Effects of Lisdexamfetamine Dimesylate on Functional Impairment Measured on the Sheehan Disability Scale in Adults With Moderate-to-severe Binge Eating Disorder: Results from Two Randomized, Placebo-controlled Trials.

Objective: In two Phase III, randomized, placebo-controlled trials (NCT01718483 and NCT01718509 at ClinicalTrials.gov), lisdexamfetamine dimesylate (LDX) reduced binge eating days/week in adults with moderate-to-severe binge eating disorder (BED). We describe the effects of LDX (50mg and 70mg) on the Sheehan Disability Scale (SDS; exploratory endpoint) from both studies. Design: The SDS was assessed at baseline, Week 6, and Week 12/early termination. Analyses included mixed-effects models for repeated measures for the examination of SDS total and domain score changes and a generalized estimating equation model to assess dichotomized remission status (remission [total score ≤6] versus nonremission [total score >6]). Results: Least squares (95% confidence interval [CI]) mean treatment differences for SDS total score change from baseline at Week 12 were -2.80 (-3.98, -1.61) in Study 1 and -3.70 (-4.81, -2.58) in Study 2 (both p<0.001). Least squares (95% CI) mean treatment differences across SDS domains favored LDX over placebo in both studies for the change from baseline at Week 12 (work/school: -0.8 [-1.2, -0.4] and -1.1 [-1.5, -0.7], both p<0.001; social life/leisure activities: -1.0 [-1.4, -0.5] and -1.4 [-1.8, -1.0], both p<0.001; and family life/home responsibilities: -1.0 [-1.4, -0.5] and -1.3 [-1.7, -0.9], both p<0.001). Odds ratios (95% CI) for SDS remission versus nonremission favored LDX over placebo at Week 12 (Study 1: 2.39 [1.44, 3.96]; p<0.001 and Study 2: 5.12 [2.80, 9.33]; p<0.001). Conclusion: These findings indicate that LDX treatment is associated with improvement on the SDS in adults with moderate-to-severe BED.

Efficacy of Lisdexamfetamine in Adults With Moderate to Severe Binge-Eating Disorder: A Randomized Clinical Trial.

Importance: The ability of pharmacotherapies to prevent relapse and maintain efficacy with long-term treatment in psychiatric conditions is important. Objective: To assess lisdexamfetamine dimesylate maintenance of efficacy in adults with moderate to severe binge-eating disorder. Design, Setting, and Participants: A multinational, phase 3, double-blind, placebo-controlled, randomized withdrawal study including 418 participants was conducted at 49 clinical research study sites from January 27, 2014, to April 8, 2015. Eligible adults met DSM-IV-R binge-eating disorder criteria and had moderate to severe binge eating disorder (≥3 binge-eating days per week for 14 days before open-label baseline; Clinical Global Impressions-Severity [CGI-S] scores ≥4 [moderate severity] at screening and open-label baseline). Following a 12-week, open-label phase (dose optimization, 4 weeks [lisdexamfetamine dimesylate, 50 or 70 mg]; dose maintenance, 8 weeks), lisdexamfetamine responders (≤1 binge eating day per week for 4 consecutive weeks and CGI-S scores ≤2 at week 12) were randomized to placebo or continued lisdexamfetamine during a 26-week, double-blind, randomized withdrawal phase. Interventions: Lisdexamfetamine administration. Main Outcomes and Measures: The primary outcome variable, time to relapse (≥2 binge-eating days per week for 2 consecutive weeks and ≥2-point CGI-S score increases from randomized withdrawal baseline), was analyzed using a log-rank test (primary analysis); the analysis was stratified for dichotomized 4-week cessation status. Safety assessments included treatment-emergent adverse events. Results: Of the 418 participants enrolled in the open-label phase of the study, 411 (358 [87.1%] women; mean [SD] age, 38.3 [10.4] years) were included in the safety analysis set. Of 275 randomized lisdexamfetamine responders (placebo, n = 138; lisdexamfetamine, n = 137), the observed proportions of participants meeting relapse criteria were 3.7% (5 of 136) for lisdexamfetamine and 32.1% (42 of 131) for placebo. Lisdexamfetamine demonstrated superiority over placebo on the log-rank test (χ21, 40.37; P < .001) for time to relapse; the hazard ratio, based on a Cox proportional hazards model for lisdexamfetamine vs placebo, was 0.09 (95% CI, 0.04-0.23). The treatment-emergent adverse events observed were generally consistent with the known profile of lisdexamfetamine. Conclusions and Relevance: Risk of binge-eating relapse over 6 months was lower in participants continuing lisdexamfetamine than in those randomized to placebo. The hazard for relapse was lower with lisdexamfetamine than placebo. Trial Registration: clinicaltrials.gov Identifier: NCT02009163.

