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Trial registered on ANZCTR


Trial ID
ACTRN12616001199404
Ethics application status
Approved
Date submitted
24/08/2016
Date registered
31/08/2016
Date last updated
8/06/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
DIAMOND - DIfferent Approaches to MOderate & late preterm Nutrition: Determinants of feed tolerance, body composition and development
Scientific title
DIfferent Approaches to MOderate & late preterm Nutrition: Determinants of feed tolerance, body composition and development
Secondary ID [1] 289583 0
Nil known
Universal Trial Number (UTN)
U111111810902
Trial acronym
DIAMOND
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Preterm nutrition 299334 0
Moderate to late preterm outcomes 299335 0
Neurodevelopmental outcome following preterm birth 299336 0
Effect of feeding strategies on microbiome composition 299337 0
Breastmilk composition of preterm babies 299338 0
Growth and body composition of moderate to late preterm babies 300002 0
Condition category
Condition code
Diet and Nutrition 299321 299321 0 0
Other diet and nutrition disorders
Reproductive Health and Childbirth 299322 299322 0 0
Complications of newborn

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Once consented participants will be randomised to one of eight conditions involving different feeding strategies. Babies will be randomized to one of eight conditions to receive either an intravenous nutrition amino acid solution or dextrose 10%, supplemental milk whilst waiting for expressed breastmilk feeds or exclusively breastmilk, and taste / smell given prior to gastric tube feeds or no taste / smell prior to gastric tube feeds. The participants will receive the allocated intervention until breastmilk feeding is fully established and the intervention is no longer required.
The eight conditions are below:
Condition 1
Parenteral nutrition, breast milk + supplemental milk to meet enteral fluid volumes,
taste/smell with tube feeds
Condition 2
Parenteral nutrition, exclusively breastmilk, taste/smell with tube feeds
Condition 3
Parenteral nutrition, breast milk + supplemental milk to meet enteral fluid volumes, no taste and smell with tube feeds
Condition 4
Parenteral nutrition, exclusively breastmilk, no taste and smell with tube feeds
Condition 5
Dextrose 10%,breast milk + supplemental milk to meet enteral fluid volumes, taste/smell with tube feeds
Condition 6
Dextrose 10%, exclusively breastmilk, taste/smell with tube feeds
Condition 7
Dextrose 10%,breast milk + supplemental milk to meet enteral fluid volumes, no taste and smell with tube feeds
Condition 8
Dextrose 10%, exclusively breastmilk, no taste and smell with tube feeds

Interventions and comparators
(i) parenteral nutrition vs 10% dextrose intravenously; (ii) supplemental milk (donor breast milk if available, else infant formula) vs only mother’s own milk as available; (iii) infants exposed to smell and taste of milk prior to every tube feed vs no exposure (milk administered only via gastric feeding tube).

All babies will receive nutrition according to individual neonatal intensive care unit practices. The volume of fluids, parenteral fluid adjustments, amount of enteral feed and frequency of increases will as per clinician's discretion and no guidelines will be given around this. In addition, babies will be randomised to one of eight conditions. It is important to note that the first two interventions only apply until the baby is established on full enteral feeds with mothers’ own milk, which remains the primary nutritional goal. If randomised to receive smell and taste prior to tube feeds, this intervention will continue until the baby is no longer receiving any gastric tube feeds.

Parenteral nutrition: if randomised to receive parenteral the baby will receive an amino acid solution P100 (according to local hospital practice) intravenously, either by peripheral or central line as deemed appropriate. Administration of intravenous lipid is at the discretion of the clinical team, as is administration of any supplementary fluids, such as 10% dextrose. Babies not randomised to parenteral nutrition will receive intravenous 10% dextrose only (according to local hospital practice).

