Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12617000990325
Ethics application status
Approved
Date submitted
1/07/2017
Date registered
10/07/2017
Date last updated
20/06/2022
Date data sharing statement initially provided
21/11/2018
Date results information initially provided
19/05/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Food 4 Health: using probiotics and prebiotic cereals to reduce blood sugar levels in adults at risk of developing type 2 diabetes
He Oranga Kai
Scientific title
Food 4 Health: A study to test whether probiotics and prebiotic cereals in adults with pre-diabetes reduces HbA1c and improves other markers of metabolic health and general well being.
He Oranga Kai
Secondary ID [1] 291997 0
None
Universal Trial Number (UTN)
U1111-1195-7561
Trial acronym
F4H
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pre-diabetes 303356 0
Cardiovascular risk factors 303357 0
Depression and Anxiety 303358 0
Condition category
Condition code
Metabolic and Endocrine 302783 302783 0 0
Diabetes
Cardiovascular 302784 302784 0 0
Hypertension
Mental Health 302785 302785 0 0
Depression

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Study participants will be randomly allocated to these treatment arms, and interventions taken daily for 6 months.
Arm 1 - 1 capsule (containing Lactobacillus rhamnosus HN001 (6x10^9 colony forming units) + 139mg maltodextrin) and cereal mix (containing 40 g Uncle Toby’s rolled oats and 8g of OatWell® 28XF oatbran. ß-glucan dose 4 g, average total fibre 7.8g ).
Arm 2 - 1 placebo capsule and cereal mix (containing 40 g Uncle Toby’s rolled oats and 8g of OatWell® 28XF oatbran. ß-glucan dose 4 g, average total fibre 7.8g).
Arm 3 - 1 capsule (containing Lactobacillus rhamnosus HN001 (6x10^9 colony forming units) + 139 mg maltodextrin) and cereal mix (containing 35g Sanitarium cornflakes and 8g Non Dairy Creamer – C35 Average total fibre 0.9g)
Arm 4 - 1 placebo capsule and cereal mix (containing 35g Sanitarium cornflakes and 8g Non Dairy Creamer – C35 Average total fibre 0.9g).
Capsules will be taken orally once a day. Cereals taken once a day using a range of recipe options including cold cereal, hot porridge, or smoothies.
Interventions will be dispensed at 3 month intervals and unused study capsules and cereals collected and counted by a member of the study not involved in fieldwork.
Intervention code [1] 298119 0
Prevention
Intervention code [2] 298121 0
Treatment: Other
Intervention code [3] 298122 0
Lifestyle
Comparator / control treatment
Probiotic placebo - 150mg (corn derived) maltodextrin
Beta glucan cereal placebo - 35g Sanitarium cornflakes and 8g Non Dairy Creamer – C35 (total fibre 0.9g)
Control group
Placebo

Outcomes
Primary outcome [1] 302173 0
HbA1c in blood sample
Timepoint [1] 302173 0
6 months after study enrolment
Secondary outcome [1] 335060 0
HbA1c in blood sample
Timepoint [1] 335060 0
At 3 and 9 months after study enrolment.
Secondary outcome [2] 335063 0
Fasting plasma glucose
Timepoint [2] 335063 0
At 3, 6 and 9 months after study enrolment.
Secondary outcome [3] 335064 0
Fasting plasma insulin levels
Timepoint [3] 335064 0
At 3, 6 and 9 months after study enrolment.
Secondary outcome [4] 335065 0
Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)
Timepoint [4] 335065 0
At 3, 6 and 9 months after study enrolment.
Secondary outcome [5] 335066 0
Fasting lipids in blood sample.
Timepoint [5] 335066 0
At 3, 6 and 9 months after study enrolment.
Secondary outcome [6] 335071 0
High sensitivity C-reactive protein (hs CRP) in blood sample.
Timepoint [6] 335071 0
At 3, 6 and 9 months after study enrolment.
Secondary outcome [7] 335274 0
Blood pressure measured using calibrated syphgmomanometer.
Timepoint [7] 335274 0
At 3, 6 and 9 months after study enrolment.
Secondary outcome [8] 335277 0
Anthropometric measures (weight, BMI, waist circumference) using standarised protocols and calibrated scales
Timepoint [8] 335277 0
At 3, 6 and 9 months after study enrolment.
Secondary outcome [9] 335279 0
Faecal sample gut microbiota
Timepoint [9] 335279 0
At 3, 6 and 9 months after study enrolment.
Secondary outcome [10] 335281 0
Health related quality of life measured on 36-Item Short Form Health Survey (SF-36 v2 Australia/New Zealand Adaptation).
Timepoint [10] 335281 0
At 3, and 9 months after study enrolment
Secondary outcome [11] 335282 0
Symptoms of depression, anxiety and stress measured by shortened version of the Depression Anxiety Stress Scales (DASS 21).
Timepoint [11] 335282 0
At 6 and 9 months after study enrolment
Secondary outcome [12] 335284 0
Acceptability of study interventions to study participants. Assessed: 1. in sub group of study participants by semi-structured individual interviews and participant focus groups 2. all participants as determined by survey designed for study.
Timepoint [12] 335284 0
At 2-3 months after commencing study interventions (interviews) At 6 month visit, when participant has finished taking study interventions (survey) At 6-9 months after enrolment, which is the period after participants have finished taking study interventions (participant focus groups).
Secondary outcome [13] 335287 0
Factors which could influence implementing the interventions in general practice/wider health care contexts. Assessed: 1. in sub group of study participants by semi-structured individual interviews and participant focus groups 2. all participants by determined by survey designed for study 3. focus groups with health providers.
Timepoint [13] 335287 0
At 2-3 months after commencing study interventions (study participant interviews) At 6 month visit, when participant has finished taking study interventions (study participant survey) At 6-9 months which is the period after participants have finished taking study interventions (participant focus groups. and health professional focus groups).

