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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
Scientific title
Dose-response study of probiotics in sick term and late preterm infants:
the PRINS-2 trial
Secondary ID [1] 313386 0
none
Universal Trial Number (UTN)
Trial acronym
PRINS 2
Linked study record

Health condition
Health condition(s) or problem(s) studied:
critical illness 335753 0
hypoxic ischaemic encephalopathy 335754 0
feed intolerance 335756 0
meconium aspiration syndrome 335905 0
persistent pulmonary hypertension of newborn 335906 0
sepsis 335907 0
gastroschisis 335908 0
congenital diaphragmatic hernia 335909 0
tracheoesophageal fistula 335910 0
Condition category
Condition code
Diet and Nutrition 332309 332309 0 0
Other diet and nutrition disorders
Reproductive Health and Childbirth 332310 332310 0 0
Complications of newborn
Surgery 332311 332311 0 0
Other surgery

Intervention/exposure
Study type
Interventional
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.

Intervention code [1] 329963 0
Treatment: Drugs
Comparator / control treatment
No probiotic group
Control group
Active

Outcomes
Primary outcome [1] 339886 0
the sum of relative abundance of potentially pathogenic families Enterococcaceae, Enterobacteriaceae, Pseudomonaceae, Yersiniaceae, Staphylococcaceae and Clostridiaceae
Timepoint [1] 339886 0
after one week of supplementation
Secondary outcome [1] 441776 0
The sum of relative abundance of potentially pathogenic families Enterococcaceae, Enterobacteriaceae, Pseudomonaceae, Yersiniaceae, Staphylococcaceae and Clostridiaceae
Timepoint [1] 441776 0
2, 3 and 4 weeks of supplementation.
Secondary outcome [2] 441777 0
The relative abundance of gamma-proteobacteria (known to contain many pathogenic gram-negative bacteria) in stool samples.
Timepoint [2] 441777 0
1, 2, 3 and 4 weeks of supplementation
Secondary outcome [3] 441778 0
Relative abundance of Bifidobacteriaceae
Timepoint [3] 441778 0
1, 2, 3 and 4 weeks after the supplementation
Secondary outcome [4] 441779 0
Faecal short chain fatty acid (SCFA) levels of stool samples
Timepoint [4] 441779 0
1, 2, 3 and 4 weeks of supplementation
Secondary outcome [5] 441780 0
Time to full feeds of 120 ml/kg/day (tolerating for three consecutive days),
Timepoint [5] 441780 0
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
Secondary outcome [6] 441781 0
all-cause mortality
Timepoint [6] 441781 0
Incidence of death during the duration NICU stay
Secondary outcome [7] 441782 0
Healthcare associated blood stream infections. This will be assessed as a composite outcome.
Timepoint [7] 441782 0
Incidence of health care associated blood stream infections during the duration of NICU stay
Secondary outcome [8] 441783 0
healthcare associated infections. This will be assessed as a composite outcome.
Timepoint [8] 441783 0
Incidence of healthcare associated infections during the duration of NICU stay
Secondary outcome [9] 441784 0
duration of parenteral nutrition
Timepoint [9] 441784 0
Number of days of parenteral nutrition during the duration of NICU stay
Secondary outcome [10] 441785 0
anthropometry at discharge
Timepoint [10] 441785 0
at discharge
Secondary outcome [11] 441786 0
Postnatal growth restriction
Timepoint [11] 441786 0
At discharge
Secondary outcome [12] 441787 0
Sepsis due to the administered bifidobacterial strains
Timepoint [12] 441787 0
Incidence of sepsis due to the administered bifidobacterial strain during the duration of NICU stay

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.
Minimum age
0 Days
Maximum age
4 Weeks
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Neonates with acquired surgical conditions such as necrotizing enterocolitis (NEC).

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)
Yes, using web-based central randomisation
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).
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
9/12/2024
Actual
Date of last participant enrolment
Anticipated
31/07/2026
Actual
Date of last data collection
Anticipated
31/12/2026
Actual
Sample size
Target
108
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA

Funding & Sponsors
Funding source category [1] 317827 0
University
Name [1] 317827 0
University of Western Australia
Country [1] 317827 0
Australia
Primary sponsor type
Government body
Name
Child and Adolescent health Service
Address
Country
Australia
Secondary sponsor category [1] 320156 0
None
Name [1] 320156 0
none
Address [1] 320156 0
Country [1] 320156 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 316514 0
Child and Adolescent Health Service Human Research Ethics Committee
Ethics committee address [1] 316514 0
Ethics committee country [1] 316514 0
Australia
Date submitted for ethics approval [1] 316514 0
01/08/2024
Approval date [1] 316514 0
27/09/2024
Ethics approval number [1] 316514 0

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

Contacts
Principal investigator
Name 138122 0
Prof Shripada Rao
Address 138122 0
Neonatal Intensive Care Unit, Perth Children's Hospital, 15 Hospital Avenue Nedlands Western Australia 6009
Country 138122 0
Australia
Phone 138122 0
+61 8 64568645
Fax 138122 0
Email 138122 0
Shripada.Rao@health.wa.gov.au
Contact person for public queries
Name 138123 0
Shripada Rao
Address 138123 0
Neonatal Intensive Care Unit, Perth Children's Hospital, 15 Hospital Avenue Nedlands Western Australia 6009
Country 138123 0
Australia
Phone 138123 0
+61 8 64568645
Fax 138123 0
Email 138123 0
Shripada.Rao@health.wa.gov.au
Contact person for scientific queries
Name 138124 0
Shripada Rao
Address 138124 0
Neonatal Intensive Care Unit, Perth Children's Hospital, 15 Hospital Avenue Nedlands Western Australia 6009
Country 138124 0
Australia
Phone 138124 0
+61 8 64568645
Fax 138124 0
Email 138124 0
Shripada.Rao@health.wa.gov.au

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.