Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12612000503820
Ethics application status
Approved
Date submitted
8/05/2012
Date registered
9/05/2012
Date last updated
3/05/2023
Date data sharing statement initially provided
30/04/2019
Date results information initially provided
30/04/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Can omega 3 fatty acids improve respiratory outcomes in preterm infants?
Scientific title
In preterm infants born at <29 weeks gestation is an emulsion containing a higher amount of docosahexaenoic acid (DHA) more effective than an emulsion with no additional DHA in reducing the incidence of bronchopulmonary dysplasia at 36 weeks post menstrual age?
Secondary ID [1] 280400 0
Nil
Universal Trial Number (UTN)
U1111-1130-2355
Trial acronym
N3RO (n-3 fatty acids for improvement of respiratory outcomes)
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Preterm infants 286377 0
Bronchopulmonary dysplasia 286378 0
Condition category
Condition code
Respiratory 286619 286619 0 0
Other respiratory disorders / diseases
Reproductive Health and Childbirth 286697 286697 0 0
Complications of newborn

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Tuna oil emulsion containing 120 mg/mL of DHA to provide 60 mg/kg/day of DHA (0.17 ml/kg three times a day). The intervention will be given enterally within 72 hours of the first enteral feed and continue until 36 weeks post menstrual age or discharge home (whichever occurs first).
Intervention code [1] 284759 0
Prevention
Comparator / control treatment
Soy oil emulsion with no additional DHA given at 0.17 mL/kg three times a day. The control will be given enterally within 72 hours of the first enteral feed and continue until 36 weeks post menstrual age or discharge home (whichever occurs first).
Control group
Placebo

