Interactions between diet and gut microbes in preterm infants
| ISRCTN | ISRCTN16799022 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN16799022 |
| IRAS number | 215037 |
| Secondary identifying numbers | CPMS 34886; IRAS Project ID: 215037; NuTH (Sponsor) Protocol number: NuTH 8360 |
- Submission date
- 24/07/2017
- Registration date
- 24/07/2017
- Last edited
- 02/03/2023
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Neonatal Diseases
Plain English summary of protocol
Background and study aims
Around 10% of babies are premature (born before 37 weeks), but feeding them is complex. Mothers own breast-milk (MOM) is best and results in better outcomes such as fewer infections, but many mothers do not produce enough milk so either donor human milk (DHM) or a cow's milk derived formula are used to make up the 'shortfall'. Current feeding practices in the UK vary as there is no clear evidence which is best, but both MOM and DHM require fortification with additional nutrients in order to support optimal growth. This currently requires the use of a ‘fortifier’ derived from cow’s milk, but new milk supplements made only from donor human milk are now used in US and Europe. The pattern of gut bacteria in early life is linked to outcomes including infections and allergies, and this is especially important in preterm infants. The aim of this study is to compare two diets in very preterm infants and study the effect on the pattern of gut bacteria and chemicals (metabolites) in stool and urine, as well as growth and body composition.
Who can participate?
Preterm infants born below 29 completed weeks of gestation
What does the study involve?
Babies are randomly allocated to either the standard diet group or the intervention group. To make up any shortfall in MOM, the standard diet group receive a cow's milk formula designed for preterm babies and a fortifier derived from cow's milk, and the intervention group receive DHM and a fortifier derived from human milk. Stool and urine samples are collected to look at patterns of gut bacteria and metabolites, and body composition is measured using an MRI scan.
What are the possible benefits and risks of participating?
There are not enough data to know whether there is any clear advantage to either diet. All babies who participate receive the same level of care regardless of being in the study. There are therefore no clear benefits to babies and parents of taking part, although the information collected may help improve care in the future. This is a dietary study and there are no known risks. Use of any human derived product carries a potential risk of side effects but this has not been reported so far with Prolacta products. The collection of samples for analysis is not associated with any risk.
Where is the study run from?
1. Newcastle Hospitals NHS Foundation Trust (UK)
2. Chelsea and Westminster Hospital (UK)
When is the study starting and how long is it expected to run for?
July 2017 to February 2020
Who is funding the study?
Prolacta Biosciences US
Who is the main contact?
Dr Nicholas Embleton
Contact information
Scientific
Ward 35 Neonatal Unit
Royal Victoria Infirmary
Richardson Road
Newcastle upon Tyne
NE1 4LP
United Kingdom
 ORCID ID |
0000-0003-3750-5566 |
|---|
Study information
| Study design | Randomised; Interventional; Design type: Treatment, Prevention, Process of Care, Dietary |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a patient information sheet |
| Scientific title | Interactions between the diet and gut microbes and metabolism in preterm infants (INDIGO study) |
| Study acronym | INDIGO |
| Study objectives | To evaluate in very preterm infants whether an exclusive human milk diet compared with exposure to cow’s milk-based products results in differences in gut bacteria (types and diversity, stool and urine metabolites and body composition. The primary hypotheses are that there are differences in the pattern of gut microbes and in body composition between the two groups. This is determined by looking at the pattern of gut bacterial DNA using a methodology called 16s which is widely used, and MRI. The study is powered to detected a difference in the presence or absence of key bacterial groups (taxa), as well as overall diversity (Shannon diversity). |
| Ethics approval(s) | North East - Tyne & Wear South Research Ethics Committee, 29/06/2017, ref: 17/NE/0169 |
| Health condition(s) or problem(s) studied | Digestive health of preterm infants |
| Intervention | All mothers are encouraged and supported to provide as much of their own breast milk ('Mothers Own Milk', MOM) as they wish to. When there is insufficient MOM to meet the infants needs this is called a 'shortfall'. Infants will be enrolled in the first 2 days after birth and before they need any other milks to make up any shortfall in MOM. Parents of infants will be consented and the infants randomised to one of two dietary strategies with equivalent nutrient intakes but where the source of milk differs. Infants will be randomised using a secure online web randomisation programme (www.sealedenvelope.com) with a 30% chance of simple random allocation and include 3 strata: hospital site, gestation <=24+6 weeks gestation or 25-28 weeks, and multiple status (twin etc). Infants will stay on their assigned diet until 34 weeks corrected gestation when the intervention completes, although infant data will be recorded until discharge home, or until the MRI scan is complete in those infants who receive it (those recruited in Imperial College London). This will mean they are part of the study for between 5-12 weeks. 1. Standard treatment arm consists of MOM with formula milk to make up shortfall, and use of a standard bovine milk derived fortifier to provide additional nutrients. 