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Effects of A2 Milk on Gastrointestinal Function in Non-lactose Milk Intolerance

Primary Purpose

Milk Intolerance

Status
Completed
Phase
Not Applicable
Locations
United Kingdom
Study Type
Interventional
Intervention
A2 milk 100
A2 milk 150
A2 milk 200
A2 milk 250
A1/A2 milk 100
A1/A2 milk 150
A1/A2 milk 200
A1/A2 milk 250
Sponsored by
University of Reading
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Milk Intolerance

Eligibility Criteria

18 Years - 56 Years (Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  • BMI: 20-35kg/m2
  • Glucose<7mmol/l (not diagnosed with diabetes)
  • Total cholesterol<7mmol/l
  • Triacylglycerol<4mmol/l
  • Normal liver and kidney function
  • Regular milk drinker with self-reported intolerance to commercial milk.
  • Suffered from mild to moderate digestive discomfort after milk consumption.
  • Have normal blood pressure 120/80 mmHg (BP <160/90 mmHg can be accepted) during quiet respiration.
  • Agree not to take any medication, supplements and other dairy products including acidophilus milk
  • Be willing to comply with all the requirements and procedures of the study.
  • Agree to sign the informed consent form;
  • Agree not to enrol in another interventional clinical research study while participating in this study.
  • Fully understand the nature, objective, benefit and the potential risks and side effects of the study.

Exclusion Criteria:

  • Females who are pregnant or planning to be a pregnant and lactating.
  • Have known dairy allergy.
  • Have stopped drinking milk for the last 6 month.
  • Have history of lactose intolerance
  • Have history of faecal impaction.
  • Received antibiotics in the previous six months
  • Smoker
  • Anemia
  • 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.
  • History of alcohol or drug misuse.
  • 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, cardiovascular diseases and known on-going allergy such as asthma.
  • Currently suffering from any gastrointestinal disorders or gastrointestinal disease, including irritable bowel syndrome, colitis, ulcerative colitis, celiac disease, irritable bowel syndrome (IBS);
  • Had hospitalizations within 3 months before screening; Currently drug frequency user of that may affect the gastrointestinal function or immune system. As judged by investigator.
  • Who take medication at least the last 6-month.
  • Who do excessive exercise not as part of a weight-loss regime, e.g. athletes.

Sites / Locations

  • Department of Food and Nutritional Sciences

Arms of the Study

Arm 1

Arm 2

Arm Type

Sham Comparator

Active Comparator

Arm Label

A1/A2 milk

A2 milk

Arm Description

Commercial conventional A1/A2 semi-skimmed fresh pasteurised cow milk. Progressive intake of intervention milk as follows: Days 1 and 2: 100 mL twice a day Days 3 and 4: 150 mL twice a day Days 5 and 6: 200 mL twice a day Days 7 to 14: 250 mL twice a day

Commercial A2 semi-skimmed fresh pasteurised cow milk. Progressive intake of intervention milk as follows: Days 1 and 2: 100 mL twice a day Days 3 and 4: 150 mL twice a day Days 5 and 6: 200 mL twice a day Days 7 to 14: 250 mL twice a day

Outcomes

Primary Outcome Measures

Change in gastrointestinal inflammation indicated by fecal calprotectin
Measurement of fecal calprotectin (ug/g feces)