The Efficacy of Crotalidae Polyvalent Immune Fab (Ovine) Antivenom Versus Placebo Plus Optional Rescue Therapy on Recovery From Copperhead Snake Envenomation: A Randomized, Double-Blind, Placebo-Controlled, Clinical Trial.

STUDY OBJECTIVE: Copperhead snake (Agkistrodon contortrix) envenomation causes limb injury resulting in pain and disability. It is not known whether antivenom administration improves limb function. We determine whether administration of antivenom improves recovery from limb injury in patients envenomated by copperhead snakes. METHODS: From August 2013 through November 2015, we performed a multicenter, randomized, double-blind, placebo-controlled, clinical trial to evaluate the effect of ovine Crotalidae polyvalent immune Fab (ovine) (CroFab; FabAV) antivenom therapy on recovery of limb function in patients with copperhead snake envenomation at 14 days postenvenomation. The study setting was 18 emergency departments in regions of the United States where copperhead snakes are endemic. Consecutive patients aged 12 years or older with mild- to moderate-severity envenomation received either FabAV or placebo. The primary outcome was limb function 14 days after envenomation, measured by the Patient-Specific Functional Scale. Additional outcomes included the Patient-Specific Functional Scale at other points; the Disorders of the Arm, Shoulder, and Hand, Lower Extremity Functional Scale, and Patient's Global Impression of Change instruments; grip strength; walking speed; quality of life (Patient-Reported Outcomes Measurement Information System Physical Fucntion-10); pain; and analgesic use. RESULTS: Seventy-four patients received study drug (45 FabAV, 29 placebo). Mean age was 43 years (range 12 to 86 years). Fifty-three percent were men, 62% had lower extremity envenomation, and 88% had mild initial severity. The primary outcome, the least square mean Patient-Specific Functional Scale score at 14 days postenvenomation, was 8.6 for FabAV-treated subjects and 7.4 for placebo recipients (difference 1.2; 95% confidence interval 0.1 to 2.3; P=.04). Additional outcome assessments generally favored FabAV. More FabAV-treated subjects experienced treatment-emergent adverse events (56% versus 28%), but few were serious (1 in each group). CONCLUSION: Treatment with FabAV reduces limb disability measured by the Patient-Specific Functional Scale 14 days after copperhead envenomation.

Time course of the effects of lisdexamfetamine dimesylate in two phase 3, randomized, double-blind, placebo-controlled trials in adults with binge-eating disorder.

OBJECTIVE: This study examined the time course of efficacy-related endpoints for lisdexamfetamine dimesylate (LDX) versus placebo in adults with protocol-defined moderate to severe binge-eating disorder (BED). METHODS: In two 12-week, double-blind, placebo-controlled studies, adults meeting DSM-IV-TR BED criteria were randomized 1:1 to receive placebo or dose-optimized LDX (50 or 70 mg). Analyses across visits used mixed-effects models for repeated measures (binge eating days/week, binge eating episodes/week, Yale-Brown Obsessive Compulsive Scale modified for Binge Eating [Y-BOCS-BE] scores, percentage body weight change) and chi-square tests (Clinical Global Impressions-Improvement [CGI-I; from the perspective of BED symptoms] scale dichotomized as improved or not improved). These analyses were not part of the prespecified testing strategy, so reported p values are nominal (unadjusted and descriptive only). RESULTS: Least squares mean treatment differences for change from baseline in both studies favored LDX over placebo (all nominal p values < .001) starting at Week 1 for binge eating days/week, binge-eating episodes/week, and percentage weight change and at the first posttreatment assessment (Week 4) for Y-BOCS-BE total and domain scores. On the CGI-I, more participants on LDX than placebo were categorized as improved starting at Week 1 in both studies (both nominal p values < .001). Across these efficacy-related endpoints, the superiority of LDX over placebo was maintained at each posttreatment assessment in both studies (all nominal p values < .001). DISCUSSION: In adults with BED, LDX treatment appeared to be associated with improvement on efficacy measures as early as 1 week, which was maintained throughout the 12-week studies.

A Phase 3, Multicenter, Open-Label, 12-Month Extension Safety and Tolerability Trial of Lisdexamfetamine Dimesylate in Adults With Binge Eating Disorder.

