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/lp/springer-journals/randomized-double-blind-placebo-controlled-crossover-study-of-the-wKdGy87Zze
- Publisher
- Springer Journals
- Copyright
- Copyright © 2010 by Wigal et al; licensee BioMed Central Ltd.
- Subject
- Biomedicine; Neurosciences; Neurology; Behavioral Therapy; Psychiatry
- eISSN
- 1744-9081
- DOI
- 10.1186/1744-9081-6-34
- pmid
- 20576091
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- See Article on Publisher Site
Abstract
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 (ADHD- RS-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 Attention- Deficit Hyperactivity Disorder (ADHD) http://www.clinicaltrials.gov/ct2/show/NCT00697515?term=NCT00697515&rank=1 Background States and 3.4% worldwide [1,2]. Adults with ADHD Attention-deficit/hyperactivity disorder (ADHD) in experience significant impairment [1,3] in multiple adults has an estimated prevalence of 4.4% in the United domains of daily living, including the workplace, home, and various social settings [3,4]. * Correspondence: tlwigal@uci.edu For many years, pharmacotherapy has been recognized Department of Pediatrics, University of California, Irvine, Child Development as having an important role in reducing the core symp- Center, Irvine, CA, USA toms of ADHD in adults [5]. Long-acting oral stimulants 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 Page 2 of 14 http://www.behavioralandbrainfunctions.com/content/6/1/34 [6-8] have demonstrated efficacy in managing ADHD with ADHD [15,22-26]. Although not included in this symptoms in adults [7,9-12]. However, in a survey study study analysis, the LSP may include additional behavioral completed over a 12-month period in 2004, the assessments such as a revised form of the Swanson, Kot- prevalence of treatment for ADHD in adults was only kin, Agler, M-Flynn, and Pelham (SKAMP) rating scale 10.9% [1]. and/or subject-reported behavioral assessment [4] to Lisdexamfetamine dimesylate (LDX) is a long-acting evaluate onset and duration of medication effects with prodrug stimulant indicated for the treatment of ADHD validated, quantitative, and reproducible measures [21]. in children 6 to 12 years of age and in adults in the United The simulated AWE is a useful tool for measuring States. LDX is a therapeutically inactive molecule. Fol- attention and behavior because structured activities, lowing oral ingestion, LDX is converted to l-lysine and designed to provoke behaviors associated with ADHD active d-amphetamine. While a small amount of LDX is symptoms, are provided throughout the day and yield hydrolyzed to d-amphetamine in the gastrointestinal quantifiable outcomes. PERMP [21], a skill-matched test tract, the conversion of LDX into active d-amphetamine consisting of simple math problems to be attempted and occurs primarily in the blood. The combination of l-lysine completed at multiple time points throughout the simu- and d-amphetamine created a new chemical entity (a lated AWE session, is used to measure the ability to stay prodrug) with sustained delivery of d-amphetamine on task and attend to work. This instrument measures [13,14]. LDX demonstrated efficacy compared with pla- how effectively a subject initiates, self-monitors, and cebo by the Permanent Product Measure of Performance completes written seatwork [21]. It is not a test of the (PERMP) and other assessments in the laboratory school ability to learn math since the difficulty of problems is setting at 12 and 13 hours postdose in children with adjusted to the existing math skill level of each subject at ADHD [15,16]. In another pediatric study, LDX was baseline to ensure that each individual achieves ≥ 95% effective throughout the day, as measured by parent rat- correct solutions. The PERMP is a validated, time sensi- ings [17]. In these studies, LDX demonstrated a safety tive, skill adjusted math test that measures attention in profile consistent with long-acting stimulant use [15-17]. ADHD. LDX was also effective, with typically mild to moderate The goal of this study was to evaluate the efficacy of adverse events (AEs), in a large placebo-controlled trial in LDX compared with placebo in adults with ADHD in the adults with ADHD [18]. Common AEs with LDX in this simulated AWE setting, and to assess the duration of study included decreased appetite, dry mouth, and effect in a highly structured, controlled environment insomnia [18]. Efficacy was assessed through weekly eval- from 2 to 14 hours postdose. uations of the ADHD Rating Scale IV (ADHD-RS-IV) with adult prompts and the Clinical Global Impressions Methods (CGI) scale. Ratings of efficacy during the course of the Subjects day were not assessed in the initial study [18]. Adults (aged 18 to 55 years) with a primary diagnosis of While the factors that determine treatment and choice ADHD were enrolled, based on criteria outlined in the of pharmacotherapy are complex, there may be a clinical Diagnostic and Statistical Manual of Mental Disorders, need for long-acting stimulant medication with efficacy Fourth Edition, Text Revision (DSM-IV-TR™). ADHD beyond 12-hours duration among adults with ADHD diagnosis was further validated by a comprehensive psy- who require symptom control that extends throughout chiatric evaluation that included a semi-structured inter- the day and into evening home and family time [19,20]. view based on the Adult ADHD Clinical Diagnostic Scale, To assess and document the duration of efficacy of LDX version 1.2 (ACDS v1.2) [27]. All subjects were also throughout the day in adults with ADHD, the present required to have scores on the ADHD-RS-IV with adult study compared LDX with placebo in the simulated adult prompts ≥ 28 at baseline and a level of intellectual func- workplace environment (AWE) setting. Assessments, tioning equivalent to an intelligence quotient of ≥ 80 on including AEs, vital signs, electrocardiogram (ECG), and the Kaufman Brief Intelligence Test [28]. Key exclusion physical examination, evaluated the safety profiles of the criteria were the presence of a comorbid psychiatric diag- 2 treatment arms. nosis with significant symptoms, a history of, or per- The simulated AWE is a structured, controlled