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Trial registered on ANZCTR


Registration number
ACTRN12622000757718
Ethics application status
Approved
Date submitted
20/05/2022
Date registered
27/05/2022
Date last updated
19/07/2022
Date data sharing statement initially provided
27/05/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Australian Immunity Trial (Trial B): The effect of milk proteins on immune function in healthy young adults
Scientific title
Effect of milk containing only a2 beta-casein protein on immunity and inflammatory markers, gastrointestinal function, and cognitive function as compared to conventional milk which contains a2 and a1 beta-casein, in healthy young adults.
Secondary ID [1] 307182 0
None
Universal Trial Number (UTN)
U1111-1278-5407
Trial acronym
AIM trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Immune Function 326400 0
Gastrointestinal Microbiome 326401 0
Cognition 326402 0
Condition category
Condition code
Inflammatory and Immune System 323687 323687 0 0
Normal development and function of the immune system
Oral and Gastrointestinal 323688 323688 0 0
Normal oral and gastrointestinal development and function
Mental Health 323689 323689 0 0
Studies of normal psychology, cognitive function and behaviour

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
250mL cow's milk containing A2/A2 beta-casein proteins. Milk will be consumed once per day for 14 days, with a 14-day run-in period, plus 14-day washout period. Participants will drink the milk as part of a test breakfast daily. Breakfast will consist of 250mL milk, weet-bix + a banana, or 250mL milk, wholemeal toast with margarine and spread (e.g. jam), and a banana.

Participants will be asked to avoid animal-based milk drinks during the run-in and wash-out periods. Compliance to the protocol will be measured through a survey administered weekly, and visual inspection of empty UHT milk tetra paks by the study co-ordinator.
Intervention code [1] 323632 0
Lifestyle
Intervention code [2] 323633 0
Prevention
Comparator / control treatment
250mL cows milk containing A1/A2 beta-casein proteins. Milk will be consumed once per day for 14 days, with a 14-day run-in period, plus 14-day washout period. Participants will drink the milk as part of a test breakfast daily. Breakfast will consist of 250mL milk, weet-bix + a banana, or 250mL milk, wholemeal toast with margarine and spread (e.g. jam), and a banana.

Participants will be asked to avoid animal-based milk drinks during the run-in and wash-out periods. Compliance to the protocol will be measured through a survey administered weekly, and visual inspection of empty UHT milk tetra paks by the study co-ordinator.
Control group
Active

Outcomes
Primary outcome [1] 331439 0
Serum IL-4
Timepoint [1] 331439 0
Day 0 (prior to intervention period commencement)

Day 14 (14 days after intervention commencement)
Secondary outcome [1] 409876 0
Serum Biomarkers:

Serum glutathione
C-reactive protein
Interleukin-6
Tumor Necrosis Factor
Immunoglobulin E
Immunoglobulin G1
Immunoglobulin G2a
Platelet count
Erythrocyte sedimentation rate
Whole blood cell count
Lymphocyte cell subsets
Timepoint [1] 409876 0
Day 0 (prior to intervention period commencement)

Day 14 (14 days after intervention commencement)
Secondary outcome [2] 409877 0
Ex vivo immune challenge - Lipopolysaccharide (LPS) challenging using peripheral blood mononuclear cells (PBMC)
Timepoint [2] 409877 0
Day 0 (prior to intervention period commencement)

Day 14 (14 days after intervention commencement)
Secondary outcome [3] 409878 0
Feacal biomarkers:

Faecal short chain fatty acids (acetate, propionate, butyrate)
Faecal myeloperoxidase
Timepoint [3] 409878 0
Day 0 (prior to intervention period commencement)

Day 14 (14 days after intervention commencement)
Secondary outcome [4] 409879 0
Gastrointestinal function measured by Gastrointestinal symptom rating score (self-reported measure)
Timepoint [4] 409879 0
Day 0 (prior to intervention period commencement)

Day 14 (14 days after intervention commencement)
Secondary outcome [5] 409880 0
Sleep Quality measured by Patient-reported outcomes measurement information system (PROMIS) Sleep Disturbance Short Form 8a
Timepoint [5] 409880 0
Day 0 (prior to intervention period commencement)

Day 14 (14 days after intervention commencement)
Secondary outcome [6] 409882 0
Stool consistency using Bristol Stool Chart
Timepoint [6] 409882 0
Day 0 (prior to intervention period commencement)

Day 14 (14 days after intervention commencement)
Secondary outcome [7] 409883 0
Self-reported sleep duration using adapted questionaire from Australian Longitudinal Study for Women's Health
Timepoint [7] 409883 0
Day 0 (prior to intervention period commencement)

Day 14 (14 days after intervention commencement)
Secondary outcome [8] 410075 0
Cognitive Performance, measured using the Subtle Cognitive Impairment Test (SCIT)
Timepoint [8] 410075 0
Day 0 (prior to intervention period commencement)

Day 14 (14 days after intervention commencement)