Secondary Outcome Measures

Change in NMR-based urinary metabolic profiles
Measured using High Resolution 700MHz proton NMR spectroscopy (Bruker) (no unit)
Change in NMR-based plasma metabolic profiles
Measured using High Resolution 700MHz proton NMR spectroscopy (Bruker) (no unit)
Change in NMR-based fecal metabolic profiles
Measured using High Resolution 700MHz proton NMR spectroscopy (Bruker) (no unit)
Change in gut microbiota ecosystem assessed by sequencing the 16S rDNA extracted from feces
Measures relative abundance of bacterial taxa
Change in systemic inflammation indicated by circulating levels of high sensitivity C-reactive protein
hs-CRP in mg/L
Change in gastrointestinal function assessed using visual analogue scale for GI symptoms
Measures gases, bloating, abdominal cramps, diarrhoea, headache, constipation, nausea and rash
Height (in m) used to detect change in BMI (kg/m^2)
Weight (in kg) used to detect change in BMI (kg/m^2)
Change in systolic blood pressure in mmHg
Change in diastolic blood pressure in mmHg
Diagnostic of lactose intolerance by breath hydrogen concentration following ingestion of 25g lactose in 250 mL water
Diagnostic of lactose intolerance by breath methane concentration following ingestion of 25g lactose in 250 mL water
Self-reported change in gut transit time
Monitoring of changes in psychological behaviour assessed by TMT
Monitoring of changes in psychological behaviour assessed by Letter Memory Test
Monitoring of changes in psychological behaviour assessed by Flanger Test
Monitoring of changes in mood measured by PANAS questionnaire
Change in stool consistency using the Bristol stool chart

Full Information

First Posted
January 17, 2017
Last Updated
April 27, 2020
Sponsor
University of Reading
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1. Study Identification

Unique Protocol Identification Number
NCT03060395
Brief Title
Effects of A2 Milk on Gastrointestinal Function in Non-lactose Milk Intolerance
Official Title
Effects of A2 Milk on Gastrointestinal Function of Volunteers Affected by Non-lactose Milk Intolerance
Study Type
Interventional

2. Study Status

Record Verification Date
April 2020
Overall Recruitment Status
Completed
Study Start Date
April 1, 2017 (Actual)
Primary Completion Date
April 30, 2018 (Actual)
Study Completion Date
March 31, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Reading

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
There is increasing evidence that a number of people experience moderate milk intolerance characterised by increased gas production, bloating and abdominal cramp, which can neither be attributed to lactose intolerance, nor to milk protein allergy. Milk digestion can lead to the formation of bioactive peptides, one of which derived from a mutated gene variant (A1) coding for milk beta-casein has been associated with increased gastrointestinal inflammation and poor gastrointestinal function. In this study, we hypothesise that consumption of non-mutated A2 milk will improve gastrointestinal symptoms in non-lactose milk intolerant individuals.
Detailed Description
Non-lactose milk intolerance is a condition that has not been defined clinically yet but the current literature reports existence of subjects who are moderately milk intolerant and whose intolerance can neither be attributed to a defect in lactose intolerance, nor to milk protein allergy. Yet, they experience at least one or two of the following symptoms following milk consumption: gases, bloating, abdominal cramp. It is known that the A1gene variant coding for beta-casein leads to the production of a bioactive peptide with opioid activity named betacasomorphin 7 (BCM7). This peptide has been associated with several metabolic health disorders including diabetes, elevated cardiovascular risk and stimulation of pro-inflammatory signals. Recently, it was reported that non-lactose milk intolerant subjects did not experience such symptoms when consuming milk containing the non-mutated A2 gene variant coding for beta-casein. In this study, we hypothesise that consumption of A2 milk will improve gastrointestinal symptoms in non-lactose milk intolerant individuals. The primary outcome of this study will be the reduction of gastrointestinal inflammation following a course of A2 milk consumption.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Milk Intolerance

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
37 (Actual)

