Clinical Therapeutics/Volume 29, Number 3, 2007

Clinical Therapeutics/Volume 29, Number 3, 27 Efficacy and Tolerability of Lisdexamfetamine Dimesylate (NRP-14) in Children with Attention-Deficit/Hyperactivity Disorder: A Phase lll, Multicenter, Randomized, Double- Blind, Forced-Dose, Parallel-Group Study Joseph Biederman, MD1; Suma Krishnan, MS2; Yuxin Zhang, PhD3; JamesJ. McGough, MD4; and Robert L. Findling, MD s 1Department of Pediatric Psychopharmacology, Massachusetts General Hospital, Boston, Massachusetts; 2New River Pharmaceuticals, Blacksburg~ Virginia; 3Xtiers Consulting~ Potomac, Maryland; 4UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, California; and SUniversity Hospitals of Cleveland, Cleveland, Ohio ABSTRACT 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 4 centers across the United States. Male and female children aged 6 to 12 years with ADHD were randomly assigned to receive LDX 3, 5, or 7 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 29 randomized patients (21 boys, 89 girls; mean [SD] age, 9 [1.8] years), 23 completed the trial (LDX 3 rag, n = 56; LDX 5 rag, n = 6; LDX 7 rag, n = 6; and placebo, n = 54). The most common reasons for study discontinuation (n = 6) were lack of efficacy (LDX 3 rag, 1%; LDX 5 rag, %; LDX 7 rag, 1%; and placebo, 17%) and adverse events (AEs) (LDX 3 mg, 9%; LDX 5 mg, 5%; LDX 7 rag, 14%; and placebo, 1%). Significant improvements in ADHD-RS-IV scores were seen with all doses of LDX compared with placebo (all, P <.1), and in CPRS scores with all LDX doses versus placebo throughout the day (all, P <.1 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, 2Z Express Track online publication March 13, 27. doi:l.116/j.clinthera.27.3.6 149-2918/$32. Printed in the USA. Reproduction in whole or part: is not: permitted. Copyright 27 Excerpta Medica, Inc. This work was presented in abstract form at the 159th Annual Meeting of the American Psychiatric Association, May 2-25, 26, Toronto, Ontario, Canada; the Society for Developmental and Behavioral Pediatrics 26 Annual Meeting, September 16-18, 26, Philadelphia, Pennsylvania; the 58th Annual Meeting of the American Psychiatric Association-Institute for Psychiatric Services, October 5-8, 26, New York, New York; the 53rd Annual Meeting of the American Academy of Child and Adolescent Psychiatry, October 24-29, 26, San Diego, California; the 18th Children and Adolescents with ADH D Conference, October 25-28, Chicago, Illinois; the 26 Annual Meeting of the American College of Clinical Pharmacy, October 26-29, 26, St. Louis, Missouri; and the 19th Congress of the US Psychiatric and Mental Health, November 16-19, 26, New Orleans, Louisiana. 45 Volume 29 Number 3

J. Biederman et al. vs 3%), upper abdominal pain (12% vs 6%), headache (12% vs 1%), irritability (1% vs %), 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 3 to 7 mg appeared to be effective and had a tolerability profile similar to those of currently marketed extended-release stimulants. (Clin Ther. 27;29:45-463) Copyright 27 Excerpta Medica, Inc. Key words: attention-deficit/hyperactivity disorder, NRP-14, lisdexamfetamine, stimulant. INTRODUCTION Attention-deficit/hyperactivity disorder (ADHD) affects an estimated 8% to 12% of children worldwide. 1 Stimulants are currently the most widely prescribed medications for the treatment of ADHD. 2 Although these medications are effective and have been used for decades, 3-6 persistent concerns about their abuse potential remain. 7-1 To mitigate these concerns, it is desirable to develop alternative stimulant products with intrinsic properties and efficacy and tolerability profiles comparable to those of the currently marketed products. Lisdexamfetamine dimesylate (LDX) is a prodrug in which d-amphetamine is covalently bound to the essential amino acid L-lysine. This chemical bond renders the amphetamine component therapeutically inactive. On oral administration, LDX is converted to the active d-amphetamine, after the amide linkage resulting from the conjugation of L-lysine to d-amphetamine in LDX is enzymatically hydrolyzed in a rate-limited manner at or after absorption. The rate-limited nature of this hydrolysis is related to the saturability of the process, and, as with any other enzymatically driven reaction, the process follows saturable kinetics. This enzyme-catalyzed reaction is a requirement for the therapeutically active moiety to be released within the body. u,12 Preclinical data suggest that LDX has a unique toxicity profile. A study in a rat modep 3 found that although LDX and d-amphetamine sulfate had similar oral bioavailability of d-amphetamine at doses within the therapeutic human equivalent dose (HED) range of 2 to 8 mg, the bioavailability of d-amphetamine from LDX decreased relative to d-amphetamine sul- fate once doses were escalated beyond this range. At an extreme HED of 8 mg, Cma x and AUCin f were reduced by -8%. Furthermore, the median lethal dose (LDs) of LDX was not reached in a preclinical toxicity study, 14 even at doses up to 1 mg/kg. In contrast, the LDs for d-amphetamine sulfate was 96.8 mg/kg. Taken together, these data suggest that the enzymatic hydrolysis of LDX may be rate limited and may reach saturation at supratherapeutic doses. If these preclinical data were confirmed in humans, it would