2. Intervention treatment arm consists of MOM with donor human milk to make up shortfall, and use of a human donor milk derived fortifier to provide additional nutrients. The study is not blinded as this would be impractical given the dietary regimens. However, the analyses of stool, urine and body composition will be conducted by teams who are blind to trial intervention so there is limited, if any, possibility of researcher bias. All infants will be routinely monitored as is standard of care on a neonatal unit. It is routine nursing practice to record the amount of milk a baby receives, their clinical condition, their weight (3-7 times per week), length and head size (once/week), whether they are tolerating their feeds or not, and whether they are unwell in any way. Clinical staff and bedside clinical nurse perform routine weight/head/length and record status continuously whilst in intensive and high dependency care. The babies will all receive the same amounts of milk and other nutrients as for standard care. In addition, as part of the study a nurse will collect a daily samples of stool from the nappy, as well as urine collected using cotton wool balls that are squeezed out. These samples will only be analysed after the study completes. In addition the laboratories will be asked to store any blood that is left over after routine tests are complete rather than being discarded. On two occasions (at full feeds and at the end of the study) the trialists will ask the parents' permission to take an extra 1mL (less than half teaspoon) of blood when the baby needs a blood test for other medical reasons. For the infants enrolled in Chelsea & Westminster body composition will be measured using whole body magnetic resonance imaging (MRI) at around 37-42 weeks gestation when the baby is ready to go home or shortly after discharge home. Infants will be accompanied by a neonatal nurse at all times and be monitored using pulse oximetry (oxygen saturation level). The scan takes around 30 minutes. No sedation is used as babies usually sleep during the procedure especially if it is done after a feed. There are no implications for the care of babies after the study completes. |
| Intervention type | Other |
| Primary outcome measure | 1. Gut microbiota bacterial diversity and proportions of specific taxa. Stool samples are collected daily and measured on <5 occasions in each infant using 16s RNA on MiSeq at 5 time points from enrolment until trial completion: days 2/3, ~7-10 (at full feeds but prior to fortifier), 10-12 (48 hours following fortifier introduction), day 21-28 and at 34 weeks corrected age (prior to trial cessation) 2. Gut microbiota derived and other metabolites by measuring stool Volatile Organic Compounds using Gas Chromatography Mass Spectrometry (MS), and urine using 1H NMR and/or Liquid Chromatography MS on >=2 occasions between enrolment until trial completion (days 10-12 full feeds) and day 28 3. Body composition by assessing adipose tissue mass and non-adipose tissue mass using whole body magnetic resonance imaging (MRI) at term (37-42 weeks postmenstrual age) |
| Secondary outcome measures | 1. Feeding related outcomes: total number of days on which feeds were withheld on any occasion after trial enrolment; age when enteral feeds ≥150ml/kg/day maintained for at least 3 days (coded as first day achieved); total days exposed to MOM prior to 34 weeks; feeding mode at discharge (breast, formula or mixed). Measured once using clinical records and recorded prior to hospital discharge. 2. Healthcare resource use: total length of stay (days); postmenstrual age at discharge; days in intensive, high-dependency and low-dependency care according to national definitions (BAPM), recorded once at discharge using medical records 3. Survival to discharge; Retinopathy of Prematurity, maximum stage and intervention; Necrotising Enterocolitis requiring surgery or leading to death; blood-culture positive sepsis; total days when any antibiotic administered; chronic lung disease (oxygen requirement or need for any pressure support at 36 weeks postmenstrual age), peri-ventricular haemorrhage (PVH) and/or presence of parenchymal damage. These will all be determined using established national definitions (National Neonatal Audit Programme), and informed using recently completed studies on NEC and agreed by investigator end-point review committee. Measured using clinical records and total morbidities confirmed prior to hospital discharge. 4. Growth and body composition including adipose tissue volume and distribution (MRI at 37-42 weeks gestation) and weight, head circumference and length measured on a weekly basis from enrolment to discharge |
| Overall study start date | 01/07/2017 |
| Completion date | 28/02/2020 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Neonate |
| Sex | Both |
| Target number of participants | Planned Sample Size: 100; UK Sample Size: 100 |
| Total final enrolment | 128 |
| Key inclusion criteria | Current inclusion criteria as of 11/03/2021: 1. Preterm infants born below 30 completed weeks of gestation (<=29 weeks and 6 days) 2. Written informed consent from parents 3. Has not received any milk other than MOM Previous inclusion criteria: 1. Preterm infants born below 29 completed weeks of gestation (<=28 weeks and 6 days) 2. Written informed consent from parents 3. Has not received any milk other than MOM |
| Key exclusion criteria | 1. Major congenital or life threatening abnormalities 2. Inability to randomise within 48 hours of birth 3. Exposure to bovine milk product prior to randomisation 4. Likelihood of transfer to another hospital before 34 weeks postmenstrual age |
| Date of first enrolment | 20/08/2017 |
| Date of final enrolment | 31/08/2019 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centres
Richardson Road
Newcastle upon Tyne
NE1 4LP
United Kingdom
Chelsea
London
SW10 9NH
United Kingdom
Sponsor information
Hospital/treatment centre
Freeman Hospital
Freeman Road
High Heaton
Newcastle-Upon-Tyne
NE7 7DN
England
United Kingdom
"ROR" |
https://ror.org/05p40t847 |
|---|
Funders
Funder type
Industry
No information available
Results and Publications
| Intention to publish date | 01/05/2022 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Other |
| Publication and dissemination plan | The trialists will publish the study protocol in 2019 and the results in Q4 2020, as well as present data at international conferences. |
| IPD sharing plan | The datasets generated and/or analysed during the current study during this study will be included in the subsequent results publication. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Results article | 01/03/2023 | 02/03/2023 | Yes | No | |
| HRA research summary | 28/06/2023 | No | No |
Editorial Notes
02/03/2023: Publication reference added.
16/03/2022: The intention to publish date was changed from 01/10/2021 to 01/05/2022.
12/03/2021: IPD sharing statement added.
11/03/2021: The following changes were made to the trial record:
1. The inclusion criteria were updated.
2. The intention to publish date was changed from 01/10/2020 to 01/10/2021.
06/03/2020: The total final enrolment was added.
03/04/2019: The condition has been changed from "Specialty: Reproductive health and childbirth, Primary sub-specialty: Other; UKCRC code/ Disease: Reproductive Health and Childbirth/ Other obstetric conditions, not elsewhere classified" to "Digestive health of preterm infants" following a request from the NIHR.
