Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618000489291
Ethics application status
Approved
Date submitted
9/03/2018
Date registered
4/04/2018
Date last updated
11/02/2021
Date data sharing statement initially provided
11/02/2021
Date results information initially provided
11/02/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Live versus heat-inactivated probiotic strains in preterm infants: The Pro-Para study
Scientific title
Safety and efficacy of live versus heat-inactivated probiotic strains in preterm infants: a pilot randomized controlled trial
Secondary ID [1] 294293 0
None
Universal Trial Number (UTN)
Trial acronym
Pro-Para study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
preterm infants 306989 0
Condition category
Condition code
Diet and Nutrition 306084 306084 0 0
Other diet and nutrition disorders
Inflammatory and Immune System 306085 306085 0 0
Other inflammatory or immune system disorders
Reproductive Health and Childbirth 306148 306148 0 0
Childbirth and postnatal care

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Intervention: Heat inactivated parabiotic containing a mixture of 3 strains (B. breve M-16V, B. longum subsp. infantis M-63 and B. longum subsp. longum BB536 (1×109 of each strain per 1 g sachet: 3-strains group), Morinaga Milk Industries, Japan. The mixture is inactivated by exposing the culture tank to 90° C for 15min.

Dose administered:
Both live and para probiotic supplementation will be commenced orally after informed consent and when baby is ready to start on enteral feeds.
When enteral feeds < 50ml/kg/day, 1 ml (1.5 billion CFU) administered once daily
When enteral feeds > 50 ml/kg/day: 1 ml twice daily (3 billion CFU/ day) will be administered

Duration of administration: From commencement of enteral feeds till 37 completed weeks of gestation

Both the live and para probiotic lyophilized dried preparation will be reconstituted using sterile techniques with distilled water and mum's own breast milk (when available).

To check adherence to the intervention: The principal investigator will be responsible for ensuring adherence to trial protocol and will report any violations to the local ethics committee (Women and Newborn Health Ethics Research Committee).
Intervention code [1] 300590 0
Treatment: Other
Comparator / control treatment
Control: Live probiotic containing a mixture of identical 3 strains as above (B. breve M-16V, B. longum subsp. infantis M-63 and B. longum subsp. longum BB536 (1×109 of each strain per 1 g sachet: 3-strains group), Morinaga Milk Industries, Japan.


Dose administered:
Both live and para probiotic supplementation will be commenced orally after informed consent and when baby is ready to start on enteral feeds.
When enteral feeds < 50ml/kg/day, 1 ml (1.5 billion CFU) administered once daily
When enteral feeds > 50 ml/kg/day: 1 ml twice daily (3 billion CFU/ day) will be administered

Duration of administration: From commencement of enteral feeds till 37 completed weeks of gestation

Both the live and para probiotic lyophilized dried preparation will be reconstituted using sterile techniques with distilled water and mum's own breast milk (when available).

To check adherence to the intervention: The principal investigator (Gayatri Jape) will be responsible for ensuring adherence to trial protocol and will report any violations to the local ethics committee (Women and Newborn Health Ethics Research Committee).
Control group
Active

Outcomes
Primary outcome [1] 305121 0
Primary outcomes:
(1) Safety: Assessed by monitoring for (a) blood culture positive sepsis by the administered probiotic strains and (b) adverse effects such as abdominal distension, vomiting, and diarrhoea leading to cessation of the supplementation.