BACKGROUND: A 12-month, open-label extension study assessed the long-term safety and tolerability of lisdexamfetamine dimesylate (LDX) in adults with binge eating disorder (BED). METHODS: Adults (aged 18-55 y) with BED who completed 1 of 3 antecedent studies were enrolled in a 52-week, open-label extension study (dose optimization, 4 weeks [initial titration dose, 30-mg LDX; target doses, 50- or 70-mg LDX]; dose maintenance, 48 weeks). Safety evaluations included the occurrence of treatment-emergent adverse events (TEAEs), vital sign and weight assessments, and Columbia-Suicide Severity Rating Scale responses. RESULTS: Of the 604 enrolled participants, 599 (521 women and 78 men) comprised the safety analysis set, and 369 completed the study. Mean (SD) LDX exposure was 284.3 (118.84) days; cumulative LDX exposure duration was 12 months or longer in 344 participants (57.4%). A total of 506 participants (84.5%) reported TEAEs (TEAEs leading to treatment discontinuation, 54 [9.0%]; severe TEAEs, 42 [7.0%]; serious TEAEs, 17 [2.8%]). Treatment-emergent adverse events reported in greater than or equal to 10% of participants were dry mouth (27.2%), headache (13.2%), insomnia (12.4%), and upper respiratory tract infection (11.4%). Mean (SD) changes from antecedent study baseline in systolic and diastolic blood pressure, pulse, and weight at week 52/early termination (n = 597) were 2.19 (11.043) and 1.77 (7.848) mm Hg, 6.58 (10.572) beats per minute, and -7.04 (7.534) kg, respectively. On the Columbia-Suicide Severity Rating Scale, there were 2 positive responses for any active suicidal ideations; there were no positive responses for suicidal behavior or completed suicides. CONCLUSIONS: In this 12-month, open-label, extension study, the long-term safety and tolerability of LDX in adults with BED were generally consistent with its established profile for attention-deficit/hyperactivity disorder.

Lisdexamfetamine Dimesylate Effects on Binge Eating Behaviour and Obsessive-Compulsive and Impulsive Features in Adults with Binge Eating Disorder.

In a published 11-week, placebo-controlled trial, 50 and 70 mg/d lisdexamfetamine dimesylate (LDX), but not 30 mg/d LDX, significantly reduced binge eating days (primary endpoint) in adults with binge eating disorder (BED). This report provides descriptions of LDX effects on secondary endpoints (Binge Eating Scale [BES]; Three-Factor Eating Questionnaire [TFEQ]; Yale-Brown Obsessive Compulsive Scale modified for Binge Eating [Y-BOCS-BE]; and the Barratt Impulsiveness Scale, version 11 [BIS-11]) from that study. Week 11 least squares mean treatment differences favoured all LDX doses over placebo on the BES (p ≤ 0.03), TFEQ Disinhibition and Hunger subscales (all p < 0.05), and Y-BOCS-BE total, obsessive, and compulsive scales (all p ≤ 0.02) and on BIS-11 total score at 70 mg/d LDX (p = 0.015) and the TFEQ Cognitive Restraint subscale at 30 and 70 mg/d LDX (both p < 0.05). These findings indicate that LDX decreased global binge eating severity and obsessive-compulsive and impulsive features of BED in addition to binge eating days.

Lisdexamfetamine Dimesylate for Adults with Moderate to Severe Binge Eating Disorder: Results of Two Pivotal Phase 3 Randomized Controlled Trials.

The efficacy and safety of lisdexamfetamine dimesylate (LDX) vs placebo in binge eating disorder (BED) was evaluated in two multicenter, double-blind, placebo-controlled trials. Adults (study 1, n=383; study 2, n=390) meeting DSM-IV-TR BED criteria were randomized (1:1) to placebo or LDX (50 or 70 mg/day) dose titration; optimized doses were maintained to the end of double-blind treatment (week 12/early termination). Change from baseline in binge eating days/week at weeks 11-12 (primary efficacy endpoint) was assessed with mixed-effects models for repeated measures. Secondary endpoints related to binge eating and medical parameters, safety, and treatment compliance were also assessed. Least squares mean (95% CI) treatment differences for change from baseline binge eating days/week at weeks 11-12 significantly favored LDX (study 1: -1.35 [-1.70, -1.01]; study 2: -1.66 [-2.04, -1.28]; both P<0.001). In both studies, treatment-emergent adverse events (TEAEs) reported by ⩾10% of LDX participants were dry mouth, insomnia, and headache. Serious TEAEs occurred in two (1.1%) placebo participants in each study and in three (1.6%) and one (0.6%) LDX participants in study 1 and study 2, respectively. Across studies, mean increases from baseline at week 12/early termination with LDX for pulse and systolic and diastolic blood pressure ranged from 4.41-6.31 b.p.m. and 0.2-1.45 and 1.06-1.83 mm Hg, respectively. LDX (50 and 70 mg/day) was superior to placebo in decreasing binge eating days/week from baseline and improving binge eating-related key secondary endpoints. Safety results appear consistent with the known safety profile of LDX.

