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Trial registered on ANZCTR


Registration number
ACTRN12622000884707
Ethics application status
Approved
Date submitted
17/06/2022
Date registered
22/06/2022
Date last updated
1/06/2023
Date data sharing statement initially provided
22/06/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Bread Related Effect on MicrobiAl Distribution (BREAD) Study.
Scientific title
Effects of defatted rice bran bread on composition of intestinal microbiota of healthy adults with low dietary fibre intake: a randomised crossover trial
Secondary ID [1] 306754 0
Nil known
Universal Trial Number (UTN)
U1111-1277-9259
Trial acronym
BREAD
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Low fibre intake 325854 0
Condition category
Condition code
Diet and Nutrition 323170 323170 0 0
Other diet and nutrition disorders
Oral and Gastrointestinal 323964 323964 0 0
Normal oral and gastrointestinal development and function

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The main intervention will consist of three (females) and four (males) slices of white bread fortified with defatted rice bran (DRB) per day, which will be eaten for 4 weeks. The main intervention consists of white toast bread with 18% replacement of the flour (cereal) weight and provides 9 g (females) and 12 g (males) of total fiber per day. Of the 9 - 12 g of fiber in three to four slices of DRB bread, 2.6 g (females), 3.4 g (males) will be fiber from wheat, and 6.7 (females), 8.9 g (males) will be from DRB. Unfortified white bread will be the placebo.

Participants will not be informed of the ingredients in the bread until study completion to maintain blinding.

The study duration is a nominal total of 14 weeks; 2-week lead-in phase, 4-week intervention phase 1, 2- week washout, 4 -week intervention phase 2, and 2-week follow-up phase.

The 2-weeks lead-in phase requires participants to record their bowel motion and bread intake on a developed app every day (from study enrolment until study completion); complete a questionnaire in regards to their socioeconomic status and general wellbeing, complete a non-consecutive 3-day food diary (2nd week of lead-in phase). Participants will provide a faecal sample, and fast overnight for 9 hours one day prior to their baseline visit (2nd week of lead-in phase). Participants will undergo anthropometry measurements (height, weight, BMI, waist circumference), blood pressure measurement, provide a blood sample, complete a set of questionnaires in regards to their mental and physical health, general well-being, and clinical variables, ingest diagnostic devices (only a subset of participants, i.e. 15 participants) in capsule form, and blue food dye to measure whole gut transit time during their baseline visit (2nd week of lead-in phase).


Participants will repeat all of the aforementioned baseline visit procedures and on their post-intervention visit 1, baseline phase 2, post-intervention visit 2, and follow up. Participants will receive compensation form of vouchers during their follow-up visit.

Attendance of clinic visits and completion of questionnaires will also be assessed to measure study adherence.

The data generated with the questionnaires will be correlated to the data of the biological samples, such as the population and genetic composition of the microbiota, the abundance of metabolites, as well as physiome data from blue food dye and/or Atmo gas sensing capsules to determine the differences between the two groups.
Intervention code [1] 323250 0
Treatment: Other
Comparator / control treatment
The placebo will be a matched, commercially produced, white toast bread without the inclusion of DRB, providing 3 - 4 g fibre for females and males, respectively.
Control group
Placebo

