit (PICU) and ward on a routine basis.
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Minimum age
0
Days
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Maximum age
4
Weeks
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
Neonates with acquired surgical conditions such as necrotizing enterocolitis (NEC).
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Yes, using web-based central randomisation
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Yes, using minimisation
In order to achieve adequate matching in important baseline characters between the groups, we will use randomisation by minimisation. With minimization, the first subjects are enrolled randomly into one of the four groups. The subsequent subjects will be allocated to treatment groups after hypothetical allocation of each subject to every group and then calculating an imbalance score. Using these imbalance scores, it will be decided to which group the new subject must be allocated, to have the minimum amount of imbalance, in terms of prognostic factors. The following variables will be taken into consideration during the minimization process: gestational age, caesarean section, medical/surgical and score for neonatal acute physiology with perinatal extension II (SNAPPE II) score (<=20 or >20).
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 2
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Type of endpoint/s
Safety/efficacy
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Statistical methods / analysis
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Recruitment
Recruitment status
Not yet recruiting
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Date of first participant enrolment
Anticipated
9/12/2024
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Actual
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Date of last participant enrolment
Anticipated
31/07/2026
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Actual
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Date of last data collection
Anticipated
31/12/2026
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Actual
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Sample size
Target
108
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Accrual to date
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Final
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Recruitment in Australia
Recruitment state(s)
WA
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Funding & Sponsors
Funding source category [1]
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University
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Name [1]
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University of Western Australia
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Address [1]
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Country [1]
317827
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Australia
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Primary sponsor type
Government body
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Name
Child and Adolescent health Service
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Address
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Country
Australia
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Secondary sponsor category [1]
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None
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Name [1]
320156
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none
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Address [1]
320156
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Country [1]
320156
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Ethics approval
Ethics application status
Approved
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Ethics committee name [1]
316514
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Child and Adolescent Health Service Human Research Ethics Committee
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Ethics committee address [1]
316514
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https://cahs.health.wa.gov.au/Research/For-researchers/Ethics-and-governance-approval
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Ethics committee country [1]
316514
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Australia
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Date submitted for ethics approval [1]
316514
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01/08/2024
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Approval date [1]
316514
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27/09/2024
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Ethics approval number [1]
316514
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Summary
Brief summary
This research is about finding the optimal dosage of probiotics for sick newborn babies with gestational age greater or equal to 35 weeks, admitted to Neonatal Intensive Care Unit (NICU) of Perth Children’s Hospital. Their sickness could have been either due to a medical illness or a surgical condition. We will find out if a dose higher than 3 billion probiotic bacteria per day reduces the load of harmful bacteria and increases the load of beneficial bacteria in their gut. We will measure the gut bacteria by examining their stool (poo) samples using sophisticated laboratory investigations. Specifically, we will compare the dose of 3 billion bacteria against doses of either 6 or 9 billion bacteria per day. We think that babies who receive higher dose of probiotics will have better intestinal bacteria profile and better overall health.
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Trial website
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Prof Shripada Rao
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Address
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Neonatal Intensive Care Unit, Perth Children's Hospital, 15 Hospital Avenue Nedlands Western Australia 6009
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Country
138122
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Australia
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Phone
138122
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+61 8 64568645
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Fax
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Email
138122
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[email protected]
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Contact person for public queries
Name
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Shripada Rao
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Address
138123
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Neonatal Intensive Care Unit, Perth Children's Hospital, 15 Hospital Avenue Nedlands Western Australia 6009
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Country
138123
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Australia
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Phone
138123
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+61 8 64568645
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Fax
138123
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Email
138123
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[email protected]
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Contact person for scientific queries
Name
138124
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Shripada Rao
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Address
138124
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Neonatal Intensive Care Unit, Perth Children's Hospital, 15 Hospital Avenue Nedlands Western Australia 6009
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Country
138124
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Australia
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Phone
138124
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+61 8 64568645
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Fax
138124
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Email
138124
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[email protected]
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Data sharing statement
Will the study consider sharing individual participant data?
No
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.
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