Validation of the yale-brown obsessive compulsive scale modified for binge eating.

OBJECTIVE: Establish the Yale-Brown obsessive compulsive scale modified for binge eating (YBOCS-BE) as a fit for purpose measure of treatment benefit in clinical trials of binge eating disorder (BED). METHODS: YBOCS-BE psychometric properties were evaluated with data from a Phase 2 randomized controlled trial of lisdexamfetamine dimesylate in 260 adults with BED. Assessments included: Cohen's effect size estimates of item-level sensitivity and scale-level external responsiveness; item-to-total correlations; Cronbach's alpha for internal consistency reliability; Spearman correlations against reference measures for construct validity; known-groups analyses for discriminating ability; t tests of within-group differences between baseline and post baseline visits for internal responsiveness; and multiple anchor-based approaches to estimate minimum clinically important change (MCIC). RESULTS: No significant distribution anomalies were seen. Items appear sensitive to treatment group differences. Item-to-total correlations were positive. Internal consistency is 0.81. Large correlations (>0.50) were seen between YBOCS-BE score change and the Clinical Global Impression-Improvement (CGI-I; 0.58) and score changes for the following; number of binge days (0.38), Clinical Global Impression-Severity (CGI-S; 0.57), the disinhibition (0.57) and hunger (0.52) subscales of the Three-Factor Eating Questionnaire (TFEQ), and the Barratt Impulsiveness Scale (BIS-11; 0.58). MCIC estimates range from -4 to -17. DISCUSSION: The YBOCS-BE was found to be a reliable and valid measure of an important and unique concept in BED-related clinical studies. Study limitations include using protocol-defined BED severity level and the exclusion of psychiatric comorbidities.

Efficacy and safety of lisdexamfetamine for treatment of adults with moderate to severe binge-eating disorder: a randomized clinical trial.

IMPORTANCE: Binge-eating disorder (BED), a public health problem associated with psychopathological symptoms and obesity and possibly with metabolic syndrome, lacks approved pharmacotherapies. OBJECTIVE: To examine the efficacy and safety of lisdexamfetamine dimesylate, a dextroamphetamine prodrug, to treat moderate to severe BED. DESIGN, SETTING, AND PARTICIPANTS: We performed a randomized, double-blind, parallel-group, forced dose titration, placebo-controlled clinical trial at 30 sites from May 10, 2011, through January 30, 2012. Safety and intention-to-treat analyses included 259 and 255 adults with BED, respectively. INTERVENTIONS: Lisdexamfetamine dimesylate at dosages of 30, 50, or 70 mg/d or placebo were provided to study participants (1:1:1:1). Dosages were titrated across 3 weeks and maintained for 8 weeks. We followed up participants for a mean (SD) of 7 (2) days after the last dose. MAIN OUTCOMES AND MEASURES: We assessed the change in binge-eating (BE) behaviors measured as days per week (baseline to week 11) with a mixed-effects model using transformed log (BE days per week) + 1. Secondary measures included BE cessation for 4 weeks. Safety assessments included treatment-emergent adverse events, vital signs, and change in weight. RESULTS: At week 11, log-transformed BE days per week decreased with the 50-mg/d (least squares [LS] mean [SE] change, -1.49 [0.066]; P = .008) and 70-mg/d (LS mean [SE] change, -1.57 [0.067]; P < .001) treatment groups but not the 30-mg/d treatment group (LS mean [SE] change, -1.24 [0.067]; P = .88) compared with the placebo group. Nontransformed mean (SD) days per week decreased for placebo and the 30-, 50-, and 70-mg/d treatment groups by -3.3 (2.04), -3.5 (1.95), -4.1 (1.52), and -4.1 (1.57), respectively. The percentage of participants achieving 4-week BE cessation was lower with the placebo group (21.3%) compared with the 50-mg/d (42.2% [P = .01]) and 70-mg/d (50.0% [P < .001]) treatment groups. The incidence of any treatment-emergent adverse events was 58.7% for the placebo group and 84.7% for the combined treatment group. In the treatment groups, 1.5% of participants had serious treatment-emergent adverse effects. Events with a frequency of at least 5% and changes in heart rate were generally consistent with the known safety profile. The mean (SD) change in body weight was -0.1 (3.09), -3.1 (3.64), -4.9 (4.43), -4.9 (3.93), and -4.3 (4.09) kg for the placebo group, the 30-, 50-, and 70-mg/d treatment groups, and the combined treatment groups, respectively (P < .001 for each dose vs placebo group comparison in post hoc analysis). CONCLUSIONS AND RELEVANCE: The 50- and 70-mg/d treatment groups demonstrated efficacy compared with the placebo group in decreased BE days, BE cessation, and global improvement. The safety profile was generally consistent with previous findings in adults with attention-deficit/hyperactivity disorder. Further investigation of lisdexamfetamine in BED is ongoing. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01291173.

