A multicentre randomized double-blind placebo controlled discontinuation trial of methylphenidate

INTERVENTION: Trade Name: Concerta Pharmaceutical Form: Capsule, hard Pharmaceutical form of the placebo: Capsule, hard Route of administration of the placebo: Oral use Trade Name: Concerta Pharmaceutical Form: Capsule, hard Trade Name: Concerta Pharmaceutical Form: Capsule, hard Trade Name: Concerta Pharmaceutical Form: Capsule, hard CONDITION: attention‐deficit/hyperactivity disorder Therapeutic area: Psychiatry and Psychology [F] ‐ Behavioral Disciplines and Activities [F04] INCLUSION CRITERIA: In order to be eligible to participate in this study, a subject must meet all of the following criteria: • Children between the ages of eight to eighteen, any ethnicity or cultural background. • Children with their first prescription of any form of methylphenidate at least two years ago. • Children who are for at least the last four weeks the subject has been using methylphenidate in the form of Concerta 36 mg or 54 mg. • Children with an IQ > 70 (based on a previous IQ test or attending regular education). • Parents (or the legal guardian) and children (= twelve years) have provided informed consent to participate in the study. Are the trial subjects under 18? yes Number of subjects for this age range: 120 F.1.2 Adults (18‐64 years) no F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range PRIMARY OUTCOME: Main Objective: Primary Objective: to investigate the effectiveness of ongoing treatment with methylphenidate beyond two years as prescribed in clinical practice in children and adolescents. We will test the hypothesis that ongoing use of methylphenidate is superior to placebo with regard to ADHD/ODD symptom severity in children and adolescents who have used methylphenidate for two years or longer. Here we will be able to establish whether or not long‐term use of methylphenidate is still effective beyond two years of treatment. Primary end point(s): The primary outcome measure will be the clinician based ADHD DSM‐5 rating scale. This is an adapted version of the ADHD Rating Scale‐IV (Zhang et al., 2005). The adaptation is based on the small changes between the DSM‐IV and DSM‐5 for the diagnosis of ADHD. The ADHD‐ IV (5) is a reliable and easy‐to‐administer instrument both for diagnosing ADHD in children and adolescents and for assessing treatment response. Containing 18 items, the scale is linked directly to DSM‐5 diagnostic criteria for ADHD. Secondary Objective: Methylphenidate is related to the dopamine neurotransmitter pathway (by increasing attention) so many of the secondary objectives are related to that. ; (1) to investigate the effects of discontinuation of methylphenidate on a number of secondary outcome measurements (clinical improvement, withdrawal effects, sleeping behaviour, quality of life, neuropsychological task performance and a number of biomarkers related to dopamine function). ; (2) to identify moderators and predictors of treatment discontinuation and long‐term outcome six months later. This includes treatment duration and compliance, child factors (age, sex, presence of comorbid psychiatric problems, genetic polymorphisms, cortisol in hair as stress regulation measure and an underaroused temperament) as well as parent factors (socio‐economic status, presence of psychiatric problems, parental stress and other family factors). Timepoint(s) of evaluation of this end point: baseline, after four and seven weeks and after a six months natural follow up. SECONDARY OUTCOME: Secondary end point(s): Secondary outcome measures: ; Rating scales ; • The Clinical Global Impression Scale of Improvement (CGI‐I). ; • The criteria of Oppositional Defiant Disorder (ODD); • Side effects and withdrawal effects will be evaluated by an adapted version of the Barkley Side Effect Rating scale (BSERS). ; • The Sleep Disturbances Scale for Children (SDSC); • The appetite of the child; • The Retrospective Overt Aggression Scale (R‐MOAS); • The Kindl‐R (quality of life); • The Parental Stress Scale (PSS); • Questions about family atmosphere questions; • The Parental Frustrations Questionnaire (PFQ); • The Child Depression Inventory (CDI); • The Strength and Difficulties Questionnaire (SDQ). We will use the parent, teacher and self‐report (ages 11‐16) versions. ; • The Conners Teacher Rating Scale‐Revised: short form (CTRS‐R:S). ; Physical measures; • Weight, height, blood pressure, pulse ; Biomarkers; • Blood draw (ferritin, zinc and cholesterol); Neuropsychological tests; • Amsterdam Neuropsychological Tasks (three subtests) ; • The Monetary incentive delay task for children; Mediators/predictors; • Treatment history, duration and compliance; Child factors; • Sex, age, ethnicity, school type; • Estimation IQ; • Psychiatric diagnoses; • Tanner stage + some questions of Physical Development Scale (PDS); • Temperament (Behavioural Avoidance and Inhibition Scale [BISBAS], Inventory of Callous and Unemotional traits [ICU], Brief Sensation Seeking Scale [BSSS]); • DNA (blood draw); • Cortisol in hair; • Stressful events; Parental factors; • Socio‐economic factors; • The Egna Minnen Beträffende Uppfostran (EMBU); • The Adult ADHD Rating scale (AARS); • The Parenting Sense of Competence Scale (PSOC); • The Maudsley Marital Questionnaire (MMQ)(subschale Marital adjustment) Timepoint(s) of evaluation of this end point: variable but all at a certain point at the follow ups or baseline. baseline, after four and seven weeks and after a six months natural follow up.