suggest that at supratherapeutic doses, LDX may be associated with a decreased risk for toxicity. In a previous 6-week, crossover, classroom analog study in 52 children aged 6 to 12 years with ADHD, is treatment with LDX at 3, 5, or 7 mg was associated with a significantly lower ADHD behavioral symptom score compared with placebo (.8 [.1] vs 1.7 [.1]; P <.1) and was generally well tolerated in this population. LDX dose strengths of 3, 5, and 7 mg have been developed to provide an amphetamine base approximately equivalent to mixed amphetamine salts 1, 2, and 3 mg, respectively. LDX 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. The present study was designed to assess the efficacy and tolerability of once-daily dosing of LDX at these doses in school-aged children with ADHD treated in the community, and to characterize the duration of action of LDX compared with placebo. We hypothesized that LDX would be effective and well tolerated in the treatment of children with ADHD, with an efficacy and tolerability profile comparable to those of other amphetamine products. PATIENTS AND METHODS This Phase III, multicenter, randomized, double-blind, forced-dose, parallel-group study was conducted at 4 centers across the United States. The study was conducted in accordance with the Guideline for Good Clinical Practice 16 and the Declaration of Helsinki and its amendments. 17 Inclusion and Exclusion Criteria The intention of this study was to enroll children who were not adequately treated with their current medication for ADHD or had not previously been treated for ADHD. The decision as to the appropriateness of en- March 27 451

Clinical Therapeutics rolling a child in this study was made by the individual investigator, based on the criteria described below. Male and female children aged 6 to 12 years who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) 18 criteria for a primary diagnosis of ADHD, combined or hyperactive-impulsive subtypes, were recruited by invitation to those patients known to the centers irrespective of current ADHD medication status. Children with an ADHD Rating Scale version IV (ADHD-RS-IV; described later) 19,2 score >28 (indicating severity of ADHD symptoms) at study baseline were eligible to participate. To determine whether the patients met enrollment criteria at screening, a standard psychiatric evaluation was conducted using 2 interviews with children and their parent or legally appointed guardian: (1) Kiddie-Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version Diagnostic Interview version 1. (1996) 21 and (2) a semistructured interview based on DSM-IV-TR criteria for ADHD. Academic functioning at age-appropriate levels, normal blood pressure and electrocardiographic (ECG) measurements, absence of a history of or current medical conditions or use of medications that might confound the results of the study or increase risk to the patient, and ability to swallow a capsule were also determined. Exclusion criteria included comorbid psychiatric diagnosis (eg, psychosis, bipolar disorder), history of seizures or current diagnosis or family history of Tourette's disorder, obesity based on the investigator's opinion, weight <25 kg (55 lb), positive screening for illicit drug use, and/or current health conditions or use of medications that might confound the results of the study or increase risk to the patient. Female patients of childbearing potential were required to have a negative result on urine pregnancy testing and were given specific instructions on avoiding pregnancy throughout the period of study drug exposure. After receiving a thorough oral and written description of study requirements, each child's parent or legally authorized guardian provided a signature of informed consent, along with documentation of patient assent, following procedures approved by each participating site's respective institutional review board. Study Visits The study consisted of 3 phases conducted over -6 weeks: 1 week to screen patients, 1 week to wash out current psychoactive medications, and 4 weeks for the double-blind treatment. After the screening visit (week-2), eligible patients (via parents/caregivers) were contacted via telephone and instructed to discontinue all treatment with ADHD medications, if any. They were also informed of dates of the baseline visit (week ; randomization, baseline assessments, and dispensation of prepackaged study medication [scheduled at least 1 week after the washout period]) and subsequent study visits to assess treatment (weeks 1, 2, 3, and 4 [each -+2 days]). Study Drug Administration Patients were randomized in a 1:1:1:1 ratio, using a computer-generated randomization schedule, to receive double-blind, oral (capsules) administration of LDX 3 mg for 4 weeks, 5 mg (3 mg/d for week 1, with forced-dose escalation to 5 mg/d for weeks 2-4), or 7 mg (3 mg/d for week 1, with forced-dose escalation to 5 mg/d for week 2 and 7 mg/d for weeks 3 and 4), or placebo capsules for 4 weeks. Both the investigator and the patient (and his/her parent/guardian) were blinded to treatment. To maintain blinding, all investigational products were supplied as white capsules identical in size, weight, and shape. The forced-dose trial design was used for the assessment of the efficacy and tolerability of each individual dose. Efficacy Outcome Measures ADHD symptoms were assessed using parent- and investigator-completed rating scales. The primary efficacy measure for this study was the ADHD-RS-W, 19,2 an 18-item scale with 1 item for each of the 18 symptoms contained in the DSM-IV-TR diagnosis of ADHD. The 18 items were grouped into 2 subscales: (1) Hyperactivity/ Impulsivity and (2) Inattentiveness. 