environ- ceived risk for future suicide attempt, a recent history of ment based on the model of the laboratory school proto- substance abuse, or other medical conditions that would col (LSP) [21], designed to monitor and quantitatively contraindicate treatment with psychostimulants or con- assess response to medication in the performance of found efficacy and safety assessments. Exclusion criteria adults during activities simulating those that occur dur- also included a history of seizures; hypertension, with a ing a typical work day [21]. The use of the LSP, and specif- resting systolic blood pressure (SBP) > 139 mm Hg or dia- ically the PERMP assessment, has been applied widely to stolic blood pressure (DBP) > 89 mm Hg; or a history of evaluate the effects of long-acting stimulants for children symptomatic cardiovascular disease; a structural cardiac Wigal et al. Behavioral and Brain Functions 2010, 6:34 Page 3 of 14 http://www.behavioralandbrainfunctions.com/content/6/1/34 abnormality; or a positive family history of sudden car- lowed by a factual quiz, time estimation tasks, practical diac death or ventricular arrhythmia. Other exclusion cri- checkbook balancing vignettes, and simple grammar teria included adverse reactions or lack of response to error search tasks. Results from these activities were not previous amphetamine therapy, concomitant medica- analyzed as formal outcome assessments, but were tions affecting the central nervous system or blood pres- included in the AWE day in order to actively involve sub- sure (with the exception of ADHD medications that were jects with effortful, repetitive, and uninteresting tasks washed out), pregnancy or lactation, a body mass index provided to challenge subjects and thereby provoke the < 18.5 and ≥ 40, or a clinically significant laboratory or usual symptoms of ADHD [21]. ECG abnormality. Subjects whose current ADHD medi- Study design cation provided effective control of symptoms with This randomized, double-blind, placebo-controlled, 2-way acceptable tolerability were also excluded. crossover study with an open-label dose-optimization Study setting phase was conducted in a simulated AWE. It was The simulated AWE is a controlled environment based designed to assess duration of efficacy, tolerability, and on the LSP, but modified for the adult 14-hour day. Sub- safety of LDX (Vyvanse®, Shire US Inc.) (30, 50, and 70 jects arrived at 6 AM and departed at approximately 9:30 mg/d) in adults with ADHD. This study was conducted at PM for both AWE sessions. The 2 AWE sessions, spaced 5 centers in the United States. 1 week apart in the double-blind phase, were organized This study was conducted in accordance with the Dec- into 3 sequential classes; each class consisting of a sched- laration of Helsinki and Good Clinical Practice according uled series of activities was designed to provoke all of the to the International Conference on Harmonisation guide- DSM-IV-TR™ symptoms of ADHD and to further provide lines. The study protocol was approved by each center's objective measures of subject performance. In contrast to institutional review board. After complete explanation of the child analog classroom design, the adult design is less the study to the subjects, written consent was obtained. reliant on behavioral observations and primarily focuses The study comprised 4 phases: screening and washout on objective measures (eg, PERMP math test). In the (6 weeks); open-label dose optimization (4 weeks); dou- adult study, other mandatory activities and assignments ble-blind crossover (2 weeks) which included 2 full-day were scheduled throughout the day, designed to provoke evaluations in the simulated AWE; and a 7-day safety fol- specific ADHD symptoms and were collected but not low-up (Figure 1). recorded as measurable assessments. Each classroom The primary objective was to evaluate the efficacy of session included several 5-minute transition periods, a LDX vs placebo by PERMP scores in adults with ADHD 10-minute PERMP test, and 10-minute academic group in the simulated AWE. A key secondary objective was to games. Key activities performed throughout the simu- assess duration of effect over the day of LDX vs placebo in lated AWE day included the presentation of a brief the simulated AWE with the PERMP administered at -0.5 instructional video on a topic of general information fol- hours predose and 2, 4, 8, 10, 12, and 14 hours postdose. Figure 1 Study design. (AWE = adult workplace environment; LDX = lisdexamfetamine dimesylate). Wigal et al. Behavioral and Brain Functions 2010, 6:34 Page 4 of 14 http://www.behavioralandbrainfunctions.com/content/6/1/34 Other objectives were to assess the efficacy of LDX for administered during the active week of the crossover improvement in ADHD symptoms using the ADHD-RS- phase. During week 4, visit 4a was to ensure quality-of- IV with adult prompts and to evaluate the improvement life assessments were completed, while visit 4b was for in ADHD symptom severity employing the CGI-Severity the practice AWE sessions. (CGI-S) scale at baseline and the CGI-Improvement Double-blind crossover phase (CGI-I) scale following LDX administration during the Subjects then entered a 2-week double-blind crossover dose-optimization and double-blind phases. phase and were randomized by a fixed-block randomiza- Screening and washout tion schedule to receive either their optimized dose of Except for stimulant medications and sedating antihista- LDX for 7 days followed by placebo for 7 days or placebo mines, which were discontinued 7 days prior to assess- for 7 days followed by their optimized dose of LDX for 7 ment of baseline measures, all prohibited medications days. On the last day of the first and second treatment were discontinued 30 days prior to screening. After wash- sequence (visits 5 and 6), assessments of efficacy and out, subjects returned to the clinic (baseline, visit 0) for safety of LDX or placebo were collected in the simulated reassessment of eligibility and to establish baseline safety AWE. Efficacy assessments collected during visits 5 and 6 and efficacy measures, including the ADHD-RS-IV with were as follows: PERMP at -0.5 hour predose and 