Developmental outcomes of long-term feed supplementation in newborn babies
| ISRCTN | ISRCTN62323236 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN62323236 |
| IRAS number | 303421 |
| Secondary identifying numbers | CPMS 51833, IRAS 303421 |
- Submission date
- 06/05/2022
- Registration date
- 16/05/2022
- Last edited
- 14/04/2025
- Recruitment status
- No longer recruiting
- Overall study status
- Ongoing
- Condition category
- Neonatal Diseases
Plain English Summary
Background and study aims
This study is designed to test whether adding a daily nutrient supplement (food substance) to the normal milk and weaning foods of babies born very early can help improve their brain development, and their neurological child development (such as how they think, communicate, play and interact with others). The supplement contains substances that occur naturally in a healthy diet and are often used as food supplements (long-chain polyunsaturated fatty acids, uridine-5’-monophosphate, cytidine-5’-monophosphate, and choline). A small UK study has been carried out and the results were promising, but we need to find out more. The aim is to include about 500 babies born very early and 500 babies who receive cooling treatment in order to be confident of finding out whether the supplement improves the babies' brain development, and neurological child development, or not. If the study shows that the supplement is effective, it might be given to babies as part of future NHS care.
Who can participate?
Babies born more than 12 weeks early and babies born less than 5 weeks early who have received cooling treatment for hypoxic-ischaemic encephalopathy (HIE)
What does the study involve?
Once consent is provided, the infant will receive either the supplement or a substance that looks the same but does not contain the nutrients (a placebo). There is a 50% chance of receiving the supplement and a 50% chance of receiving placebo. The supplement will be given daily to the infant until he/she is 12 months after the Estimated Date of Delivery (EDD). Parents will be asked to complete questionnaires when they join the study, at hospital discharge and at 3, 6, 12, 18 and 24 months of age.
What are the possible risks and benefits of participating?
The supplement has been used in a smaller study of around 100 babies and infants without any problems or side effects. All babies will be monitored very closely throughout the study by the clinical team in the Neonatal Intensive Care or Special Care Unit, and by the local NHS Paediatrician and clinical team following discharge from hospital. Participants who take part in the trial to the time their child is age 24 months will receive a £25 voucher.
Where is the study run from?
The National Perinatal Epidemiology Unit, Clinical Trials Unit (NPEU CTU) at the University of Oxford, in partnership with Newcastle University (UK)
When is the study starting and how long will it run for?
September 2021 to May 2027
Who is funding the study?
The National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme (UK)
Who is the main contact?
NPEU Clinical Trials Unit National Perinatal Epidemiology Unit (NPEU)
dolfin@npeu.ox.ac.uk
Contact information
Principal Investigator
University of Newcastle upon Tyne
Level 3, Sir James Spence Institute
Royal Victoria Infirmary
Newcastle Upon Tyne
NE1 4LP
United Kingdom
| Phone | +44 (0)1912825966 |
|---|---|
| Jeremy.parr@newcastle.ac.uk |
Scientific
National Perinatal Epidemiology Unit (NPEU)
Oxford Population Health (Nuffield Department of Population Health)
University of Oxford
Richard Doll Building, Old Road Campus
Oxford
OX3 7LF
United Kingdom
 ORCID ID |
0000-0001-5157-7043 |
|---|---|
| Phone | +44 (0)1865 617924 |
| dolfin@npeu.ox.ac.uk |
Study information
| Study design | Randomized; Both; Design type: Treatment, Dietary, Health Economic |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | https://www.npeu.ox.ac.uk/dolfin/parents/resources |
| Scientific title | Developmental Outcomes of Long term Feed supplementation In Neonates (DOLFIN) |
| Study acronym | DOLFIN |
| Study hypothesis | This study is designed to test whether adding a daily nutrient supplement (food substance) to the normal milk and weaning foods of babies born with hypoxic ischaemic encephalopathy (where the brain did not receive enough oxygen around the time of birth) or babies born premature (born less than 28 weeks of gestation) can help improve their neurological development in later childhood (such as how they think, play and interact with others). |
| Ethics approval(s) | Approved 14/03/2022, Bristol Research Ethics Committee Centre, Ground Floor, Temple Quay House, BS1 6PN, UK; +44 (0)207 104 8029; centralbristol.rec@hra.nhs.uk), ref: 22/SW/0009 |
| Condition | Babies born with hypoxic ischaemic encephalopathy (where the brain did not receive enough oxygen around the time of birth) or babies born premature (born less than 28 weeks of gestation) |