Milk supplement: if randomised to receive milk supplement, the baby will receive donor breastmilk or infant formula (according to local practice) whilst waiting for mother's breastmilk to meet prescribed fluid amounts, any breastmilk the mother provides will be given to the baby in preference of formula and formula will only be used to make up any deficit as per medical team fluid prescription. Babies with a birthweight < 2 Kg will receive preterm infant formula; babies with a birthweight > 2 Kg will receive standard infant formula. Babies not randomised to receive milk supplement will only receive mother’s breastmilk as available which is standard practice given it takes a couple of days for mother's breastmilk to come in. If the baby's birth weight is < 2000g breastmilk will be fortified once receiving 5 mL every 2 hours as is standard practice in both units. As it is a pragmatic trial we anticipate that after a certain number of days some clinician's will not be happy to wait any longer for breastmilk it will then be up to their discretion on whether to start formula or intravenous nutrition depending on their "normal"practice". We do not propose any recommendations on number of days to wait as currently there is no evidence to guide practice therefore we cannot make any assumptions. The preterm infant formula will be either PreNan or Aptamil preterm formula depending on the site. The standard infant formula will change as both sites rotate there standard formula's every 4 months between Aptamil gold +1, S26 Gold Newborn and Nestle Nan Starter formula.

Taste and smell: If randomised to receive taste and smell, the baby will be exposed to the taste and smell of the milk feed prior to every enteral feed. If the baby is receiving both breast milk and supplementary formula, the smell and taste will be of breast milk if available, but if there is insufficient breastmilk, then smell and taste can be of formula. However, if the baby is randomised to not receive supplementary infant formula then smell and taste can only be provided with breastmilk and taste should be given in preference to smell. To administer smell place 0.1 – 0.5 mL of milk onto a piece of gauze or cotton swab and place by the baby’s nose to remain in place until completion of the enteral feed. To administer taste for preterm babies give 0.2 mL of milk in a syringe on to the tip of babies tongue. Both smell and taste should be given immediately prior to administering the tube feed.

The goal for all babies enrolled in the study is to transition to full feeds of expressed breastmilk as soon as possible. If at any time the responsible clinician feels that any of the randomised interventions is no longer appropriate, they may withdraw the baby from the relevant intervention for clinical reasons. They will be encouraged to discuss this with the trial Lead Investigator, Principal Investigator or another member of Steering Group before making the decision. The baby will remain in the allocated condition group for the purposes of analysis (intention-to-treat principle).
Intervention code [1] 295256 0
Treatment: Other
Comparator / control treatment
Absence of the intervention
For PN, the control is 10% dextrose
For human milk substitute, the control is mother's milk only
For exposure to taste and smell, the control is absence of exposure to taste and smell before tube feeds.
Control group
Active