Eligibility
Key inclusion criteria

Humans.
Aged 18-40 years inclusive.
Any sex or gender.
BMI: 18.5-30kg/m2 inclusive.
Can speak and read English.
Consume cow’s milk 3 or more times per week, with at least 250ml consumed in one day.
Agree to limit alcohol consumption to a maximum of 2 standard drinks per day during the study period.
Agree to limit caffeine to two caffeinated beverages per day (one in the morning and one in the afternoon) during the study period.
Agree to avoid nicotine (e.g., via cigarettes, vape, patch, or gum) during the study period.
Agree to avoid prebiotic and probiotic supplements during the study period.
Agree to avoid artificial sweeteners during the study period.
Live in a stable residence and are able to receive and safely store weekly food deliveries throughout the intervention period.
Minimum age
18 Years
Maximum age
40 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Unable to provide informed consent.
Participant enrolled in or previously completed any AIM trial studies
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.
History of elevated blood pressure (>140/90mmHg) at rest on 2 or more subsequent occasions, or told by a doctor that the participant has “high blood pressure” or “hypertension”.
Experienced infectious disease, injury, or trauma in the past 6-months which led to hospitalisation, systemic (oral) steroid, or oral antibiotic prescription.
Pregnant, breastfeeding, or attempting to become pregnant.
Received a tetanus toxoid vaccination within the past 5-years.
Received any other vaccination not previously mentioned in the past 6-months.
Hospitalised within the past 3-months for any reason.
Use of prescribed or recreational drugs, including steroids, CBD or cannabis, NSAIDs, proton-pump-inhibitors, or antihistamines within the past 2-months.
- Paracetamol and ibuprofen are permitted.
- Over-the-counter prescriptions permitted unless otherwise listed above or known to impact immunity and systemic inflammation.
Change of oral contraception within past 6-months or planned change within the study period.
Tobacco used within the past 2-years.
Known or self-diagnosed allergy or intolerance to any food or ingredient.
Seasonal allergy, e.g., rhinitis.
Irritable bowel syndrome (self-diagnosis is valid).
On a self- or healthcare professional prescribed diet (e.g., Paleo diet, vegan, gluten free diet, low sodium diet, FODMAPS diet).
- Red meat vegetarian, lacto-ovo vegetarian, and pescatarian are permitted.
Participated in a biomedical or medical study in the past 3-months; including participation in any AIM trials

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)
Allocation to the treatment group will be conducted by a researcher not directly involved with the study.

Intervention products will be blinded by the manufacturer prior to being received by the study investigators. Blinding codes will be provided to the Principal Investigator in a sealed opaque envelope
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomly allocated to treatment groups using a computer-generated sequence. Participants will be randomised in blocks of 8 with no stratification.
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
Statistical analysis will be performed using Excel, SPSS, STATA, and/or R software.

All variables will be described using descriptive statistics. 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 (%).

The washout period was designed to be long enough to minimise the chance of any carryover effect, taking into consideration the half-life of primary and secondary inflammatory markers. Results will be tested for any carryover effect by testing for a treatment*period interaction.

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 >20% and multiple imputation is not advisable. Statistical significance will be set at p<0.05.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
3/06/2022
Actual
6/06/2022
Date of last participant enrolment
Anticipated
3/05/2023
Actual
Date of last data collection
Anticipated
3/07/2023
Actual
Sample size
Target
50
Accrual to date
22
Final
Recruitment in Australia
Recruitment state(s)
QLD

Funding & Sponsors
Funding source category [1] 311485 0
Commercial sector/Industry
Name [1] 311485 0
A2 Milk Company
Country [1] 311485 0
New Zealand
Primary sponsor type
Other Collaborative groups
Name
Nutrition Research Australia
Address
Level 10,
20 Martin Place,
Sydney,
NSW, 2000
Country
Australia
Secondary sponsor category [1] 312885 0
None
Name [1] 312885 0
Address [1] 312885 0
Country [1] 312885 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310948 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 310948 0
Ethics committee country [1] 310948 0
Australia
Date submitted for ethics approval [1] 310948 0
23/02/2022
Approval date [1] 310948 0
08/04/2022
Ethics approval number [1] 310948 0
2022-02-161

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

Contacts
Principal investigator
Name 119462 0
Dr Flavia Fayet-Moore
Address 119462 0
Nutrition Research Australia
Level 10, 20 Martin Place, Sydney NSW 2000
Country 119462 0
Australia
Phone 119462 0
+61 415 990 050
Fax 119462 0
Email 119462 0
flavia@nraus.com
Contact person for public queries
Name 119463 0
Michelle Blumfield
Address 119463 0
Nutrition Research Australia,
Level 10, 20 Martin Place, Sydney NSW 2000
Country 119463 0
Australia
Phone 119463 0
+61 413 276 801
Fax 119463 0
Email 119463 0
michelle@nraus.com
Contact person for scientific queries
Name 119464 0
Michelle Blumfield
Address 119464 0
Nutrition Research Australia,
Level 10, 20 Martin Place, Sydney NSW 2000
Country 119464 0
Australia
Phone 119464 0
+61 413 276 801
Fax 119464 0
Email 119464 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.