title: Effect of Pycnogenol® on attention-deficit hyperactivity disorder (ADHD): study protocol for a randomised controlled trial.
abstract: Methylphenidate (MPH), the first choice medication for attention-deficit hyperactivity disorder (ADHD), is associated with serious adverse effects like arrhythmia. Evidence on the association of ADHD with immune and oxidant-antioxidant imbalances offers potential for antioxidant and/or immunomodulatory nutritional supplements as ADHD therapy. One small randomised trial in ADHD suggests, despite various limitations, therapeutic benefit from Pycnogenol®, a herbal, polyphenol-rich extract.
  
  
  
  This phase III trial is a 10-week, randomised, double-blind, placebo and active treatment controlled multicentre trial with three parallel treatment arms to compare the effect of Pycnogenol® to MPH and placebo on the behaviour of 144 paediatric ADHD and attention-deficit disorder (ADD) patients. Evaluations of behaviour (measured by the ADHD-Rating Scale (primary endpoint) and the Social-emotional Questionnaire (SEQ)), immunity (plasma cytokine and antibody levels, white blood cell counts and faecal microbial composition), oxidative stress (erythrocyte glutathione, plasma lipid-soluble vitamins and malondialdehyde and urinary 8-OHdG levels, as well as antioxidant enzyme activity and gene expression), serum zinc and neuropeptide Y level, urinary catecholamines and physical complaints (Physical Complaints Questionnaire) will be performed in week 10 and compared to baseline. Acceptability evaluations will be based on adherence, dropouts and reports of adverse events. Dietary habits will be taken into account.
  
  
  
  This trial takes into account comorbid behavioural and physical symptoms, as well as a broad range of innovative immune and oxidative biomarkers, expected to provide fundamental knowledge on ADHD aetiology and therapy. Research on microbiota in ADHD is novel. Moreover, the active control arm is rather unseen in research on nutritional supplements, but of great importance, as patients and parents are often concerned with the side effects of MPH.
  
  
  
  Clinicaltrials.gov number: NCT02700685 . Registered on 18 January 2016. EudraCT 2016-000215-32 . Registered on 4 October 2016.
authors.affiliation: Department of Pharmaceutical Sciences, Laboratory of Nutrition and Functional Food Science, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium. Annelies.verlaet@uantwerpen.be.
authors.forename: Annelies A J
authors.initials: AA
authors.lastname: Verlaet
authors.affiliation: Neurology, University Hospital Antwerp, Wilrijkstraat 10, 2650, Edegem, Belgium.
authors.forename: Berten
authors.initials: B
authors.lastname: Ceulemans
authors.affiliation: Paediatric Neurology, University Hospital Ghent, De Pintelaan 185, 9000, Gent, Belgium.
authors.forename: Helene
authors.initials: H
authors.lastname: Verhelst
authors.affiliation: Hospital Networtk Antwerp, Universitary Child and Adolescent Psychiatry, Lindendreef 1, 2020, Antwerp, Belgium.
authors.forename: Dirk
authors.initials: D
authors.lastname: Van West
authors.affiliation: Department of Pharmaceutical Sciences, Laboratory of Nutrition and Functional Food Science, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium.
authors.forename: Tess
authors.initials: T
authors.lastname: De Bruyne
authors.affiliation: Department of Pharmaceutical Sciences, Laboratory of Nutrition and Functional Food Science, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium.
authors.forename: Luc
authors.initials: L
authors.lastname: Pieters
authors.affiliation: Cell Biology and Immunology Group, Wageningen University, De Elst 1, 6709 PG, Wageningen, The Netherlands.
authors.forename: Huub F J
authors.initials: HF
authors.lastname: Savelkoul
authors.affiliation: Department of Pharmaceutical Sciences, Laboratory of Nutrition and Functional Food Science, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium.
authors.forename: Nina
authors.initials: N
authors.lastname: Hermans
mesh_terms: D000276:Adjuvants, Immunologic / Q000009:adverse effects / Q000627:therapeutic use*; D000975:Antioxidants / Q000009:adverse effects / Q000627:therapeutic use*; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000523:psychology; D001530:Belgium; D015415:Biomarkers / Q000097:blood / Q000652:urine; D000697:Central Nervous System Stimulants / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D002652:Child Behavior / Q000187:drug effects*; D002985:Clinical Protocols; D016207:Cytokines / Q000097:blood; D004311:Double-Blind Method; D005145:Face / Q000382:microbiology; D005247:Feeding Behavior; D005260:Female; D005419:Flavonoids / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008774:Methylphenidate / Q000009:adverse effects / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects; D010936:Plant Extracts; D012107:Research Design; D011795:Surveys and Questionnaires; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000276:Adjuvants, Immunologic; D000975:Antioxidants; D015415:Biomarkers; D000697:Central Nervous System Stimulants; D016207:Cytokines; D005419:Flavonoids; D010936:Plant Extracts; D008774:Methylphenidate; C024070:pycnogenols
keywords: ADD; ADHD; Antioxidant; Behaviour; Catecholamines; Immunity; Oxidative stress; Polyphenols; Pycnogenol®