Outcomes
Primary outcome [1] 287083 0
The primary outcome bronchopulmonary dysplasia will be defined on a physiologic basis that combines oxygen and ventilation support with an assessment of saturation.
Timepoint [1] 287083 0
The diagnosis of bronchopulmonary dysplasia will be determined at 36 weeks postmenstrual age (36 weeks and 0 days to 36 weeks and 6 days inclusive) or day of discharge home, whichever occurs first.
Primary outcome [2] 332334 0
Intelligence, as reflected by a Full Scale Intelligence Quotient score.
Overall intelligence will be assessed by a psychologist using the Wechsler Preschool and Primary Scale of Intelligence - Fourth Edition (WPPSI-IV) Australian and New Zealand Standardised Edition. A pre-defined subsample of n=707 children will be eligible to participate in the cognitive assessment. Children will be eligible if they have not died or withdrawn from the trial, and if were born and enrolled at the following centres 1. Women’s & Children’s Hospital 2. Royal Women’s Hospital 3. Mercy Hospital for Women 4. King Edward Memorial Hospital 5. John Hunter Hospital
Timepoint [2] 332334 0
5 years (corrected age)
Secondary outcome [1] 297334 0
Severity of bronchopulmonary dysplasia as defined by US National Institute of Child Health and Human Development/National Heart, Lung and Blood Institute/Office of Rare Diseases Workshop on Bronchopulmonary Dysplasia.
Timepoint [1] 297334 0
36 weeks postmenstrual age (36 weeks and 0 days to 36 weeks and 6 days inclusive) or day of discharge home, whichever occurs first.
Secondary outcome [2] 297335 0
Respiratory support requirements including the duration of respiratory support, the requirement for any supplemental oxygen or respiratory support and the use of steroids, caffeine or diuretics for lung disease.
Timepoint [2] 297335 0
36 weeks postmenstrual age (36 weeks and 0 days to 36 weeks and 6 days inclusive) or day of discharge home, whichever occurs first.
Secondary outcome [3] 297336 0
The safety and tolerability of DHA supplementation as assessed by number of days to full enteral feeds and number of days on which feeds were interrupted.
Timepoint [3] 297336 0
Up to 36 weeks postmenstrual age (36 weeks and 0 days to 36 weeks and 6 days inclusive) or day of discharge home, whichever occurs first.
Secondary outcome [4] 297337 0
The length of hospital stay, respiratory support requirements, growth rate, grade of intra-ventricular haemorrhage (IVH), confirmed sepsis, confirmed necrotising enterocolitis (NEC), grade of retinopathy of prematurity (ROP) and death.
Timepoint [4] 297337 0
Up to 40 weeks postmenstrual age or discharge home whichever occurs first; length of hospital stay will be calculated from birth to first hospital discharge
Secondary outcome [5] 313600 0
Attention (ability to resist distraction) and other aspects of attention in a side study to the N3RO trial.
A small subsample (n=80) of the N3RO trial children born at the Flinders Medical Centre and the Women's and Children's Hospital will be eligible inclusion in the side study for this secondary outcome. Assessments will take place when children reach 2 years corrected age (plus or minus 3 months) and will commence in March 2015.
Attention will be assessed with an exploratory measure used in the field of developmental psychology. Children will be given a series of toys to play with, whilst sitting on their caregivers lap. The toy-play will be videorecorded, so that their eye movements to and from the toys can be measured, as an indication of their attention to the toys.
Timepoint [5] 313600 0
2 years (corrected age) plus or minus 3 months
Secondary outcome [6] 319327 0
Composite outcome of death before 36 weeks postmenstrual age or bronchopulmonary dysplasia
Timepoint [6] 319327 0
36 weeks postmenstrual age or discharge home, whichever occurs first.
Secondary outcome [7] 339970 0
Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III): A psychologist-administered Cognitive Scale, Motor Scale and Language Scale are standardized according to (corrected) age to have mean of 100 and standard deviation of 15. The cognitive scale evaluates sensorimotor development, exploration and manipulation, object relatedness, concept formation, memory, and simple problem solving. The language scale is a composite of receptive communication (verbal comprehension, vocabulary) and expressive communication (babbling, gesturing, and utterances). The motor scale evaluates both gross and fine motor functioning.
Timepoint [7] 339970 0
approximately 24 months (corrected age)
Secondary outcome [8] 339971 0
Child behaviour as assessed by the Total Difficulties score of the Strengths and Difficulties Questionnaire via survey.
Timepoint [8] 339971 0
5 years (corrected age for premature birth)
Secondary outcome [9] 339972 0
Child behavioural manifestations of executive functioning as assessed by the Behaviour Rating Inventory of Executive Function-Preschool (BRIEF-P) via survey.
Timepoint [9] 339972 0
5 years (corrected age for premature birth)
Secondary outcome [10] 339974 0
General well-being as assessed by the PedsQL (Pediatric Quality of Life Inventory) via survey and paren- reported severe hearing loss, blindness, respiratory-related hospital admissions
Timepoint [10] 339974 0
5 years (corrected age for premature birth)
Secondary outcome [11] 347204 0
Child cognitive abilities will be assessed by a psychologist using the Wechsler Preschool and Primary Scale of Intelligence - Fourth Edition (WPPSI-IV) Australian and New Zealand Standardised Edition. A pre-defined subsample of n=707 children will be eligible to participate in the cognitive assessment. Children will be eligible if they have not died or withdrawn from the trial, and if were born and enrolled at the following centres 1. Women’s & Children’s Hospital 2. Royal Women’s Hospital 3. Mercy Hospital for Women 4. King Edward Memorial Hospital 5. John Hunter Hospital.
Indices from the WPPSI-IV to be compared are Verbal Comprehension Composite, Fluid Reasoning Composite, Working Memory Composite, Processing Speed Index, General Ability Index, and Cognitive Proficiency Index.
Timepoint [11] 347204 0
5 years (corrected for preterm birth)
Secondary outcome [12] 347205 0
Study of Asthma and Allergies in Childhood (ISAAC) questionnaire via survey
Timepoint [12] 347205 0
5 years (corrected for preterm birth)
Secondary outcome [13] 347206 0
Executive functioning as measured with the Fruit Stroop test.
A pre-defined subsample of n=707 children will be eligible to participate in the assessment. Children will be eligible if they have not died or withdrawn from the trial, and if were born and enrolled at the following centres
1. Women’s & Children’s Hospital
2. Royal Women’s Hospital
3. Mercy Hospital for Women
4. King Edward Memorial Hospital
5. John Hunter Hospital
Timepoint [13] 347206 0
5 years (corrected for preterm birth)