21 Each item was scored on a range of to 3 ( = no symptoms; 1 = mild symptoms; 2 = moderate symptoms; and 3 = severe symptoms). The ADHD-RS-IV was used to assess each patient's symptom severity during the previous week, based on an investigator's interview with the parent/guardian and child. A total score between and 54 ( = no symptoms to 54 = the most severe symptoms) was calculated as the sum of the scores on each of the 18 items. Scores were also calculated for the 2 subscales ( = no symptoms to 27 = the most severe symptoms). Secondary efficacy measures included the Conners' Parent Rating Scale-Revised: Short Form (CPRS-R), 22 452 Volume 29 Number 3

J. Biederman et al. a parent-rated scale designed to assess the symptomatic behaviors of ADHD in the morning (-1 Am), afternoon (-2 Pm), and evening (-6 Pm). The CPRS-R comprised 27 questions grouped into 4 subscales: Oppositional, Cognitive Problems, Hyperactivity, and ADHD Index. Also used as a secondary efficacy measure was the Clinical Global Impression (CGI) scale. 23 At the baseline visit, an investigator performed a CGI-Severity (CGI-S) assessment for ADHD, rating the patient's condition on a 7-point scale (1 = normal, no symptoms to 7 = very severe symptoms). At subsequent visits, an investigator assessed the patient's improvement relative to ADHD symptoms at baseline, using the 7-point CGI-Improvement (CGI-I) scale (1 = very much improved to 7 = very much worse). Tolerability Assessments Tolerability assessments, conducted throughout the study, included identifying adverse events (AEs) using observation and by asking a nonleading question (eg, "How are you feeling?"), ECG, physical examination including vital signs (blood pressure, heart rate measured after the patient had been seated for at least 5 minutes), and clinical laboratory tests (biochemistry, hematology, and urinalysis profiles; at the screening and final study visits only). Nonserious AEs were collected from the time informed consent was signed until study completion. Serious AEs were collected from the time informed consent was signed until and including -3 days after the last dose of study medication. Treatment-emergent AEs were coded using the Medical Dictionary for Regulatory Activities version 7.1. 24 Independent clinician raters were not used for outcome measures and tolerability assessments. Compliance to medication was assessed using a pill count at each visit. Noncompliance was defined as the use of <8% or >12% of study medication during any assessment period. Statistical Analyses The intent-to-treat (ITT) population--the primary population for efficacy assessment--was defined as all patients who had baseline and at least 1 postrandomization primary efficacy measurement (ADHD-RS-IV total score) available for assessment. Based on a review 25 of previous studies of mixed-salts amphetamine products, 64 patients in each treatment arm were necessary to detect a significant between-group (active treatment versus placebo) difference in effect size of.5 (considered a medium-effect size effect) 26 using ADHD-RS-IV at a power of >8% and an ~ level of.5 (2-sided) using a 2-sample t test. The primary efficacy analysis was performed on the change in mean ADHD-RS-IV total score calculated for the ITT population from baseline to treatment end point, defined as the last postrandomization treatment week for which a score was obtained, using a 2-way analysis of covariance (ANCOVA) model with dose group and (pooled) study site as the model effects and baseline score as the covariate. Based on resuits from the ANCOVA model, the Dunnett test for multiple mean comparisons with least-squares (LS) adjustment was employed to compare the change from baseline in ADHD-RS-IV scores between the 3 activetreatment groups versus placebo. The secondary efficacy analyses were performed in the ITT population using measurements at treatment end point. As with the ADHD-RS-IV, the same ANCOVA model with Dunnett test was used to analyze the response of individual LDX doses versus placebo at each assessment time for the CPRS-R ADHD Index. As planned, an analysis of variance model with 2 effects of dose group and (pooled) study site was used to assess the CGI-I at treatment end point. The Dunnett test for multiple mean comparisons with LS adjustment was employed to compare the mean CGI-I scores of the 3 active-treatment groups with that of the placebo group. In addition, the nonparametric Cochran- Mantel-Haenszel test adjusting for (pooled) study site was used to assess the CGI-I at treatment end point. Before the analysis, this variable was dichotomized to 2 categories, with "very much improved" and "much improved" combined into 1 category and the remaining levels into the other. With reference to placebo, LDX effect size was calculated for each dose by dividing the difference in group means at the treatment end point by the model-based SD (ie, the square root of the model residual). 26 The safety population was defined as all enrolled patients, which included all patients who completed the washout phase of the stud> Of those, the children randomized to treatment were analyzed for tolerability parameters per the study protocol. A post hoc analysis using the (1-sided) Fisher exact test was conducted to assess between-group differences in treatment-emergent AEs. Outlier analyses of systolic and diastolic blood pressure (BP) and pulse were also conducted, with the March 27 453

