A1 Versus A2® Milk on the Gastrointestinal Physiology, Symptoms and Cognitive Behaviour for the Preschool Children

Comparative Effects of A1 Versus A2® Milk on the Gastrointestinal Physiology, Symptoms and Cognitive Behaviour for the Preschool Children: a Double-blinded Randomized Controlled Cross-over Study

This is a multiple-sites, double-blinded, randomized, controlled, parallel-designed, cross-over study among healthy preschoolers with 5 days consumption of A2 or A1 milk to compare the effects on gut inflammation, gastrointestinal symptoms and behavioral well-being.

Study Overview

• Status: Completed
• Conditions: Gut Inflammation
• Intervention / Treatment: Dietary supplement: Oral consumption of milk A1 in study phase 1; Dietary supplement: Oral consumption of milk A2 in study phase 2; Dietary supplement: Oral consumption of milk A2 in study phase 1; Dietary supplement: Oral consumption of milk A1 in study phase 2

Detailed Description

Gut inflammation is reflected by serum C-Reactive Protein (CRP), hemoglobin (HB), interleukin-4 (IL-4), Immunoglobulin G (IgG), Immunoglobulin E (IgE), Immunoglobulin G1 (IgG1), Immunoglobulin G2a (IgG2a), β-Casomorphin-7 (BCM-7), Glutathione, calcium (Ca), iron (Fe) and zinc (Zn) concentration; gastrointestinal (GI) symptoms are measured via Visual Analog Scale (VAS) for gut tolerance, including borborygmus, bloating, break wind, abdominal pain, and diarrhea; behavioral well-being is assessed using Subtle Cognitive Impairment Test (SCIT).

The total duration of study was 24 weeks, including subject enrollment, study intervention, laboratory testing, and providing clinical study report. The cross-over study consisted of 5 days of each product intervention; 10 days of wash-out in phase 1 and phase 2, respectively; and then followed by 6 weeks of statistical analysis and clinical report completion.

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Phase 4

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 6 years (CHILD)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Non-regular milk drinker;
• Suffered from mild to moderate milk intolerance;
• Agree not to take any medication, supplements, nutrition or other dairy products including acidophilus milk;
• Parent(s) or legal guardian's consent to the study and willing to comply with study procedures;
• Parent(s) or guardian of infant agrees not to enroll infant another clinical study while participating in this study;
• Fully understand the nature, objective, benefit and the potential risks and side effects of the study.

Exclusion Criteria:

• Have known dairy allergy;
• Suffered from severe milk intolerance;
• Unable to give written informed consent;
• Use of antibiotics at the time of screening, or during the past two weeks;
• Have history of fecal impaction;
• Trying to lose weight by following a diet or exercise regimen designed for weight loss, or taking any drug influencing appetite and any drug for weight loss for the last three months;
• Have participated in similar dairy or probiotics-containing product's clinical trials within 3 months before the screening;
• Currently taking medicines for cardiovascular or metabolic disease;
• Have history of or be diagnosed of any of the following diseases that may affect the study results: gastrointestinal disorders, hepatopathy, nephropathy, endocrine disease, blood disorders, respiratory and cardiovascular diseases;
• Currently suffering from any gastrointestinal disorders or gastrointestinal disease , including but not limited to: irritable bowel syndrome, colitis, ulcerative colitis, celiac disease, irritable bowel syndrome (IBS);
• Had hospitalizations within 3 months before screening;
• According to investigator's judgment, current frequent users of drugs may affect the gastrointestinal function or immune system.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Sequence A1-A2; Oral consumption of milk A1 in study phase 1. Oral consumption of milk A2 in study phase 2.	Dietary supplement: Oral consumption of milk A1 in study phase 1; Oral consumption of 250 ml of milk containing both A1 and A2 type beta casein 2 times per day after meal for 5 days in study phase 1.; Dietary supplement: Oral consumption of milk A2 in study phase 2; Oral consumption of 250 ml of milk containing only A2 type beta casein 2 times per day after meal for 5 days in study phase 2.
EXPERIMENTAL: Sequence A2-A1; Oral consumption of milk A2 in study phase 1. Oral consumption of milk A1 in study phase 2.	Dietary supplement: Oral consumption of milk A2 in study phase 1; Oral consumption of 250 ml of milk containing only A2 type beta casein 2 times per day after meal for 5 days in study phase 1.; Dietary supplement: Oral consumption of milk A1 in study phase 2; Oral consumption of 250 ml of milk containing both A1 and A2 type beta casein 2 times per day after meal for 5 days in study phase 2.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline of gastrointestinal symptom VAS scores	were self-measured by study subjects on a scale from 0 (never) to 3 (always) at baseline (day 1 for phase 1 and day 15 for phase 2, before product consumption) and at the end of the 5-day product consumption (day 5 for phase 1 and day 19 for phase 2).	Baseline (day 1 for phase 1 and day 15 for phase 2, before product consumption), at the end of the 5-day product consumption (day 5 for phase 1 and day 19 for phase 2)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stool frequency	In each study phase, the number of defecation per day measured during the last 5 days of wash-out period (day -4, -3, -2, -1, 0 in phase 1 and day 10, 11, 12, 13, 14 in phase 2) and the 5 days of product intervention (day 1, 2, 3, 4, 5 in phase 1 and day 15, 16, 17, 18, 19 in phase 2).	Day -4, -3, -2, -1, 0, 1, 2, 3, 4, 5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19
Stool consistency	In each study phase, the score of stool consistency assessed using Bristol Stool Chart during the last 5 days of wash-out period (day -4, -3, -2, -1, 0 in phase 1 and day 10, 11, 12, 13, 14 in phase 2) and the 5 days of product intervention (day 1, 2, 3, 4, 5 in phase 1 and day 15, 16, 17, 18, 19 in phase 2).	Day -4, -3, -2, -1, 0, 1, 2, 3, 4, 5, 10, 11, 12, 13, 14, 5, 16, 17, 18, 19
Serum C-reactive protein (CRP) concentration	Only measured in phase 1	Day 1 before intervention (baseline), and day 5 (post-intervention)
Serum Hemoglobin (HGB) concentration	Only measured in phase 1	Day 1 before intervention (baseline), and day 5 (post-intervention)
Serum Interleukin-4 (IL-4) concentration	Only measured in phase 1	Day 1 before intervention (baseline), and day 5 (post-intervention)
Serum Immunoglobulin G (IgG) concentration	Only measured in phase 1	Day 1 before intervention (baseline), and day 5 (post-intervention)
Serum Immunoglobulin E (IgE) concentration	Only measured in phase 1	Day 1 before intervention (baseline), and day 5 (post-intervention)
Serum Immunoglobulin G1 (IgG1) concentration	Only measured in phase 1	Day 1 before intervention (baseline), and day 5 (post-intervention)
Serum Immunoglobulin G2a (IgG2a) concentration	Only measured in phase 1	Day 1 before intervention (baseline), and day 5 (post-intervention)
Serum β-Casomorphin-7 (BCM-7) concentration	Only measured in phase 1	Day 1 before intervention (baseline), and day 5 (post-intervention)
Serum Glutathione concentration	Only measured in phase 1	Day 1 before intervention (baseline), and day 5 (post-intervention)
Serum calcium (Ca) concentration	Only measured in phase 1	Day 1 before intervention (baseline), and day 5 (post-intervention)
Serum iron (Fe) concentration	Only measured in phase 1	Day 1 before intervention (baseline), and day 5 (post-intervention)
Serum zinc (Zn) concentration	Only measured in phase 1	Day 1 before intervention (baseline), and day 5 (post-intervention)
Fecal short chain fatty acids (SCFA) concentration	Measured at baseline and post-intervention in each study phase	Day 1, Day 5, Day 15, Day 19
myeloperoxidase (MPO)	Measured at baseline and post-intervention in each study phase	Day 1, Day 5, Day 15, Day 19
Subtle Cognitive Impairment Test (SCIT)	Subject response time and error rate at stimulus exposure duration of 16, 32, 48, 64, 80, 96, 112 and 128 millisecond, as well as their head and tail means were recorded at baseline (day 1 for phase 1 and day 15 for phase 2) and the end of intervention (day 5 for phase 1 and day 19 for phase 2).	16, 32, 48, 64, 80, 96, 112 and 128 millisecond on day 1; 16, 32, 48, 64, 80, 96, 112 and 128 millisecond on day 5; 16, 32, 48, 64, 80, 96, 112 and 128 millisecond on day 15; 16, 32, 48, 64, 80, 96, 112 and 128 millisecond on day 19

Collaborators and Investigators

• Sponsor: a2 Milk Company Ltd.

Publications and helpful links

General Publications

• Sheng X, Li Z, Ni J, Yelland G. Effects of Conventional Milk Versus Milk Containing Only A2 beta-Casein on Digestion in Chinese Children: A Randomized Study. J Pediatr Gastroenterol Nutr. 2019 Sep;69(3):375-382. doi: 10.1097/MPG.0000000000002437.

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 13, 2016
• Primary Completion (ACTUAL): October 14, 2016
• Study Completion (ACTUAL): January 20, 2017

Study Registration Dates

• First Submitted: February 28, 2017
• First Submitted That Met QC Criteria: March 10, 2017
• First Posted (ACTUAL): March 16, 2017

Study Record Updates

• Last Update Posted (ACTUAL): March 16, 2017
• Last Update Submitted That Met QC Criteria: March 10, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Inflammation
• Other Study ID Numbers: 15-SC-5-A2-002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No