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Trial registered on ANZCTR


Registration number
ACTRN12623000628640
Ethics application status
Approved
Date submitted
28/05/2023
Date registered
7/06/2023
Date last updated
1/11/2023
Date data sharing statement initially provided
7/06/2023
Date results information initially provided
1/11/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Effect of a2 milk on brain health, immune function, inflammatory markers, gastrointestinal function and skin health, compared to regular cow's milk, in healthy older adolescents and adults in a real world setting.
Scientific title
Effect of milk containing only a2 beta-casein protein on brain function, immune function and inflammatory markers, gastrointestinal function, and skin health as compared to conventional milk which contains A2 and A1 beta-casein, in healthy older adolescents and adults in a real world setting.
Secondary ID [1] 309747 0
None
Universal Trial Number (UTN)
U1111-1290-1964
Trial acronym
BIGS trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Gastrointestinal Health 330144 0
Immune function 330145 0
Cognition 330146 0
General wellbeing 330167 0
Condition category
Condition code
Oral and Gastrointestinal 327023 327023 0 0
Normal oral and gastrointestinal development and function
Diet and Nutrition 327043 327043 0 0
Other diet and nutrition disorders
Inflammatory and Immune System 327044 327044 0 0
Normal development and function of the immune system
Mental Health 327045 327045 0 0
Studies of normal psychology, cognitive function and behaviour
Skin 327046 327046 0 0
Normal skin development and function

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants (n=1000) will be randomised to each study arm. The study period goes for 30 days including: 2 day run-in and 28-day intervention. Outcomes will be measured at the start, middle and end of the intervention period.

The intervention group will consume fresh, full cream (4% fat) cow’s milk, containing A2 ß-casein proteins only. Participants will be asked to consume a minimum of 250mL of milk each day for 28 days, with no maximum amount set. Participants in the intervention group will be asked to avoid conventional cow's milk containing both A1 and A2 ß-casein proteins for the duration of the study and restrict all other dairy to one serving per day, with no other changes to their usual diet, medications, or lifestyle.

The first 260 participants enrolled into the study (n=130 intervention group; n=130 control group) will be required to complete (i) two saliva samples, (ii) one faecal sample, and (iii) one cognitive function test called the SCIT test both pre and post intervention at Day 0 and Day 28 (four saliva, two faecal and two cognitive tests in total) and complete questionnaires at each time point (start, middle and end of intervention period). The remaining 740 participants will complete questionnaires at each time point only.

Compliance to the protocol will be measured through a survey administered twice a week to record their milk intake, and reconciling milk purchases via receipt upload with reported milk consumption.

In addition, participants from the intervention group only who complete the intervention study will be randomly selected and invited to participate in a virtual nested qualitative study. After completing the final study visit, investigators will add each participant’s unique identifier number to a secondary database. Five participant IDs will be randomly selected at weekly intervals using an online randomisation program, and these participants will be invited to participate in the nested qualitative study where they will attend a 1 hour semi-structured interview with researchers via zoom. The semi-structured interviews will be scheduled approximately 1 week post-completion of the 28-day intervention period. IDs will be removed from the database after selection, or after 21 days if not selected. This process will continue until the predetermined sample size has been reached (n=17 - 30 depending on what is required to achieve saturation.
Intervention code [1] 326188 0
Lifestyle
Intervention code [2] 326207 0
Prevention
Comparator / control treatment
The comparator group will consume fresh, full cream (4% fat) conventional cow’s milk, containing both A1 and A2 ß-casein proteins. Participants will be asked to consume a minimum of 250mL of milk each day for 28 days, with no maximum amount set.

Participants in the intervention group will be asked to avoid A2 cow's milk which contains only A2 ß-casein protein for the duration of the study and restrict all other dairy to one serving per day, with no other changes to their usual diet, medications, or lifestyle.

