Clinical trial NCT03440346: Biomarker Research in ADHD: the Impact of Nutrition
Official title: Biomarker Research in ADHD: the Impact of Nutrition (BRAIN). An Open-label Trial to Investigate the Mechanisms Underlying the Effects of a Few-foods Diet on ADHD Symptoms in Children
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Attention Deficit-Hyperactivity Disorder
Keywords: Attention Deficit Hyperactivity Disorder
ADHD
child
human
diet
few-foods diet
brain
gut
microbiota
Lead sponsor: Wageningen University
Sponsor class: OTHER
Collaborators: name: ADHD Research Centre
First posted: 2018-02-22
Enrollment: 100
Sex: MALE
Minimum age (years): 8
Maximum age (years): 10
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

Brief summary: Attention deficit hyperactivity disorder (ADHD) is the most common childhood behavioural disorder, causing significant impediment to a child's development. The exact aetiology of ADHD is still unknown. It is a complex disorder with numerous contributing (epi)genetic and environmental factors. Currently, treatment predominantly consists of behavioural and pharmacological therapy. However, medication use is associated with several side effects and concerns about long-term effects and efficacy exist. Therefore, there is considerable interest in the development of alternative treatment options.

Double-blind research investigating the effect of a few-foods diet (FFD) has demonstrated large improvements in ADHD symptoms. However, following an FFD requires great effort of both the child and parents. To make this treatment easier or potentially obsolete, it is important to understand how and in which children an FFD affects ADHD symptoms.

The investigators hypothesise that an FFD affects brain function and behaviour, including ADHD symptoms, via the complex network of communication between the microbiota, gut and brain, i.e. the MGB axis. The aim of this study is to identify potential mechanism(s) underlying the impact of an FFD on ADHD symptoms and to identify biomarkers that predict the response to the FFD.

100 boys with ADHD will follow the FFD for 5 weeks. After inclusion, all participants will start with a baseline period, during which they will maintain their regular diet. The baseline period ends at the end of week 2. Thereafter, participants will follow a 5-week FFD, preceded by a 1-week transition period. The FFD period ends at the end of week 8.

At the end of the baseline period (i.e. at the end of week 2) and at the end of the FFD (i.e. at the end of week 8), fMRI scans will be made, blood and buccal saliva will be collected, and stool and urine will be handed in. Children will do computer tasks and parents will complete questionnaires to monitor ADHD and physical complaints. All samples will be analysed by researchers blinded to behavioural responses to the FFD. To assess the impact of the FFD on brain function and the MGB axis, associations between ADHD behavioural changes and changes in other primary and secondary study outcomes will be analysed.

This study may lead to the identification of biomarkers that can predict the response to an FFD. Understanding which changes - induced by an FFD - lead to improvements in ADHD symptoms may provide new avenues for developing treatments. Ultimately, the findings may enable personalised intervention strategies based on an individuals' configuration of the MGB axis.


Eligibility criteria: Inclusion Criteria:

* Meeting DSM-IV ADHD criteria
* Male
* Aged 8 up to and including 10 years
* Right-handed
* Available to visit Wageningen University for 4 sessions (i.e. intake, screening, T1 and T2), of which 3 sessions including the child (screening, T1, T2)
* Upon study start, fully understanding and agreeing to the study objectives and having dated and signed an informed consent to participate in the study, including permission that material will be used or archived for (epi)genetic testing
* Willing to be informed about chance-findings that may have implications for the health of the child or his family, and approving of reporting this to the child's medical specialist or family's general physician.
* If the child uses "over the counter" medication, e.g. laxatives, melatonin for sleeping problems or hay fever medication, parents are asked to share the information leaflet, and if necessary participants are asked to change to alternatives that are free of additives that may affect ADHD, e.g. laxatives free of artificial sweeteners, sugar and cacao.

Exclusion Criteria:

* Diagnosis Autism Spectrum Disorder
* Diagnosis Developmental Coordination Disorder
* Premature birth (\< 36 weeks) and/or oxygen deprivation during birth
* Diagnosed chronic gastrointestinal disorder, i.e. inflammatory bowel disease, irritable bowel syndrome, celiac disease, non-celiac gluten-intolerance (gluten-sensitivity) or lactose-intolerance
* Auto-immune disorder (e.g. diabetes mellitus type 1)
* Vegetarian/vegan
* Diagnosis dyslexia and/or dyscalculia
* IQ \< 85
* Following behavioural therapy
* Use of ADHD medication
* Use of systemic antibiotics, antifungals, antivirals or antiparasitics in the past six months
* Insufficient command of the Dutch language by either parents or child that may affect understanding and execution of study and dietary instructions
* Family circumstances that may compromise following or completion of the diet, including but not limited to family relational problems
* Having a contra-indication to MRI scanning (including, but not limited to): pacemakers and defibrillators, intraorbital or intraocular metallic fragments, ferromagnetic implants, claustrophobia.
* Two weeks prior to the start of the study, dietary supplements (e.g. antioxidants, minerals, vitamins) or pro- or prebiotics use has to be stopped.

