Efficacy and tolerability of lisdexamfetamine dimesylate (NRP-104) in children with attention-deficit/hyperactivity disorder: A Phase III, multicenter, randomized, double-blind, forced-dose, parallel-group study

• Published in: Clinical therapeutics Vol. 29; no. 3; pp. 450 - 463
• Main Authors: Biederman, Joseph, MD, Krishnan, Suma, MS, Zhang, Yuxin, PhD, McGough, James J., MD, Findling, Robert L., MD
• Format: Journal Article
• Language: English
• Published: Belle Mead, NJ EM Inc USA 01-03-2007; Excerpta Medica; Elsevier Limited
• Subjects: Administration, Oral; Attention Deficit Disorder with Hyperactivity - drug therapy; Attention deficit disorders. Hyperactivity; Attention deficit hyperactivity disorder; Biological and medical sciences; Central Nervous System Stimulants - administration & dosage; Central Nervous System Stimulants - adverse effects; Central Nervous System Stimulants - therapeutic use; Child; Child & adolescent psychiatry; Child clinical studies; Children & youth; Clinical medicine; Delayed-Action Preparations; Dextroamphetamine - administration & dosage; Dextroamphetamine - adverse effects; Dextroamphetamine - therapeutic use; Diagnostic and Statistical Manual of Mental Disorders; Double-Blind Method; Drug dosages; Female; Humans; Hyperactivity; Internal Medicine; lisdexamfetamine; Lisdexamfetamine Dimesylate; Lysine; Male; Medical Education; Medical sciences; Mental disorders; Mental health; NRP-104; Pediatrics; Pharmacology. Drug treatments; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychopharmacology; Quality improvement; stimulant; Substance abuse treatment; Teenagers; Treatment Outcome; New York; California; United States > US; Massachusetts; attention-deficit/hyperactivity disorder; stimulant; NRP-104; lisdexamfetamine; Human; Stimulant; Hyperactivity; Toxicity; Treatment efficiency; Multicenter study; Sympathomimetic; Prodrug; Lisdexamfetamine; Randomization; Attentional disorder; Double blind study; Attention disorder with hyperactivity; Dose; Child
• ISSN: 0149-2918; 1879-114X
• DOI: 10.1016/S0149-2918(07)80083-X

Abstract Background: Lisdexamfetamme 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 (CPR′), 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 mg, n = 56; LDX 50 mg, n = 60; LDX 70 mg, n = 60; and placebo, n = 54). The most common reasons for study discontinuation (n = 60) were lack of efficacy (LDX 30 mg, 1%; LDX 50 mg, 0%; LDX 70 mg, 1 %; and placebo, 17%) and adverse events (AEs) (LDX 30 mg, 9%; LDX 50 mg, 5%; LDX 70 mg, 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% vs 3%), upper abdominal pain (12% vs 6%), headache (12% vs 10%), irritability (10% vs 0%), vomiting (9% vs 4%), weight decrease (9% vs 1%), and nausea (6% vs 3%); most were mild to moderate and occurred in the first week. Conclusion: In this population of children with ADHD, treatment once daily with the prodrug LDX at doses of 30 to 70 mg appeared to be effective and had a tolerability profile similar to those of currently marketed extended-release stimulants.