A generalized estimating equation approach to analysis of maintenance of wakefulness testing in a study of lisdexamfetamine dimesylate, armodafinil, and placebo in sleep-deprived adults.

In a study of acute sleep deprivation in healthy male volunteers randomized to double-blind treatment with lisdexamfetamine dimesylate (20, 50, or 70 mg), placebo control, or an active control (armodafinil 250 mg), Maintenance of Wakefulness Test data were compared using a generalized estimating equation analysis to eliminate the need for unequivocal sleep latency imputation. Compared with placebo across all Maintenance of Wakefulness Tests, all active treatments were associated with lower risk of falling asleep (risk ratio [95% confidence interval]): 0.45 (0.27-0.76; P = 0.0026), 0.10 (0.05-0.20; P < 0.0001), and 0.05 (0.02-0.14; P < 0.0001) for 20, 50, and 70 mg lisdexamfetamine dimesylate, respectively, and 0.11 (0.06-0.21; P < 0.0001) for the active control. Sleep-risk ratios were similar for lisdexamfetamine dimesylate 50 or 70 mg and for the active control, but lisdexamfetamine 20 mg was associated with a greater risk of falling asleep compared with the active control (4.13 [1.97-8.67]; P = 0.0002). Generalized estimating equation analysis detected wake-promoting effects of active treatments and eliminating data imputation, suggesting model utility in future studies.

Maintenance of wakefulness with lisdexamfetamine dimesylate, compared with placebo and armodafinil in healthy adult males undergoing acute sleep loss.

This study evaluated daytime alertness and performance with lisdexamfetamine dimesylate during acute sleep loss. In a randomized, double-blind study in healthy adult men (n = 135) undergoing 24-hour sleep loss, the alerting effects of single oral lisdexamfetamine dimesylate doses (20, 50, or 70 mg) were compared with a placebo and an active control (armodafinil 250 mg). Primary end point was mean unequivocal sleep latency on the 30-minute maintenance of wakefulness test taken every 2 hours from midnight to 8:00 A.M. Secondary end points included the Karolinska sleepiness scale and psychomotor vigilance task. Safety assessments included treatment-emergent adverse events (TEAEs) and vital signs. Least squares mean (SE) maintenance of wakefulness test unequivocal sleep latency (in minutes) was longer with lisdexamfetamine dimesylate 20, 50, and 70 mg, or armodafinil 250 mg (23.3 [1.10], 27.9 [0.64], 29.3 [0.44], or 27.6 [0.63], respectively) versus placebo (15.3 [1.00]; P < 0.0001). Longer mean unequivocal sleep latency was seen with lisdexamfetamine dimesylate 70 mg versus armodafinil (P = 0.0351) and armodafinil versus lisdexamfetamine dimesylate 20 mg (P = 0.0014). On Karolinska sleepiness scale, lisdexamfetamine dimesylate 50 and 70 mg improved estimated sleepiness versus placebo (P ≤ 0.0002) and armodafinil (P ≤ 0.03). Active treatments improved psychomotor vigilance task performance versus placebo (P < 0.0001). The TEAEs were mild/moderate. No serious adverse events occurred. The most common TEAE was headache with lisdexamfetamine dimesylate and armodafinil (7.4% each) versus placebo (3.7%). Small mean increases in vital signs were observed with lisdexamfetamine dimesylate and armodafinil. In sleep-deprived healthy men, alertness was greater with lisdexamfetamine dimesylate and armodafinil versus placebo on the primary end point. Studies are needed in clinical populations and using longer durations of administration.

Participant-perceived quality of life in a long-term, open-label trial of lisdexamfetamine dimesylate in adolescents with attention-deficit/hyperactivity disorder.