| Intervention | This trial aims to establish whether or not early life nutritional supplementation with a nutrient blend of long-chain polyunsaturated fatty acids (LCPUFAs), choline, uridine-5'-monophosphate (UMP), and cytidine-5’-monophosphate (CMP) improves infants’ cognitive development at 24 months post Estimated Date of Delivery (EDD), compared to controls, in two clearly defined strata: 1. Preterm stratum: Infants born less than 28 weeks of gestation 2. HIE stratum: Infants born at 35 weeks of gestation or more, receiving therapeutic hypothermia for HIE. 1,010 infants; 538 preterm and 472 infants born at or after 35 weeks of gestation with HIE cared for in neonatal units across the UK participate. A 9-month internal pilot phase incorporates “stop-go” criteria to evaluate the feasibility of recruitment and other trial processes. With informed consent from parents, clinicians in each unit will use a randomisation website to randomly allocate infants to receive either: 1. Treatment supplement: micronutrient breast milk/formula milk/food supplement containing LCPUFAs, choline, UMP, and CMP. or 2. Matched placebo control supplement: identically packaged and delivered powder supplement indistinguishable from the active treatment. Parents will be offered information about the trial and will have ample time to consider whether they wish their baby to take part. Eligible babies will be recruited up to 40 weeks of gestation plus 28 days. Powder supplement will be added daily to the usual milk feed (breast or formula) on the neonatal unit when infants reach full milk feeds (120–150 ml/kg/day), and have reached 1 kg body weight. Supplementation will be continued on discharge and given at home by parents until 12 months of age post EDD. Neither the clinicians, nor the caregivers, parents or carers will be aware of whether each individual infant is receiving active treatment or a placebo. No additional (trial-specific) blood tests or other investigations will be required. Parents will receive support from their local clinical teams whilst on the Neonatal unit and throughout the entire trial period. Data will be collected on bespoke data collection forms from the time of randomisation up until the child reaches 24 months of age, post EDD. Parents will be asked to complete questionnaires when their child reaches 6, 12, 18 months of age post EDD and record if the supplement has been given on an App (or alternative method of parents choosing). The researchers will undertake an economic evaluation to determine whether supplementation is a cost-effective treatment. Consent will be obtained to facilitate future school-age follow-up. |
| Intervention type | Supplement |
| Primary outcome measure | Cognitive development measured using the non-verbal cognitive scale standardised score of the Parent Report of Children’s Abilities-Revised (PARCA-R) questionnaire at age 24 months |
| Secondary outcome measures | 1. Secondary neurodevelopmental outcomes measured at 24 months of age post EDD: 1.1. Language Development Scale standardised score of the PARCA R questionnaire 1.2. Parent-reported emotional, conduct, peer problems, hyperactivity, prosocial and total score measured using the Strengths and Difficulties Questionnaire 1.3. Parent-reported motor skills measured using the fine and gross motor scales score of the Ages and Stages Questionnaire (ASQ-3) 2. Infant growth outcomes measured at 24 months of age post EDD: 2.1. Weight standard deviation score 2.2. Head circumference standard deviation score 2.3. Overweight or obese (BMI ≥85th percentile) 3. Clinical outcomes measured at discharge home from the neonatal unit: 3.1. Microbiologically confirmed late-onset invasive infection 3.2. Necrotising enterocolitis requiring surgery 3.3. Retinopathy of prematurity treated medically/surgically (preterm stratum only) 3.4. Chronic lung disease (preterm stratum only) 4. Safety, infant tolerability, adherence to and parental acceptability measured using: 4.1. Safety and adverse events until age 12 months plus 2 weeks after the end of the intervention period 4.2. Parent-reported infant tolerability of supplement (IGSQ) at discharge home from neonatal unit, 3, 6 and 12 months 4.3. Parent-reported adherence until age 12 months 4.4. Parent-reported acceptability of the supplement at 6 and 12 months 5. Maternal health-related quality of life measured using: 5.1. EuroQol EQ-5D-5L questionnaire at baseline, 6, 12, 18 and 24 months 5.2. Maternal quality-adjusted life years (QALYs) up to 24 months 6. Healthcare and social care resource use and costs, costs borne by families, and wider societal implications including family expenses and employment, measured using: 6.1. Health and social care resource use and costs and out-of-pocket costs incurred by families up to 24 months 6.2. Productivity costs and informal care up to 24 months 6.3. Cost per life-year without moderate/severe neurodevelopmental impairment (within-trial cost-effectiveness analysis) at 24 months 6.4. Cost per QALY gained (long-term cost-effectiveness analysis) modelled to 18 years of age |
| Overall study start date | 01/09/2021 |
| Overall study end date | 31/05/2027 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Neonate |
