a2 Milk for Autism and Attention-deficit Hyperactivity Disorder (ADHD)

Study Overview
=================
Brief Summary
-----------------
Under double-blind, placebo-controlled, cross-over conditions, the short-term effects of use of A1 beta casein free milk (a2 milk) and milk containing A1 beta casein will be compared in a sample of pre-pubescent boys diagnosed with an autism spectrum disorder (ASD) with concurrent features of attention-deficit hyperactivity disorder (ADHD).

Detailed Description
-----------------
Previous preliminary research studies have suggested that a diet devoid of milk and dairy products might be useful for some people on the autism spectrum in reducing certain types of behaviours or other symptoms that can affect quality of life. Aggravation of some of the symptoms of autism has been suggested to be linked to some of the constituents of milk, in particular a natural breakdown product of the milk protein called beta-casomorphin 1-7 (BC 1-7 or BCM-7) found in the majority of mammalian dairy products. A dairy-free diet (casein-free diet) can however be a difficult diet to follow and may increase the risk that certain nutrients are missing from the diet. Anecdotal evidence suggests that different types of milk from different breeds of cattle (cows) may not carry the same biological effects for some on the autism spectrum. Milk typically found in supermarkets naturally contains BC1-7 as a function of the type of cows producing the milk and the protein it contains (A1 variant of the beta casein protein). The investigators are aiming to test whether a particular type of milk (A1 beta casein free milk also called a2 Milk™) might be able to replace a casein-free diet for children on the autism spectrum also presenting with attention-deficit hyperactivity disorder (ADHD) type symptoms. The investigators will be looking at the potential effects of A1 beta casein free milk on behaviour and various biological processes going on in the body. The source of A1 beta casein free milk will be commercially available a2 Milk™ branded milk that is directly comparable to regular supermarket bought milk with the exception of the beta casein component and is already available to buy. In this double-blind, randomised, placebo-controlled trial, the effects of milk free of A1 beta casein (a branded milk called a2 milk™) and milk containing A1 beta casein will be compared in a sample of pre-pubescent children diagnosed with an autism spectrum disorder with concurrent features of attention-deficit hyperactivity disorder (ADHD). Forty children based in North East England will be initially recruited; all possessing communicative speech and language. A baseline assessment will be conducted to include behavioural, psychometric and health-related parameters. Following random allocation, participants will be assigned to group A or group B and given A1 milk or a2 Milk™ initially for a period of 4 weeks. At this point, baseline assessment measures will be repeated. Milk types will be crossed for groups for a further 4 weeks. At study endpoint, baseline assessment measures will be repeated again. Data derived from the study will be analysed and outcomes reported in peer-review format. During the course of the study, all other forms of dairy product consumption (cheese, yogurts, etc) will be excluded from the diet of all participants irrespective of their treatment allocation. Data from supervised baseline, midpoint and endpoint psychometric and behavioural assessments will be made and stored via a secure survey website accessed via tablets supplied to all participants.

Official Title
-----------------
A1 Beta Casein Free Milk (a2 Milk) for Autism and Attention-deficit Hyperactivity Disorder

Conditions
-----------------
Autism, Attention Deficit Hyperactivity Disorder, Autism Spectrum Disorder

Intervention / Treatment
-----------------
* Dietary Supplement: a2 milk
* Dietary Supplement: a1 containing milk


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis of autism spectrum disorder (autism, Asperger syndrome, Autism Spectrum Disorder) Diagnosis or fulfilling the diagnostic criteria for / presenting with the symptoms of attention-deficit hyperactivity disorder (ADHD) Regular milk drinker Functional use of spoken language (for ability to self-report) Access to internet connection (WiFi) Exclusion Criteria: Undergoing current medical treatment (and an inpatient at a state hospital) Current or past 3 month use of a gluten- and/or casein-free diet Co-morbid diagnoses of Fragile-X syndrome, epilepsy or tuberous sclerosis Indications or diagnosis of cows milk protein allergy (IgE)

Ages Eligible for Study
-----------------
Minimum Age: 5 Years
Maximum Age: 10 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>a2 milk intervention period | Dietary Supplement: a2 milk<br>* replace all milk with a2 milk<br>|
| Placebo Comparator: Control<br>a1 containing milk (normal) intervention period | Dietary Supplement: a1 containing milk<br>* use a1 containing milk<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Childhood Autism Rating Scale (CARS2-HF) Value during intervention | Difference in CARS raw scores and severity group between baseline and 4 weeks and 8 weeks. | Baseline to Week 4 to Week 8 | 
| Change in Conners' Rating Scale - Revised (L) value during intervention. | Difference in Conners' raw scores and totalled scores between baseline and 4 weeks and 8 weeks | Baseline to Week 4 to Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Amino acid analysis of urine samples by mass spectroscopy. | Analysis of urine samples via non-targeted and targeted liquid chromatography mass spectrometry analysis. The targeted compounds to be measured include urinary metabolites of intestinal bacterial species (specifically related to the aromatic amino acids, tryptophan, tyrosine and phenylalanine) and urinary concentrations of compounds related to the methionine cycle (including methionine, homocysteine, cystathione and cysteine). | Baseline to Week 4 to Week 8 | 
| Metabolomic analysis of blood spot samples by mass spectroscopy. | Where blood spot samples are/can be provided by participants, non-targeted and targeted liquid chromatography mass spectrometry analysis will be undertaken. The targeted compounds to be measured include various amino acids including the aromatic amino acids and the branched chain amino acids. Blood spot concentrations of compounds related to the methionine cycle (including methionine, homocysteine, cystathione and cysteine) will also be examined. | Baseline to Week 4 to Week 8 | 
| Changes to the gut microbiome profile. | Gene sequencing of stool samples to characterise the gut microbiome measured by operational taxonomic units (OTUs) of individual bacterial species. | Baseline to Week 4 to Week 8 | 
| Changes to stool appearance measured using the Bristol Stool Chart. | At time of stool sample collection, the presentation of the stool will be recorded using the Bristol Stool Chart. | Baseline to Week 4 to Week 8 |