Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620000026921
Ethics application status
Approved
Date submitted
27/11/2019
Date registered
17/01/2020
Date last updated
3/05/2022
Date data sharing statement initially provided
17/01/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Seeding throUgh FeediNg: nourishing the infant microbiome to support immune health
Scientific title
Seeding throUgh FeediNg: nourishing the infant microbiome to support immune health 'The SUN' randomised controlled trial
Secondary ID [1] 299683 0
None
Universal Trial Number (UTN)
U1111-1244-9285
Trial acronym
SUN Study
Linked study record
ACTRN12618000157279 is the identifier for the feasibility study that preceded this present study and gave guidance on how to conduct this larger RCT.
The study design and prebiotic intervention for the present study have been modeled on findings from the feasibility study, where the prebiotic intervention proved to be an acceptable food to be introduced to infants at around 6 months of age.

Health condition
Health condition(s) or problem(s) studied:
Immune health 315035 0
Gut microbiome 315036 0
Condition category
Condition code
Diet and Nutrition 313365 313365 0 0
Other diet and nutrition disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study remains a double-blind, randomised controlled trial with 300 infants who have not yet started solids and their mothers. Infants will be randomised into one of three groups: control arm (C), standard kumara intervention (K), and a kumara intervention with added resistant starch from bananas (K+) to be consumed daily for a period of 4 months, until the infant is approximately 10 months old. The kumara intervention product for the K and K+ groups will be the same freeze-dried kumara product that was used in the feasibility study (ACTRN12618000157279) and approved for use in the original study design. The banana resistant starch will be added to the K+ kumara to provide a product which is 8g/100g of resistant starch. This will provide approximately 2g of resistant starch per serving per day. Food Standards Australia New Zealand permit the addition of inulin derived substances (non- starch polysaccharides) to infant foods at 1.6 g/serve (Standard 2.9.2 and 2.9.3). Studies of infants provided with 4.5g of inulin per day in weaning foods have demonstrated that this is well tolerated with no adverse effects reported.

The kumara powder is intended to commence as soon as parents /caregivers introduce the first complementary food to their infant and is to be offered daily until infants are consuming approximately 5 g (1 tsp) of powder per day. The kumara powder is prepared by mixing the powder with hot (not boiling) water to form an age-and stage-appropriate paste, where it can be eaten alone or added to infant food(s). The kumara powder has been shown to be acceptable food for infants with no recorded adverse effects, in a previous pilot study (ACTRN12618000157279). It is provided in a form that can be consumed ad libitum and the required daily amount will not displace other foods of important nutrient composition in the infant’s diet.

Parents/caregivers of infants randomised to the K and K+ groups will be supplied with all the intervention food for participation in this research for a total of 4 months, where the study will be completed when infants are around 10 months of age. Adherence to the intervention will be measured using a prospective daily record completed by parents/caregivers and information from a monthly questionnaire on the average amount of kumara powder consumed per day in the previous month.
Intervention code [1] 315949 0
Prevention
Comparator / control treatment
The addition of a control group (C) will allow us to compare usual feeding practice to usual feeding practice + kumara on health outcomes, microbiome diversity, reported sleep, and growth. We acknowledge that adding a control arm has some limitations in that participation and retention in the trial may be challenging. All parents in the trial will be provided with a koha and parents in the control arm will be provided with a supermarket voucher valued at $5.00 per week – equivalent to the cost of the kumara intervention.

Adherence to the comparator kumara group will be measured using a daily record completed by parents/caregivers prospectively and information from a monthly questionnaire on the average amount of kumara consumed per day in the previous month. Participants in the control group will not have to complete an adherence record.
Control group
Active