Compliance to the protocol will be measured through a survey administered twice a week to record their milk intake, and reconciling milk purchases via receipt upload with reported milk consumption.
Control group
Active

Outcomes
Primary outcome [1] 334912 0
Compositional (relative abundance and diversity) analysis of microbiome. This will be assessed using metagenomic analysis of bacterial strains in a self-collected stool sample from a subset of participants.
Timepoint [1] 334912 0
Day 0 (prior to intervention)
Day 28 (intervention end)
Primary outcome [2] 334976 0
Functional analysis of microbiome. This will be assessed using metagenomic analysis of bacterial strains in a self-collected stool sample from a subset of participants.
Timepoint [2] 334976 0
Day 0 (prior to intervention)
Day 28 (intervention end)
Secondary outcome [1] 422343 0
Cognitive function as measured by the Patient-Reported Outcomes Measurement Information System (PROMIS) short form survey: PROMIS-SF Cognitive Function 6a
Timepoint [1] 422343 0
Day 0 (prior to intervention period commencement)
Day 14
Day 28 (28 days after intervention commencement)
Secondary outcome [2] 422385 0
Cognitive function as measured by Subtle Cognitive Impairment Test (SCIT) in a subset of participants
Timepoint [2] 422385 0
Day 0 (prior to intervention period commencement)
Day 28 (28 days after intervention commencement)
Secondary outcome [3] 422386 0
The immune marker, secretory sIgA, will be measured through a self-collected saliva sample in a sub-set of participants.
Timepoint [3] 422386 0
Day 0 (prior to intervention period commencement)
Day 28 (28 days after intervention commencement)
Secondary outcome [4] 422387 0
The inflammation marker, salivary tumour necrosis factor-alpha (TNF-a), will be measured in a self-collected saliva sample in a sub-set of participants.
Timepoint [4] 422387 0
Day 0 (prior to intervention period commencement)
Day 28 (28 days after intervention commencement)
Secondary outcome [5] 422388 0
Self-reported immune health will be measured using the Immune Status Questionnaire.
Timepoint [5] 422388 0
Day 0 (prior to intervention period commencement)
Day 14
Day 28 (28 days after intervention commencement)
Secondary outcome [6] 422389 0
Skin health will be self-reported using the Skin Complaints Questionnaire to assess skin morbidity and dermatologic life quality.
Timepoint [6] 422389 0
Day 0 (prior to intervention period commencement)
Day 14
Day 28 (28 days after intervention commencement)
Secondary outcome [7] 422390 0
Mental health will be measured using the Depression, Anxiety and Stress Scale-21 Items (DASS 21)
Timepoint [7] 422390 0
Day 0 (prior to intervention period commencement)
Day 14
Day 28 (28 days after intervention commencement)
Secondary outcome [8] 422391 0
Self-reported sleep quality will be measured using the Patient-Reported Outcomes Measurement Information System-short form (PROMIS-SF) survey: PROMIS-SF Sleep Disturbance 6a
Timepoint [8] 422391 0
Day 0 (prior to intervention period commencement)
Day 14
Day 28 (28 days after intervention commencement)
Secondary outcome [9] 422392 0
Self-reported respiratory health will be measured using the Respiratory Symptoms Questionnaire
Timepoint [9] 422392 0
Day 0 (prior to intervention period commencement)
Day 14
Day 28 (28 days after intervention commencement)
Secondary outcome [10] 422393 0
Self-reported well-being will be measured using the World Health Organisation-5 Well-being Index (WHO-5).
Timepoint [10] 422393 0
Day 0 (prior to intervention period commencement)
Day 14
Day 28 (28 days after intervention commencement)
Secondary outcome [11] 422607 0
Gastrointestinal health and function as self-reported by participants using the Bristol Stool Chart (BSC).
Timepoint [11] 422607 0
Day 0 (prior to intervention period commencement)
Day 14
Day 28 (28 days after intervention commencement)
Secondary outcome [12] 422608 0
Gastrointestinal health and function as self-reported by participants using the Gastrointestinal symptoms rating scale (GSRS).
Timepoint [12] 422608 0
Day 0 (prior to intervention period commencement)
Day 14
Day 28 (28 days after intervention commencement)
Secondary outcome [13] 422609 0
Cognitive function, specifically fatigue, as measured by the Patient-Reported Outcomes Measurement Information System (PROMIS) short form survey: PROMIS-SF Fatigue 4
Timepoint [13] 422609 0
Day 0 (prior to intervention period commencement)
Day 14
Day 28 (28 days after intervention commencement)
Secondary outcome [14] 422610 0
The immune marker, salivary glutathione, will be measured through a self-collected saliva sample in a sub-set of participants.
Timepoint [14] 422610 0
Day 0 (prior to intervention period commencement)
Day 28 (28 days after intervention commencement)
Secondary outcome [15] 422611 0
The immune marker, glutathione:oxidised glutathione ratio, will be measured through a self-collected saliva sample in a sub-set of participants.
Timepoint [15] 422611 0
Day 0 (prior to intervention period commencement)
Day 28 (28 days after intervention commencement)
Secondary outcome [16] 422612 0
The immune marker, salivary cortisol, will be measured through a self-collected saliva sample in a sub-set of participants.
Timepoint [16] 422612 0
Day 0 (prior to intervention period commencement)
Day 28 (28 days after intervention commencement)
Secondary outcome [17] 422613 0
The inflammation marker, salivary interleukin 6 (IL-6), will be measured in a self-collected saliva sample in a sub-set of participants.
Timepoint [17] 422613 0
Day 0 (prior to intervention period commencement)
Day 28 (28 days after intervention commencement)
Secondary outcome [18] 422614 0
The inflammation marker, salivary interleukin 1-beta (IL-1ß), will be measured in a self-collected saliva sample in a sub-set of participants.
Timepoint [18] 422614 0
Day 0 (prior to intervention period commencement)
Day 28 (28 days after intervention commencement)
Secondary outcome [19] 422615 0
Self-reported quality of life will be measured using a visual analogue scale.
Timepoint [19] 422615 0
Day 0 (prior to intervention period commencement)
Day 14
Day 28 (28 days after intervention commencement)

