Efficacy and Tolerability of Lisdexamfetamine Dimesylate ( NRP-104 ) in Children with Attention-Deficit / Hyperactivity Disorder : A Phase lll , Multicenter , Randomized , Double-Blind , Forced-Dose , Parallel-Group Study

Background: Lisdexamfetamine dimesylate (LDX) is a therapeutically inactive amphetamine prodrug. It was developed with the goal of providing an extended duration of effect that is consistent throughout the day, with a reduced potential for abuse, overdose toxicity, and drug tampering. Following ingestion, the pharmacologically active d-amphetamine molecule is gradually released by rate-limited hydrolysis. Objectives: The aims of this study were to assess the efficacy and tolerability of LDX in school-aged children with attention-deficit/hyperactivity disorder (ADHD) treated in the community, and to characterize the duration of action of LDX compared with placebo. Methods: This Phase III, multicenter, randomized, double-blind, forced-dose, parallel-group study was conducted at 40 centers across the United States. Male and female children aged 6 to 12 years with ADHD were randomly assigned to receive LDX 30, 50, or 70 mg with forced-dose titration, or placebo, PO QD for 4 weeks. Efficacy was assessed using the ADHD Rating Scale Version IV (ADHD-RS-IV), the Conners' Parent Rating Scale (CPRS), and the Clinical Global Impression of Improvement scale. Tolerability was assessed throughout the study. Results: Of the 290 randomized patients (201 boys, 89 girls; mean [SD] age, 9 [1.8] years), 230 completed the trial (LDX 30 rag, n = 56; LDX 50 rag, n = 60; LDX 70 rag, n = 60; and placebo, n = 54). The most common reasons for study discontinuation (n = 60) were lack of efficacy (LDX 30 rag, 1%; LDX 50 rag, 0%; LDX 70 rag, 1%; and placebo, 17%) and adverse events (AEs) (LDX 30 mg, 9%; LDX 50 mg, 5%; LDX 70 rag, 14%; and placebo, 1%). Significant improvements in ADHD-RS-IV scores were seen with all doses of LDX compared with placebo (all, P < 0.001), and in CPRS scores with all LDX doses versus placebo throughout the day (all, P < 0.001 for all comparisons). Efficacy was observed by the first week of treatment, and improvements were observed throughout the day up to -6 PM. The most frequently reported AEs among patients receiving LDX were typical of amphetamine products: decreased appetite (39% with active treatment vs 4% with placebo), insomnia (19% Accepted for publication January 31, 200Z Express Track online publication March 13, 2007. doi:l 0.1016/j.clinthera. 2007.03. 006 0149-2918/$32.00 Printed in the USA. Reproduction in whole or part: is not: permitted. Copyright © 2007 Excerpta Medica, Inc. This work was presented in abstract form at the 159th Annual Meeting of the American Psychiatric Association, May 20-25, 2006, Toronto, Ontario, Canada; the Society for Developmental and Behavioral Pediatrics 2006 Annual Meeting, September 16-18, 2006, Philadelphia, Pennsylvania; the 58th Annual Meeting of the American Psychiatric Association-Institute for Psychiatric Services, October 5-8, 2006, New York, New York; the 53rd Annual Meeting of the American Academy of Child and Adolescent Psychiatry, October 24-29, 2006, San Diego, California; the 18th Children and Adolescents with ADH D Conference, October 25-28, Chicago, Illinois; the 2006 Annual Meeting of the American College of Clinical Pharmacy, October 26-29, 2006, St. Louis, Missouri; and the 19th Congress of the US Psychiatric and Mental Health, November 16-19, 2006, New Orleans, Louisiana. 450 Volume 29 Number 3