OBJECTIVES: The purpose of this study was to assess long-term improvement in quality of life (QOL) in adolescents with attention-deficit/hyperactivity disorder (ADHD) treated with lisdexamfetamine dimesylate (LDX). METHODS: Adolescents with ADHD treated for ≥3 weeks in a 4 week, placebo-controlled study entered a 1 year, open-label study. After the 4 week dose optimization (30, 50, and 70 mg/day LDX) period, treatment was maintained for 48 additional weeks. Change from baseline (of prior study) to week 52/early termination (ET) (of open-label study) in ADHD Rating Scale IV (ADHD-RS-IV) assessed effectiveness, and the Youth QOL-Research Version (YQOL-R) assessed participant-perceived QOL. Post-hoc analyses described effectiveness and QOL for participants with self-perceived poor QOL at baseline (≥1 SD below the mean) versus all others, and for study completers versus study noncompleters. RESULTS: These post-hoc analyses included 265 participants. Participants with baseline self-perceived poor QOL (n=32) versus all others (n=232) exhibited robust YQOL-R perceptual score changes (improvement) with LDX, emerging by week 28 and maintained to week 52/ET. Week 52/ET mean change score ranged from +9.8 to +17.6 for participants with baseline self-perceived poor QOL and +0.4 to +5.1 for all others; week 52/ET improvements in ADHD-RS-IV total scores were similar, regardless of baseline YQOL-R total score. At week 52/ET, study completers had greater YQOL-R improvements than did noncompleters; ADHD-RS-IV total score changes were also numerically larger at week 52/ET for completers than for noncompleters. CONCLUSION: Participant-perceived QOL and ADHD symptoms improved from baseline with LDX in adolescents with ADHD; greatest improvements occurred among participants with baseline self-perceived poor QOL.

Maintenance of efficacy of lisdexamfetamine dimesylate in children and adolescents with attention-deficit/hyperactivity disorder: randomized-withdrawal study design.

OBJECTIVE: In this phase 3 extension study, the long-term maintenance of efficacy of lisdexamfetamine dimesylate (LDX) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) was evaluated using a randomized-withdrawal study design. METHOD: European and US patients (6-17 years; N = 276) with ADHD were entered into a 26-week open-label trial of LDX treatment. Those who completed the open-label period (n = 157) were randomized 1:1 to their optimized dose of LDX (30, 50, or 70 mg per day) or placebo for a 6-week randomized-withdrawal period (RWP). The primary efficacy measure was the proportion of patients meeting treatment failure criteria (≥50% increase in ADHD Rating Scale IV total score and ≥2-point increase in Clinical Global Impressions-Severity of Illness [CGI-S] score, compared with RWP start point). Safety and tolerability were also evaluated. RESULTS: During the RWP (LDX, n = 78; placebo, n = 79), significantly fewer patients receiving LDX met treatment failure criteria (15.8%) compared with those receiving placebo (67.5%; difference = -51.7%; 95% confidence interval = -65.0, -38.5; p < .001 ). Most treatment failures occurred at or before the week 2 visit after randomization. Treatment-emergent adverse events were reported in 39.7% and 25.3% of patients receiving LDX and placebo, respectively, during the RWP. CONCLUSIONS: These data demonstrate the maintenance of efficacy of LDX during long-term treatment in children and adolescents with ADHD. The rapid return of symptoms on LDX withdrawal demonstrates the need for continuing treatment. The safety profile of LDX was consistent with that of other stimulants. Clinical trial registration information-Double-Blind, Placebo-Controlled, Randomized Withdrawal, Extension, Safety and Efficacy Study of LDX in Children and Adolescents Aged 6-17; http://clinicaltrials.gov; NCT00784654.

A long-term open-label safety and effectiveness trial of lisdexamfetamine dimesylate in adolescents with attention-deficit/hyperactivity disorder.