Eligibility
Key inclusion criteria
Humans that live in Australia.
Aged 16-65 years inclusive
Any sex or gender.
BMI: 18.5 to 35kg/m2 inclusive.
Can speak and read English.
Consume conventional (A1/A2) cow’s milk 5 or more times per week.
Agree to maintain current dietary practices, including any medications and supplements, during the study period.
Willing to consume at least 250mL cow’s milk every day for 28 days.
Minimum age
16 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
- Unable to provide informed consent.
- Diagnosed with a chronic disease, including autoimmune conditions, kidney or liver disease, cardiovascular disease, and diabetes.
- Diagnosed with one or more of the following mental health conditions: Major depressive disorder, Psychotic disorder such as schizophrenia, Anorexia nervosa, Bulimia nervosa, Substance abuse disorder, Bipolar disorder, Personality disorder.
- Currently pregnant or breastfeeding.
- Hospitalisation or antibiotic use in the past 4weeks.
- Planned change of oral contraception within past 3-months or planned change within the study period.
- Currently participating in another biomedical or medical study

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 participants’ group allocation will be maintained by a designated investigator that does not have any contact with the participants.

In a password protected document, accessible only to the team member performing randomisation and the BIGS Trial PI Dr Flavia Fayet-Moore, the sequence of intervention and control for each group will be accessible.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomized to either intervention or comparator groups using a computer-generated randomisation sequence.. The sequence will be generated in blocks of 8, with no blocking or stratification.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



The people analysing the results/data
Intervention assignment
Parallel
Other design features
A subset of participants from the intervention group will be randomly selected and invited to participate in a semi-structured 1:1 interview with a qualitative researcher after they have completed the intervention.
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Demographic data will be used to characterise the population and as confounding variables, as appropriate.

All variables will be described using descriptive statistics to characterise the study population by randomisation group. All continuous variables will be tested for normality using Q-Q plots; and non-parametric variables will be attempted to be log-transformed to normal variables when possible. Normal continuous data will be described as mean (SD) or median (IQR) for parametric and non-parametric variables respectively; and categorical variables will be presented as participant number (n) and proportion (%). Study group comparisons will initially be made using the independent t-test (or Mann Whitney U/Wilcoxon Signed Rank tests for non-parametric as appropriate) for continuous data; and Chi-squared (or Fischers Exact Test as appropriate) for categorical data.
Next, both primary and secondary outcomes will be analysed using general linear models for continuous outcome variables, and logistic regression for categorical outcome variables with treatment and sequence as independent factors. Confounding variables meeting assumption criteria will be included in the models. Variables which may be considered confounding include participant adherence, background diet, change to body weight, sex, age, and other lifestyle and medical factors.