Outcomes
Primary outcome [1] 321847 0
Difference in GP-confirmed respiratory infections at 10 months [Follow up of the infants will be performed at 2 months and 4 months of intervention]. Parent self-report of respiratory infections validated by GP records collected via a weekly health record.
Timepoint [1] 321847 0
Measured at 10 months.
Secondary outcome [1] 376459 0
Infant health assessed using daily records of illness (reporting frequency, illness type, medication prescribed, use of antibiotics, antibiotic course length), verified using medical records from GP/health practitioners for infection-related visits, medication use, and hospitalisation events between 6 to 10 months of age.
Timepoint [1] 376459 0
Measured at <6 months of age, 8 months of age, 10 months of age.
Secondary outcome [2] 376576 0
Height assessed by measuring mat
Timepoint [2] 376576 0
Measured at <6 months of age, 8 months of age, 10 months of age.
Secondary outcome [3] 376577 0
Weight assessed by infant scales
Timepoint [3] 376577 0
Measured at <6 months of age, 8 months of age, 10 months of age.
Secondary outcome [4] 376578 0
Differences in concentrations of infant immune markers and protective antibody responses to the oral rota virus vaccine assessed using gas chromatography-mass-spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) methods for global metabolite profiling and total antibody titres.
Timepoint [4] 376578 0
Measured at <6 months of age, 10 months of age.
Secondary outcome [5] 376579 0
Difference in breast milk vaccine-specific titre quantification and concentration of secretory IgA (sIgA) factors (breastfeeding mothers only), assessed using 16S rRNA gene sequencing, human milk oligosaccharides (HMOs) characterised using High Performance Liquid Chromatography (HPLC), and the lipidome characterised using Liquid Chromatography-Mass Spectrometry (LCMS)
Timepoint [5] 376579 0
Measured at <6 months of age, 8 months of age, 10 months of age.
Secondary outcome [6] 376580 0
Difference in infant dietary intake assessed using a complementary feeding food frequency questionnaire (CFFQ) and 3-day weighed food records.

Judd AL, Beck KL, McKinlay C, Jackson A, Conlon CA. Validation of a Complementary Food Frequency Questionnaire to assess infant nutrient intake. Maternal & child nutrition. 2020 Jan;16(1):e12879..
Timepoint [6] 376580 0
Measured at 8 months of age, 10 months of age.
Secondary outcome [7] 376581 0
Difference in maternal dietary intake assessed using a food frequency questionnaire

Sam CH, Skidmore P, Skeaff S, Parackal S, Wall C, Bradbury KE. Relative Validity and Reproducibility of a Short Food Frequency Questionnaire to Assess Nutrient Intakes of New Zealand Adults. Nutrients. 2020 Mar;12(3):619.
Timepoint [7] 376581 0
Measurements at baseline and completion (infant age 10 months).
Secondary outcome [8] 376582 0
Difference in maternal stool microbiota assessed using shotgun sequencing of metagenetic DNA using Illumina HiSeq platform in conjunction with microbial profiling by pyrotag sequencing of bacteria 16S sRNA gene amplicons
Timepoint [8] 376582 0
Measured at <6 months of age, 8 months of age, 10 months of age.
Secondary outcome [9] 377892 0
Difference in concentrations of infant immune biomarkers and protective antibody responses to the intramuscular pneumococcal vaccination assessed using gas chromatography-mass-spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) methods for global metabolite profiling and total antibody titres.
Timepoint [9] 377892 0
Measured at <6 months of age, 8 months of age, 10 months of age.
Secondary outcome [10] 409289 0
Differences in infant faecal microbiome abundance, diversity and protective antibody response assessed using shotgun sequencing of metagenetic DNA using Illumina HiSeq platform in conjunction with microbial profiling by pyrotag sequencing of bacteria 16S sRNA gene amplicons
Timepoint [10] 409289 0
Measured when infant is <6 months of age, 8 months of age, 10 months of age
Secondary outcome [11] 409290 0
Differences in infant faecal microbiome production of short chain fatty acids (SCFA) and intermediate metabolites.
Timepoint [11] 409290 0
<6 months, 8 months and 10 months
Secondary outcome [12] 409291 0
Difference in night-time sleep, day-time sleep and activity of infants assessed using actigraphy and sleep dairies.
Timepoint [12] 409291 0
<6 months, 8 months, 10 months