Outcomes
Primary outcome [1] 298882 0
For parenteral nutrition (i) and milk supplement (ii) factors: body composition assessment at 4 months’ corrected age when infant adiposity is predictive of childhood fat mass (8) measured by air displacement plethysmography (ADP) or skinfold thickness measurements.
Timepoint [1] 298882 0
4 months corrected gestational age
Primary outcome [2] 298883 0
For smell/taste (iii) factor, time to full enteral feeds defined as 150 ml.Kg-1.day-1
Timepoint [2] 298883 0
Birth to discharge
Secondary outcome [1] 325530 0
Time to full sucking feeds - Defined as removal of enteral feeding tube.
Prospective recording of data from the medical notes and nursing charts. Date of final removal will be entered into the appropriate CRF.
Timepoint [1] 325530 0
Birth to discharge
Secondary outcome [2] 325531 0
Number of days in hospital - Assessed by date of discharge on CRF
Timepoint [2] 325531 0
Birth to discharge
Secondary outcome [3] 325532 0
Body composition measurement as close to discharge as feasible - measured by air displacement plethysmography (PEAPOD)
Timepoint [3] 325532 0
Discharge
Secondary outcome [4] 325533 0
Growth: length, weight and head circumference Z scores and Z-score change from birth to 4 months’ corrected age and at 2 years;
Crown-heel length will be measured with a Harpenden neonatometer (Holtain Ltd, Dyfed, Wales). Babies will be weighed naked using electronic scales accurate to +/- 10 g. Head circumference will be measured using a non-stretch tape measure. All staff taking anthropometric measurements will be trained to ensure standardisation and accuracy. All growth data Z-scores will be calculated individually for each baby using Fenton 2013 normative data, transitioning to WHO growth standards at 50 weeks’ post-conceptional age.
Timepoint [4] 325533 0
Birth then weekly until discharge, 10 days of age, 4 months corrected age and at 2 years corrected age
Secondary outcome [5] 325535 0
Bayley Scales of Infant Development Edition III at 24 months of age
Timepoint [5] 325535 0
2 years corrected age
Secondary outcome [6] 325536 0
Fully breast fed rates at 4 and 6 months’ corrected age - This outcome will be assessed through self-report of mothers through a questionnaire administered face-to-face at 4 months and by ‘phone at 6 months. The breastfeeding survey was designed specifically for this study and has not been validated.
Timepoint [6] 325536 0
4 and 6 months corrected age
Secondary outcome [7] 326991 0
Gut microbial composition at 10 days of age and 4 months’ corrected age.
Gut microbiome composition assessed by transcriptomics of stool using an Illumina platform (20 million 100 bp reads per sample), reads will be filtered for quality and to remove human contamination and analysed using MetaPhlAn to enable identification of microbial species
Timepoint [7] 326991 0
10 days of age and 4 months corrected age
Secondary outcome [8] 326992 0
In-depth analysis of maternal milk composition on day 3, 5 and 10 days after birth and at 4 months’ corrected age
Timepoint [8] 326992 0
Day 3, 5, 10 and 4 months' corrected age
Secondary outcome [9] 326993 0
Analysis of infants saliva including cortisol concentration and metabolic hormones
Timepoint [9] 326993 0
Day 5 of life
Secondary outcome [10] 327270 0
Gut microbial activity at 10 days of age and 4 months’ corrected age.
Gut microbiome activity assessed by metagenomics of stool and analysed using HUMAnN to identify microbial metabolic pathways.
Timepoint [10] 327270 0
10 days of age and 4 months corrected age
Secondary outcome [11] 336140 0
Maternal stress and anxiety questionnaire during hospital admission and at 4-month follow-up.
Timepoint [11] 336140 0
During hospital admission and at 4 months' corrected age follow-up
Secondary outcome [12] 336141 0
Maternal weight, height and body composition will also be assessed at the 4-month follow-up visit.
Timepoint [12] 336141 0
4 months' corrected age

Eligibility
Key inclusion criteria
Babies born between 32+0 and 35+6 weeks’ gestation
Babies whose mothers intend to breast-feed
Babies admitted to the Neonatal Care Unit
Babies requiring insertion of intravenous lines on admission

Only babies admitted to the Neonatal unit will be entered to the study some healthy babies within the gestation criteria may go straight to postnatal wards and not require intensive care support. All babies within the gestation criteria will receive enteral feeds as they have immature suck, swallow, breath as per standard practice in the care and management of preterm infants. The enteral tube will remain in place until they are able to fully orally feed to meet nutritional goals and grow.
Minimum age
No limit
Maximum age
24 Hours
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Babies in whom a particular mode of nutrition is clinically indicated
Babies with a congenital abnormality that is likely to affect growth, body composition or neurodevelopmental outcome

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 not concealed from parents, babies or clinical staff
Allocation will be concealed from assessors at 4 months and 2 years.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer generated random sequence stratified by sex, gestational age (32+0 - 33+6; 34 - 35+6) and study centre.