The suitability for replacing missing values via multiple imputation will be considered. Intention-to-treat analyses will be used to evaluate outcomes if the attrition rate is less than or equal to 20%; and per-protocol analysis will be used if attrition is greater than 20% and multiple imputation is not advisable. Statistical significance will be set at p<0.05.

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
1/07/2023
Actual
1/07/2023
Date of last participant enrolment
Anticipated
1/06/2024
Actual
30/09/2023
Date of last data collection
Anticipated
30/11/2023
Actual
Sample size
Target
1000
Accrual to date
Final
1000
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC

Funding & Sponsors
Funding source category [1] 313936 0
Commercial sector/Industry
Name [1] 313936 0
The a2 Milk Company
Country [1] 313936 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Nutrition Research Australia
Address
Level 10, 20 Martin Place,
Sydney NSW 2000 Australia
Country
Australia
Secondary sponsor category [1] 315823 0
None
Name [1] 315823 0
None
Address [1] 315823 0
None
Country [1] 315823 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313079 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 313079 0
123 Glen Osmond Road Eastwood Adelaide South Australia 5063
Ethics committee country [1] 313079 0
Australia
Date submitted for ethics approval [1] 313079 0
12/05/2023
Approval date [1] 313079 0
08/06/2023
Ethics approval number [1] 313079 0
2023-04-459

Summary
Brief summary
This study is a mixed-methods study, combining an open-label pragmatic parallel group randomised controlled trial (RCT) with qualitative methodology investigating the effect of different milk proteins on brain, immunity, gut and skin health outcomes. There is evidence that different forms of beta-casein proteins, found naturally in milk, have different effects on health. There is also some evidence of an interconnection between the brain, immune, and skin systems linked by the gut microbiome. This study aims to determine the effect of milk containing only a2 beta-casein protein on brain health, immunity and inflammatory markers, gastrointestinal function, and skin health as compared to conventional milk which contains A2 and A1 beta-casein, in healthy older adolescents and adults (16-65 years) in a real world setting.

Participants (n=1000) will be randomised to each study arm. The study period goes for 30 days including a 2 day run-in and 28-day intervention. Outcomes will be measured at the start, middle and end of the intervention period. The first 260 participants will be required to have a saliva sample and faecal sample collected pre and post intervention and complete questionnaires at each time point. The remaining 740 participants will complete questionnaires at each time point only. There will additionally be a short (1 min) survey sent twice a week to monitor for adverse events. Participants from the intervention group will be
randomly selected and invited to participate in the nested qualitative study (n=30).

The study has been planned in accordance with the Declaration of Helsinki, National Health and Medical Research Council National Statement on Ethical Conduct in Human Research. All staff with direct participant contact have completed Good Clinical Practice Guideline training and certification.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 126922 0
Dr Flavia Fayet-Moore
Address 126922 0
Nutrition Research Australia Level 10, 20 Martin Place, Sydney NSW 2000
Country 126922 0
Australia
Phone 126922 0
+61 415 990 050
Fax 126922 0
Email 126922 0
flavia@nruas.com
Contact person for public queries
Name 126923 0
Ms Lucy Downey
Address 126923 0
Nutrition Research Australia Level 10, 20 Martin Place, Sydney NSW 2000
Country 126923 0
Australia
Phone 126923 0
+61 474 198 960
Fax 126923 0
Email 126923 0
bigstrial@nraus.com
Contact person for scientific queries
Name 126924 0
Dr Michelle Blumfield
Address 126924 0
Nutrition Research Australia Level 10, 20 Martin Place, Sydney NSW 2000
Country 126924 0
Australia
Phone 126924 0
+61 413 276 801
Fax 126924 0
Email 126924 0
michelle@nraus.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


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.