Eligibility
Key inclusion criteria
Healthy infants under 4 months of age and their mothers are able to enroll with the expectation that the infants will be introduced to their first complimentary foods before 6 months of age, as per the New Zealand Ministry of Health Food and Nutrition Guidelines.
Minimum age
2 Months
Maximum age
6 Months
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Infants will be ineligible for enrollment if they:
Were born <32 weeks’ gestation;
Have a developmental disability (i.e.,autism, intellectual disability);
An illness likely to influence their nutritional status (e.g., a chronic illness known to cause malabsorption, digestive or metabolic disorders);
Have health conditions that affect feeding;
Are undergoing treatment with antibiotics;
Are receiving a supplement with a pre and/or probiotic;
Or whose parents written or spoken English comprehension is likely to make participation difficult for them.

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)
The randomisation list will be prepared by a statistician working independently of the study team. The numbers will be supplied to the food manufacturer, where an independent person not involved in the research will place labels on the prebiotic intervention. The researchers will be blinded to this process and the allocation sequence will be concealed throughout the trial.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Eligible participants will be randomised at a 1:1:1 ratio to (1) kumara intervention (K), or (2) kumara intervention with added resistant starch from bananas (K+), or (3) usual feeding practice (control), using computer-generated randomisation sequences. One group will receive a standard kumara powder (K), another group will receive a kumara powder with an increased amount of resistant starch (K+), achieved by adding resistant starch from freeze-dried green banana. The third group will not receive any kumara powder (control)..
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
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Participants’ data will be stored in secure study database and imported to SAS version 9.4 for data analysis at the end of the trial. The final results will be reported in concordance with the CONSORT guidelines (CONSORT 2010 statement) and international good clinical practice (GCP). The trial statistician is Yannan Jiang (YJ).

Demographic and baseline characteristics of all randomised participants will be summarised for each group using descriptive statistics. Categorical variables will be described as frequencies and percentages. Continuous variables will be described as mean and standard deviation (SD), or median and interquartile range (IQR) as appropriate. Descriptive data on important subgroups (sex and ethnicity) will also be presented if enough number of participants are recruited. No formal statistical tests will be conducted to compare the two groups at baseline, as recommended by the CONSORT guidelines.
Primary outcome analysis will be conducted by intention-to-treat (where participants are analysed according to their allocated treatment arm). This will include all randomised participants where a valid outcome is obtained at follow up. The impact of missing data on the primary outcome will be explored in sensitivity analysis using different imputation strategies to test the robustness of the main results.

A secondary analysis of outcomes will be conducted using a per-protocol (PP) population, including those participants in the ITT population who have no major protocol deviations. Inclusion in the PP population and analysis will be based on degree of intervention compliance, define as the total number of days where less than the pre-defined amount of intervention food was consumed per day within the last study month. This information will be determined using a monthly intervention adherence record completed by parents or caregivers. Adherence will be defined as consumption of 5 g of the intervention food per day on 80% of the days within the monitored interval.

Generalised linear regression models will be used on the primary and secondary outcomes to test the group differences at 2- and 4-months follow up, using a link function appropriate to the distribution of the outcome measure. All regression analyses will be adjusted for baseline outcome value (if available) and stratification variables (gender and ethnicity). The effect of the intervention will be estimated and tested using model-adjusted point estimate on the group difference with 95% confidence interval (CI). Statistical tests will be two-sided at a 5% significance level. Multiple testing on secondary outcomes will not be adjusted as they are considered exploratory and provide supporting information on the primary outcome. A random-effects mixed model will be used on the outcomes collected repeatedly over time, to account for correlated data collected from the same participants and take into account any missing data in maximum likelihood estimates. The consistency of the short and long-term effects of the dietary intervention will be assessed using the interaction term between treatment group and visit. The effects of the intervention on pre-defined subgroups will also be assessed, and separate subgroup analyses will be considered if enough number of participants are recruited. A detailed statistical analysis plan (SAP) will be written prior to study completion and final analysis. This will include the planned trial analysis for the primary outcome and all proposed secondary outcomes and subgroup analyses.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
3/01/2022
Actual
27/01/2022
Date of last participant enrolment
Anticipated
31/05/2023
Actual
Date of last data collection
Anticipated
30/09/2023
Actual
Sample size
Target
300
Accrual to date
42
Final
Recruitment outside Australia
Country [1] 21977 0
New Zealand
State/province [1] 21977 0
Auckland

