‘Off-label use of Risperidone in Children and Adolescents (ORCA): a double-blind placebo-controlled discontinuation trial’

INTERVENTION: Product Name: risperidone Pharmaceutical Form: Oral solution INN or Proposed INN: risperidone Other descriptive name: RISPERIDONE Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 1‐ Pharmaceutical form of the placebo: Oral solution Route of administration of the placebo: Oral use CONDITION: no specific condition, we will investigate children who have been using risperidone on an off‐label basis for at least one year. Therapeutic area: Psychiatry and Psychology [F] ‐ Behavioral Disciplines and Activities [F04] SECONDARY OUTCOME: Secondary end point(s): Secondary outcome measures:; ‐ Strength and Difficulties Questionnaire (SDQ); ‐ Retrospective Modified Overt Aggression Scale (R‐MOAS); ‐ Conner's Teacher Rating Scale‐Revised: short form (CTRS‐R:S); ‐ Clinical Global Impression Scale (CGI); ‐ Children's Global Assessment Scale (CGAS); ‐ Kindl‐R (quality of life) ; ‐ Parental Frustration Questionnaire (PFQ) ; ‐ Amsterdam Neuropsychological Tasks (ANT); ‐ UKU side effect rating scale (UKU‐SERS); ‐ Abnormal Involuntary Movement Scale (AIMS); ‐ Barnes Akathisia Scale (BARS); ‐ Unified Parkinson's disease rating scale (UPDRS); ‐ Sleep Disturbances Scale for Children (SDSC); ‐ appetite and life style; ‐ Physical Activity Questionnaire (PAQ); ‐ Physical measures: length, weight, waist circumference, heart rate and blood pressure; ‐ Blood counts; •Metabolism: fasting glucose, insulin, triglycerides, high‐density lipoproteins (HDL), low‐density lipoproteins (LDL), leptine, and total cholesterol.; •Endocrine parameters: prolactin, testosterone, and estradiol.; •Bone turnover: P1NP, CTx, osteocalcine, vitamin D, and calcium.; •Thyroid function: TSH, T4, and parathyreoid hormone.; •Kidney function: creatinine, sodium, and potassium.; •Pharmacokinetics: risperidone and 9‐hydroxyrisperidone concentrations.; •Albumine levels.; ; Predictor variables:; ‐ Demographic data and socio‐economic status; ‐ Treatment history and psychiatric diagnosis; ‐ Tanner stages of pubertal development; ‐ genetic polymorphisms (e.g. CYP2D6, CYP3A); ‐ Nijmeegse Ouderlijke Stress Index‐kort (NOSI‐K); ‐ Alabama Parenting Questionnaire (APQ) ; ‐ Parent‐rating scale for Reactive and Proactive Aggression (PRPA) Timepoint(s) of evaluation of this end point: Secondary outcome measures will be measured at at baseline, eight weeks, fourteen weeks and after six months naturalistic follow up. Predictor variables will be measured at baseline. INCLUSION CRITERIA: In order to be eligible to participate in this study, a subject must meet all of the following criteria: • Be between the ages of six and seventeen years and eight months • Current risperidone use = one year. • Current risperidone doses = 5 mg/day. • 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: To investigate the behavioral effects of controlled discontinuation as well as the feasibility of discontinuing currently ongoing treatment with risperidone in children and adolescents with behavioral problems who have used risperidone for at least one year. Here, we will be able to establish whether or not long‐term use of risperidone is still effective beyond one year of treatment. We will also be able to study physical health correlates after discontinuation. Primary end point(s): Problem behavior will be assessed by the Nisonger Child Behavior Rating Form‐Typical IQ (NCBRF‐TIQ; Aman et al, 2008). This 64‐item, parent‐reported scale contains a Positive Social subscale (10 items) and six Problem Behavior subscales (54 items): (1) Conduct Problems, (2) Oppositional, (3) Hyperactive, (4) Inattentive, (5) Withdrawn/Dysphoric, and (6) Overly Sensitive. A total Disruptive Behavior Disorder score (D‐total) and a total ADHD score (ADHD‐total) can be calculated. The primary study parameter will be the D‐total, which is calculated by adding the scores on the Conduct problems and the Oppositional behavior scale. Secondary Objective: (1) to investigate the effects of discontinuation of risperidone on a number of secondary outcome variables (problem behavior and comorbidity, clinical improvement, general functioning and quality of life, parental and family functioning, and neuropsychological functioning) and tolerability ratings (side effects and withdrawal effects, physical measures, and blood counts).; (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, temperamental traits, biologic factors and genetic factors) as well as parent factors (socio‐economic status, parental and family factors).; Timepoint(s) of evaluation of this end point: at baseline, eight weeks, fourteen weeks and after six months naturalistic follow up