2, 4, 8, adult prompts, the CGI-S scale, vital signs, and ECG. 10, 12, and 14 hours postdose; ADHD-RS-IV and CGI-I Open-label dose optimization at specified times during the simulated AWE day, as well Following screening and washout, eligible subjects as safety assessments including weight measurements entered the open-label dose-optimization phase, during and a 12-lead ECG. Vital signs (ie, SBP, DBP, and pulse) which they began receiving LDX and were evaluated for were also collected at 1 hour predose and 4.5 and 14 efficacy and tolerability at weekly visits. The dosage was hours postdose (± 45 minutes for each). A pregnancy test initiated at 30 mg/d of LDX and upwardly titrated to the and a physical exam were performed during visit 6. next available dose at weekly intervals until the optimal Follow-up dose was reached. The optimal dose was defined as the A follow-up by telephone was conducted 1 week after dose that produced an overall minimum reduction in each subject's last dose of study drug to obtain informa- ADHD-RS-IV with adult prompts symptom score ≥ 30%, tion about any ongoing or new AEs or serious AEs and a CGI-I rating of 1 or 2, with tolerable side effects. Tolera- concomitant medications. bility was determined by the investigator, based on a Outcome measures review of AEs and clinical judgment. Once reached, the Efficacy measures optimal dose was maintained for the remainder of the The primary efficacy endpoint, designed to evaluate the dose-optimization phase and was used for the double- efficacy of LDX vs placebo, was the total PERMP scale blind phase. scores averaged over all postdose time points assessed in Overall response was assessed and categorized accord- AWE classroom sessions during visits 5 and 6. A second- ing to 3 possible conditions: intolerable response (pres- ary outcome measure, designed to evaluate the duration ence of intolerable AEs); ineffective response (response to of effect of LDX vs placebo, was the total PERMP scores LDX of < 30% reduction from baseline in the ADHD-RS- at each of the following time points: 2, 4, 8, 10, 12, and 14 IV score or a CGI-I rating > 2); and acceptable response hours postdose. (response with ≥ 30% reduction in the ADHD-RS-IV The PERMP, a 10-minute skill-adjusted math test, was score and a CGI-I rating of 1 or 2, very much or much used to evaluate effortful performance in the simulated improved, but with tolerable AEs). AWE as a measure of treatment efficacy. The appropriate Subjects who experienced an intolerable response were difficulty level for each subject for the PERMP was deter- permitted to be down-titrated only once by 20 mg/d to mined at screening based on results of a timed math pre- the next available lower dose. If dose reduction was toler- test. The total PERMP score was the sum of the number ated and ADHD symptom control was acceptable, that of math problems attempted (PERMP-A) and the number dose was maintained for the remainder of the study. Sub- of math problems answered correctly (PERMP-C) in a jects with an ineffective response were titrated to the next 10-minute session. The PERMP was completed through- higher dose (eg, 50 or 70 mg/d), provided AEs were toler- out both AWE assessment days (visits 5 and 6). able. For subjects with an acceptable response and toler- The ADHD-RS-IV with adult prompts is a clinician- ance of all prior doses, a further increase to achieve rated scale that assesses symptoms of ADHD based on additional symptom reduction was permitted (to the DSM-IV-TR™ criteria [29]. The ADHD-RS-IV consists of maximum of 70 mg/d) at the clinician's discretion. The last visit at which dosage adjustments could be 18 items that are grouped into 2 subscales: hyperactivity/ made was visit 3 of the dose-optimization phase. For all impulsivity and inattention. Each item is scored on a scale randomized subjects, the dose dispensed at visit 3 was of 0 (no symptoms) to 3 (severe symptoms), yielding a Wigal et al. Behavioral and Brain Functions 2010, 6:34 Page 5 of 14 http://www.behavioralandbrainfunctions.com/content/6/1/34 total score of 0 to 54 [29]. The ADHD-RS-IV was admin- LDX/placebo differences and within-subject standard istered at baseline, visits 1 to 3 and visit 4b of the dose- deviation was anticipated to be ≥ 0.49 at the 14-hour optimization phase, and during the 2 AWE sessions, visits postdose time point, necessitating 90 subjects to com- 5 and 6. The clinician-rated scale was administered by plete the study to achieve 90% power for a 2-tailed test at trained raters utilizing adult prompts developed at New the significance level of 0.05. With an anticipated dropout York University and Massachusetts General Hospital rate of 15% abstracted from previous studies, 106 subjects [30,31]. were targeted for enrollment. The CGI provides a global evaluation of baseline sever- The intention-to-treat population, defined as subjects ity and assesses improvement over time [32]. At baseline, who were randomized and had ≥ 1 primary efficacy mea- the investigator used the CGI-S scale to rate severity of surement (average postdose PERMP total) collected, was illness on a scale that ranged from 1 (normal, not at all ill) used for primary efficacy analysis of PERMP scores. A to 7 (among the most extremely ill subjects). At each visit linear mixed effects analysis of variance model, including thereafter (visits 1 to 3 and 4b of the dose-optimization treatment, period, and sequence as fixed effects and sub- phase and the 2 AWE sessions, visits 5 and 6 during the jects as a random effect, was used for the primary efficacy double-blind phase), the clinician used the CGI-I to rate analysis. All efficacy tests were conducted as 2-sided and improvement relative to baseline on a scale ranging from at the significance level of 0.05. Two-sided confidence 1 (very much improved) to 7 (very much worse) [32]. intervals were constructed with 95% coverage. No impu- tation of missing data was performed for the PERMP Safety assessments. For other secondary efficacy measures, Safety assessments included monitoring AEs, concomi- missing scores were imputed if the number of missing tant medications, vital signs, 12-lead ECGs, and physical items was < 20% of the