Randomisation via a web-based interface managed by an independent database controller (IDC).
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Factorial
Other design features
Phase
Not Applicable
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Unlike multi-arm, parallel RCT or comparative experiments, factorial experiments are designed to estimate main effects and their interactions. Each main effect and interaction analysis is, therefore, based upon the total sample size which is chosen to be large enough to detect all primary outcomes; having more factors does not increase total sample size. We have based our estimate on 90% power, overall type 1 error rate of 5%, alpha per main effect = 0.0167; estimated 10-15% loss to follow-up managed by multiple imputation. For interventions (i) and (ii): to detect a minimal clinically significant difference in % fat mass of 3% (lower 95% confidence interval) with a standard deviation of 4% and assuming a distance of 1% or more from the mean difference between the two groups with and without the intervention of interest requires 140 babies in the intervention and 140 babies without the intervention. The expected effect size is based on an estimated 3% increase in % fat mass in moderate to late preterm infants compared to term infants and an estimated 27% fat mass in term infants at 4 months of age. There are no good data on % fat mass beyond 4 months of age; therefore, this age has been used for the primary outcome. For (iii) To decrease time to full enteral feeds from 10 to 7 days (hazard ratio 1.43), requires 265 babies in the intervention and 265 in the non-intervention arms. Sample size is therefore 2 x 265=530. This sample size also provides >80% power on a one-sided test with an alpha of 0.05 to detect a decrease in the proportion of 2 year olds surviving free from neurodisability from 80% to 70%.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 8018 0
New Zealand
State/province [1] 8018 0
Auckland

Funding & Sponsors
Funding source category [1] 294019 0
Government body
Name [1] 294019 0
Health Research Council of New Zealand
Address [1] 294019 0
PO Box 5541, Wellesley Street, Auckland 1141
Country [1] 294019 0
New Zealand
Primary sponsor type
Individual
Name
Professor Frank Bloomfield
Address
Liggins Institute
University of Auckland
Private Bag 92019
Auckland 1142
Country
New Zealand
Secondary sponsor category [1] 292838 0
Individual
Name [1] 292838 0
Dr Jane Alsweiler
Address [1] 292838 0
AUCKLAND HOSPITAL - Bldg 599
Level 12, Room 12052
2 PARK RD
GRAFTON
AUCKLAND 1023
Country [1] 292838 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295431 0
HDEC
Ethics committee address [1] 295431 0
Ministry of Health
Freyberg Building
20 Aitken Street
PO Box 5013
Wellington
6011
Ethics committee country [1] 295431 0
New Zealand
Date submitted for ethics approval [1] 295431 0
21/06/2016
Approval date [1] 295431 0
22/07/2016
Ethics approval number [1] 295431 0
16/NTA/90

Summary
Brief summary
Our aims are to investigate the impact of different feeding strategies, all of which are in current use in NZ, on feed tolerance, body composition and on developmental outcome in MLPT babies, and to determine whether these differ by sex. We will address these aims through a factorial design randomised trial which will enable us to assess the effects of each intervention separately, whilst also exploring the effects of interactions. For the research questions being asked, this is a more appropriate and more efficient design than a multi-arm, parallel randomised controlled trial.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 67082 0
Prof Frank Bloomfield
Address 67082 0
Liggins Institute
University of Auckland
Private Bag 92019
Auckland 1142
New Zealand
Country 67082 0
New Zealand
Phone 67082 0
+64 9 9236107
Fax 67082 0
Email 67082 0
f.bloomfield@auckland.ac.nz
Contact person for public queries
Name 67083 0
Mrs Tanith Alexander
Address 67083 0
Liggins Institute
University of Auckland
Private Bag 92019
Auckland 1142
New Zealand
Country 67083 0
New Zealand
Phone 67083 0
+64 9 276 0090
Fax 67083 0
Email 67083 0
t.alexander@auckland.ac.nz
Contact person for scientific queries
Name 67084 0
Prof Frank Bloomfield
Address 67084 0
Liggins Institute
University of Auckland
Private Bag 92019
Auckland 1142
New Zealand
Country 67084 0
New Zealand
Phone 67084 0
+64 9 9236107
Fax 67084 0
Email 67084 0
f.bloomfield@auckland.ac.nz