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
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 approximately 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.
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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.
“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].”
From A 13-hour laboratory school study of lisdexamfetamine dimesylate in school-aged children with attention-deficit/hyperactivity disorder (2009) · cites this paper as [10]
As in the previous study, LDX was generally well tolerated, with an AE profile similar to that of other extended-release stimulant products.
“As in the previous study, LDX was generally well tolerated, with an AE profile similar to that of other extended-release stimulant products [10].”
From A 13-hour laboratory school study of lisdexamfetamine dimesylate in school-aged children with attention-deficit/hyperactivity disorder (2009) · cites this paper as [10]
Significant improvements in ADHD-RS-IV scores were noted for all doses of LDX compared with placebo (all, P < .001).
“Significant improvements in ADHD Rating Scale Version IV (ADHD-RS-IV) [15] scores were noted for all doses of LDX compared with placebo (all, P < .001) [10].”
From A 13-hour laboratory school study of lisdexamfetamine dimesylate in school-aged children with attention-deficit/hyperactivity disorder (2009) · cites this paper as [10]
LDX produced significant improvement in ADHD symptom control as early as the first week of treatment, compared with placebo (P < .001).
“LDX produced significant improvement in ADHD symptom control as early as the first week of treatment, compared with placebo (P < .001) [10].”
From A 13-hour laboratory school study of lisdexamfetamine dimesylate in school-aged children with attention-deficit/hyperactivity disorder (2009) · cites this paper as [10]
The adverse events reported in this study were similar in nature to those reported in studies of other stimulants and included decreased appetite, insomnia, headache, irritability, upper abdominal pain, and affect lability.
“The AEs reported here were similar in nature to those reported in studies of other stimulants and included decreased appetite, insomnia, headache, irritability, upper abdominal pain, and affect lability [10,13,27-29].”
From A 13-hour laboratory school study of lisdexamfetamine dimesylate in school-aged children with attention-deficit/hyperactivity disorder (2009) · cites this paper as [10]
The rate of discontinuations related to TEAEs was consistent with those seen for other stimulants in similar settings.
“The rate of discontinuations related to TEAEs was consistent with those seen for other stimulants in similar settings [10,30,31].”
From A 13-hour laboratory school study of lisdexamfetamine dimesylate in school-aged children with attention-deficit/hyperactivity disorder (2009) · cites this paper as [10]
Lisdexamfetamine is synthesized by covalently linking d-amphetamine to the amino acid l-lysine.
“Lisdexamfetamine, the first prodrug approved for ADHD (16, 17) and binge eating disorder (18) treatment, is synthesized by covalently linking d-amphetamine to the amino acid l-lysine (19).”
In Biederman et al Phase III trial of 290 children aged 6-12 years with ADHD, compared with placebo, ADHD-RS-IV score reductions were 4-5-fold greater in the lisdexamfetamine groups, with the largest reductions recorded in the 70 mg lisdexamfetamine group.
“Compared with the placebo group, ADHD Rating Scale Version IV (ADHD-RS-IV) score reductions were 4–5-fold (P < 0.001) greater in the lisdexamfetamine groups, with the largest reductions recorded in the 70 mg lisdexamfetamine group.”
From Update on optimal use of lisdexamfetamine in the treatment of ADHD (2013) · cites this paper as [18]
In that trial, adverse effects were reported mainly during the first week of treatment and included decreased appetite, weight loss, insomnia, upper abdominal pain, headache, irritability, nausea, and vomiting; these resolved over the course of the study for the majority of subjects.
“Adverse effects were reported mainly during the first week of treatment, and included decreased appetite, weight loss, insomnia, upper abdominal pain, headache, irritability, nausea, and vomiting. These resolved over the course of the study for the majority of subjects.”
From Update on optimal use of lisdexamfetamine in the treatment of ADHD (2013) · cites this paper as [18]
In that trial, 9% of the subjects withdrew due to adverse effects.
“However, 9% of the subjects withdrew due to adverse effects.”
From Update on optimal use of lisdexamfetamine in the treatment of ADHD (2013) · cites this paper as [18]
In that trial, there were no significant changes in the subjects' electrocardiograms, but there was a mild increase in heart rate of 4-5 beats per minute.
“There were no significant changes in the subjects’ electrocardiograms, but there was a mild increase in heart rate of 4–5 beats per minute.”
From Update on optimal use of lisdexamfetamine in the treatment of ADHD (2013) · cites this paper as [18]
In that trial, consistent improvements were noted on the Conner's Parent Rating Scale-Revised Short Form at 10 am, 2 pm, and 6 pm.
