A 13-hour laboratory school study of lisdexamfetamine dimesylate in school-aged children with attention-deficit/hyperactivity disorder

Child and Adolescent Psychiatry and Mental Health BioMed Central Research Open Access A 13-hour laboratory school study of lisdexamfetamine dimesylate in school-aged children with attention-deficit/hyperactivity disorder Sharon B Wigal*1, Scott H Kollins2, Ann C Childress3, Liza Squires4 for the 311 Study Group Address: 1University of California, Irvine, Child Development Center, Irvine, California, USA, 2Duke University Medical Center, Durham, North Carolina, USA, 3Center for Psychiatry and Behavioral Medicine, Las Vegas, Nevada, USA and 4Shire Development Inc, Wayne, Pennsylvania, USA Email: Sharon B Wigal* - ; Scott H Kollins - ; Ann C Childress - ; Liza Squires - ; the 311 Study Group - * Corresponding author Published: 9 June 2009 Child and Adolescent Psychiatry and Mental Health 2009, 3:17 doi:10.1186/1753-2000-3-17 Received: 11 February 2009 Accepted: 9 June 2009 This article is available from: http://www.capmh.com/content/3/1/17 © 2009 Wigal et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: Lisdexamfetamine dimesylate (LDX) is indicated for the treatment of attention-deficit/ hyperactivity disorder (ADHD) in children 6 to 12 years of age and in adults. In a previous laboratory school study, LDX demonstrated efficacy 2 hours postdose with duration of efficacy through 12 hours. The current study further characterizes the time course of effect of LDX. Methods: Children aged 6 to 12 years with ADHD were enrolled in a laboratory school study. The multicenter study consisted of open-label, dose-optimization of LDX (30, 50, 70 mg/d, 4 weeks) followed by a randomized, placebo-controlled, 2-way crossover phase (1 week each). Efficacy measures included the SKAMP (deportment [primary] and attention [secondary]) and PERMP (attempted/correct) scales (secondary) measured at predose and at 1.5, 2.5, 5, 7.5, 10, 12, and 13 hours postdose. Safety measures included treatment-emergent adverse events (AEs), physical examination, vital signs, and ECGs. Results: A total of 117 subjects were randomized and 111 completed the study. Compared with placebo, LDX demonstrated significantly greater efficacy at each postdose time point (1.5 hours to 13.0 hours), as measured by SKAMP deportment and attention scales and PERMP (P < .005). The most common treatment-emergent AEs during dose optimization were decreased appetite (47%), insomnia (27%), headache (17%), irritability (16%), upper abdominal pain (16%), and affect lability (10%), which were less frequent in the crossover phase (6%, 4%, 5%, 1%, 2%, and 0% respectively). Conclusion: In school-aged children (6 to 12 years) with ADHD, efficacy of LDX was maintained from the first time point (1.5 hours) up to the last time point assessed (13.0 hours). LDX was generally well tolerated, resulting in typical stimulant AEs. Trial registration: Official Title: A Phase IIIb, Randomized, Double-Blind, Multi-Center, PlaceboControlled, Dose-Optimization, Cross-Over, Analog Classroom Study to Assess the Time of Onset of Vyvanse (Lisdexamfetamine Dimesylate) in Pediatric Subjects Aged 6–12 With Attention-Deficit/ Hyperactivity Disorder. ClinicalTrials.gov Identifier: NCT00500149 http://clinicaltrials.gov/ct2/show/NCT00500149 Page 1 of 15 (page number not for citation purposes) Child and Adolescent Psychiatry and Mental Health 2009, 3:17 Background Stimulants are the mainstay of pharmacotherapy for attention-deficit/hyperactivity disorder (ADHD). Their safety and efficacy have been well documented [1-3]. Within this class of medications, amphetamine and methylphenidate are the most widely prescribed agents for the treatment of ADHD [4]. An early double-blind, parallelgroup study of dexamphetamine in 38 children with hyperkinetic disorder demonstrated efficacy for dexamphetamine with 62% considered greatly improved overall vs 17% for placebo [5]. Target symptoms such as hyperactivity and distractibility were also significantly improved by treatment. The adverse events associated with dexamphetamine in this study were those typically seen with stimulants, including reduction in appetite, weight loss, insomnia, stomach ache and changes in emotional expression [5]. A second arm of the study with methylphenidate found substantial similarity between the 2 medications in efficacy and safety. In the years since, immediateand sustained-release formulations of d-amphetamine have been used extensively to treat ADHD with a number of reports concluding that there is a high degree of similarity in efficacy and tolerability between d-amphetamine and methylphenidate and that differences are subtle and often subject-specific ([1,6-8]. There is an important clinical need for long-acting stimulant medications with efficacy beyond 12 hours' duration among children with ADHD who require symptom control that extends into the later hours of the day [9]. Lisdexamfetamine dimesylate (LDX; Vyvanse®; Shire US Inc) is a prodrug stimulant indicated for the treatment of ADHD. LDX is a therapeutically inactive molecule that subsequently upon ingestion is hydrolyzed by endogenous enzymes to l-lysine, a naturally occurring essential amino acid, and active d-amphetamine, which is responsible for its therapeutic effect [10]. Preliminary nonclinical data suggest that conversion of LDX to damphetamine and l-lysine may also occur in the blood [11]. The conversion of LDX to d-amphetamine is unlikely to be affected by gastrointestinal pH and variations in normal gastrointestinal transit times [12]. Clinical studies of LDX have been completed in schoolaged children (6–12 years) with ADHD. A 6-week, randomized, double-blind, crossover study in a laboratory school setting [13] similar to the current study showed that LDX was significantly more effective in reducing ADHD symptoms compared with placebo (P < .0001), as measured by the Swanson, Kotkin, Agler, M-Flynn, and Pelham deportment (SKAMP-D) subscale throughout the day [14]. The SKAMP-D (see methods section for further details on SKAMP and all subscales) was used to assess behavioral manifestations of ADHD during analog classroom sessions [14]. Efficacy in LDX-treated subjects com- http://www.capmh.com/content/3/1/17 pared with placebo was significant beginning at 2 hours postdose and lasted up to 12 hours postdose, the last time point measured. LDX was generally well tolerated with adverse events (AEs) similar to those seen with other once-daily stimulants [13]. A second 4-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial in children with ADHD evaluated the efficacy and safety of LDX (30, 50, and 70 mg/d) over 4 weeks of treatment [10]. Significant improvements in ADHD Rating Scale Version IV (ADHDRS-IV) [15] score (...truncated)