total number of items in the scale examination. At each study visit, AEs and concomitant or subscale. medications were recorded. Resting SBP and DBP, pulse, Due to the small and varied number of subjects temperature, weight, and respiratory rate were assessed enrolled per site and the within-subject design of statisti- at all study visits, except visit 4a. During AWE days (visit cal analyses in this study, analysis by site was not per- 5 and 6), SBP, DBP, and pulse were assessed at 3 specified formed and site was not included as a factor in inferential time points. ECGs were conducted at screening, baseline, analyses. and visits 5 and 6. A physical examination was conducted CGI-I ratings are reported in 2 dichotomized groups: at screening, baseline, and the end-of-study visit. The improved, comprising very much and much improved vital signs and ECG results were summarized according (CGI-I ratings of 1 or 2), and not improved, comprising to the actual dose received. Treatment-emergent AEs all other scores (CGI-I ratings of ≥ 3) excluding scores of (TEAEs), referring to events with onset after the first date 0 (not assessed). Prescott's test was used to compare of treatment, and no later than 3 days following termina- dichotomized CGI-I outcomes during the crossover tion of treatment, were recorded separately for the dose- phase. optimization and the double-blind crossover phases of The safety population included all subjects who entered the study. TEAEs that continued uninterrupted from the the dose-optimization phase and received ≥ 1 dose of dose-optimization to the crossover phase without a LDX, and the randomized safety population included all change in severity were counted only in the dose-optimi- subjects who were randomized and received ≥ 1 dose of zation phase category. TEAEs with a change in severity blinded study drug during the double-blind crossover across phases or that resolved and then restarted in the phase. crossover phase were counted both in the dose-optimiza- tion and crossover arms. TEAEs for which a missing or Results incomplete start date made it impossible to determine in Demographics and disposition which phase of the study they started were counted as The study enrolled 142 subjects from 5 study centers (n = starting in the dose-optimization phase. TEAEs were 36, 33, 28, 33, and 12) in the United States and was con- reported as number and percentage of subjects according ducted from July to December 2008. All enrolled subjects to system-organ class, preferred term, treatment group, were included in the safety population. The demograph- and by last dose received at AE onset. AEs were collected ics appeared generally balanced between final dose levels at all visits by soliciting subject report with nonleading in the dose-optimization phase (Table 1). The safety pop- questions, and were coded using the Medical Dictionary ulation had a mean age of 30.5 years and was predomi- for Regulatory Activities (MedDRA). nantly white (89.4%), and male (62.0%), with a predominant combined ADHD subtype (69.0%). Of enrolled subjects, Statistics 127 were randomized and administered a dose of study Based on estimates from earlier simulated AWE and medication in the crossover phase, 103 (72.5%) com- pediatric laboratory school studies, the ratio between Wigal et al. Behavioral and Brain Functions 2010, 6:34 Page 6 of 14 http://www.behavioralandbrainfunctions.com/content/6/1/34 Table 1: Demographic and baseline characteristics (safety population) by last dose in the dose-optimization phase Characteristic, mean (SD) LDX LDX LDX LDX 30 mg/d 50 mg/d 70 mg/d All Doses (n = 28) (n = 70) (n = 44) (N = 142) Age (years) 30.5 (9.54) 29.7 (10.71) 31.8 (11.46) 30.5 (10.70) Weight (lb) 174.7 (43.64) 176.7 (35.22) 182.4 (36.17) 178.1 (37.14) Height (in) 65.8 (4.30) 68.3 (3.73) 68.3 (3.77) 67.8 (3.97) Body mass index (lb/in ) 28.2 (5.45) 26.6 (4.79) 27.4 (5.10) 27.2 (5.02) Gender, n(%) Male/female 16 (57.1)/12 (42.9) 45 (64.3)/25 (35.7) 27 (61.4)/17 (38.6) 88 (62.0)/54 (38.0) Race, n (%) White 21 (75.0) 65 (92.9) 41 (93.2) 127 (89.4) Black/African American 4 (14.3) 2 (2.9) 0 6 (4.2) Native Hawaiian/Pacific Islander 2 (7.1) 0 0 2 (1.4) Asian 1 (3.6) 2 (2.9) 2 (4.5) 5 (3.5) American Indian/Alaskan Native 0 0 1 (2.3) 1 (0.7) Other 0 1 (1.4) 0 1 (0.7) Ethnicity, n (%) Hispanic or Latino/ 2 (7.1)/26 (92.9) 7 (10.0)/63 (90.0) 4 (9.1)/40 (90.9) 13 (9.2)/129 (90.8) Not Hispanic or Latino ADHD subtype, n (%) Inattentive 8 (28.6) 20 (28.6) 11 (25.0) 39 (27.5) Hyperactive/impulsive 1 (3.6) 3 (4.3) 1 (2.3) 5 (3.5) Combined 19 (67.9) 47 (67.1) 32 (72.7) 98 (69.0) ADHD-RS-IV with adult prompts: scores at baseline, mean (SD) Total 37.8 (6.06) 35.8 (4.85) 38.4 (6.12) 37.0 (5.61) Inattentive 20.9 (3.15) 19.7 (3.45) 20.8 (3.66) 20.3 (3.49) Hyperactivity/impulsivity 16.9 (5.52) 16.1 (4.35) 17.6 (4.86) 16.7 (4.77) ADHD = attention-deficit/hyperactivity disorder; ADHD-RS-IV = ADHD Rating Scale IV; LDX = lisdexamfetamine dimesylate. Wigal et al. Behavioral and Brain Functions 2010, 6:34 Page 7 of 14 http://www.behavioralandbrainfunctions.com/content/6/1/34 pleted the study, and 39 (27.5%) discontinued prema- Efficacy turely (Table 2). No subject discontinued due to lack of LDX demonstrated efficacy vs placebo on the primary efficacy, whereas 6 subjects attributed withdrawal to endpoint, the average total PERMP score from all post- TEAEs. Of the subjects who withdrew during the dose- dose assessments during the AWE sessions. The mean optimization phase due to TEAEs, 3 withdrew due to ele- average postdose PERMP total score was significantly vated blood pressure, and 1 due to cardiac arrhythmia greater (F = 35.47; df [1, 101]; P < .0001) for adults while (frequent premature ventricular complexes). Two sub- receiving LDX vs placebo (Table 3). PERMP was assessed jects withdrew due to TEAEs during the crossover phase: in 105 subjects, with 1 subject withdrawing from each of 1 for gastroenteritis and 1 for viral infection. Additionally, the 2 treatment sequences after the first crossover assess- 17 subjects withdrew prematurely from the study during ment period (visit 5). Analysis of absolute values of total the crossover phase because their study participation