Eligibility
Key inclusion criteria
Born at less than 29 weeks gestational age
Within 3 days of commencing enteral feeds
Has a legally acceptable representative capable of understanding the informed consent document and providing consent on the infant’s behalf
Minimum age
No limit
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Infants who have a major congenital or chromosomal abnormality will be excluded from the study
Women providing breast milk who are taking supplements providing >250 mg DHA per day and do not wish to stop taking supplements.
Infants participating in another fatty acid study.
Infants receiving intravenous lipid emulsions containing fish oil given as early lipid parenteral nutrition support.

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)
Upon consent, infants will be randomised using a customised, purpose built web-based randomisation service. A unique study ID with a matching study pack will be assigned. Each study pack will contain either treatment or control emulsion, pre-packed according to the randomisation schedule.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A computer generated randomisation schedule using balanced variable block design will be generated by an independent statistician who is not involved with trial participants or data analysis. Stratification will occur for sex, study centre and gestational age less than 27 completed weeks and 27 to 28 completed weeks. Multiple births will be randomised individually.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
4/06/2012
Actual
12/07/2012
Date of last participant enrolment
Anticipated
Actual
30/09/2015
Date of last data collection
Anticipated
26/02/2021
Actual
22/05/2022
Sample size
Target
1244
Accrual to date
Final
1273
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA,VIC
Recruitment postcode(s) [1] 7604 0
2031 - Randwick
Recruitment postcode(s) [2] 7603 0
2170 - Liverpool
Recruitment postcode(s) [3] 5273 0
2310
Recruitment postcode(s) [4] 5269 0
3052
Recruitment postcode(s) [5] 5270 0
3084
Recruitment postcode(s) [6] 5271 0
3168
Recruitment postcode(s) [7] 12345 0
4101 - South Brisbane
Recruitment postcode(s) [8] 5268 0
5006
Recruitment postcode(s) [9] 5267 0
5042
Recruitment postcode(s) [10] 7602 0
6008 - Subiaco
Recruitment outside Australia
Country [1] 4094 0
New Zealand
State/province [1] 4094 0
Wellington
Country [2] 4095 0
Singapore
State/province [2] 4095 0
Country [3] 4096 0
New Zealand
State/province [3] 4096 0
Waikato

Funding & Sponsors
Funding source category [1] 285212 0
Government body
Name [1] 285212 0
National Health and Medical Research Council
Country [1] 285212 0
Australia
Funding source category [2] 299548 0
Charities/Societies/Foundations
Name [2] 299548 0
Women's and Children's Hospital Foundation
Country [2] 299548 0
Australia
Primary sponsor type
Other
Name
South Australian Health and Medical Research Institute
Address
72 King William Road
North Adelaide South Australia 5006
Country
Australia
Secondary sponsor category [1] 284084 0
None
Name [1] 284084 0
Address [1] 284084 0
Country [1] 284084 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 287213 0
Southern Adelaide Clinical Human Research Ethics Committee
Ethics committee address [1] 287213 0
Flinders Medical Centre
Flinders Drive
Bedford Park South Australia 5042
Ethics committee country [1] 287213 0
Australia
Date submitted for ethics approval [1] 287213 0
Approval date [1] 287213 0
21/03/2012
Ethics approval number [1] 287213 0
35.12
Ethics committee name [2] 306935 0
Women's and Children's Health Network Human Researach Ethics Committee
Ethics committee address [2] 306935 0
Women's and Children's Hospital,
72 King William Road, North Adelaide, South Australia, 5006
Ethics committee country [2] 306935 0
Australia
Date submitted for ethics approval [2] 306935 0
22/11/2017
Approval date [2] 306935 0
22/03/2018
Ethics approval number [2] 306935 0
HREC/17/WCHN/187