Clinical Therapeutics cutoff values defined as systolic BP _>12 mm Hg; diastolic BP _>8 mm Hg; and heart rate _>(mean + 2[SD]) or _<(mean - 2[SD]), whereas the mean and SD were determined by the values observed at baseline. RES U LTS Patient Disposition and Baseline Characteristics A total of 297 children were enrolled at 4 study sites. Seven children discontinued before randomization, 29 (21 boys, 89 girls; mean [SD] age, 9 [1.8] years) received the randomized and blinded treatment, 285 were included in the ITT population, 23 completed the study (LDX 3 mg, n = 56; LDX 5 mg, n = 6; LDX 7 mg, n = 6; and placebo, n = 54), and 6 were withdrawn before study completion (Figure 1). Patients were primarily male (69%) and white (53%) (Table I). The median of daily dosing time was reportedly in the range of 7:3 AM to 8 AM among the 4 treatment groups across the 4 weeks. The most com- mon reasons for study discontinuation (n = 6) were lack of efficacy (LDX 3 mg, 1%; LDX 5 mg, %; LDX 7 mg, 1%; and placebo, 17%) and AEs (LDX 3 mg, 9%; LDX 5 mg, 5%; LDX 7 mg, 14%; and placebo, 1%). In general, treatment compliance was comparable among the treatment groups, with 84% (243/29) of the subjects in the randomized population found compliant with the study medication for all of the 4 treatment weeks. Primary Efficacy Improvement in the primary outcome measure (mean change from baseline to end point in ADHD-RS-IV total score) was significantly greater with each of the 3 LDX doses compared with placebo (P <.1, d[ = 3256, F = 35.16) (Figure 2). ADHD-RS-IV total score reductions across active-treatment groups were -4- to 5-fold greater than in the placebo group, with the greatest mean (SD) improvement in the Enrolled (N = 297) Excluded (n = 7) Loss to follow-up (n = 5) Withdrawn consent (n = 1) Ineligible for randomization (n = 1 ) Randomized (n = 29) LDX 3 mg (n=71) LDX 5 mg (n = 74) LDX 7 mg (n = 73) Placebo (n = 72) Completed (n = 56) Discontinued (n = 15) Adverse events (n = 6) Loss to follow-up (n = 4) Withdrawn consent (n = 2) Lack ofemcacy (n = 1 ) Other (n = 2)* Completed (n = 6) Discontinued (n = 14) Adverse events (n = 4) Loss to follow-up (n = 4) Protocol violation (n = 2) Physician decision (n = 2)f Withdrawn consent (n = 1) Other (n = 1)t Completed (n = 6) Discontinued (n = 13) Adverse events (n = 1) Loss to follow-up (n = 2) Lack of efticacy (n = 1 ) Completed (n = 54) Discontinued (n = 18) Lack of efficacy (n = 12) Withdrawn consent (n =2) Adverse events (n = I) Protocol violation (n = I ) Loss to follow-up (n = I) Other (n = 1) Figure I. Patient disposition. LDX = lisdexamfetamine dimesylate. *Borderline prolonged QT interval (n = I); inability to attend follow-up visit (n = I); tdue to a severe adverse event (n = I) and noncompliance (n = I ); ~Difficulty swallowing medication; Noncompliance. 454 Volume 29 Number 3

J. Biederman et al. Table I. Baseline demographic and clinical characteristics of all randomized patients. LDX 3 mg LDX SO mg LDX Characteristic (n = 71) (n = 74) (n 7 mg = 73) Age, mean (SD), y 9. (1.9) 8.9 (1.8) 8.7 (1.8) Age group, no. (%) 6-9 y 44 (62.) 47 (63.5) 48 (65.8) 1-12 y 27 (38.) 27 (36.5) 25 (34.2) Sex, no. (%) Male 53 (74.6) 46 (62.2) 52 (71.2) Female 18 (25.4) 28 (37.8) 21 (28.8) Race/ethnicity, no. (%) White 37 (52.1) 34 (45.9) 41 (56.2) Black 18 (25.4) 19 (25.7) 17 (23.3) Hispanic 1 (14.1) 17 (23.) 12 (16.4) Native American 2 (2.8) Asian 1(1.4) 1(1.4) Native Hawaiian/Pacific Islander Other 3 (4.2) 4 (5.4) 2 (2.7) Diagnosis, no. (%) Combined 67 (94.4) 71 (9,5.9) 71 (97.3) Hyperactive 4 (5.6) 3 (4.1) 2 (2.7) Age at ADHD onset, mean (SD), y 6.9 (2.2) 7. (2.3) 7. (2.2) Duration of disease, mean (SD), y 2.1 (2.S) 2. (2.3) 1.8 (2.S) Previous therapy for ADHD, no. (%) Amphetamine 7 (9.9) 7 (9.5) 2 (2.7) Methylphenidate 14 (19.7) 13 (17.6) 8 (11.) Stimulant 3 (4.2) 3 (4.1) S (6.8) Atomoxetine 2 (2.8) 2 (2.7) Stimulant/Atomoxetine 1 (1.4) 2 (2.7) 3 (4.1) Other 2 (2.8) 1 (1.4) 2 (2.7) None (past 12 rod) 42 ($9.2) 48 (64.9) $1 (69.9) CGI-S score, no. (%) Mild 1 (1.4) Moderate 26 (36.6) 25 (33.8) 25 (34.2) Marked 36 (5.7) 36 (48.6) 32 (43.8) Severe 9 (12.7) 9 (12.2) 16 (21.9) Extreme 3 (4.1) Placebo (n = 72) 9.4 (1.7) 35 (48.6) 37 (51.4) SO (69.4) 22 (3.6) 43 (59.7) 16 (22.2) 9(12.5) 1(1.4) 1(1.4) 2 (2.8) 69 3 7.6 1.8 (9s.8) (4.2) (2.2) (2.4) 6 (8.3) 12 (16.7) 2 (2.8) 1(1.4) 4 (5.6) 1(1.4) 46 (63.9) 27 (37.5) 33 (45.8) 11 (15.3) 1(1.4) LDX = lisdexamfetamine dimesylate; ADHD = attention-deficit~hyperactivity disorder; CGI-S = Severity. Clinical Global Impression- 7-mg group (-26.7 [1.54] vs -6.2 [1.56] in the placebo group). During week 1, and after all treated patients received LDX 3 mg, ADHD-RS-IV scores were significantly improved in these patients compared with those in the placebo group (Figure 3). Continued improvement among the LDX treatment groups occurred in week 2, when both the 5- and 7-mg groups received 5 mg/d, and in weeks 3 and 4, when all groups received their assigned doses (3, 5, 7 mg). Compared with placebo, all LDX groups also showed significantly greater improvement in both the ADHD-RS-IV Inattention and Hyperactivity sub- March 27 455