PERMP scores at postdose time points demonstrated sig- coincided with the occurrence of a natural disaster (ie, nificant efficacy for adults while receiving LDX vs placebo at hurricane) in the vicinity of the participating study site, each time point (P ≤ .0017). LS mean (SE) change from leading to site closure (listed as Other in Table 2). predose of the PERMP total score (n = 104) for adults Table 2: Subject disposition by treatment sequence Randomization Sequence n (%) Discontinued Prior to Randomization LDX/Placebo Placebo/LDX All Subjects (n = 15) (n = 63) (n = 64) (N = 142) Safety population 15 (100.0) 63 (100.0) 64 (100.0) 142 (100.0) Randomized safety population - 63 (100.0) 64 (100.0) 127 (89.4) Intention-to-treat population - 53 (84.1) 52 (81.3) 105 (73.9) Per protocol population - 49 (77.8) 49 (76.6) 98 (69.0) Completed study - 52 (82.5) 51 (79.7) 103 (72.5) Discontinuations 15 (100.0) 11 (17.5) 13 (20.3) 39 (27.5) Reasons for discontinuations Total 15 (100.0) 11 (17.5) 13 (20.3) 39 (27.5) AE 4 (26.7) 0 2 (3.1) 6 (4.2) Lack of efficacy 0 0 0 0 Refused further participation 5 (33.3) 3 (4.8) 2 (3.1) 10 (7.0) Protocol nonadherence/ 00 0 0 subject noncompliant Lost to follow-up 2 (13.3) 0 0 2 (1.4) a a Other 4 (26.7) 21 (14.8) 8 (12.7) 9 (14.1) Seventeen subjects withdrew from the study during the double-blind crossover phase due to a natural disaster-related study site closure (ie, hurricane). AE = adverse event; LDX = lisdexamfetamine dimesylate. Wigal et al. Behavioral and Brain Functions 2010, 6:34 Page 8 of 14 http://www.behavioralandbrainfunctions.com/content/6/1/34 while receiving LDX demonstrated significant (P < .001) were also shown with ADHD-RS-IV inattention and efficacy vs placebo at all time points evaluated from hyperactivity/impulsivity subscores (P < .0001 for each). 2 hours to 14 hours postdose (Figure 2). Improvement in Mean (SD) ADHD-RS-IV inattention subscores were average postdose scores was also significantly greater (P < 20.3 (3.49) at baseline, and mean (SD) change from base- .0001) for adults receiving LDX vs placebo for PERMP-A line at dose-optimization endpoint was -11.6 (4.33). and PERMP-C scores as measured by the difference in LS Mean (SD) ADHD-RS-IV hyperactivity/impulsivity sub- mean (Table 3). Analysis of absolute values of PERMP-A scores were 16.7 (4.77) at baseline, and mean (SD) change and PERMP-C scores at postdose time points demon- from baseline at dose-optimization endpoint was -9.8 strated significant efficacy for adults while receiving LDX (4.38). vs placebo at each time point (P ≤ .0031). LDX also dem- The mean (SD) percent change in ADHD-RS-IV total onstrated efficacy vs placebo as measured by change from scores from baseline at visits 5 and 6 (double-blind, cross- predose at each postdose time point from 2 hours to over period) for adults while receiving LDX (all doses) 14 hours with higher LS mean (SE) PERMP-A and was -51.5% (24.24) and while receiving placebo was -21.3% PERMP-C scores for LDX vs placebo (Figure 3). (24.41). The mean ADHD-RS-IV total score was signifi- During the open-label dose-optimization phase with all cantly lower, indicating better symptom control, for adults subjects receiving LDX, ADHD-RS-IV total scores while receiving LDX vs placebo (P < .0001) as measured decreased. At baseline, mean (SD) ADHD-RS-IV total by the differences (LDX vs placebo) in LS mean ADHD- scores were 37.0 (5.61). At visits 1, 2, 3, 4b and at dose- RS-IV total scores during visits 5 and 6 (Figure 4). Signifi- optimization endpoint, mean (SD) change from baseline cant improvements for adults while receiving LDX vs pla- scores were -12.3 (8.32), -16.8 (7.83), -20.6 (7.07), -21.6 cebo were also seen for inattention and hyperactivity/ (7.40), and -21.4 (7.31), respectively (P < .0001). impulsivity subscales as measured by the difference in LS Decreases from baseline to dose-optimization endpoint mean scores (95% CI) during visits 5 and 6: -6.3 (-7.7, Figure 2 LS Mean (SE) change from predose in PERMP total score from 2 to 14 hours postdose (n = 104/104). (LDX = lisdexamfetamine dime- sylate; LS = least squares; PERMP = Permanent Product Measure of Performance). LDX-purple diamonds; Placebo-green circles. * P < .001 LDX vs pla- cebo. Wigal et al. Behavioral and Brain Functions 2010, 6:34 Page 9 of 14 http://www.behavioralandbrainfunctions.com/content/6/1/34 Figure 3 LS mean (SE) change from predose in PERMP-A and PERMP-C scores from 2 to 14 hours postdose (n = 104/104). (LDX = lisdexamfe- tamine dimesylate; LS = least squares; PERMP-A/-C = Permanent Product Measure of Performance-Attempted/-Correct). PERMP-A: LDX-purple dia- monds; Placebo-green diamonds; PERMP-C: LDX-blue circles; Placebo-orange circles.* P < .001 LDX vs placebo. -4.9; P < .0001) for inattention scores and -5.2 (-6.6, -3.7; ity. During the dose-optimization phase, the most com- P < .0001) for hyperactivity-impulsivity scores. mon TEAEs of decreased appetite, dry mouth, headache, At baseline, all subjects (n = 142) were rated moderately insomnia, upper respiratory tract infection, irritability, (64.8%), markedly (32.4%), or severely (2.8%) ill by CGI-S nausea, anxiety, and feeling jittery were reported by ≥ 5% with a mean (SD) score of 4.4 (0.5). During the double- of subjects (Table 4). blind crossover phase, CGI-I ratings suggested that 88 During the crossover phase, the overall incidence of (76.5%) of 115 subjects improved while taking LDX (all TEAEs was greater while subjects received placebo vs doses) and 27 (23.1%) of 117 subjects improved while tak- LDX (Table 5). There were no TEAEs that were reported ing placebo. For subjects with valid CGI-I ratings at both by ≥ 5% of subjects while receiving LDX. The TEAEs of visits 5 and 6, of those randomized to the LDX/placebo fatigue and upper respiratory tract infection were sequence in the crossover phase, 27 of 52 subjects dem- reported by ≥ 5% of subjects while receiving placebo, onstrated improvement (much or very much improved which contributed to the increased incidence of TEAEs on the CGI-I) only while receiving LDX; 9 improved only in subjects receiving placebo vs LDX (12.0% vs 0.9%, while receiving placebo. For subjects randomized to the respectively, for