A Randomized, Double-Blind, Placebo-Controlled, Two-Way Crossover Clinical Trial of
      ORADUR-Methylphenidate for Treating Children and Adolescents with Attention-Deficit/Hyperactivity
      Disorder

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Abstract

Objective: Methylphenidate (MPH) is efficacious in reducing symptoms of attention-deficit/hyperactivity disorder (ADHD), but there are no data about the efficacy and safety of its new formulation (ORADUR ^®-MPH extended release, ORADUR-MPH) in patients with ADHD, which is the study objective.

Method: This was a Phase III, multicenter, randomized, double-blind, placebo-controlled, two-way crossover clinical trial. One hundred children and adolescents with a clinical diagnosis of ADHD (72.7% male) received at least one dose of ORADUR-MPH or a placebo during the 2-week treatment period of each phase. The primary efficacy measure was the Swanson, Nolan, and Pelham-IV-teacher (SNAP-IV-T) form. Secondary efficacy measures included the SNAP-IV-parent form, the Clinical Global Impression: ADHD-Severity score, the Conner's Teacher's Rating Scale score, and the investigator's rating for 18 Diagnostic and Statistical Manual of Mental Disorders, 5th edition ADHD symptoms. In addition, data related to vital signs, body weight, physical examination, laboratory testing, and adverse events (AEs) were also collected. All data were analyzed on an intent-to-treat basis.

Results: Without adjusting for differences in demographics and baseline measures, both treatment groups showed significant reductions in ADHD and oppositional defiant disorder symptoms after a 2-week treatment with greater effect sizes (Cohen's d) in the ORADUR-MPH group (Cohen's d ranging from −0.41 to −1.64; placebo, Cohen's d ranging from −0.26 to −1.18), except for oppositional symptoms, regardless of the informants. For the primary efficacy measure, ORADUR-MPH was significantly superior to the placebo, as evidenced by lower values for and greater reductions in the SNAP-IV-T scores at the endpoint (Cohen's d = −0.16, p = 0.005) and from baseline to the endpoint (Cohen's d = −0.19, p = 0.006), respectively. There were no serious AEs during the clinical study period. The most frequently observed AE was decreased appetite (49.1%). Most physical and laboratory test variables remained within the normal range.

Conclusions: Once-daily ORADUR-MPH is an effective, well-tolerable, and safe treatment for children and adolescents with ADHD. ClinicalTrials.gov number, NCT02450890.

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Calculating and reporting effect sizes to facilitate cumulative science: a practical primer for t-tests and ANOVAs

Daniël Lakens (2013)

Effect sizes are the most important outcome of empirical studies. Most articles on effect sizes highlight their importance to communicate the practical significance of results. For scientists themselves, effect sizes are most useful because they facilitate cumulative science. Effect sizes can be used to determine the sample size for follow-up studies, or examining effects across studies. This article aims to provide a practical primer on how to calculate and report effect sizes for t-tests and ANOVA's such that effect sizes can be used in a-priori power analyses and meta-analyses. Whereas many articles about effect sizes focus on between-subjects designs and address within-subjects designs only briefly, I provide a detailed overview of the similarities and differences between within- and between-subjects designs. I suggest that some research questions in experimental psychology examine inherently intra-individual effects, which makes effect sizes that incorporate the correlation between measures the best summary of the results. Finally, a supplementary spreadsheet is provided to make it as easy as possible for researchers to incorporate effect size calculations into their workflow.

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Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder

Ditte Demontis, Raymond K Walters, Joanna Martin … (2019)

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.

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Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis

Samuele Cortese, Nicoletta Adamo, Cinzia Del Giovane … (2018)

