Randomized, Double-Blind, Placebo-Controlled Acute Comparator Trials of Lisdexamfetamine and Extended-Release Methylphenidate in Adolescents With Attention-Deficit/Hyperactivity Disorder

Jeffrey H Newcorn, Peter Nagy, Ann C Childress, Glen Frick, Brian Yan, Steven Pliszka, Jeffrey H Newcorn, Peter Nagy, Ann C Childress, Glen Frick, Brian Yan, Steven Pliszka

Abstract

Background: Psychostimulants are considered first-line pharmacotherapy for youth with attention-deficit/hyperactivity disorder (ADHD), but questions remain regarding the comparative efficacy of amphetamine- and methylphenidate-based agents.

Objective: Our objective was to describe two acute randomized, double-blind, placebo-controlled, head-to-head studies of lisdexamfetamine dimesylate (LDX) and osmotic-release oral system methylphenidate (OROS-MPH) in adolescents with ADHD.

Methods: Adolescents (13-17 years) diagnosed with ADHD according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria were enrolled in an 8-week flexible-dose study [LDX 30-70 mg/day (n = 186 randomized); OROS-MPH 18-72 mg/day (n = 185 randomized); placebo (n = 93 randomized)] or a 6-week forced-dose study [LDX 70 mg/day (n = 219 randomized); OROS-MPH 72 mg/day (n = 220 randomized); placebo (n = 110 randomized)]. Attention-Deficit/Hyperactivity Disorder Rating Scale IV (ADHD-RS-IV) total score changes from baseline (primary endpoint) at week 8 (flexible-dose study) or week 6 (forced-dose study) were assessed with mixed-effects models for repeated measures. Secondary endpoints included improvement on the dichotomized Clinical Global Impressions-Improvement scale (CGI-I; key secondary endpoint) and changes from baseline on the ADHD-RS-IV subscales. Safety assessments included treatment-emergent adverse events (TEAEs) and vital signs.

Results: Least squares (LS) mean ± standard error of the mean (SEM) ADHD-RS-IV total score changes from baseline to end of treatment were -17.0 ± 1.03 with placebo, -25.4 ± 0.74 with LDX, and -22.1 ± 0.73 with OROS-MPH in the forced-dose study and -13.4 ± 1.19 with placebo, -25.6 ± 0.82 with LDX, and -23.5 ± 0.80 with OROS-MPH in the flexible-dose study. LS mean ± SEM treatment difference for the change from baseline significantly favored LDX over OROS-MPH in the forced-dose [-3.4 ± 1.04, p = 0.0013, effect size (ES) -0.33] but not the flexible-dose (-2.1 ± 1.15, p = 0.0717, ES -0.20) study. The percentage of improved participants on the dichotomized CGI-I at end of treatment was significantly greater with LDX than with OROS-MPH in the forced-dose study (81.4 vs. 71.3%, p = 0.0188) but not the flexible-dose study (LDX 83.1%, OROS-MPH 81.0%, p = 0.6165). The LS mean ± SEM treatment differences for change from baseline on the ADHD-RS-IV hyperactivity/impulsivity and inattentiveness subscales nominally favored LDX in the forced-dose study (hyperactivity/impulsivity subscale -1.3 ± 0.49, nominal p = 0.0081, ES -0.27; inattentiveness subscale -2.0 ± 0.63, nominal p = 0.0013, ES -0.33), but there were no significant differences between active treatments in the flexible-dose study. In both studies, LDX and OROS-MPH were superior to placebo for all efficacy-related endpoints (all nominal p < 0.0001; ES range -0.43 to -1.16). The overall frequency of TEAEs for LDX and OROS-MPH, respectively, were 66.5 and 58.9% in the forced-dose study and 83.2 and 82.1% in the flexible-dose study. TEAEs occurring in ≥ 5% of participants that were also reported at two or more times the rate of placebo were decreased appetite, decreased weight, insomnia, initial insomnia, dry mouth, and nasopharyngitis (LDX and OROS-MPH), irritability and dizziness (LDX only), and increased heart rate (OROS-MPH only) in the forced-dose study and decreased appetite, decreased weight, insomnia, and dizziness (LDX and OROS-MPH) and dry mouth and upper abdominal pain (LDX only) in the flexible-dose study. Mean ± standard deviation (SD) increases from baseline in vital signs (systolic and diastolic blood pressure, pulse) were observed in the forced-dose study [LDX 1.6 ± 9.65 and 3.3 ± 8.11 mmHg, 6.7 ± 12.78 beats per minute (bpm); OROS-MPH 2.6 ± 10.15 and 3.3 ± 9.13 mmHg, 7.6 ± 12.47 bpm] and the flexible-dose study (LDX 2.4 ± 9.46 and 2.8 ± 8.41 mmHg, 4.7 ± 11.82 bpm; OROS-MPH 0.4 ± 9.90 and 2.2 ± 8.64 mmHg, 6.0 ± 10.52 bpm) at the last on-treatment assessment.