fatigue and 7.7% vs 1.7%, respectively, for placebo/LDX sequence, 43 of 51 subjects demonstrated upper respiratory tract infection). improvement only while receiving LDX and 4 improved At baseline, the mean (SD) for SBP, DBP, and pulse were while only on placebo. LDX was associated with signifi- 119.6 (10.28) mm Hg, 73.8 (7.87) mm Hg, and 72.4 cantly (P < .0001) lower CGI-I ratings vs placebo in the (11.23) bpm, respectively. At the endpoint of the dose- crossover phase (Prescott's test). optimization phase, the mean (SD) for SBP, DBP, and pulse were 119.3 (10.40) mm Hg, 73.6 (7.65) mm Hg, and Safety 75.6 (9.80) bpm, respectively. During the double-blind No deaths or serious AEs were reported in this study. crossover phase, the mean at predose and postdose time Most reported TEAEs were mild and moderate in sever- Wigal et al. Behavioral and Brain Functions 2010, 6:34 Page 10 of 14 http://www.behavioralandbrainfunctions.com/content/6/1/34 Table 3: Predose and average postdose PERMP scores: PERMP total, PERMP-A, and PERMP-C (n = 104) Predose PERMP Mean Average Postdose Difference in Postdose P Value (SD) PERMP Mean LS Mean (SD) (95% CI) (LDX/Placebo) PERMP total While receiving LDX 260.1 (86.23) 312.7 (94.42) 23.4 (15.6, 31.2) < .0001 While receiving placebo 261.4 (74.96) 287.6 (81.45) PERMP-A While receiving LDX 132.2 (43.28) 158.4 (47.53) 12.0 (8.1, 15.8) < .0001 While receiving placebo 132.6 (37.62) 145.7 (41.06) PERMP-C While receiving LDX 127.9 (43.02) 154.3 (46.96) 11.5 (7.6, 15.4) < .0001 While receiving placebo 128.8 (37.39) 141.9 (40.44) CI = confidence interval; LDX = lisdexamfetamine dimesylate; LS = least squares; PERMP = Permanent Product Measure of Performance; PERMP-A = PERMP-Attempted; PERMP-C = PERMP-Correct. points on visits 5 and 6 of the AWE days ranged from adults with ADHD in a structured setting (ie, simulated 118.0 to 120.5 mm Hg for SBP, 71.5 to 73.7 mm Hg for AWE) where objective measures of efficacy could be DBP, and 71.4 to 74.8 bpm for pulse in subjects while assessed throughout the day and the first to demonstrate receiving placebo; and from 117.2 to 123.4 mm Hg for efficacy (vs placebo) of an approved oral stimulant medi- SBP, 73.3 to 75.5 mm Hg for DBP, and 77.0 to 81.0 bpm cation at 14 hours postdose. While similar studies in for pulse in subjects while receiving LDX (all doses). Con- adults are limited, efficacy of long-acting stimulants in sistent with prior clinical studies of LDX, ECG interval the laboratory school setting has been demonstrated for data showed no clinically meaningful trends. At baseline, children with ADHD across the day and at 12 the mean (SD) QTcF interval was 384.8 (19.68) msec and [15,22,25,33,34] and 13 hours postdose [16]. The findings during the double-blind crossover phase (visits 5 and 6) of the current study align closely with the results seen in was 388.8 (20.65) msec for subjects while receiving LDX, children in a laboratory school setting [16]. In both stud- and the mean (SD) QTcF interval at visits 5 and 6 was ies, LDX demonstrated significant separation from pla- 389.0 (21.52) for subjects while receiving placebo. cebo through the last postdose time points assessed on an The mean (SD) change in weight at dose-optimization objective measure of task productivity and accuracy endpoint vs baseline was -4.0 (4.27) lb. During the cross- throughout the day. over phase, the mean (SD) change in weight vs baseline In this study, LDX demonstrated efficacy compared for subjects administered placebo was -2.7 (3.98) and for with placebo as measured by the average postdose subjects administered LDX was -4.4 (4.72) lb. The inci- PERMP math test total scores in this controlled trial in dence of subjects who experienced a decrease in weight the simulated AWE setting. Moreover, LDX exhibited that was categorized as a TEAE (based on subject's self- efficacy at all time points measured during the AWE ses- report and clinician's judgment) was 3.5% (5 of 142 sub- sions: from 2 hours to 14 hours postdose. Since ADHD jects) during the dose-optimization phase with none in symptoms may extend late into the day [20], the availabil- the crossover phase. ity of treatments that provide efficacy throughout the day, is important. Discussion LDX demonstrated efficacy compared with placebo in This is the first study of a medication approved for the this study in decreasing symptoms of ADHD as measured treatment of ADHD to examine efficacy and safety in by the ADHD-RS-IV with adult prompts. LDX also dem- Wigal et al. Behavioral and Brain Functions 2010, 6:34 Page 11 of 14 http://www.behavioralandbrainfunctions.com/content/6/1/34 Figure 4 ADHD-RS-IV total scores at baseline and visit 5/6 and difference in LS mean (95% CI) between LDX and placebo during the double- blind crossover phase. (ADHD-RS-IV = Attention-Deficit/Hyperactivity Disorder Rating Scale IV; CI = confidence interval; LDX = lisdexamfetamine dimesylate; LS = least squares). * P < .0001 LDX vs placebo. onstrated efficacy based on improvements in global rent study was associated with modest effects on cardio- assessment of symptom severity as assessed by clinicians vascular parameters of blood pressure and pulse. Four on the CGI-I scale. These findings support and extend subjects withdrew during dose optimization due to car- previous findings that LDX reduced the symptoms and diovascular-related TEAEs, supporting the importance of severity of ADHD compared with placebo in adults in a monitoring cardiovascular parameters during treatment 4-week controlled trial [18] with measures assessed at with stimulants. As with all stimulants, careful attention weekly intervals (eg, CGI-I ratings and ADHD-RS-IV to cardiovascular history, symptoms, and clinical findings with adult prompts scores). In that randomized, forced- in adults with ADHD prior to, and during treatment with, dose escalation, double-blind, placebo-controlled study stimulants is advisable. for adult subjects with ADHD, LDX significantly reduced Strengths of the study included experimental design ADHD symptoms at each dose and at each weekly assess- features, such as the multicenter, double-blind, placebo- ment beginning at week 1 and through study endpoint