Primary outcomes:
measure: Change in neural activation patterns during execution of tasks
timeFrame: Before and at the end of the FFD intervention (i.e. at the end of week 2 and at the end of week 8)
measure: Change in peripheral blood metabolite concentrations
timeFrame: Before and at the end of the FFD intervention (i.e. at the end of week 2 and at the end of week 8)
measure: Change in functional composition of the gut microbiota
timeFrame: Before and at the end of the FFD intervention (i.e. at the end of week 2 and at the end of week 8)
measure: Change in ADHD symptom scores
timeFrame: Before and at the end of the FFD intervention (i.e. at the end of week 2 and at the end of week 8)
Secondary outcomes:
measure: Change in whole brain neural activation patterns during the execution of tasks
timeFrame: Before and at the end of the FFD intervention (i.e. at the end of week 2 and at the end of week 8)
measure: Change in whole brain functional connectivity at rest
timeFrame: Before and at the end of the FFD intervention (i.e. at the end of week 2 and at the end of week 8)
measure: Change in taxonomic and functional composition of the gut microbiota
timeFrame: Before and at the end of the FFD intervention (i.e. at the end of week 2 and at the end of week 8)
measure: Change in metabolite profiles
timeFrame: Before and at the end of the FFD intervention (i.e. at the end of week 2 and at the end of week 8)
measure: Change in peripheral blood cell gene expression profiles
timeFrame: Before and at the end of the FFD intervention (i.e. at the end of week 2 and at the end of week 8)
measure: Change in a panel of peripheral blood protein biomarkers related to immune, metabolic and neurological status
timeFrame: Before and at the end of the FFD intervention (i.e. at the end of week 2 and at the end of week 8)
measure: DNA genotype
timeFrame: Before the FFD diet intervention (i.e. at the end of week 2)
measure: Change in DNA methylation profiles
timeFrame: Before and at the end of the FFD intervention (i.e. at the end of week 2 and at the end of week 8)
measure: Change in executive function
timeFrame: Before and at the end of the FFD intervention (i.e. at the end of week 2 and at the end of week 8)
measure: Change in ADHD symptoms
timeFrame: Before and at the end of the FFD intervention (i.e. at the end of week 2 and at the end of week 8)
measure: Change in oppositional defiant disorder symptoms
timeFrame: Before and at the end of the FFD intervention (i.e. at the end of week 2 and at the end of week 8)
measure: Change in social behavioural problems
timeFrame: Before and at the end of the FFD intervention (i.e. at the end of week 2 and at the end of week 8)
measure: Change in physical complaints
timeFrame: Before and at the end of the FFD intervention (i.e. at the end of week 2 and at the end of week 8)
measure: Change in stool frequency
timeFrame: Before and at the end of the FFD intervention (i.e. at the end of week 2 and at the end of week 8)
measure: Change in stool type
timeFrame: Before and at the end of the FFD intervention (i.e. at the end of week 2 and at the end of week 8)
Other outcomes:
measure: IQ-score
timeFrame: At the screening session, prior to inclusion of participant in the study
measure: Change in taxonomic and functional composition of the gut microbiota
timeFrame: Prior to the screening (i.e. week 0) and after the baseline period (i.e. at the end of week 2)
Locations:
city: Wageningen
country: Netherlands
facility: Wageningen University
Study officials:
affiliation: Wageningen University
name: Michiel Kleerebezem, Prof. dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Pelsser LM, Frankena K, Toorman J, Savelkoul HF, Dubois AE, Pereira RR, Haagen TA, Rommelse NN, Buitelaar JK. Effects of a restricted elimination diet on the behaviour of children with attention-deficit hyperactivity disorder (INCA study): a randomised controlled trial. Lancet. 2011 Feb 5;377(9764):494-503. doi: 10.1016/S0140-6736(10)62227-1.
citation: Pelsser LM, Frankena K, Toorman J, Rodrigues Pereira R. Diet and ADHD, Reviewing the Evidence: A Systematic Review of Meta-Analyses of Double-Blind Placebo-Controlled Trials Evaluating the Efficacy of Diet Interventions on the Behavior of Children with ADHD. PLoS One. 2017 Jan 25;12(1):e0169277. doi: 10.1371/journal.pone.0169277. eCollection 2017.
citation: Stobernack T, de Vries SPW, Rodrigues Pereira R, Pelsser LM, Ter Braak CJF, Aarts E, van Baarlen P, Kleerebezem M, Frankena K, Hontelez S. Biomarker Research in ADHD: the Impact of Nutrition (BRAIN) - study protocol of an open-label trial to investigate the mechanisms underlying the effects of a few-foods diet on ADHD symptoms in children. BMJ Open. 2019 Nov 5;9(11):e029422. doi: 10.1136/bmjopen-2019-029422.