Eligibility
Key inclusion criteria
For the Factorial design randomised controlled trial ( RCT):
English speaking adults aged between 18 and 80 years with pre-diabetes defined as an HbA1c 41 - 49 mmol/mol. Participants will be included if their HbA1c is 41 - 44 mmol/mol within the four months before study enrolement, or 45-49 mmol/mol within 12 months.

For Qualitative aspects of study:
1. Population for semi structured individual interviews, and participant focus groups. Four sub groups from the study participants of the RCT who self identify as Maori, Pacific, Indian/South Asian and Other, and who are allocated to Oat intervention arms of study.
2. Population for Health care provider focus groups - a purposeful sampling of disciplines identified as those who would implement study findings into practice if a clinically meaningful benefit of study interventions is demonstrated. For example, general practitioners, nurses, pharmacists, dietitians, health promoters, community health workers and health navigators, ,
Minimum age
18 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
For RCT
Pre-existing type 1 or type 2 diabetes or previous bariatric surgery
Current pregnancy or planning to conceive during the duration of study enrolment
Breastfeeding
Current use of medications that modify blood sugar levels
Unstable body weight (active weight loss/gain > 5 kg in prior 3 months)
Weight > or equal to 200kg
Abnormal thyroid function
Has a serious immunological disorder that suppresses immune function
A medical condition requiring immune suppressant drugs
Requires long-term use of systemic antibiotics
Structural heart disease (known valve abnormality or replacement history of endocarditis) or vascular implants except cardiac stents.
Has coeliac disease or allergy or intolerance to any cereal components
Does not agree to refrain from taking probiotic supplements during study period (except where medically advised).
Uses fibre/prebiotic, (including beta glucan) supplements and is unable or unwilling to cease using these for the study duration
Presence of a gastrointestinal disorder or medication that alters the digestion and absorption of nutrients
Current significant renal disease (eGFR <30)
Is participating in, or, has recently participated in another research study involving an intervention
Plans to move from study centre during the period of the participant’s study enrolment
Lives with another participant who is already enrolled in this study.
Does not agree to refrain from donating blood for 2 months prior to each study visit
Any other condition or situation, which in the view of investigators would affect the compliance or safety of the individual taking part.