controlled, crossover design, and use of the simulated compared with placebo. AWE setting and the validated PERMP to provide assess- In the current study, LDX demonstrated a safety profile ments of medication efficacy and safety compared with consistent with long-acting stimulant use. The common placebo throughout the day. While studies assessing the AEs in the current study, including decreased appetite, effects of treatment on symptom reduction over an dry mouth, headache, and insomnia, are consistently seen extended time course (eg, weeks to months) is very useful in studies of long-acting stimulant medications adminis- in determining global efficacy and safety of medications tered to adults [12,18,35,36]. As demonstrated in these for ADHD, it is also important to understand the effects other studies, most AEs were mild to moderate in sever- of medications for ADHD in settings over the course of ity. The effects seen in the current study on weight and the day. cardiovascular parameters were consistent with those previously reported for stimulants, including LDX, in Limitations adults [7-9,18,37]. As previously seen for LDX in adult There are limitations on the interpretation of the results patients with ADHD [18], LDX administration in the cur- of this study. The duration of the study was relatively Wigal et al. Behavioral and Brain Functions 2010, 6:34 Page 12 of 14 http://www.behavioralandbrainfunctions.com/content/6/1/34 Table 4: TEAEs during the dose-optimization phase for all Table 5: TEAEs during the crossover phase for all TEAEs TEAEs with incidence ≥ 5% in either the dose-optimization with incidence ≥ 5% in either the dose-optimization and/or and/or the crossover phases the crossover phases AE Dose-Optimization Phase AE Crossover Phase Preferred Term, % (n) (Safety Population) Preferred Term, % (n) (Randomized Population) LDX-All Doses LDX-All Doses Placebo a a a (n = 142) (n = 115) (n = 117) Any TEAE 79.6 (113) Any TEAE 27.8 (32) 35.9 (42) Anxiety 5.6 (8) Anxiety 1.7 (2) 0 Decreased appetite 36.6 (52) Decreased appetite 3.5 (4) 1.7 (2) Dry mouth 30.3 (43) Dry mouth 3.5 (4) 0.9 (1) Fatigue 4.9 (7) Fatigue 0.9 (1) 12.0 (14) Feeling jittery 5.6 (8) Feeling jittery 0 0 Headache 19.7 (28) Headache 1.7 (2) 2.6 (3) Insomnia 18.3 (26) Insomnia 2.6 (3) 1.7 (2) Irritability 8.5 (12) Irritability 0 0.9 (1) Nausea 7.7 (11) Nausea 1.7 (2) 0 Upper respiratory tract infection 9.9 (14) Upper respiratory tract 1.7 (2) 7.7 (9) infection TEAEs were assigned to either the open-label dose-optimization phase or the double-blind crossover phase of the study and were TEAEs were assigned to either the open-label dose-optimization summarized separately. TEAEs that continued uninterrupted from phase or the double-blind crossover phase of the study and were the dose-optimization to the crossover phase without a change in summarized separately. TEAEs that continued uninterrupted from severity were counted only in the dose-optimization phase the dose-optimization to the crossover phase without a change in category. TEAEs with a change in severity across phases or that severity were counted only in the dose-optimization phase resolved and then restarted in the crossover phase were counted category. TEAEs with a change in severity across phases or that both in the dose-optimization and crossover arms. TEAEs for resolved and then restarted in the crossover phase were counted which a missing or incomplete start date made it impossible to both in the dose-optimization and crossover arms. TEAEs for determine in which phase of the study they started were counted which a missing or incomplete start date made it impossible to as starting in the dose-optimization phase. determine in which phase of the study they started were counted Percentages are based on the number of subjects who received as starting in the dose-optimization phase. each dose at any point during the dose-optimization phase. Percentages are based on the number of subjects who received AE = adverse event; LDX = lisdexamfetamine dimesylate, TEAE = each dose at any point during the crossover phase. treatment-emergent adverse event. AE = adverse event; LDX = lisdexamfetamine dimesylate, TEAE = treatment-emergent adverse event. short. As an assessment of attention to task, ability to stay be analogous to real-world employment settings only in on task, and to monitor during repetitive task completion the sense of requiring adults to engage in activities that throughout the day, it should be kept in mind that, by its require attention, mental effort, and a quantifiable out- design, the PERMP math test setting may result in come (ie, written work). In this way the AWE is a setting increased testing-related arousal. However, the simulated to elicit ADHD symptoms that might manifest in a work- AWE, which includes multiple practice sessions and place where adults with ADHD are occupied with repeti- repeated testing sessions is designed to dampen such tive, effortful tasks. The exclusion of subjects with active arousal. Additionally, the simulated AWE is intended to Wigal et al. Behavioral and Brain Functions 2010, 6:34 Page 13 of 14 http://www.behavioralandbrainfunctions.com/content/6/1/34 Systems, and Michael Pucci, PhD, an employee of Health Learning Systems. Edi- cardiovascular conditions, other unstable medical condi- torial assistance in the form of proofreading, copy editing, and fact checking tions, or comorbid psychiatric disorders may limit the was also provided by Health Learning Systems. Health Learning Systems was applicability of results to the clinically encountered popu- funded by Shire Development Inc. for authorship support in writing and edit- lation. Additionally, the expected dropout rate of 15% was ing this manuscript. Although the sponsor was involved in the design, collec- tion, analysis, interpretation, and fact checking of information, the ultimate exceeded because of an unexpected natural disaster (ie, interpretation was made by the independent authors, as was the content of hurricane) that resulted in the closure of 1 study site. this manuscript and the decision to submit it for publication in Behavioral and Brain Functions. The 316 study group comprised Matthew Brams, MD, Ann