Summary
Brief summary
The purpose of this study is to determine the degree to which Docosahexaenoic acid (DHA) supplementation reduces the incidence of bronchopulomonary dysplasia (BPD), as assessed by the requirement for supplemental oxygen and/or assisted ventilation at 36 weeks post menstrual age.
Trial website
Trial related presentations / publications
Collins, C. T., Gibson, R. A., Makrides, M., McPhee, A. J., Sullivan, T. R., Davis, P. G., Thio, M., Simmer, K., Rajadurai, V. S.
The N3RO trial: a randomised controlled trial of docosahexaenoic acid to reduce bronchopulmonary dysplasia in preterm infants < 29 weeks' gestation
BMC Pediatric. 2016. 16.

Collins CT, Makrides M, McPhee AJ, Sullivan TR, Davis PG, Thio M, Simmer K, Rajadurai VS, Travadi J, Berry MJ, Liley HG, Opie GF, Tan K, Lui K, Morris SA, Stack J, Stark MJ, Chua M, Jayagobi PA, Holberton J, Bolisetty S, Callander IR, Harris DL, Gibson RA.
Docosahexaenoic Acid and Bronchopulmonary Dysplasia in Preterm Infants
New Engl J Med 2017;376:1245-1255.

Gould JF, Makrides M, Sullivan TR, Anderson PJ, Gibson RA, Best KP, A. J. McPhee, L. W. Doyle, G. Opie, J. Travadi, J. L. Y. Cheong, P. G. Davis, M. Sharp, K. Simmer and C. T. Collins. A protocol for assessing whether cognition of preterm infants <29 weeks’ gestation can be improved by an intervention with the omega-3 long-chain polyunsaturated fatty acid docosahexaenoic acid (DHA): a follow-up of a randomised controlled trial. BMJ Open 2021;11(2).

Gould JF, Roberts R, Anderson PJ, Makrides M, Sullivan TR, Gibson RA, A. J. McPhee, L. W. Doyle, G. Opie, J. Travadi, J. L. Y. Cheong, P. G. Davis, M. Sharp, K. Simmer, K. Tan, S. Morris, K. Lui, S. Bolisetty, H. Liley, J. Stack, K. P. Best and C. T. Collins. Protocol for assessing if behavioural functioning of infants born <29 weeks’ gestation is improved by omega-3 long-chain polyunsaturated fatty acids: follow-up of a randomised controlled trial. BMJ Open 2021; 11(5).

Gould JF, Colombo J, Collins CT, Makrides M, Hewawasam E, Smithers LG. Assessing whether early attention of very preterm infants can be improved by an omega-3 long-chain polyunsaturated fatty acid intervention: a follow-up of a randomised controlled trial. BMJ Open 2018;8(5):e020043.

Hewawasam E, Collins CT, Muhlhausler BS, Yelland LN, Smithers LG, Colombo JC, Makrides M, McPhee AJ, Gould JF. Docosahexaenoic acid supplementation in infants born preterm and the effect on attention at 18 months' corrected age: follow-up of a subset of the N3RO randomised controlled trial. Br J Nutr 2020;125(4):420-431
Public notes
Attachments [1] 2737 2737 0 0
/AnzctrAttachments/362028-Collins_2016_N3RO_protocol.pdf (Protocol)
Attachments [2] 2738 2738 0 0
/AnzctrAttachments/362028-Collins_2016_N3RO_NEJM.pdf (Publication)