Funding & Sponsors
Funding source category [1] 304160 0
Government body
Name [1] 304160 0
Ministry of Business, Innovation and Employment Science Challenge
Country [1] 304160 0
New Zealand
Primary sponsor type
University
Name
The University of Auckland, Faculty of Medical and Health Science
Address
85 Park Road
Grafton
Auckland 1023
Country
New Zealand
Secondary sponsor category [1] 304647 0
None
Name [1] 304647 0
Address [1] 304647 0
Country [1] 304647 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304637 0
Health and Disabilities ethics Committee
Ethics committee address [1] 304637 0
Ministry of Health
No 1 The Terrace
PO Box 5013
Wellington 6145
Ethics committee country [1] 304637 0
New Zealand
Date submitted for ethics approval [1] 304637 0
05/12/2019
Approval date [1] 304637 0
19/05/2020
Ethics approval number [1] 304637 0
20/NTA/9

Summary
Brief summary
The SUN RCT is a double-blind, randomised controlled trial and will involve 300 infants who have not yet started solids and their mothers. The food-based intervention (kumara powder) will start at around 6 months of age (the recommended age for introduction of complementary feeding, according to the NZ Ministry of Health and World Health Organisation recommendations). The study will be completed four months after the introduction of solids (i.e., when your baby is around 10 months of age).

Participants will be randomised to one of three groups (100 infants in each group). One group will receive a standard kumara powder, another group will receive the kumara powder with an increased amount of resistant starch (prebiotic) from banana, and a third group will be the control group. The control group will not be required to give their child any kumara powder. If randomised to a kumara group, participants will be asked to gradually introduce the kumara powder their baby is consuming approximately 5 g (1 tsp) of powder per day. The kumara is prepared by mixing the powder with hot (not boiling) water to form an age-and stage-appropriate paste and adding it to infant food(s). Participants will be supplied with all the kumara powder required for participation in this study at no cost. The kumara powder will be provided every 2 months at your clinic visit. Both kumara groups involve the use of an accepted ingredient in infant nutrition (kumara) which is manufactured in a registered facility that complies with Food Standards Australia and New Zealand Guidelines, with respect to manufacturing standards and compliance with food safety requirements, including allergy management. If randomised to control group, participants will receive a gift voucher to the value of the provided kumara.

The purpose of the SUN RCT is to determine whether a food (kumara), consumed as a first food, will be beneficial to the development of the infant microbiome (the bacteria within the digestive tract) and whether this can support infant immune health (including illness frequency and sleep behaviours). Resistant starch is a carbohydrate that resists digestion and acts as a prebiotic food for the good gut bacteria. This study will be conducted in Auckland, New Zealand.
Trial website
www.thesunstudy.auckland.ac.nz
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 97674 0
Prof Clare R Wall
Address 97674 0
Academic Director Nutrition and Dietetics
Discipline of Nutrition,
School of Medical Science
Medical School Campus
University of Auckland
Private Bag 92019
Auckland 1142
Country 97674 0
New Zealand
Phone 97674 0
+64 9 923 9875
Fax 97674 0
Email 97674 0
[email protected]
Contact person for public queries
Name 97675 0
Ms Hannah Eriksen
Address 97675 0
Clinical Trial Coordinator, Discipline of Nutrition, School of Medical Science, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019 Auckland 1142
Country 97675 0
New Zealand
Phone 97675 0
+64 9 923 9875
Fax 97675 0
Email 97675 0
[email protected]
Contact person for scientific queries
Name 97676 0
Prof Clare R Wall
Address 97676 0
Academic Director Nutrition and Dietetics
Discipline of Nutrition,
School of Medical Science
Medical School Campus
University of Auckland
Private Bag 92019
Auckland 1142
Country 97676 0
New Zealand
Phone 97676 0
+64 9 923 9875
Fax 97676 0
Email 97676 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
No IPD sharing has been approved under the ethics approval for this study.


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.