efficacy and safety of lisdexamfetamine dimesylate in adults with attention-deficit / hyperactivity disorder : novel findings using a simulated adult workplace environment design Permalink

Background: Duration of efficacy and safety of lisdexamfetamine dimesylate (LDX) was assessed in adults (18-55 years) with attention-deficit/hyperactivity disorder (ADHD) using the simulated adult workplace environment. Methods: After open-label dose optimization (4-week) with LDX, 30-70 mg/d, subjects entered a 2-week randomized, double-blind, placebo-controlled crossover phase. Efficacy assessments included the Permanent Product Measure of Performance (PERMP) total score (attempted+correct) measured predose and from 2 to 14 hours postdose, averaged across postdose sessions (primary) and at each time point vs placebo (secondary), and ADHD Rating Scale IV (ADHDRS-IV) with adult prompts at baseline and crossover visits. Safety assessments included treatment-emergent adverse events (TEAEs), vital signs, and electrocardiograms. Results: Of 127 randomized subjects, 105 were in the intention-to-treat population and 103 completed the study. While receiving LDX vs placebo, adults had greater improvement (P < .0001) in average PERMP total scores as measured by difference in least squares (LS) mean (95% CI): 23.4 (15.6, 31.2). Absolute (P ≤ .0017 for each time point) and change from predose (P < .001 for each time point) PERMP total scores were greater at all postdose time points from 2 to 14 h for adults while receiving LDX vs placebo. LDX demonstrated efficacy vs placebo (P < .0001) by the difference in LS mean (95% CI) for ADHD-RS-IV total scores: -11.5 (-14.2, -8.9). TEAEs (≥ 10%) during dose optimization were decreased appetite, dry mouth, headache, and insomnia; no TEAEs ≥ 5% were reported during crossover phase for adults receiving LDX. Conclusions: LDX significantly improved PERMP scores vs placebo and maintained improvement throughout the day from the first (2 hours) to last (14 hours) postdose time point vs placebo in adults with ADHD. Trial Registration: ClinicalTrials.gov Identifier: NCT00697515 Safety and Efficacy Workplace Environment Study of Lisdexamfetamine Dimesylate (LDX) in Adults With AttentionDeficit Hyperactivity Disorder (ADHD) http://www.clinicaltrials. gov/ct2/show/NCT00697515? term=NCT00697515&rank=1 Background Attention-deficit/hyperactivity disorder (ADHD) in adults has an estimated prevalence of 4.4% in the United States and 3.4% worldwide [1,2]. Adults with ADHD experience significant impairment [1,3] in multiple domains of daily living, including the workplace, home, and various social settings [3,4]. For many years, pharmacotherapy has been recognized as having an important role in reducing the core symptoms of ADHD in adults [5]. Long-acting oral stimulants * Correspondence: tlwigal@uci.edu 1 Department of Pediatrics, University of California, Irvine, Child Development Center, Irvine, CA, USA Full list of author information is available at the end of the article © 2010 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. Wigal et al. Behavioral and Brain Functions 2010, 6:34 http://www.behavioralandbrainfunctions. com/content/6/1/34 Page 2 of 14 [6-8] have demonstrated efficacy in managing ADHD symptoms in adults [7,9-12]. However, in a survey study completed over a 12-month period in 2004, the prevalence of treatment for ADHD in adults was only 10.9% [1]. Lisdexamfetamine dimesylate (LDX) is a long-acting prodrug stimulant indicated for the treatment of ADHD in children 6 to 12 years of age and in adults in the United States. LDX is a therapeutically inactive molecule. Following oral ingestion, LDX is converted to l-lysine and active d-amphetamine. While a small amount of LDX is hydrolyzed to d-amphetamine in the gastrointestinal tract, the conversion of LDX into active d-amphetamine occurs primarily in the blood. The combination of l-lysine and d-amphetamine created a new chemical entity (a prodrug) with sustained delivery of d-amphetamine [13,14]. LDX demonstrated efficacy compared with placebo by the Permanent Product Measure of Performance (PERMP) and other assessments in the laboratory school setting at 12 and 13 hours postdose in children with ADHD [15,16]. In another pediatric study, LDX was effective throughout the day, as measured by parent ratings [17]. In these studies, LDX demonstrated a safety profile consistent with long-acting stimulant use [15-17]. LDX was also effective, with typically mild to moderate adverse events (AEs), in a large placebo-controlled trial in adults with ADHD [18]. Common AEs with LDX in this study included decreased appetite, dry mouth, and insomnia [18]. Efficacy was assessed through weekly evaluations of the ADHD Rating Scale IV (ADHD-RS-IV) with adult prompts and the Clinical Global Impressions (CGI) scale. Ratings of efficacy during the course of the day were not assessed in the initial study [18]. While the factors that determine treatment and choice of pharmacotherapy are complex, there may be a clinical need for long-acting stimulant medication with efficacy beyond 12-hours duration among adults with ADHD who require symptom control that extends throughout the day and into evening home and family time [19,20]. To assess and document the duration of efficacy of LDX throughout the day in adults with ADHD, the present study compared LDX with placebo in the simulated adult workplace environment (AWE) setting. Assessments, including AEs, vital signs, electrocardiogram (ECG), and physical examination, evaluated the safety profiles of the 2 treatment arms. The simulated AWE is a structured, controlled environment based on the model of the laboratory school protocol (LSP) [21], designed to monitor and quantitatively assess response to medication in the performance of adults during activities simulating those that occur during a typical work day [21]. The use of the LSP, and specifically the PERMP assessment, has been applied widely to evaluate the effects of long-acting stimulants for children with ADHD [15,22-26]. Although not included in this study analysis, the LSP may include additional behavioral assessments such as a revised form of the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) rating scale and/or subject-reported behavioral assessment [4] to evaluate onset and duration of medication effects with validated, quantitative, and reproducible measures [21]. The simulated AWE is a useful tool for measuring attention and behavior because structured activities, designed to provoke behaviors associated with ADHD symptoms, are provided throughout the day and yield quantifiable outcomes. PERMP [21], a skill-matched test consisting of simple math problems to be attempted and completed at multiple time points throughout the simulated AWE session, is used to measure the ability to stay on task and attend to work. This instrument measures how effectively a subject initiates, self-monitors, and completes written seatwork [21]. It is not a test of the ability to learn math since the difficulty of problems is adjusted to the existing math skill level of each subject at baseline to ensure that each individual achieves ≥ 95% correct solutions. The PERMP is a validated, time sensitive, skill adjusted math test that measures attention in ADHD. The goal of this study was to evaluate the efficacy of LDX compared with placebo in adults with ADHD in the simulated AWE setting, and to assess the duration of effect in a highly structured, controlled environment from 2 to 14 hours postdose.