Outcomes
Primary outcome [1] 330942 0
Differences in relative abundance of a composite of selected key genera and species of the gut microbiota known to be involved in plant glycan metabolism and/or known to be modulated by DRB after intervention with three (females)/ four (males) slices of DRB fortified bread as measured from stool samples compared to three (females)/ four (males) slices of placebo white toast bread. The composite microbiota will include genera from five phyla found in the gut microbiota of healthy human adults.
- Prevotella and Barnesiella genera and Bacteroides ovatus and Bacteroides xylanisolvens from the Bacteriodetes phylum
- Roseburia, Anaerostipes, Blautia, Eubacterium, Ruminococcus, Faecalibacterium, Lactobacillus genera from the Firmicutes (Bacillota) phylum
- Bifidobacterium and Eggerthella genera from the Actinobacteria (Actinomycetota) phylum
- Akkermansia genera from the Verrucomicrobiota phylum
- Methanobrevibacter genera from the Euryarcheaota phylum.
Timepoint [1] 330942 0
Participants will collect stool samples at baseline 1 (2nd week of lead-in phase), immediately after the intervention 1 is concluded (6th week), at baseline 2 (8th week), immediately after the intervention 2 is concluded (12th weeks), and at follow-up (2 weeks after the intervention 2 is concluded, 14th week).
Secondary outcome [1] 408152 0
Changes in predictive function (gene abundances or frequencies) of the stool microbiome after DRB bread as measured from stool samples compared to white toast bread.
Timepoint [1] 408152 0
Data will be collected at five time points: at baseline 1 (2nd week of lead-in phase), immediately after the intervention 1 is concluded (6th week), at baseline 2 (8th week), immediately after the intervention 2 is concluded (12th week), and at follow-up (2 weeks after intervention 2 is concluded).
Secondary outcome [2] 408153 0
Changes in stool metabolome and known metabolites/proteins after DRB bread compared to white toast bread.
Timepoint [2] 408153 0
Data will be collected at five time points: at baseline 1 (2nd week of lead-in phase), immediately after the intervention 1 is concluded (6th week), at baseline 2 (8th week), immediately after the intervention 2 is concluded (12th week), and at follow-up (2 weeks after intervention 2 is concluded).
Secondary outcome [3] 408154 0
A change in the composite cardiovascular risk profile measure by lipid profile assessed using a blood sample, height using a stadiometer, weight using weighing scales, waist circumference using measuring tape and blood pressure using electronic BP apparatus.
Timepoint [3] 408154 0
Data will be collected at five time points: at baseline 1 (2nd week of lead-in phase), immediately after the intervention 1 is concluded (6th week), at baseline 2 (8th week), immediately after the intervention 2 is concluded (12th week), and at follow-up (2 weeks after intervention 2 is concluded).
Secondary outcome [4] 408155 0
A change in the stool form is measured through a bowel habit diary (mobile phone app).
Timepoint [4] 408155 0
Daily starting from 2 weeks prior to intervention 1 commencement and finishing 2 weeks after intervention 2 has concluded.
Secondary outcome [5] 408156 0
To determine habitual food intake and dietary fibre intake before and after each intervention using a three-day food diary.
Timepoint [5] 408156 0
Data will be collected at five time points: at baseline 1 (2nd week of lead-in phase), immediately after the intervention 1 is concluded (6th week), at baseline 2 (8th week), immediately after the intervention 2 is concluded (12th week), and at follow-up (2 weeks after intervention 2 is concluded).
Secondary outcome [6] 408157 0
A change in gastrointestinal symptoms using the (validated) Gastrointestinal Symptoms Rating Scale (GSRS) questionnaire.
Timepoint [6] 408157 0
Data will be collected at five time points: at baseline 1 (2nd week of lead-in phase), immediately after the intervention 1 is concluded (6th week), at baseline 2 (8th week), immediately after the intervention 2 is concluded (12th week), and at follow-up (2 weeks after intervention 2 is concluded).
Secondary outcome [7] 408159 0
A change in current wellbeing using World Health Organisation - Five question Well-Being Index (WHO-5).
Timepoint [7] 408159 0
Data will be collected at five time points: at baseline 1 (2nd week of lead-in phase), immediately after the intervention 1 is concluded (6th week), at baseline 2 (8th week), immediately after the intervention 2 is concluded (12th week), and at follow-up (2 weeks after intervention 2 is concluded).
Secondary outcome [8] 408160 0
A change in mental wellbeing covering feeling and functioning aspects in relation to the past two weeks, adjusted to one week using the Warwick-Edinburgh Mental Wellbeing Scales (WEMWBS).
Timepoint [8] 408160 0
Data will be collected at five time points: at baseline 1 (2nd week of lead-in phase), immediately after the intervention 1 is concluded (6th week), at baseline 2 (8th week), immediately after the intervention 2 is concluded (12th week), and at follow-up (2 weeks after intervention 2 is concluded).
Secondary outcome [9] 408162 0
A change in fatigue scores using Multidimensional Fatigue Inventory (MFI).
Timepoint [9] 408162 0
Data will be collected at five time points: at baseline 1 (2nd week of lead-in phase), immediately after the intervention 1 is concluded (6th week), at baseline 2 (8th week), immediately after the intervention 2 is concluded (12th week), and at follow-up (2 weeks after intervention 2 is concluded).
Secondary outcome [10] 408163 0
A change in anxiety scores using Patient-Reported Outcomes Measurement Information System Questionnaire (PROMIS Anxiety).
Timepoint [10] 408163 0
Data will be collected at five time points: at baseline 1 (2nd week of lead-in phase), immediately after the intervention 1 is concluded (6th week), at baseline 2 (8th week), immediately after the intervention 2 is concluded (12th week), and at follow-up (2 weeks after intervention 2 is concluded).
Secondary outcome [11] 408165 0
A change in depression scores using Patient-Reported Outcomes Measurement Information System Questionnaire (PROMIS Depression).
Timepoint [11] 408165 0
Data will be collected at five time points: at baseline 1 (2nd week of lead-in phase), immediately after the intervention 1 is concluded (6th week), at baseline 2 (8th week), immediately after the intervention 2 is concluded (12th week), and at follow-up (2 weeks after intervention 2 is concluded).
Secondary outcome [12] 408167 0
Changes in small and large gastrointestinal transit time, gastrointestinal gas content, and gas composition assessed as a composite outcome measured by ingesting blue food dye (Royal Blue Liqua-gel® food colouring, 12 drops/1.5g) in water, and swallowing of Atmo gas capsule (a subset of participants only i.e. 15 participants).