Contacts
Principal investigator
Name 33706 0
Dr Carmel Collins
Address 33706 0
Child Nutrition Research Centre
A division of Healthy Mothers Babies and Children
South Australian Health and Medical Research Institute
72 King William Road
North Adelaide SA 5006
Country 33706 0
Australia
Phone 33706 0
+61 8 8128 4409
Fax 33706 0
Email 33706 0
carmel.collins@sahmri.com
Contact person for public queries
Name 16953 0
Dr Jacqueline Gould
Address 16953 0
SAHMRI Women and Kids, South Australian Health and Medical Research Institute, 72 King William Road North Adelaide SA 5006
Country 16953 0
Australia
Phone 16953 0
+61 8 81284423
Fax 16953 0
Email 16953 0
jacqueline.gould@sahmri.com
Contact person for scientific queries
Name 7881 0
Dr Jacqueline Gould
Address 7881 0
SAHMRI Women and Kids, South Australian Health and Medical Research Institute, 72 King William Road North Adelaide SA 5006
Country 7881 0
Australia
Phone 7881 0
+61 8 84284423
Fax 7881 0
Email 7881 0
jacqueline.gould@sahmri.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Individual participant data, including data dictionaries, may be shared after deidentification on reasonable request.
When will data be available (start and end dates)?
Data will be available for sharing from 01/01/2024, with no planned end date.
Available to whom?
De-identified data may be made available to researchers.
Available for what types of analyses?
Data will be available for scientifically and methodologically sound analyses.
How or where can data be obtained?
Proposals to access the data must be scientifically and methodologically sound and must be reviewed and approved by the N3RO trial steering committee and the Women’s and Children’s Human Research Ethics Committee. To gain access, data requestors will need to sign a data access agreement. Proposals should be directed to Jacqueline Gould through email (Jacqueline. gould@sahmri.com).


What supporting documents are/will be available?

TypeCitationLinkEmailOther DetailsAttachment
Study protocolCollins CT, Gibson RA, Makrides M, et al. The N3RO trial: a randomised con- trolled trial of docosahexaenoic acid to reduce bronchopulmonary dysplasia in pre- term infants < 29 weeks’ gestation. BMC Pediatr 2016;16:72.  
Statistical analysis planCollins CT, Makrides M, McPhee AJ, et al. Docosahexaenoic Acid and Bronchopulmonary Dysplasia in Preterm Infants. N Engl J Med 2017;376:1245-1255. See the Supplementary Appendix, available at NEJM.org  
Clinical study reportCollins CT, Makrides M, McPhee AJ, et al. Docosahexaenoic Acid and Bronchopulmonary Dysplasia in Preterm Infants. N Engl J Med 2017;376:1245-1255.  


Results publications and other study-related documents

Documents added manually

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseThe N3RO trial: A randomised controlled trial of docosahexaenoic acid to reduce bronchopulmonary dysplasia in preterm infants <29 weeks' gestation.2016https://dx.doi.org/10.1186/s12887-016-0611-0
EmbaseProtocol for assessing if behavioural functioning of infants born 29 weeks' gestation is improved by omega-3 long-chain polyunsaturated fatty acids: Follow-up of a randomised controlled trial.2021https://dx.doi.org/10.1136/bmjopen-2020-044740
EmbaseProtocol for assessing whether cognition of preterm infants <29 weeks' gestation can be improved by an intervention with the omega-3 long-chain polyunsaturated fatty acid docosahexaenoic acid (DHA): A follow-up of a randomised controlled trial.2021https://dx.doi.org/10.1136/bmjopen-2020-041597
EmbaseDocosahexaenoic acid and bronchopulmonary dysplasia in preterm infants.2017https://dx.doi.org/10.1056/NEJMoa1611942
EmbaseAssessing whether early attention of very preterm infants can be improved by an omega-3 long-chain polyunsaturated fatty acid intervention: A follow-up of a randomised controlled trial.2018https://dx.doi.org/10.1136/bmjopen-2017-020043
EmbaseRetinopathy of prematurity: New developments bring concern and hope.2015https://dx.doi.org/10.1111/jpc.12860
EmbaseNeonatal Docosahexaenoic Acid in Preterm Infants and Intelligence at 5 Years.2022https://dx.doi.org/10.1056/NEJMoa2206868
EmbaseHigh-Dose Docosahexaenoic Acid in Newborns Born at Less Than 29 Weeks' Gestation and Behavior at Age 5 Years: Follow-Up of a Randomized Clinical Trial.2024https://dx.doi.org/10.1001/jamapediatrics.2023.4924
EmbaseNew methodologies for conducting maternal, infant, and child nutrition research in the era of covid-19.2021https://dx.doi.org/10.3390/nu13030941
N.B. These documents automatically identified may not have been verified by the study sponsor.