Clinical Therapeutics Baseline [] End point [] Change (LS mean) LDX 3 mg LDX 5 mg LDX 7 mg Placebo (n = 69) (n = 71) (n = 73) (n = 72) ~+ O u t.q,e > i t.q O/ 6 I f] < c o3 N -4 Figure 2. Improvements in Attention-Deficit/Hyperactivity Disorder Rating Scale Version IV (ADHD-RS-IV) 19,2 total scores from baseline to end point in children with ADHD randomly assigned to receive 4 weeks of treatment with once-daily lisdexamfetamine dimesylate (LDX) or placebo. LS = least squares. *P <.1 versus baseline; tp <.1 versus placebo. scales from baseline to end point (all, P <.1) (Figure 4). The greatest improvements were seen in the 7-mg group. At treatment end point, the effect sizes based on the ADHD-RS-IV were 1.21, 1.34, and 1.6 in the 3-, 5-, and 7-mg groups, respectively, determined by the corresponding between-group differences and the model-based SD of 12.84. Dose comparisons were conducted, and comparisons between the 7- and 3-rag strengths were statistically significant. The difference in LS mean ADHD-RS-IV change from baseline scores between the 3- and 7-mg groups was -4.91 (P <.5). Secondary Efficacy Starting at the first postbaseline week and continuing throughout the study (P <.1), parents/ guardians of patients in each LDX dose group reported significantly greater improvement in symptom control throughout the day, assessed using CPRS-R scores in the morning (-1 AM), afternoon (-2 PM), and evening (-6 PM), compared with parents/guardians of patients who received placebo (all, P <.1) (Figure 5). At all time points, the greatest improvements were seen in the 7-mg group compared with the placebo group. Clinical Global Impressions LS mean values for CGI scale scores also showed a significantly greater improvement from baseline to treatment end point for all active-treatment groups compared with placebo (all, P <.1, df = 3257, F = 35.57) (Figure 6). CGI-I ratings were either "very much improved" or "much improved" in _>7% of patients in the active-treatment groups, compared with 18% of patients receiving placebo. In addition, a post hoc responder analysis showed that, compared with patients who received placebo, the patients treated with LDX 3, 5, and 7 mg were more likely to meet the responder criteria of a _>3% decrease in ADHD-RS-IV total score and a CGI of 1 or 2 ("very much improved" or "much improved") over time (Figure 7). 456 Volume 29 Number 3

j. Biederman et al. 6 LDX 3 mg (n = 69) -II- LDXS mg(n = 71) LDX 7 mg (n = 73) -O- Placebo (n = 72) bq 4.m > 5 4- i E] I E] < 3-2- c 1- I I I I I 1 2 3 4 Study Week Figure 3. Improvements in Attention-Deficit/Hyperactivity Disorder Rating Scale Version IV (ADHD-RS-IV) 19,2 total scores over the treatment course of 4 weeks in children with ADHD randomly assigned to receive once-daily lisdexamfetamine dimesylate (LDX) or placebo. *All doses, P <.1 versus placebo. Adverse Events Overall, AEs were experienced by 72% of patients in the 3-rag group, 68% in the 5-rag group, and 84% in the 7-rag group, compared with 47% in the placebo group. The most frequently reported AEs among patients receiving LDX were typical of amphetamine products: decreased appetite (39% with active treatment vs 4% with placebo; P <.5), insomnia (19% vs 3%; P <.5), upper abdominal pain (12% vs 6%; P = NS), headache (12% vs 1%; P = NS), irritability (1% vs %; P <.5), vomiting (9% vs 4%; P = NS), weight decrease (9% vs 1%; P <.5), and nausea (6% vs 3%; P = NS) (Table II). Rash occurred in 3% and % of patients (not included in the statistical analysis because it occurred in <5% of patients). More than 95% of treatmentemergent AEs were mild or moderate in intensity. No serious AEs were observed. Most AEs began during the first week of treatment and abated over time (Table III). A total of 21 randomized and treated patients were withdrawn from the study because of AEs: 6 (8%) patients in the LDX 3-rag group, 4 (5%) in the LDX 5-rag group, 1 (14%) in the LDX 7-mg group, and 1 (1%) in the placebo group. LDX treatment was not associated with any significant changes in mean ECG parameters, including corrected QT intervals, laboratory values, and systolic and diastolic BE Children in the active-treatment groups were found to have an increase in mean heart rate and ECG heart rate. A significant increase in heart rate relative to the placebo group was observed in the LDX groups, and the highest placebo-adjusted mean increase of -4 to 5 bpm was observed in the 7-mg group at end point, although no significant differences were found at each treatment week. The distributions of vital-sign and ECG outliers at each week and end point were similar across the treatment groups and treatment weeks. DISCUSSION The strengths of this study include the large sample size and the use of several validated efficacy measures in the evaluation of ADHD across different perspectives (clinician and parents). The patients were school-aged children, the population most often treated for ADHD. March 27 457