OBJECTIVE: Information on psychostimulant treatment in long-term studies for attention-deficit/hyperactivity disorder (ADHD) in adolescents is limited. This study aimed to assess the safety and effectiveness of lisdexamfetamine dimesylate (LDX) over 52 weeks in adolescents with ADHD. METHODS: This open-label multicenter study enrolled eligible participants after their participation in a randomized, double-blind, placebo-controlled 4 week trial in adolescents with ADHD. Following a 4 week dose-optimization phase, participants were maintained on treatment for up to ∼48 weeks on an optimal dose. Safety assessments included treatment-emergent adverse events (TEAEs), vital signs, laboratory findings, and electrocardiograms. Effectiveness measures included the ADHD Rating Scale IV (ADHD-RS-IV; primary) and Clinical Global Impressions-Improvement (CGI-I). The Youth Quality of Life-Research Version (YQOL-R) was also included in this study; raw scores are transformed to a 0-100 point scale. RESULTS: Of 269 enrolled (from the antecedent study), 265 (98.5%) were in the safety population and effectiveness population. Common TEAEs (≥5%) with LDX included upper respiratory tract infection (21.9%), decreased appetite (21.1%), headache (20.8%), decreased weight (16.2%), irritability (12.5%), insomnia (12.1%), nasopharyngitis (7.2%), influenza (6.8%), dizziness (5.3%), and dry mouth (5.3%). At end point, for all LDX doses in the overall safety population, mean (SD) increase from baseline in systolic blood pressure was 2.3 (10.53) mm Hg, diastolic blood pressure was 2.5 (8.37) mm Hg, and pulse rate was 6.3 (12.74) bpm. No clinically meaningful electrocardiogram or vital sign changes were observed. At end point with LDX treatment, the ADHD-RS-IV mean (SD) total score change from antecedent study baseline was -26.2 (9.75) (p<0.001); 87.2% of participants were improved (CGI-I=1 or 2). Baseline (antecedent study) mean (SD) YQOL-R perceptual total score was 79.8 (11.28) and increased by 3.9 (9.73) at end point (p<0.001). CONCLUSIONS: LDX demonstrated a long-term safety profile similar to that of other long-acting psychostimulants and was effective, as indicated by improvements in ADHD symptoms and participant-perceived YQOL, in adolescents with ADHD. CLINICAL TRIAL REGISTRATION: NCT00764868, http://www.clinicaltrials.gov/ct2/show/NCT00764868?term=SPD489-306&rank=1.

Maintenance of efficacy of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder: randomized withdrawal design.

OBJECTIVE: To evaluate lisdexamfetamine dimesylate maintenance of efficacy in adults with attention-deficit/hyperactivity disorder (ADHD). METHOD: Adults (aged 18-55 years) who had ADHD meeting DSM-IV-TR criteria, baseline ADHD Rating Scale-IV (ADHD-RS-IV) with adult prompts total scores of < 22, and Clinical Global Impressions-Severity of Illness (CGI-S) ratings of 1, 2, or 3 were enrolled. After previously receiving commercially available lisdexamfetamine dimesylate (30, 50, or 70 mg/d) for ≥ 6 months with acceptable tolerability and maintaining response during a 3-week open-label phase at a stable lisdexamfetamine dimesylate dose, the participants entered a 6-week double-blind randomized withdrawal phase on treatment with lisdexamfetamine dimesylate (same dose) or placebo. Data were collected from April 2009 to July 2010. The primary outcome was the proportion of participants having symptom relapse (≥ 50% increase in ADHD-RS-IV score and ≥ 2 rating-point increase in CGI-S score). RESULTS: A total of 116 participants were randomized (lisdexamfetamine dimesylate n = 56; placebo n = 60). At the randomized withdrawal phase baseline, mean (SD) ADHD-RS-IV scores for lisdexamfetamine dimesylate and placebo were 10.6 (4.96) and 10.6 (4.82), respectively. At endpoint, 8.9% (5/56) of adults taking lisdexamfetamine dimesylate and 75.0% (45/60) taking placebo (P < .0001) showed symptom relapse; most showed relapse after 1 and 2 weeks of the randomized withdrawal phase (4 and 0 adults taking lisdexamfetamine dimesylate, 26 and 10 taking placebo, respectively). During the randomized withdrawal phase, treatment-emergent adverse events were reported in 48.2% and 30.0% of participants in the lisdexamfetamine dimesylate and placebo groups, respectively. Treatment-emergent adverse events with incidence ≥ 5% in the lisdexamfetamine dimesylate and placebo groups were headache (14.3% and 5.0%), insomnia (5.4% and 5.0%), and upper respiratory tract infection (8.9% and 0%). CONCLUSIONS: In adults with ADHD on medium- to long-term treatment, lisdexamfetamine dimesylate demonstrated maintenance of efficacy vs placebo upon randomized withdrawal. A majority of patients given placebo showed symptom relapse by 2 weeks. The safety profile of lisdexamfetamine dimesylate was generally consistent with previous lisdexamfetamine dimesylate studies. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00877487.

Clinical utility of ADHD symptom thresholds to assess normalization of executive function with lisdexamfetamine dimesylate treatment in adults.