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)
At enrolement field staff will allocate the next numbered container of capsules.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A random order sequence will be computer generated in blocks by an independent external person.
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
The people analysing the results/data
Intervention assignment
Factorial
Other design features
Blinding/masking applies to study capsules only.
Due to the different appearance of cereals blinding is not possible for this component of the study, however participants are not informed about which is the control cereal.
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Analyses will be by intention-to-treat based on the randomization. With the relatively modest sample size we are not planning to stratify randomisation but important co-variates will be collected and an important selection of these will be used as a sensitivity analysis. The primary analysis of the primary outcome variable will be by ANCOVA, with the six-month HbA1c as the response variable, and with the baseline measurement of HbA1c as a continuous co-variate as well as the randomized treatments and the interaction between randomized treatments as categorical explanatory variables. We plan to estimate the main effects of the interventions if the interaction term is not statistically significant. For the other continuous outcome variables we also plan to use ANCOVA. Normality assumptions will be checked and either data transformations or rank-based estimates used if normality assumptions are strongly violated. Logistic regression for assessment of dichotomous variables in relation to randomised treatments will be used. As a form of sensitivity analysis the following important co-variates: ethnicity, BMI, fasting glucose, and HOMA; will be assessed in ANCOVA models to check that conclusions are robust to possible maldistribution of important covariates.
There are few published studies reporting HbA1c change with lifestyle or pharmaceutical intervention in pre-diabetes. In a trial by Defronzo et al Pioglitazone reduced HbA1c by 0.24% (2.6 mmol/mol) relative to placebo (DeFronzo et al., 2011). Past research reports the standard deviation (SD) of HbA1c in similar clinical samples is between 4 and 6 mmol/mol (Parker, Byham-Gray, Denmark, & Winkle, 2014). If we use a clinically important difference of HbA1c of 5mmol/mol, as for established T2DM, and the larger SD then a sample size of 32 in each main effects arm has 90% power to detect this with a Type I error rate of 5%. Accounting for 25% drop-out a total sample size of 88 is needed (22 in each factorial combination). The power to detect differences is likely to be improved by using baseline HbA1c as a continuous co-variate. However, an uncertainty for this study is whether the minimal clinically important difference (MCID) for reduction of HbA1c in the setting of pre-diabetes should be anticipated to be closer to that seen in the Pioglitazone study (increasing the required sample size) and that the SD of the HbA1c is likely to be smaller in pre-diabetes than T2DM (decreasing the required sample size). For 80% power to detect a difference of 2.6 mmol/mol with an SD of 4 and 25% drop-out a total recruitment of 92 is needed, and for 90% power n=136. For a difference of 3.8 mmol/mol, half-way between the two values, and the larger SD of 6, a total sample size of 152 participants with 38 in each factorial combination, will be recruited for this study.
We have chosen not to use a co-primary outcome variable but we are interested in an important secondary outcome variable in the assessment of differences in mood variables. The nominated sample size has 80% power to detect an effect size (mean divided by standard deviation) of 0.6 Although this is a relatively large effect size by the standards of psychological variables this is in fact the effect size is reported for pharmacological interventions in depression in those with T2DM from a Cochrane review (Baumeister, Hutter, & Bengel, 2014).
If efficacy of study interventions is proven in stage 3 a thematic analysis of data will be undertaken looking for themes in relation to intervention acceptability and uptake and it is possible participants may record comments about health beliefs about pre-diabetes and food interventions, health literacy, lifestyle behaviour change and self-management strategies. Depending on survey return, it may be possible for the analysis to take account of cultural difference
In addition, a per protocol analysis will be undertaken.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
19/02/2018
Actual
19/02/2018
Date of last participant enrolment
Anticipated
29/03/2019
Actual
29/03/2019
Date of last data collection
Anticipated
31/03/2020
Actual
19/12/2019
Sample size
Target
152
Accrual to date
Final
153
Recruitment outside Australia
Country [1] 8912 0
New Zealand
State/province [1] 8912 0
Wellington

Funding & Sponsors
Funding source category [1] 296511 0
Government body
Name [1] 296511 0
Health Research Council
Country [1] 296511 0
New Zealand
Funding source category [2] 296516 0
Government body
Name [2] 296516 0
Ministry of Health
Country [2] 296516 0
New Zealand
Funding source category [3] 296517 0
Other Collaborative groups
Name [3] 296517 0
Healthier Lives National Science Challenge
Country [3] 296517 0
New Zealand
Funding source category [4] 296579 0
Commercial sector/Industry
Name [4] 296579 0
Fonterra Co-operative Group Limited
Country [4] 296579 0
New Zealand
Primary sponsor type
University
Name
University of Otago, Wellington
Address
PO Box 7343
Wellington South 6242
Country
New Zealand
Secondary sponsor category [1] 295478 0
None
Name [1] 295478 0
Address [1] 295478 0
Country [1] 295478 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297732 0
Central Health and Disability Ethics Committee
Ethics committee address [1] 297732 0
Ministry of Health
133 Molesworth Street
PO Box 5013
Wellington
6011
Ethics committee country [1] 297732 0
New Zealand
Date submitted for ethics approval [1] 297732 0
08/05/2017
Approval date [1] 297732 0
22/06/2017
Ethics approval number [1] 297732 0
17/CEN/88

Summary
Brief summary
A quarter of New Zealanders have pre-diabetes which is a condition that can progress to type 2 diabetes and cause significant long term health problems including cardiovascular disease, There is now exciting research demonstrating that microbes in our gut affect our health in many ways, including how our bodies process foods and sugars. We can modify our gut microbes by taking supplements of probiotics (which contain live bacteria that give health benefits) and cereals (which contain substances that support the growth of gut microbes). This study is a blinded randomised placebo-controlled trial with four groups. Adults with pre-diabetes will take a study capsule containing either a probiotic or a placebo and a daily portion of one of two different cereals daily for 6 months. Study followup will continue for 3 months after stopping the study interventions.

The study will examine changes in blood tests including HbA1c ( a measure of blood glucose levels over the previous 8-12 weeks), fasting glucose, insulin and lipids. In addition, it will examine changes in blood pressure, weight, and waist circumference, body mass index and general well being/health related quality of life.