Summary Background The benefits and safety of medications for attention-deficit hyperactivity disorder (ADHD) remain controversial, and guidelines are inconsistent on which medications are preferred across different age groups. We aimed to estimate the comparative efficacy and tolerability of oral medications for ADHD in children, adolescents, and adults. Methods We did a literature search for published and unpublished double-blind randomised controlled trials comparing amphetamines (including lisdexamfetamine), atomoxetine, bupropion, clonidine, guanfacine, methylphenidate, and modafinil with each other or placebo. We systematically contacted study authors and drug manufacturers for additional information. Primary outcomes were efficacy (change in severity of ADHD core symptoms based on teachers' and clinicians' ratings) and tolerability (proportion of patients who dropped out of studies because of side-effects) at timepoints closest to 12 weeks, 26 weeks, and 52 weeks. We estimated summary odds ratios (ORs) and standardised mean differences (SMDs) using pairwise and network meta-analysis with random effects. We assessed the risk of bias of individual studies with the Cochrane risk of bias tool and confidence of estimates with the Grading of Recommendations Assessment, Development, and Evaluation approach for network meta-analyses. This study is registered with PROSPERO, number CRD42014008976. Findings 133 double-blind randomised controlled trials (81 in children and adolescents, 51 in adults, and one in both) were included. The analysis of efficacy closest to 12 weeks was based on 10 068 children and adolescents and 8131 adults; the analysis of tolerability was based on 11 018 children and adolescents and 5362 adults. The confidence of estimates varied from high or moderate (for some comparisons) to low or very low (for most indirect comparisons). For ADHD core symptoms rated by clinicians in children and adolescents closest to 12 weeks, all included drugs were superior to placebo (eg, SMD −1·02, 95% CI −1·19 to −0·85 for amphetamines, −0·78, −0·93 to −0·62 for methylphenidate, −0·56, −0·66 to −0·45 for atomoxetine). By contrast, for available comparisons based on teachers' ratings, only methylphenidate (SMD −0·82, 95% CI −1·16 to −0·48) and modafinil (−0·76, −1·15 to −0·37) were more efficacious than placebo. In adults (clinicians' ratings), amphetamines (SMD −0·79, 95% CI −0·99 to −0·58), methylphenidate (−0·49, −0·64 to −0·35), bupropion (−0·46, −0·85 to −0·07), and atomoxetine (−0·45, −0·58 to −0·32), but not modafinil (0·16, −0·28 to 0·59), were better than placebo. With respect to tolerability, amphetamines were inferior to placebo in both children and adolescents (odds ratio [OR] 2·30, 95% CI 1·36–3·89) and adults (3·26, 1·54–6·92); guanfacine was inferior to placebo in children and adolescents only (2·64, 1·20–5·81); and atomoxetine (2·33, 1·28–4·25), methylphenidate (2·39, 1·40–4·08), and modafinil (4·01, 1·42–11·33) were less well tolerated than placebo in adults only. In head-to-head comparisons, only differences in efficacy (clinicians' ratings) were found, favouring amphetamines over modafinil, atomoxetine, and methylphenidate in both children and adolescents (SMDs −0·46 to −0·24) and adults (−0·94 to −0·29). We did not find sufficient data for the 26-week and 52-week timepoints. Interpretation Our findings represent the most comprehensive available evidence base to inform patients, families, clinicians, guideline developers, and policymakers on the choice of ADHD medications across age groups. Taking into account both efficacy and safety, evidence from this meta-analysis supports methylphenidate in children and adolescents, and amphetamines in adults, as preferred first-choice medications for the short-term treatment of ADHD. New research should be funded urgently to assess long-term effects of these drugs. Funding Stichting Eunethydis (European Network for Hyperkinetic Disorders), and the UK National Institute for Health Research Oxford Health Biomedical Research Centre.

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Author and article information

Journal

Journal ID (nlm-ta): J Child Adolesc Psychopharmacol

Journal ID (iso-abbrev): J Child Adolesc Psychopharmacol

Journal ID (publisher-id): cap

Title: Journal of Child and Adolescent Psychopharmacology

Publisher: Mary Ann Liebert, Inc., publishers (140 Huguenot Street, 3rd FloorNew Rochelle, NY 10801USA )

ISSN (Print): 1044-5463

ISSN (Electronic): 1557-8992

Publication date (Print): April 2021

Publication date (Electronic): 16 April 2021

Publication date PMC-release: 16 April 2021

Volume: 31

Issue: 3

Pages: 164-178

Affiliations

[ ¹ ]Department of Child Psychiatry, Chang Gung Memorial Hospital and University, Taoyuan, Taiwan.

[ ² ]Department of Psychiatry, Tri-Service General Hospital and University, Taipei, Taiwan.

[ ³ ]Department of Psychiatry, Chang Gung Memorial Hospital and University, Chiayi, Taiwan.

[ ⁴ ]Department of Psychiatry, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan.

Author notes

Funding: This work was supported by Orient PHarma Co., Ltd. (OP-2PN012-301).

[*]

These two authors have an equal contribution as the first authors.

[*]Address correspondence to: Susan Shur-Fen Gau, MD, PhD, Department of Psychiatry, National Taiwan University Hospital and College of Medicine, No. 7, Chung-Shan South Road, Taipei 10002, Taiwan gaushufe@ 123456ntu.edu.tw

Article

Publisher ID: 10.1089/cap.2020.0104

DOI: 10.1089/cap.2020.0104

PMC ID: 8066345

PubMed ID: 33395356

SO-VID: c2e36481-e949-4919-b486-2b7f90ad5377

License:

This Open Access article is distributed under the terms of the Creative Commons License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

A Randomized, Double-Blind, Placebo-Controlled, Two-Way Crossover Clinical Trial of ORADUR-Methylphenidate for Treating Children and Adolescents with Attention-Deficit/Hyperactivity Disorder

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Most cited references 101

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Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis

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