8. Arms, Groups, and Interventions

Arm Title
A1/A2 milk
Arm Type
Sham Comparator
Arm Description
Commercial conventional A1/A2 semi-skimmed fresh pasteurised cow milk. Progressive intake of intervention milk as follows: Days 1 and 2: 100 mL twice a day Days 3 and 4: 150 mL twice a day Days 5 and 6: 200 mL twice a day Days 7 to 14: 250 mL twice a day
Arm Title
A2 milk
Arm Type
Active Comparator
Arm Description
Commercial A2 semi-skimmed fresh pasteurised cow milk. Progressive intake of intervention milk as follows: Days 1 and 2: 100 mL twice a day Days 3 and 4: 150 mL twice a day Days 5 and 6: 200 mL twice a day Days 7 to 14: 250 mL twice a day
Intervention Type
Dietary Supplement
Intervention Name(s)
A2 milk 100
Intervention Description
Days 1 and 2: 100 mL A2 milk twice a day
Intervention Type
Dietary Supplement
Intervention Name(s)
A2 milk 150
Intervention Description
Days 3 and 4: 150 mL A2 milk twice a day
Intervention Type
Dietary Supplement
Intervention Name(s)
A2 milk 200
Intervention Description
Days 5 and 6: 200 mL A2 milk twice a day
Intervention Type
Dietary Supplement
Intervention Name(s)
A2 milk 250
Intervention Description
Days 7 to 14: 250 mL A2 milk twice a day
Intervention Type
Dietary Supplement
Intervention Name(s)
A1/A2 milk 100
Intervention Description
Days 1 and 2: 100 mL A1/A2 milk twice a day
Intervention Type
Dietary Supplement
Intervention Name(s)
A1/A2 milk 150
Intervention Description
Days 3 and 4: 150 mL A1/A2 milk twice a day
Intervention Type
Dietary Supplement
Intervention Name(s)
A1/A2 milk 200
Intervention Description
Days 5 and 6: 200 mL A1/A2 milk twice a day
Intervention Type
Dietary Supplement
Intervention Name(s)
A1/A2 milk 250
Intervention Description
Days 7 to14: 250 mL A1/A2 milk twice a day
Primary Outcome Measure Information:
Title
Change in gastrointestinal inflammation indicated by fecal calprotectin
Description
Measurement of fecal calprotectin (ug/g feces)
Time Frame
baseline, 14 days, 28 days, 42 days and 56 days
Secondary Outcome Measure Information:
Title
Change in NMR-based urinary metabolic profiles
Description
Measured using High Resolution 700MHz proton NMR spectroscopy (Bruker) (no unit)
Time Frame
baseline, 14 days, 28 days, 42 days and 56 days
Title
Change in NMR-based plasma metabolic profiles
Description
Measured using High Resolution 700MHz proton NMR spectroscopy (Bruker) (no unit)
Time Frame
baseline, 14 days, 28 days, 42 days and 56 days
Title
Change in NMR-based fecal metabolic profiles
Description
Measured using High Resolution 700MHz proton NMR spectroscopy (Bruker) (no unit)
Time Frame
baseline, 14 days, 28 days, 42 days and 56 days
Title
Change in gut microbiota ecosystem assessed by sequencing the 16S rDNA extracted from feces
Description
Measures relative abundance of bacterial taxa
Time Frame
baseline, 14 days, 28 days, 42 days and 56 days
Title
Change in systemic inflammation indicated by circulating levels of high sensitivity C-reactive protein
Description
hs-CRP in mg/L
Time Frame
baseline, 14 days, 28 days, 42 days and 56 days
Title
Change in gastrointestinal function assessed using visual analogue scale for GI symptoms
Description
Measures gases, bloating, abdominal cramps, diarrhoea, headache, constipation, nausea and rash
Time Frame
14 days
Title
Height (in m) used to detect change in BMI (kg/m^2)
Time Frame
baseline
Title
Weight (in kg) used to detect change in BMI (kg/m^2)
Time Frame
baseline, 14 days, 28 days, 42 days and 56 days
Title
Change in systolic blood pressure in mmHg
Time Frame
baseline, 14 days, 28 days, 42 days and 56 days
Title
Change in diastolic blood pressure in mmHg
Time Frame
baseline, 14 days, 28 days, 42 days and 56 days
Title
Diagnostic of lactose intolerance by breath hydrogen concentration following ingestion of 25g lactose in 250 mL water
Time Frame
screening visit, 14 days, 42 days and 56 days
Title
Diagnostic of lactose intolerance by breath methane concentration following ingestion of 25g lactose in 250 mL water
Time Frame
screening visit, 14 days, 42 days and 56 days
Title
Self-reported change in gut transit time
Time Frame
14 days, 42 days and 56 days
Title
Monitoring of changes in psychological behaviour assessed by TMT
Time Frame
baseline, 14 days, 28 days, 42 days and 56 days
Title
Monitoring of changes in psychological behaviour assessed by Letter Memory Test
Time Frame
baseline, 14 days, 28 days, 42 days and 56 days
Title