Some study participants will also take part in individual interviews and group discussions aimed at helping us learn about the acceptability of the study interventions, and factors that would support long-term use of the interventions if they are proven to be effective.

If the interventions are found to have clinically important beneficial effects group discussions will also be held with health professionals and others who might recommend the interventions. This is to find the best ways to ensure that the interventions are adopted.
Trial website
http://www.otago.ac.nz/food4health 
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 74970 0
Prof Jeremy Krebs
Address 74970 0
Department of Medicine
University of Otago, Wellington
PO Box 7343
Newtown
Wellington 6242
Country 74970 0
New Zealand
Phone 74970 0
+64 4 3855999
Fax 74970 0
Email 74970 0
Jeremy.Krebs@otago.ac.nz
Contact person for public queries
Name 74971 0
Ms Christine Barthow
Address 74971 0
Department of Medicine
University of Otago, Wellington
PO Box 7343
Newtown
Wellington 6242
Country 74971 0
New Zealand
Phone 74971 0
+64 4 9186237
Fax 74971 0
Email 74971 0
christine.barthow@otago.ac.nz
Contact person for scientific queries
Name 74972 0
Prof Jeremy Krebs
Address 74972 0
Department of Medicine
University of Otago, Wellington
PO Box 7343
Newtown
Wellington 6242
Country 74972 0
New Zealand
Phone 74972 0
+64 4 3855999
Fax 74972 0
Email 74972 0
Jeremy.Krebs@otago.ac.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
The datasets generated and analysed during the current study are not publicly available, but reasonable requests to the corresponding author will be considered on a case-by-case basis.
When will data be available (start and end dates)?
May 2022 onwards with no end date determined
Available to whom?
Not pre-specified as availability of data will be determined upon request
Available for what types of analyses?
Not pre-specified as availability of data will be determined upon request
How or where can data be obtained?
Christine.barthow@otago.ac.nz


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
7996Study protocolBarthow, C., F. Hood, E. McKinlay, J. Hilder, C. Cleghorn, M. Huthwaite, M. Weatherall, A. Parry-Strong, S. Pullon, B. Gray, K. Wickens, J. Crane, and J. Krebs. 2019. “Food 4 Health - He Oranga Kai: Assessing the Efficacy, Acceptability and Economic Implications of Lactobacillus Rhamnosus HN001 and ß-Glucan to Improve Glycated Haemoglobin, Metabolic Health, and General Well-Being in Adults with Pre-Diabetes: Study Protocol for a 2 × 2 factorial design, parallel group, placebo-controlled randomized controlled trial, with embedded qualitative study and economic analysis.” Trials 20(1):464.  
7997Statistical analysis planBarthow, C., F. Hood, E. McKinlay, J. Hilder, C. Cleghorn, M. Huthwaite, M. Weatherall, A. Parry-Strong, S. Pullon, B. Gray, K. Wickens, J. Crane, and J. Krebs. 2019. “Food 4 Health - He Oranga Kai: Assessing the Efficacy, Acceptability and Economic Implications of Lactobacillus Rhamnosus HN001 and ß-Glucan to Improve Glycated Haemoglobin, Metabolic Health, and General Well-Being in Adults with Pre-Diabetes: Study Protocol for a 2 × 2 factorial design, parallel group, placebo-controlled randomized controlled trial, with embedded qualitative study and economic analysis.” Trials 20(1):464.https://doi.org/10.1186/s13063-019-3553-7 
7998Informed consent form  Christine.Barthow@otago.ac.nz Consent forms available on request
7999Ethical approval    372978-(Uploaded-09-03-2020-18-41-04)-Study-related document.pdf


Results publications and other study-related documents

Documents added manually
TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
Study results articleYes Barthow C, Hood F, Crane J, Huthwaite M, Krebs J, ... [More Details]
Study results articleYes McKinlay E, Hilder J, Hood F, Morgan S, Barthow C,... [More Details]

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseInsights on beta-glucan as a prebiotic coadjuvant in the treatment of diabetes mellitus: A review.2022https://dx.doi.org/10.1016/j.fhfh.2022.100056
EmbaseA randomised controlled trial of a probiotic and a prebiotic examining metabolic and mental health outcomes in adults with pre-diabetes.2022https://dx.doi.org/10.1136/bmjopen-2021-055214
EmbaseFood 4 Health - He Oranga Kai: Assessing the efficacy, acceptability and economic implications of Lactobacillus rhamnosus HN001 and beta-glucan to improve glycated haemoglobin, metabolic health, and general well-being in adults with pre-diabetes: Study protocol for a 2 x 2 factorial design, parallel group, placebo-controlled randomized controlled trial, with embedded qualitative study and economic analysis.2019https://dx.doi.org/10.1186/s13063-019-3553-7
N.B. These documents automatically identified may not have been verified by the study sponsor.