Timepoint [1] 305121 0
The duration of supplementation (from starting enteral feeds and probiotic product till 37 weeks completed gestational age)
Primary outcome [2] 305164 0
(2) Faecal calprotectin levels: Calprotectin an intestinal-specific biomarker and is elevated in different inflammatory bowel conditions including NEC. Hence we have selected it as a marker of intestinal inflammation, which is reduced by probiotic supplementation.
Timepoint [2] 305164 0
After 1 week and 3 weeks of commencement of supplementation with the live or para probiotic preparation.
Secondary outcome [1] 344251 0
Secondary laboratory based outcomes:
(a) Metagenomics: 16S ribosomal RNA (rRNA) for microbial diversity.
Timepoint [1] 344251 0
Stool samples will be collected at 1 and 3 weeks after commencement of supplementation
Secondary outcome [2] 344369 0
(b) Short chain fatty acids (SCFA): Probiotics may benefit the host via altering the luminal SCFA concentrations in the gut. Hence analysis of SCFA levels will be indicative of efficacy of the HI vs. live probiotic preparation.
Timepoint [2] 344369 0
SCFA levels will be analysed in the stool samples at 1 and 3 weeks after commencement of supplementation.
Secondary outcome [3] 344370 0
(c) Metabolomics: Metabolites in stool which are markers of inflammation will be measured 1 and 3 weeks in the stools after commencement of supplementation.
Timepoint [3] 344370 0
Metabolite profile in the stools samples will be analysed after 1 and 3 weeks of commencement of supplementation.
Secondary outcome [4] 344371 0
(d) Faecal cytokine levels (e.g.; TNF alpha): Cytokines play a predominant role in immune and inflammatory reactions in inflammatory bowel disease such as NEC. Cytokines produced locally as a result of gut inflammation may leak into the bowel lumen and appear in the stools.
Timepoint [4] 344371 0
Faecal cytokine levels will be analysed in the stool samples at 1 and 3 weeks after commencement of supplementation.
Secondary outcome [5] 344372 0
(e) Composite outcome of gut barrier integrity and urinary lactose: mannitol ratio (sugar absorption test)
Timepoint [5] 344372 0
checked 1 and 3 weeks after commencement of supplementation
Secondary outcome [6] 344373 0
(f) Intestinal transit time (ITT): Whole gut transit time will be assessed by measuring the time to appearance of Carmine red dye in the stools after orogastric administration, using a method validated for use in preterm neonates.
Timepoint [6] 344373 0
Carmine red dye will be administered 3 weeks after commencement of supplementation of the live or para probiotic. Intestinal transit time will be indicated when the red dye is first noticed in stools.
Secondary outcome [7] 344374 0
Secondary clinical outcomes:
NEC (from clinical notes and discussion with the clinical team)
Timepoint [7] 344374 0
From recruitment in the trial till completion of protocol at 37 corrected weeks of gestational age.
Secondary outcome [8] 344767 0
All cause mortality (clinical notes)
Timepoint [8] 344767 0
from recruitment in the trial till 37 corrected weeks of gestation
Secondary outcome [9] 344769 0
NEC related mortality (clinical notes)
Timepoint [9] 344769 0
from recruitment in the trial till 37 corrected weeks of gestation
Secondary outcome [10] 344770 0
time to full feeds (150 ml/kg/day), collected from clinical notes and observation charts
Timepoint [10] 344770 0
from recruitment in the trial till 37 corrected weeks of gestation
Secondary outcome [11] 344772 0
duration of parenteral nutrition, collected from clinical notes
Timepoint [11] 344772 0
from recruitment in the trial till 37 corrected weeks of gestation
Secondary outcome [12] 344774 0
duration of hospital stay, collected from clinical notes
Timepoint [12] 344774 0
from recruitment in the trial till discharge from the hospital
Secondary outcome [13] 344775 0
suspected and blood culture positive LOS, collected from clinical notes and pathology results database
Timepoint [13] 344775 0
from recruitment in the trial till 37 corrected weeks of gestation

Eligibility
Key inclusion criteria
Eligibility criteria: (1) Gestation <32 weeks at birth (2) ready to commence on feeds or on feeds for less than or equal to 12 hours (3) Informed parental consent
Minimum age
1 Hours
Maximum age
7 Days
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria: (1) Congenital malformations (2) Chromosomal aberrations (3) Not ready for feeds or on feeds for >12 hours

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)
Allocation concealment: Opaque, sealed, coded envelopes will be used for allocation concealment. Neonates of multiple pregnancies will be considered as separate individuals.
This will be optimised by prescribing allocation only after informed parental consent and recording the basic neonatal data.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation: Group assignment will be allocated by a computer generated randomisation sequence in randomly ordered block sizes of 2 and 4.
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
Pilot trial
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Based on the data by Pergialiotis et al, the conservative assumption of unequal variance was made for the sample calculations due to the reported variability in faecal calprotectin levels, and recruitment of 70 infants (35 per arm) is estimated to be adequate for detecting one pooled standard deviation difference in faecal calprotectin levels (mg/ml) between the two arms of the trial, based on the null hypothesis that both group means are zero with standard deviation of one, with power=80% and alpha=0.05 when using a two-sided two-sample unequal-variance t-test (PASS Power and Sample Size Program, version 15).

