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

Yu-Shu Huang,Chin-Bin Yeh,Chi-Yung Shang,Susan Shur-Fen Gau,Chin-Hung Chen

doi:10.1089/cap.2020.0104

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.

Highlights

Attention-deficit/hyperactivity disorder (ADHD), which is characterized by developmentally inappropriate inattention, hyperactivity, and impulsivity, is a common neuropsychiatric disorder that affects 2%–7% of individuals all over the world (Sayal et al 2018); the frequency of this disorder is higher in the United States and Taiwan, being 8.5%–9.5% (Zablotsky et al 2019) and 7%–8% (Gau et al 2005; Chen et al 2019), respectively
Each clinical diagnosis was made by a senior child psychiatrist according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) diagnostic criteria for attention-deficit/hyperactivity disorder (ADHD) (American Psychiatric Association 2013), and this diagnosis was further confirmed by psychiatric interview using the Chinese version of the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children-Epidemiological (K-SADS-E) Version, which is used for the diagnosis of ADHD and other psychiatric disorders (Gau et al 2005; Chen et al 2017)
There was no difference between the two treatment groups in terms of demographic data, vital signs, and the dosage of medication, or in all efficacy measures (Table 1)

Summary

Introduction

Attention-deficit/hyperactivity disorder (ADHD), which is characterized by developmentally inappropriate inattention, hyperactivity, and impulsivity, is a common neuropsychiatric disorder that affects 2%–7% of individuals all over the world (Sayal et al 2018); the frequency of this disorder is higher in the United States and Taiwan, being 8.5%–9.5% (Zablotsky et al 2019) and 7%–8% (Gau et al 2005; Chen et al 2019), respectively. The core symptoms of ADHD last until adulthood (Reimherr et al 2015) and are associated with a high frequency of psychiatric comorbid conditions during both adolescence (Gau et al 2010) and adulthood (Lin et al 2016); these are associated with long-term functional impairment and reduced life quality (Lin et al 2015). Due to its high prevalence, the pervasiveness of the impairment, and its tremendous impact on the individual, their family, and society in general, treatment of ADHD, which can include pharmacotherapy (Nageye and Cortese 2019) and psychosocial interventions, is crucial (Faraone et al 2015). Converging evidence supports the conclusion that MPH efficaciously reduces ADHD symptoms (Gau et al 2006a) and other related emotional and behavioral symptoms (Shih et al 2019) in children and adolescents with ADHD, while at the same time improving academic achievement (Kortekaas-Rijlaarsdam et al 2019), social functioning (Shang et al 2019), neuropsychological performance (Chou et al 2015), and brain functioning (Shang et al 2016)

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