The first 15 participants to volunteer to this measurement will be included in the sub study.
Timepoint [12] 408167 0
Blue dye be ingested at baseline 1 (2nd week of lead-in phase), immediately after intervention 1 is concluded (6th week), baseline 2 (8th week), and immediately after the intervention 2 is concluded (12th weeks).
Secondary outcome [13] 408168 0
A change in the subjective vitality by validated Subjective Vitality Scale (SVS).
Timepoint [13] 408168 0
Data will be collected at five time points: at baseline 1 (2nd week of lead-in phase), immediately after the intervention 1 is concluded (6th week), at baseline 2 (8th week), immediately after the intervention 2 is concluded (12th week), and at follow-up (2 weeks after intervention 2 is concluded).
Secondary outcome [14] 411041 0
Changes in plasma metabolome, and known metabolites/proteins after DRB bread compared to white toast bread.
Timepoint [14] 411041 0
Data will be collected at five time points: at baseline 1 (2nd week of lead-in phase), immediately after the intervention 1 is concluded (6th week), at baseline 2 (8th week), immediately after the intervention 2 is concluded (12th week), and at follow-up (2 weeks after intervention 2 is concluded).

Eligibility
Key inclusion criteria
1) Low baseline intake of dietary fibre i.e. Males: under 22 g/day and females under 18 g/day
2) No history of bowel disease
3) Non-smokers
4) Not on fibre supplement consumption during the last month prior screening
5) Regular bread consumption
6) Adults (18-65)
7) Good general health
8) A body mass index (BMI) between 18 and 35.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Inability to give informed consent
2. Indication of inability to comply with study procedures
3. Antibiotic use within the last month
4. Hypersensitivity to wheat or rice
5. Pregnant, breastfeeding, or planning a pregnancy in the three months post selection/during (study period)
6. Alarm features associated with bowel habits such as recent changes in bowel habits (onset < three months), rectal bleeding, sudden weight loss, occult blood in stool, anaemia, anal fissures, bleeding haemorrhoids, and family history of gastrointestinal cancer at an early age
7. Known significant gut disorder and disease: Chronic constipation or diarrhoea, irritable bowel syndrome (IBS), Inflammatory Bowel Disease (IBD), diverticulitis, coeliac disease, or previous bowel resection
8. Chronic disease such as cardiovascular disease, cancer, renal failure, previous upper or lower GI surgery other than cholecystectomy or appendectomy, neurological conditions such as multiple sclerosis, spinal cord injury, or stroke
9. Known systemic conditions (heart disease, kidney disease, diabetes, metabolic syndrome, psychological disorder) that could influence the gut directly or through medication use such as diabetes, opiate, or non-steroidal anti-inflammatory drugs use)
10. Fasting blood glucose less than or equal to 6.0 mmol/L
11. Laxative, pre- and probiotic use, and inability or unwillingness to stop using for the seven days before sample collections.