“Consistent improvements were also noted on the Conner’s Parent Rating Scale-Revised Short Form at 10 am, 2 pm, and 6 pm.”
From Update on optimal use of lisdexamfetamine in the treatment of ADHD (2013) · cites this paper as [18]
In a 12-week, placebo-controlled, double-blinded, crossover trial of 75 boys with ADHD, methylphenidate produced significant reductions in emotional lability on the Conners' Parent and Teacher ADHD rating scale, with effect sizes of 0.42-0.46 for parent reports and 0.45-0.79 for teacher reports.
“Significant reductions in emotional lability were noted on the emotional lability subscale of the Conners’ Parent and Teacher ADHD rating scale. Effect sizes ranged from 0.42–0.46 and 0.45–0.79 for parent and teacher reports, respectively.”
From Using Stimulants to Treat ADHD-Related Emotional Lability (2014) · cites this paper as [41]
Multiple randomized, double-blind, placebo-controlled trials have shown LDX to be an effective treatment for children, adolescents and adults with ADHD, with a tolerability and safety profile consistent with the known effects of psychostimulant therapy.
“Multiple randomized, double-blind, placebo-controlled trials have shown LDX to be an effective treatment for children, adolescents and adults with ADHD, with a tolerability and safety profile consistent with the known effects of psychostimulant therapy [9–15].”
Both therapies displayed safety profiles consistent with findings from previous studies.
“Both therapies displayed safety profiles consistent with findings from previous studies [9, 11–13, 28–30].”
These results support previous placebo-controlled trials of LDX, which have demonstrated a robust treatment response in a range of patient groups.
“These results support previous placebo-controlled trials of LDX, which have demonstrated a robust treatment response in a range of patient groups [9, 11–13].”
The most frequently reported TEAEs in the LDX treatment group (decreased appetite, decreased weight, headache, nausea and insomnia) and in patients receiving ATX (headache, nausea, somnolence, decreased appetite and fatigue) are consistent with findings from previous studies.
“The most frequently reported TEAEs in the LDX treatment group (decreased appetite, decreased weight, headache, nausea and insomnia) and in patients receiving ATX (headache, nausea, somnolence, decreased appetite and fatigue) are consistent with findings from previous studies [9, 11–13, 28–30].”
In a randomized controlled trial, lisdexamfetamine dimesylate was associated with improvements in clinical symptoms of ADHD in children while maintaining a safety profile similar to other stimulant medications.
“In a randomized controlled trial (RCT), LDX was associated with improvements in clinical symptoms of ADHD in children while maintaining a safety profile similar to other stimulant medications [17].”
More than 95% of treatment-emergent adverse events were mild or moderate in intensity, and most began during the first week of treatment and abated over time.
“More than 95% of TEAEs were mild or moderate in intensity and most began during the first week of treatment and abated over time [17].”
CPRS-R ADHD index score data in nonremitters on prior methylphenidate were similar to those observed in the overall population.
“These data were similar to the CPRS-R ADHD index scores observed in the overall population [17].”
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References 26 · Cited by 404
- Authors
- Biederman, J., Krishnan, S., Zhang, Y., McGough, J. J., & Findling, R. L.
- Affiliations
- Massachusetts General Hospital (US)
- University of California, Los Angeles (US)
- University Hospitals of Cleveland (US)
- Corresponding author
- Biederman, Joseph
- Venue
- Clinical Therapeutics
- Publisher
- Elsevier BV
- Published
- 2007-03
- Volume
- 29
- Issue
- 3
- Pages
- 450-463
- ISSN
- 0149-2918 (ISSN-L)
- OpenAlex
- W2129620184
- Cited by
- 404
- References
- 26
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 10 · 2023: 7 · 2022: 7 · 2021: 4 · 2020: 164 · 2019: 4 · 2018: 12 · 2017: 6 · 2016: 9 · 2015: 9 · 2014: 22 · 2013: 19 · 2012: 15
- FWCI
- 18.12
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
- Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
- Keywords
- lisdexamfetamine dimesylate, attention deficit hyperactivity disorder, children, ADHD-RS-IV, Conners' Parent Rating Scale, tolerability, adverse events, stimulant efficacy, school-aged children, dose comparison, placebo comparison
- MeSH terms
- Lisdexamfetamine Dimesylate, Administration, Oral, Central Nervous System Stimulants, Attention Deficit Disorder with Hyperactivity, Child, Delayed-Action Preparations, Dextroamphetamine, Double-Blind Method, Female, Humans, Lysine, Male, Treatment Outcome, Diagnostic and Statistical Manual of Mental Disorders
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