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
20/08/2018
Actual
10/12/2018
Date of last participant enrolment
Anticipated
31/01/2019
Actual
30/09/2019
Date of last data collection
Anticipated
30/08/2019
Actual
30/04/2020
Sample size
Target
70
Accrual to date
Final
91
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 10362 0
King Edward Memorial Hospital - Subiaco
Recruitment postcode(s) [1] 22033 0
6008 - Subiaco

Funding & Sponsors
Funding source category [1] 298940 0
Charities/Societies/Foundations
Name [1] 298940 0
Women and Infant's Research Foundation
Country [1] 298940 0
Australia
Primary sponsor type
Hospital
Name
King Edward Memorial Hospital
Address
374 Bagot road, Subiaco, Perth, WA, 6008
Country
Australia
Secondary sponsor category [1] 298152 0
None
Name [1] 298152 0
Address [1] 298152 0
Country [1] 298152 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299877 0
Women and Newborn Health Research Ethics Committee
Ethics committee address [1] 299877 0
King Edward Memorial Hospital
374 Bagot road, Subiaco, WA, 6008
Ethics committee country [1] 299877 0
Australia
Date submitted for ethics approval [1] 299877 0
06/03/2018
Approval date [1] 299877 0
04/04/2018
Ethics approval number [1] 299877 0

Summary
Brief summary
Background
Probiotics significantly reduce the risk of death, and serious complications (e.g. necrotising enterocolitis- an inflammatory bowel condition with high risk of death and disability, and hospital acquired infections), and improve nutrition in premature babies. However, despite the overwhelming evidence, acceptance of probiotics as a standard of care for premature babies has been slow considering the associated risks including infection due to probiotic bacteria, development of antibiotic resistance, and altered immune responses.
Emerging evidence indicates that heat inactivated/killed probiotic bacteria (‘Paraprobiotics’) may provide a safe and effective alternative to probiotics (live bacteria) by overcoming their risks while retaining their benefits.
Objectives
The objectives of our novel pilot study comparing paraprobiotic vs. probiotic focus on finding a safe and effective alternative to probiotics. Results of our study have the potential to guide research on paraprobiotics for reducing death and disability in a wide range of population across the world (e.g. mature infants with surgical conditions of the intestine, children with inflammatory bowel disease, and immunocompromised adults) where probiotics are not used or evaluated due to their risks.
Trial plan
This pilot double blinded randomized controlled trial will be conducted over a period of 12-18 months (May 2018- November 2019) at King Edward Memorial Hospital. Very preterm infants < 32 weeks with specified inclusion and exclusion criteria will be recruited. Approval will be obtained from the KEMHW ethics committee. Therapeutic Goods Administration (TGA) and Clinical Trial Notification (CTN) approval will be obtained for importing the live and heat inactivated/killed probiotics from Japan. The trial protocol will be registered with the Australia New Zealand Clinical Trial Registry. Specified primary and secondary outcomes (clinical and laboratory based) will be measured.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 81838 0
Prof Sanjay Patole
Address 81838 0
Neonatal Directorate
King Edward Memorial Hospital
374 Bagot road, Subiaco, Perth, WA, 6008
Country 81838 0
Australia
Phone 81838 0
+61864581258
Fax 81838 0
Email 81838 0
sanjay.patole@health.wa.gov.au
Contact person for public queries
Name 81839 0
Dr Gayatri Jape
Address 81839 0
Neonatal Directorate
King Edward Memorial Hospital
374 Bagot road, Subiaco, Perth, WA, 6008
Country 81839 0
Australia
Phone 81839 0
+61413441501
Fax 81839 0
Email 81839 0
gayatri.jape@health.wa.gov.au
Contact person for scientific queries
Name 81840 0
Prof Sanjay Patole
Address 81840 0
Neonatal Directorate
King Edward Memorial Hospital
374 Bagot road, Subiaco, Perth, WA, 6008
Country 81840 0
Australia
Phone 81840 0
+61864581258
Fax 81840 0
Email 81840 0
sanjay.patole@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
At present we have not obtained HREC approval for data sharing. Once we have more published evidence in our population of interest and collate information from systematic reviews, we will review this approval.


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.