| Upper age limit | 3 Months |
| Sex | Both |
| Target number of participants | Planned Sample Size: 1143; UK Sample Size: 1143 |
| Participant inclusion criteria | 1. Preterm stratum: Infants born less than 28 weeks of gestation, up to discharge home from neonatal unit (NNU) or step-down site, and no more than 3 months post-estimated date of delivery (EDD) 2. Hypoxic ischaemic encephalopathy (HIE) stratum: Infants born at 35 weeks of gestation or more, who have received therapeutic hypothermia for HIE, up to 40 weeks of gestation plus 28 days 3. Individual with parental responsibility able to give consent. In the event that the mother is unable to give consent, or does not have parental responsibility consent can be given by another person who has parental responsibility. Maternal consent for the purposes of maternal data collection will be sought as soon as practical 4. Parents able to comply with the protocol 5. Infants likely to tolerate full enteral feeds 6. Infant has a realistic prospect of survival beyond discharge |
| Participant exclusion criteria | 1. Infants with middle cerebral artery infarcts 2. Infants with major congenital brain malformation, or genetic condition with abnormal brain development 3. Infants with galactosaemia 4. Infants receiving continuous enteral feeds, including jejunal feeds |
| Recruitment start date | 10/10/2022 |
| Recruitment end date | 15/04/2025 |
Locations
Countries of recruitment
- England
- Northern Ireland
- United Kingdom
- Wales
Study participating centres
Cambridge
CB2 0QQ
United Kingdom
Birmingham
B9 5SS
United Kingdom
Birmingham
B4 6NH
United Kingdom
Bradford
BD9 6RJ
United Kingdom
London
SW10 9NH
United Kingdom
Middlesbrough
TS4 3BW
United Kingdom
Leeds
LS1 3EX
United Kingdom
Crown Street
Liverpool
L8 7SS
United Kingdom
Gillingham
ME7 5NY
United Kingdom
Heath Town
Wolverhampton
WV10 0QP
United Kingdom
Colney
Norwich
NR4 7UY
United Kingdom
Nottingham
NG5 1PB
United Kingdom
Lenton
Nottingham
NG7 2UH
United Kingdom
Headington
Oxford
OX3 9DU
United Kingdom
Southampton
SO16 5YA
United Kingdom
Cosham
Portsmouth
PO6 3LY
United Kingdom
London
E1 1BB
United Kingdom
Belfast
BT12 6BA
United Kingdom
Newcastle upon Tyne
TS1 4LP
United Kingdom
Westbury-on-trym
Bristol
BS10 5NB
United Kingdom
Manchester
M13 9WL
United Kingdom
Bristol
BS2 8EG
United Kingdom
Lyne
Chertsey
KT16 0PZ
United Kingdom
Sunderland
SR4 7TP
United Kingdom
Cwmbran
NP44 8YN
United Kingdom
Cardiff
CF14 4XW
United Kingdom
Coventry
CV2 2DX
United Kingdom
Leicester
LE1 5WW
United Kingdom
Willesborough
Ashford
TN24 0LZ
United Kingdom
Stoke-on-trent
ST4 6QG
United Kingdom
Minerva Road
Farnworth
Bolton
BL4 0JR
United Kingdom
Burnley
BB10 2PQ
United Kingdom
Sponsor information
Hospital/treatment centre
Newcastle Joint Research Office
Level 1, Regent Point
Regent Farm Road
Gosforth
Newcastle-Upon-Tyne
NE3 3HD
England
United Kingdom
| Phone | +44 (0)1912824454 |
|---|---|
| tnu-tr.sponsormanagement@nhs.net | |
| Website | http://www.newcastle-hospitals.org.uk/ |
"ROR" |
https://ror.org/05p40t847 |
Funders
Funder type
Government
No information available
Results and Publications
| Intention to publish date | 31/12/2027 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Other |
| Publication and dissemination plan | Planned publication in a high-impact peer-reviewed journal. |
| IPD sharing plan | At the end of the trial, all participant clinical and parent-reported data will be transferred to the research team at Newcastle University and NuTH (Trial Sponsor). In addition, all participant names and NHS numbers, and parent names and contact details, will be transferred to the research team at Newcastle University and NUTH in order to allow Newcastle University and NuTH to contact parents if required at the end of the study or (for those who have consented) with regards to planned long-term follow-up, and in compliance with any applicable Data Sharing Agreement. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol file | version 3.0 | 09/06/2022 | 18/10/2022 | No | No |
| HRA research summary | 28/06/2023 | No | No | ||
| Protocol file | version 6.0 | 10/10/2024 | 21/03/2025 | No | No |
Additional files
Editorial Notes
14/04/2025: The recruitment end date was changed from 30/04/2025 to 15/04/2025.
21/03/2025: The following changes were made:
1. Protocol Version 6.0 uploaded (not peer review).
2. The recruitment end date was changed from 31/05/2024 to 30/04/2025.
13/11/2023: Bolton NHS Foundation Trust and Burnley General Hospital have been added to the study participating centres.
19/10/2022: Royal Hallamshire Hospital was removed as a trial participating centre.
18/10/2022: The following changes were made to the trial record:
1. Protocol uploaded (not peer review).
2. Participant information sheet added.
3. The recruitment start date was changed from 01/07/2022 to 10/10/2022.
4. Royal Stoke University Hospital was added as a trial participating centre.
17/06/2022: A study contact has been added.
07/06/2022: Internal review.
06/05/2022: Trial's existence confirmed by the NIHR.