Childress, MD, John Conclusions Giblin, MD, Bradley Vince, DO, Timothy Wigal, PhD LDX demonstrated consistent efficacy compared with placebo in a structured simulated AWE from 2 hours to Author Details 14 hours postdose as assessed by PERMP, a measure 1 Department of Pediatrics, University of California, Irvine, Child Development Center, Irvine, CA, USA, Private Practice, Bayou City Research, Houston, TX, USA aimed at assessing attention, ability to stay on task, and to 3 4 , Global Clinical Medicine, Shire Development Inc., Wayne, PA, USA, Biostats, monitor tasks throughout the day. LDX was also effica- Shire Development Inc., Wayne, PA, USA and Clinical Study Centers, LLC, Little cious in providing overall improvement in the majority of Rock, AR, USA patients and demonstrated a safety profile consistent with Received: 30 December 2009 Accepted: 24 June 2010 long-acting stimulant use. Published: 24 June 2010 T © T Bh h e 2010 Wi h i is s a a iv sr i an t or icle al O g an is p ae a l d n e v B t A a al; li ricce a la in ble ce F ss arti u fr n ns o c e t m e icl o Bi :e n h d s o t 2 t M is p 0 t:/ e 10, ri d /bu w C 6 w te e :34 n w d t.be u ral n L h da te d v r th .io ra ela te nrm dbr s a oif n th fue n C ctrio ea nti sve .co C m o /m co m nt o e n n st / A 6 ttri /1/b 3u 4tion 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. Competing interests References TW financial disclosures are for the past 10 years and include research support, 1. Kessler RC, Adler L, Barkley R, Biederman J, Conners CK, Demler O, Faraone SV, consulting honoraria, and/or speaker's bureau from the following pharmaceu- Greenhill LL, Howes MJ, Secnik K, Spencer T, Ustun TB, Walters EE, tical companies: Celltech, Cephalon, Eli Lilly, Janssen, McNeil, Novartis, Otsuka, Zaslavsky AM: The prevalence and correlates of adult ADHD in the and Shire. He has no stock or equity interests. Since July 2008, the list would be United States: results from the National Comorbidity Survey limited to Eli Lilly, McNeil, Otsuka, and Shire for either research support or con- Replication. Am J Psychiatry 2006, 163:716-723. sulting honoraria. In addition, he has received funding from NIMH, NICHD, and 2. Fayyad J, De Graaf R, Kessler R, Alonso J, Angermeyer M, Demyttenaere K, NIDA. De GG, Haro JM, Karam EG, Lara C, Lepine JP, Ormel J, Posada-Villa J, MB has been a speaker for Cephalon, Eli Lilly, McNeil, Novartis, Pfizer, Shire, and Zaslavsky AM, Jin R: Cross-national prevalence and correlates of adult Wyeth. attention-deficit hyperactivity disorder. Br J Psychiatry 2007, MG is a full-time employee of Shire Development Inc. 190:402-409. JG is a full-time employee of Shire Development Inc. 3. Biederman J, Faraone SV, Spencer TJ, Mick E, Monuteaux MC, Aleardi M: LS is a full-time employee of Shire and has held stock and/or options in the fol- Functional impairments in adults with self-reports of diagnosed lowing companies: Johnson & Johnson, Pfizer, and Shire. ADHD: a controlled study of 1001 adults in the community. J Clin JGn is/has receives/d research/grant support, is/has been on the speaker's Psychiatry 2006, 67:524-540. bureau of or is/has been a consultant for the following pharmaceutical compa- 4. Biederman J, Mick E, Fried R, Aleardi M, Potter A, Herzig K: A simulated nies: Addrenex, Cephalon, GlaxoSmithKline, Johnson & Johnson, Novartis, workplace experience for nonmedicated adults with and without Ortho-McNeil, Pfizer, Sanofi-Aventis, Sepracor, and Shire. ADHD. Psychiatr Serv 2005, 56:1617-1620. 5. Wilens TE, Biederman J, Spencer TJ, Prince J: Pharmacotherapy of adult Authors' contributions attention deficit/hyperactivity disorder: a review. J Clin TW was the principal investigator on this study, made substantial contributions Psychopharmacol 1995, 15:270-279. to the conception and design of the study, enrolled patients, participated in 6. Faraone SV, Spencer TJ, Montano CB, Biederman J: Attention-deficit/ data acquisition, analysis, interpretation, and presentation. He was deeply hyperactivity disorder in adults: a survey of current practice in involved in drafting the manuscript and revising the intellectual content. He psychiatry and primary care. Arch Intern Med 2004, 164:1221-1226. has given final approval of this version. 7. Greenhill LL, Pliszka S, Dulcan MK, Bernet W, Arnold V, Beitchman J, MB was an investigator on the study, enrolled patients, and participated in data Benson RS, Bukstein O, Kinlan J, McClellan J, Rue D, Shaw JA, Stock S: acquisition, analysis, interpretation, and presentation. He was deeply involved Practice parameter for the use of stimulant medications in the in drafting the manuscript and revising the intellectual content. He has given treatment of children, adolescents, and adults. J Am Acad Child Adolesc final approval of this version. Psychiatry 2002, 41(2 suppl):26S-49S. MG was the Associate Director, Global Clinical Medicine for this study and 8. Wilens TE, Dodson W: A clinical perspective of attention-deficit/ made substantial contributions to the analysis and interpretation of the data. hyperactivity disorder into adulthood. J Clin Psychiatry 2004, She was deeply involved in drafting the manuscript and revising the intellec- 65:1301-1313. tual content. She has given final approval of this version. 9. Fallu A, Richard C, Prinzo R, Binder C: Does OROS-methylphenidate JG was the statistician for this study and made substantial contributions to the improve core symptoms and deficits in executive function? Results of analysis and interpretation of the data. He was deeply involved in drafting the an open-label trial in adults with attention deficit hyperactivity manuscript and revising the intellectual content. He has given final approval of disorder. Curr Med Res Opin 2006, 22:2557-2566. this version. 10. Spencer T, Biederman J, Wilens T, Faraone S, Prince J, Gerard K, Doyle R, LS was the Senior Director, Global Clinical Medicine for this study and made Parekh A, Kagan J, Bearman SK: Efficacy of a mixed amphetamine salts substantial contributions to the analysis and interpretation of the data. 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Behavioral and Brain Functions – Springer Journals
Published: Jun 24, 2010