Non-exclusion Criteria
Diagnosed and stable systemic conditions for more than three months.
The use of selective serotonin reuptake inhibitors, tricyclics, or NSAIDs will be permitted if the medication has been used continually and the condition has been stable for more than three months.
Stable and controlled diabetes for more than three months
Inability to swallow capsules (for the ATMO sub study)

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)
Sealed opaque envelopes, with the manufacturer responsible for labelling the bread.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomly selected (by using randomised permuted blocks, block size 4) to either begin the first study phase on the DRB intervention or the placebo (white toast bread), and will receive the opposite treatment after the washout phase. Sealed envelopes with 4 pieces of paper (A,A,B,B) to be pulled out
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
Crossover
Other design features

Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
All statistical analyses will be completed by blinded researchers under the guidance of an independent biostatistician. Statistical analyses will describe the relationship between the consumption of DRB bread and the gut microbiota parameters measured.
This study is conducted as a superiority trial. The Guidelines of the CPMP do require the use of ITT analysis. ITT means that every participant that is enrolled is included in the analysis, despite dropout or non-compliance.
Categorical variables will be applied to Chi-squared tests (or Fisher’s exact tests for small samples). Continuous variables will be applied to (parametric) t-tests and (non-parametric) Mann-Whitney/Kruskal –Wallis tests for symmetrically and asymmetrically distributed data, respectively.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/07/2022
Actual
1/07/2022
Date of last participant enrolment
Anticipated
1/05/2023
Actual
30/09/2022
Date of last data collection
Anticipated
31/08/2023
Actual
22/12/2022
Sample size
Target
60
Accrual to date
Final
63
Recruitment outside Australia
Country [1] 24742 0
New Zealand
State/province [1] 24742 0
Canterbury

Funding & Sponsors
Funding source category [1] 311094 0
Government body
Name [1] 311094 0
Ministry of Business Innovation and Employment
Country [1] 311094 0
New Zealand
Funding source category [2] 311349 0
Commercial sector/Industry
Name [2] 311349 0
Goodman Fielder
Country [2] 311349 0
New Zealand
Primary sponsor type
University
Name
University of Otago
Address
Dr Martin Gagnon,
Director, Research and Enterprise, Department: Research and Enterprise, Centre for Innovation, 87 St David Street, Dunedin North, Dunedin 9016
Country
New Zealand
Secondary sponsor category [1] 312745 0
None
Name [1] 312745 0
Address [1] 312745 0
Country [1] 312745 0
Other collaborator category [1] 282274 0
Other Collaborative groups
Name [1] 282274 0
AgResearch
Address [1] 282274 0
AgResearch Tennent Drive 11 Dairy Farm Road Fitzherbert Palmerston North 4442
Country [1] 282274 0
New Zealand
Other collaborator category [2] 282275 0
Other Collaborative groups
Name [2] 282275 0
The Riddet Institute
Address [2] 282275 0
The Riddet Institute
University Avenue Fitzherbert Palmerston North 4474
Country [2] 282275 0
New Zealand
Other collaborator category [3] 282276 0
Other Collaborative groups
Name [3] 282276 0
Plant and Food Research
Address [3] 282276 0

120 Mt Albert Road Sandringham Auckland 1025
Country [3] 282276 0
New Zealand
Other collaborator category [4] 282326 0
Other Collaborative groups
Name [4] 282326 0
ATMO Bioscience
Address [4] 282326 0
Ground Floor/436 Elgar Rd, Box Hill VIC 3128, Australia
Country [4] 282326 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310627 0
The University of Otago Human Ethics Committee (Health)
Ethics committee address [1] 310627 0
Ethics committee country [1] 310627 0
New Zealand
Date submitted for ethics approval [1] 310627 0
09/05/2022
Approval date [1] 310627 0
23/05/2022
Ethics approval number [1] 310627 0
H22/061.

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 118314 0
Prof Nicole Roy
Address 118314 0
Department of Human Nutrition,
University of Otago
7n8, Level 7, Science 2 Building
70 Union Street West
Dunedin North
Dunedin 9016
Country 118314 0
New Zealand
Phone 118314 0
+64 3 479 7959
Fax 118314 0
Email 118314 0
[email protected]
Contact person for public queries
Name 118315 0
Simone Bayer
Address 118315 0
Department of Medicine,
University of Otago, Christchurch,
2 Riccarton Avenue
Christchurch Central
Christchurch 8011
Country 118315 0
New Zealand
Phone 118315 0
+64 21 279 1519
Fax 118315 0
Email 118315 0
[email protected]
Contact person for scientific queries
Name 118316 0
Simone Bayer
Address 118316 0
Department of Medicine,
University of Otago, Christchurch,
2 Riccarton Avenue
Christchurch Central
Christchurch 8011
Country 118316 0
New Zealand
Phone 118316 0
+64 21 279 1519
Fax 118316 0
Email 118316 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
Individual data is not available to the public. it would be a breach of data security.


What supporting documents are/will be available?




Results publications and other study-related documents

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No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.