Monitoring of changes in psychological behaviour assessed by Flanger Test
Time Frame
baseline, 14 days, 28 days, 42 days and 56 days
Title
Monitoring of changes in mood measured by PANAS questionnaire
Time Frame
baseline, 14 days, 28 days, 42 days and 56 days
Title
Change in stool consistency using the Bristol stool chart
Time Frame
baseline, 14 days, 28 days, 42 days and 56 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
56 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: BMI: 20-35kg/m2 Glucose<7mmol/l (not diagnosed with diabetes) Total cholesterol<7mmol/l Triacylglycerol<4mmol/l Normal liver and kidney function Regular milk drinker with self-reported intolerance to commercial milk. Suffered from mild to moderate digestive discomfort after milk consumption. Have normal blood pressure 120/80 mmHg (BP <160/90 mmHg can be accepted) during quiet respiration. Agree not to take any medication, supplements and other dairy products including acidophilus milk Be willing to comply with all the requirements and procedures of the study. Agree to sign the informed consent form; Agree not to enrol in another interventional clinical research study while participating in this study. Fully understand the nature, objective, benefit and the potential risks and side effects of the study. Exclusion Criteria: Females who are pregnant or planning to be a pregnant and lactating. Have known dairy allergy. Have stopped drinking milk for the last 6 month. Have history of lactose intolerance Have history of faecal impaction. Received antibiotics in the previous six months Smoker Anemia 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. History of alcohol or drug misuse. 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, cardiovascular diseases and known on-going allergy such as asthma. Currently suffering from any gastrointestinal disorders or gastrointestinal disease, including irritable bowel syndrome, colitis, ulcerative colitis, celiac disease, irritable bowel syndrome (IBS); Had hospitalizations within 3 months before screening; Currently drug frequency user of that may affect the gastrointestinal function or immune system. As judged by investigator. Who take medication at least the last 6-month. Who do excessive exercise not as part of a weight-loss regime, e.g. athletes.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sandrine P Claus, PhD
Organizational Affiliation
University of Reading
Official's Role
Principal Investigator
Facility Information:
Facility Name
Department of Food and Nutritional Sciences
City
Reading
State/Province
Berkshire
ZIP/Postal Code
RG6 6AP
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
We do not plan to share IPD with other researchers outside the University of Reading. Anonymous data may be made available upon publication of the study outcome in appropriate repositories (e.g. metabolomic profiles).
Citations:
PubMed Identifier
24166511
Citation
Ul Haq MR, Kapila R, Sharma R, Saliganti V, Kapila S. Comparative evaluation of cow beta-casein variants (A1/A2) consumption on Th2-mediated inflammatory response in mouse gut. Eur J Nutr. 2014 Jun;53(4):1039-49. doi: 10.1007/s00394-013-0606-7. Epub 2013 Oct 29.
Results Reference
background
PubMed Identifier
24986816
Citation
Ho S, Woodford K, Kukuljan S, Pal S. Comparative effects of A1 versus A2 beta-casein on gastrointestinal measures: a blinded randomised cross-over pilot study. Eur J Clin Nutr. 2014 Sep;68(9):994-1000. doi: 10.1038/ejcn.2014.127. Epub 2014 Jul 2.
Results Reference
background
PubMed Identifier
27039383
Citation
Jianqin S, Leiming X, Lu X, Yelland GW, Ni J, Clarke AJ. Effects of milk containing only A2 beta casein versus milk containing both A1 and A2 beta casein proteins on gastrointestinal physiology, symptoms of discomfort, and cognitive behavior of people with self-reported intolerance to traditional cows' milk. Nutr J. 2016 Apr 2;15:35. doi: 10.1186/s12937-016-0147-z. Erratum In: Nutr J. 2016;15(1):45.
Results Reference
background
PubMed Identifier
8438774
Citation
Johnson AO, Semenya JG, Buchowski MS, Enwonwu CO, Scrimshaw NS. Correlation of lactose maldigestion, lactose intolerance, and milk intolerance. Am J Clin Nutr. 1993 Mar;57(3):399-401. doi: 10.1093/ajcn/57.3.399.
Results Reference
background

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Effects of A2 Milk on Gastrointestinal Function in Non-lactose Milk Intolerance

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