Conclusions: LDX was superior to OROS-MPH in adolescents with ADHD in the forced-dose but not the flexible-dose study. Safety and tolerability for both medications was consistent with previous studies. These findings underscore the robust acute efficacy of both psychostimulant classes in treating adolescents with ADHD. CLINICALTRIALS.

Gov registry numbers: NCT01552915 and NCT01552902.

Conflict of interest statement

Funding

The clinical research described in this paper was funded by Shire Development LLC (Lexington, MA, USA). Shire Development LLC also provided funding to CHC for support in writing and editing this manuscript and provided the funding for the open access fee for this paper. The sponsor, Shire Development LLC, was involved in the study design, data collection and analysis, and data interpretation. The sponsor was also involved in the writing of the manuscript and in the decision to submit the article for publication, but the final content and decision to submit the manuscript to CNS Drugs was made by the authors.

Conflicts of interest

Jeffrey Newcorn has been an advisor and/or consultant to Arbor, Akili Interactive, Alcobra, Enzymotec, Ironshore, KemPharm, Lundbeck, Medici, Neos, NLS, Pearson, Shire, Sunovion, and Supernus and has received research support from Enzymotec, Lundbeck, and Shire. Peter Nagy has served on an advisory board for Lilly Hungaria and Medice and has received research support from the Tourette Syndrome Association of the USA, the Hungarian Ministry of Education, the National Development Agency of Hungary, Otsuka, and Shire Pharmaceuticals. Ann Childress has been a consultant for Arbor, Ironshore, Neos, NextWave Pharmaceuticals, Novartis Pharmaceutical Corporation, Rhodes, and Shire Pharmaceuticals; has served as a speaker for Arbor, Bristol-Myers Squibb, Novartis Pharmaceutical Corporation, Pfizer, Shire Pharmaceuticals, and Shionogi; has received research support from Arbor, Bristol-Myers Squibb, Forest Research Institute, Ironshore, Johnson & Johnson Pharmaceutical Research & Development, Lilly USA, LLC, Medgenics, Neos, Neurovance, NextWave Pharmaceuticals, Novartis Pharmaceutical Corporation, Noven, Otsuka, Pfizer, Purdue, Rhodes, Sepracor Inc, Shire Pharmaceuticals, Shionogi, Sunovion, Theravance, and Tris; and has served on advisory boards for Arbor, Ironshore, Neos, Pfizer¸ Rhodes, and Shionogi. Glen Frick is a former employee of Shire Development LLC and holds stock/stock options in Shire. Brian Yan is an employee of Shire Development LLC and holds stock/stock options in Shire. Steven Pliszka has received research support from Ironshore, Shire, and Purdue University; has received consulting fees or an honorarium from Ironshore; and has served as an expert witness for Janssen.

Ethical approval and informed consent

Each study was conducted in accordance with the International Conference on Harmonisation of Good Clinical Practice and the Declaration of Helsinki. Study protocols and related information were approved by either a central review board or institution specific review boards and appropriate regulatory agencies (US FDA, Therapeutic Product Directorate of Canada, Medical Products Agency of Sweden, Medical Research Council of Hungary, The Federal Institute for Drugs and Medical Devices [Bundesinstitut für Arzneimittel und Medizinprodukte] of Germany) before study initiation. The participant’s parent or legally authorized representative must have provided informed consent and been willing and able to comply with all study requirements.

Figures

Fig. 1
Fig. 1
Participant disposition. Flexible flexible-dose study, forced forced-dose study, LDX lisdexamfetamine dimesylate, OROS-MPH osmotic controlled-release methylphenidate
Fig. 2
Fig. 2
ADHD-RS-IV total score by treatment week, full analysis set, in the flexible-dose study (A) and the forced-dose study (B). ADHD-RS-IV Attention-Deficit/Hyperactivity Disorder Rating Scale IV, LDX lisdexamfetamine dimesylate, OROS-MPH osmotic-release oral system methylphenidate, SD standard deviation

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Source: PubMed

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