Clinical Therapeutics LDX 3 mg (n = 69) LDX 5 mg (n = 71 ) [] LDX 7 mg (n = 73) [] Placebo (n = 72) I naeeeneion Su bscale I Hyperactivity Subscale I -2 -~ -4 > ~L 6 I -8 c -I "-~ -12 c m.! N -14 Figure 4. Improvements from baseline to end point (A) in Attention-Deficit~Hyperactivity Disorder Rating Scale Version IV (ADHD-RS-IV) 19,2 Inattention and Hyperactivity subscale scores in children with ADHD randomly assigned to receive 4 weeks of treatment with once-daily lisdexamfetamine dimesylate (LDX) or placebo. *P <.1 versus placebo. The efficacy and tolerability results in this study were strikingly similar to those reported for extendedrelease mixed amphetamine salts in an earlier clinical trial in 584 school-aged children with ADHD using the same study design. 27 Significant clinical benefits were observed in the present trial within the first week of treatment compared with placebo and were confirmed by parent observation throughout the day, continuing through the last observation at -6 PM. Similarly, the tolerability profile in the earlier study was comparable to that observed in the present trial, in which the most frequently reported treatmentrelated AEs were anorexia, headache, insomnia, and abdominal pain, which is similar to the tolerability profile seen with other currently marketed stimulants.27,28 The improvement from baseline in the CPRS-R ADHD Index was assessed separately for morning (-1 AM), afternoon (-2 PM), and evening (-6 PM) re- sponses. This finding supports the hypothesis that the gradual release of d-amphetamine from LDX after a single dose may provide an extended duration of action sufficient for once-daily dosing, a critical advantage for the management of children with ADHD, whose forgetfulness and distractibility can lead to noncompliance with a multiple-dose daily regimen. 29 Study Limitations The findings reported should be viewed in light of some methodologic limitations. The 4-week duration of this study limits extrapolation of efficacy and tolerability findings to the long-term treatment that is generally required in the management of ADHD symptoms. In addition, several of our findings were based in part on parental assessments (CPRS ratings). Although parents are good reporters of ADHD symptoms when their children are receiving long-acting treatments, 3 obtaining classroom assessments from 458 Volume 29 Number 3

J. Biederman et al. LDX 3 mg LDX 5 mg [] LDX 7 mg [] Placebo Morning Afternoon Evening (-I AM) (-2 PM) (-6 PM) n = 67 68 7 72 67 66 71 72 67 69 69 72 u bq -4- bq C~ -6- u ~ -8 - ~" -lobq "-" -12- -14- -16 *t *t *t *T Figure 5. Changes from baseline to end point (A) in durations of response throughout the day as assessed using the Conners' Parent Rating Scale (CPRS) in children with attention-deficit/hyperactivity disorder randomly assigned to receive 4 weeks of treatment with once-daily lisdexamfetamine dimesylate (LDX) or placebo. *P <.1 versus placebo; tp <.1 versus baseline. teachers would have provided additional support for our conclusions. In patients randomized to receive the 5- and 7-mg doses of LDX, doses were escalated quickly, regardless of efficacy and tolerability, which is unlike standard clinical practice, and may have led to an increase in AEs in these groups. All 3 doses studied were effective, and clinical assessment of lower and higher doses would be helpful. Despite these limitations, the initial results of this study provide support for further studies of LDX in the treatment of ADHD. CONCLUSIONS In this population of children with ADHD, oncedaily LDX 3, 5, and 7 mg appeared to be effective and well tolerated, with an effect size >1.2 for all dosage strengths. LDX treatment provided consistent symptom control that lasted through the day, up to -6 PM. Drug efficacy was observed within the first week of treatment. AEs with LDX were similar to and typical of amphetamine products. These study results suggest that LDX is a promising alternative to currently available extended-release stimulants for the treatment of ADHD. ACKNOWLEDGM ENTS This research was supported by New River Pharmaceuticals Inc., Radford, Virginia, and Shire Development Inc., Wayne, Pennsylvania. Editorial assistance was provided by NeoHealth, Inc., Hasbrouck Heights, New Jersey. Dr. Biederman has received research support from Abbott Laboratories, AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb Company, Cephalon Inc., Eli Lilly and Company, Forest Laboratories Inc., GlaxoSmithKline, Janssen Pharmaceutica Products LP, Lilly Foundation, McNeil Pharmaceutical, National Institute of Child Health and Human March 27 459

Clinical Therapeutics Baseline [] End point [] Placebo-adjusted difference 6 q LDX 3 mg / (n = 69) 5 / LDX 5 mg LDX 7 mg Placebo (n = 71) (n = 73) (n = 72) P u 3 ~ u v c -3 f f Figure 6. Clinical Global Impression (CGI) scores at baseline (Severity) and at end point (Improvement) in children with attention-deficit/hyperactivity disorder randomly assigned to receive 4 weeks of treatment with either once-daily lisdexamfetamine dimesylate (LDX) or placebo. *P <.1 versus baseline; tp <.1 versus placebo. Development, National Institute of Mental Health, National Institute on Drug Abuse, NeuroSearch, New River Pharmaceuticals, Novartis Pharmaceuticals Corporation, Pfizer Inc., Heinz C. Prechter Foundation, Shire, and Stanley Medical Research Institute. Dr. Biederman is a member of the following speaker's bureaus: Cephalon Inc., Eli Lilly and Company, McNeil, Novartis Pharmaceuticals Corporation, Shire, and UCB Pharma, Inc. He is a member of the advisory boards of the following pharmaceutical companies: Cephalon Inc., Eli Lilly and Company, Janssen Pharmaceutica Products LP, McNeil, Novartis Pharmaceuticals Corporation, and Shire. Dr. Zhang is a consultant for New River Pharmaceuticals. Dr. McGough has received research support from Eli Lilly, Pfizer, and Shire Pharmaceuticals. He is a member of the following speaker's bureaus: Eli Lilly, McNeil, Novartis, and Shire Pharmaceuticals. Dr. McGough is a member of the advisory boards of the following pharmaceutical companies: Eli Lilly, McNeil, Novartis, and Shire Pharmaceuticals. Dr. Findling has received research support from Abbott, AstraZeneca, Bristol-Myers Squibb, CellTech, Eli Lilly, Forest Laboratories, GlaxoSmithKline, Johnson and Johnson Pharmaceutical Research and Development, Novartis, Otsuka, Pfizer, Shire Pharmaceuticals Group, Solvay Pharmaceuticals, and Wyeth Pharmaceuticals. He is a member of the following speaker's bureaus: Abbott, AstraZeneca, Bristol-Myers Squibb, CellTech, Eli Lilly, Forest Laboratories, GlaxoSmithKline, Johnson and Johnson Pharmaceutical Research and Development, Novartis, Otsuka, Pfizer, Shire Pharmaceuticals Group, Solvay Pharmaceuticals, and Wyeth Pharmaceuticals. Dr. Findling is a member of the advisory boards of the following pharmaceutical companies: Abbott, AstraZeneca, Bristol-Myers Squibb, CellTech, Eli Lilly, Forest Laboratories, GlaxoSmithKline, Johnson and Johnson Pharmaceutical Research and Development, Novartis, Otsuka, Pfizer, Shire Pharmaceuticals Group, Solvay Pharmaceuticals, and Wyeth Pharmaceuticals. 46 Volume 29 Number 3

J. Biederman et al. 9-8- 7- t t t LDX 3 mg LDX S mg* [] LDX 7 mg*f [] Placebo e~ "D C O O_ iii bq v 6-5- 4-3- 2-1- - n = I I I I 21372 6313569 59 63 66 6 57 58 5954 76 71 6672 1 2 3 4 End Point Study Week Figure 7. Responder analysis by week (responders were defined as patients with a >3% improvement in Attention- Deficit/Hyperactivity Disorder Rating Scale version IV 19,2 total score and a Clinical Global Impression of 1 or 2 after treatment). LDX = lisdexamfetamine dimesylate. *At week 1, these patients received the 3-mg dose and thus were included in the 3-mg group; tat week 2, these patients received the 5-mg dose and thus were included in the 5-mg group; CP <.1 versus placebo. Table II. Incidence of treatment-emergent adverse events (AEs) with incidence >5% in any study group. LDX 3 mg LDX 5 mg LDX 7 mg Treatment-Emergent AEs (n = 71) (n = 74) (n = 73) Any events, no. (%) 51 (71.8)* 5 (67.6)* 61 (83.6)* AE Decreased appetite 26 (36.6)* 23 (31.1)* 36 (49.3)* Insomnia 11 (15.5)* 12 (16.2)* 18 (24.7)* Upper abdominal pain 1 (14.1) 5 (6.8) 11 (15.1) Irritability 8 (11.3)* 6 (8.1)* 7 (9.6)* Headache 7 (9.9) 7 (9.5) 12 (16.4) Dizziness 5 (7.)* 4 (5.4) 2 (2.7) Vomiting 5 (7.) 4 (5.4) 1 (13.7)* Nasopharyngitis 4 (5.6) 3 (4.1) 4 (5.5) Weight loss 4 (5.6) 2 (2.7) 14 (19.2)* Nasal congestion 3 (4.2) Nausea 3 (4.2) 2 (2.7) 8 (11.) Cough 2 (2.8) 1 (1.4) Dry mouth 2 (2.8) 2 (2.7) 6 (8.2)* LDX = lisdexamfetamine dimesylate. *P _<.5 versus placebo. All LDX Doses (n = 218) 162 (74.3)* 85 (39.)* 41 (18.8)* 26(11.9) 21 (9.6)* 26(11.9) 11 (5.)* 1 9 (8.7) 11 (5.) 2 (9.2)* 3 (1.4) 13 (6.) 3 (1.4) 1 (4.6) Placebo (n = 72) 34 (47.2) 3 (4.2) 2 (2.8) 4 (5.6) 7 (9.7) 3 (4.2) 4 (5.6) 1(1.4) 4 (5.6) 2 (2.8) 4 (5.6) March 27 461

Clinical Therapeutics Table III. Incidence of treatment-emergent adverse events (AEs) in patients treated with dimesylate (LDX), by time of onset. Values are % of patients. lisdexamfetamine All LDX Doses Treatment-Emergent AEs/ Week 1 Week 2 Week 3 Week 4+ Total Placebo Preferred Term (n = 218) (n = 27) (n = 194) (n = 181) (N = 218) (n = 72) Patients with any AE 54.1 31.9 25.8 26.5 74.3* 47.2 Gastrointestinal disorders Upper abdominal pain 8.3 1.9.5 2.8 11.9 5.6 Nausea 4.1 1. 1.5. 6. 2.8 Vomiting 5. 1. 3.6 1.7 8.7 4.2 Infections and infestations Naso p haryngitis.9 1. 2.1 1.7 5. 5.6 Investigations Weight decreased 1.8 1.4 1.5 5.5 9.2* 1.4 Metabolism and nutritional disorders Decreased appetite 25.7 11.6* 2.1 2.8 39.* 4.2 Nervous system disorders Headache 7.3 1.4 2.6 3.3 11.9 9.7 Dizziness 3.7..5 1.1 5.* Psychiatric disorders Insomnia 13.8* 1.9 4.6 3.3 18.8* 2.8 Irritability 2.8 3.4 3.6 2.2 9.6* *P _<.5 versus placebo. REFERENCES 1. Faraone SV, Sergeant J, Gillberg C, Biederman J. The worldwide prevalence of ADHD: Is it an American condition? World Psychiatry. 23;2:14-113. 2. Greenhill LL, Pliszka S, Dulcan MK, et al, for the American Academy of Child and Adolescent Psychiatry. Practice parameter for the use of stimulant medications in the treatment of children, adolescents, and adults.jam Acad Child Adolesc Psychiatry. 22;41(Suppl 2):26S-49S. 3. Stein M, Baren M. Welcome progress in the diagnosis and treatment of ADHD in adolescence. Contemp Pediatr. 23; 2:83-11. 4. Brown RT, Amler RW, Freeman WS, et al, for the American Academy of Pediatrics Committee on Quality Improvement and the American Academy of Pediatrics Subcommittee on Attention-Deficit/Hyperactivity Disorder. Treatment of attention-deficit/hyperactivity disorder: Overview of the evidence. Pediatrics. 25;115:e749-e757. 5. Rappley MD. Clinical practice. Attention deficit-hyperactivity disorder. N EnglJ Med. 25 ;352:165-173. 6. Jadad AR, Boyle M, Cunningham C, et al. Treatment of attention-deficit/hyperactivity disorder. Evid Rep Technol Assess (Suture). 1999;11 :i-viii, 1-341. 7. Liana ME, Crismon ML. Methylphenidate: Increased abuse or appropriate use? J Am Pharm Assoc (Wash). 1999;39: 526-53. 8. McCabe SE, Teter CJ, Boyd CJ, Guthrie SK. Prevalence and correlates of illicit methylphenidate use among 8th, 1th, and 12th grade students in the United States, 21. JAdolesc Health. 24;35:51-54. 9. Wolraich ML, Wibbelsman CJ, Brown TE, et al. Attentiondeficit/hyperactivi W disorder among adolescents: A review of the diagnosis, treatment, and clinical implications. Pediatrics. 25;115:1734-1746. 1. Stockl KM, HughesTE, Jarrar MA, et al. Physician perceptions of the use of medications for attention deficit hyperactivity disorder.j Manag Care Pharm. 23;9:416-423. 11. Stryer L. Biochemistry. WH Freeman & Co; 1995. 12. Vyvanse TM (risdexamfetamine dimesylate). Wayne, Pa: Shire Pharmaceuticals. New drug application. 13. Boyle L, Moncrief S, Krishnan S. Pharmacokinetics of NRP14 (lisdexamfetamine dimesylate) following administration of a single intranasal, intravenous or oral dose in rats. Paper presented at: 46th Annual New Clinical Drug 462 Volume 29 Number 3

J. Biederman et al. Evaluation Unit (NCDEU) Meeting; June 12-15, 26; Boca Raton, Fla. 14. Krishnan S. Toxicity profile of lisdexamfetamine dimesylate (LDX, NRP14) in three independent rat toxicology studies. Basic Clin Pkarmacol Toxicol. In press. 15. Biederman J, Boellner SW, Childress A, et al. Improvements in symptoms of attention-deficit/hyperactivity disorder in school-aged children with lisdexamfetamine (N RP14) and mixed amphetamine salts, extendedrelease versus placebo. Poster presented at: Annual Meeting of the American Psychiatric Association; May 24, 26; Toronto, Ontario, Canada. 16. European Agency for the Evaluation of Medicinal Products, International Conference on Harmonisation- World Health Organization. Guideline for Good Clinical Practice [EMEA Web site]. ICH Topic E6. Geneva, Switzerland: WHO; 22. Available at: http://www.emea.eu.int. Accessed February 22, 27. 17. World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects [WMA Web site]. Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the 52nd WMA General Assembly, Edinburgh, Scotland, October 2. Available at: http://www.wma.net/e/policy/ bb.htm. Accessed February 22, 27. 18. American Psychiatric Association, Task Force on DSM-IV. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision ( DSM-IV- TR). Washington, DC: American Psychiatric Association; 2. 19. DuPaul GJ, PowerTJ, Anastopoulos AD, et al. ADHD Rating Scale-IV: Checklists, Norms, and Clinical Interpretation. New York, NY: Guilford Press; 1998. 2. Faries DE, Yalcin I, Harder D, Heiligenstein JH. Validation of the ADHD Rating Scale as a clinician administered and scored instru- ment. J Atten Disord. 21;5:17-115. 21. Kaufman J, Birmaher B, Brent D, et al. Kiddie-SADS Present and Lifetime Version Diagnostic Interview version 1.. Kaufman, Birmaher, Brent, Rao & Ryan; 1996. 22. Conners CK, Sitarenios G, Parker JD, Epstein JN. The revised Conners' Parent Rating Scale (CPRS-R): Factor structure, reliability, and criterion validiw. J Abnorm Child Psychol. 1998; 26:257-268. 23. Guy W. Clinical Global Impression (CGI). ECDEU Assessment Manual for Psychopharmacology. Rockville, Md: US Dept of Health, Education, and Welfare, Alcohol, Drug Abuse, and Mental Health Administration, NIMH Psychopharmacology Research Branch, Division of Extramural Research Programs; 1976:218-222. DHEW Publication 76-338. 24. Medical Dictionary for RegulatoryActivities [MedDRA Web site]. Available at: http://www.meddramsso. com/mssoweb/index.htm. Accessed February 22, 27. 25. Weiss MD, Gadow K, Wasdell MB. Effectiveness outcomes in attention deficit/hyperactivity disorder. J Clin Psychiatry. 26:67(Suppl 8):38-45. 26. Cohen J. Statistical Power Analysis for the Behavioral Sciences. 2nd ed. Hillsdale, N J: Lawrence Erlbaum Associates; 1988. 27. Biederman J, Lopez FA, Boellner SW, Chandler MC. A randomized, double-blind, placebo-controlled, parallel-group study of SLI381 (Adderall XR) in children with attention-deficit/hyperactivi W disorder. Pediatrics. 22;11:258-266. 28. American Academy of Pediatrics. Subcommittee on Attention-Deficit/ Hyperactivity Disorder and Committee on Quality Improvement. Clinical practice guideline: Treatment of the school-aged child with attention-deficit/hyperactivi W disorder. Pediatrics. 21 ;18:133-144. 29. Steinhoff KVV. Attention-deficit/ hyperactivity disorder: Medication treatment-dosing and duration of action. Am J Manag Care. 24;1 (Suppl 4):$99-$16. 3. BiedermanJ, Faraone SV, Monuteaux MC, Grossbard JR. How informative are parent reports of attentiondeficit/hyperactivi W disorder symptoms for assessing outcome in clinical trials of long-acting treatments? A pooled analysis of parents' and teachers' reports. Pediatrics. 24;113:1667-1671. Address correspondence to: Joseph Biederman, MD, Pediatric Psychopharmacology Unit, Yawkey Center Suite 6A, Massachusetts General Hospital, Boston, MA 2114. E-mail: jbiederman@partners.org March 27 463