OBJECTIVES: This analysis assessed the relationship of various cutoff scores of the ADHD Rating Scale IV (ADHD-RS-IV) to levels of improvement in ADHD-related executive function (EF), measured by the Brown ADD Scale for Adults (BADDS), which may provide a measure of clinically meaningful EF improvement after ADHD treatment. METHODS: Post hoc analysis of a 4-week, open-label, dose-optimization phase in a double-blind, placebo-controlled study of lisdexamfetamine dimesylate (LDX) in adults with ADHD. The BADDS for Adults, a validated, normed, self-report measure of EF in ADHD, provides a qualitative measure to rate treatment progress. The ADHD-RS-IV assesses current symptom status based on DSM-IV criteria. Postbaseline ADHD-RS-IV scores were categorized according to four cutoff criteria of symptom remission: (1) ADHD-RS-IV total score ≤ 18; (2) ADHD-RS-IV total score ≤ 10; (3) no ADHD-RS-IV item scored >1; and (4) ADHD-RS-IV total score ≤ 18 and ≤ 2 items per subscale with a score of 2. Sensitivity and specificity of criteria for identifying participants with optimal BADDS scores were assessed using receiver operating characteristics (ROC). Safety evaluation included treatment-emergent adverse events (TEAEs). RESULTS: At endpoint, 85/127 participants had optimal BADDS scores. Linear ANOVA indicated limited overlap between BADDS and ADHD-RS-IV scores (r (2) = 0.20; P < 0.0001). Specificity was similar for criteria 1-4 (0.46, 0.39, 0.39, and 0.42), as were ROC (0.699, 0.776, 0.732, and 0.668). Sensitivity was high for criteria 2 and 3 (0.96, 0.92), lower for criteria 1 and 4 (0.72, 0.75). TEAEs were consistent with those of stimulants. CONCLUSION: Criteria 2 and 3 had satisfactorily high sensitivity, but no criteria had adequate specificity. AUC comparison indicated that criteria 2 and 3 ADHD-RS-IV thresholds may be more accurate assessments of EF normalization as measured by the BADDS. The open-label design, small sample size, and selection criteria limit the applicability of these results to a larger treatment population.

Effects of open-label lisdexamfetamine dimesylate on self-reported quality of life in adults with ADHD.

OBJECTIVE: To assess improvements in quality of life measurements during the open-label portion of a trial examining duration of efficacy of lisdexamfetamine dimesylate in a simulated adult workplace environment. METHODS: A 4-week, open-label, dose-optimization phase followed by a randomized, double-blind, multicenter, placebo-controlled, 2-way crossover phase to evaluate safety and efficacy of lisdexamfetamine dimesylate in the adult workplace environment was conducted. Clinical assessments included the ADHD Impact Module for Adults (AIM-A) to assess the effect of lisdexamfetamine dimesylate on perception of quality of life and the Clinical Global Impressions-Severity/Improvement to assess symptom severity at baseline and improvement over time. Safety assessments included physical examination, treatment-emergent adverse events, vital signs, and electrocardiogram measurements. RESULTS: Questions 1 and 4 of the AIM-A suggest improvement from baseline in overall quality of life at week 4 with lisdexamfetamine dimesylate treatment. Post-hoc analysis revealed no significant differences attributable to either age or sex. Overall responses to questions 2 and 3, which related to overall life goals, did not change in a majority of participants during the 4-week open-label phase of this study. For all lisdexamfetamine dimesylate doses combined, treatment-emergent adverse events occurring in ≥ 5% of participants during the dose-optimization phase were decreased appetite (36.6%), dry mouth (30.3%), headache (19.7%), insomnia (18.3%), upper respiratory tract infection (9.9%), irritability (8.5%), nausea (7.7%), anxiety (5.6%), and feeling jittery (5.6%). CONCLUSIONS: At the end of the dose-optimization phase, lisdexamfetamine dimesylate treatment suggested quality of life improvements in adults with ADHD, with a safety profile consistent with long-acting stimulant use.

Effect size of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder.

OBJECTIVE: To examine duration of efficacy of lisdexamfetamine dimesylate (LDX) in adults with attention-deficit/hyperactivity disorder (ADHD) by effect size in performance and symptom improvement in a simulated adult workplace environment (AWE). METHODS: Adults (aged 18-55 years) with ADHD enrolled in the AWE study of LDX with open-label dose-optimization and randomized, placebo-controlled, double-blind, 2-way crossover phases. Efficacy measures included the Permanent Product Measure of Performance (PERMP)-Attempted (-A) and PERMP-Correct (-C) scores assessed throughout the day and the ADHD Rating Scale IV (ADHD-RS-IV) with adult prompts. Model-based least-squares (LS) mean effect size was assessed for PERMP and post-hoc ADHD-RS-IV with adult prompts. Remission was defined as an ADHD-RS-IV total scores ≤ 18. Safety assessments included treatment-emergent adverse events (TEAEs) and vital signs. RESULTS: Least-squares mean (standard error [SE]) effect sizes were 0.9 (0.17) for PERMP-A and 0.8 (0.16) for PERMP-C for all postdose sessions. For PERMP-A, postdose LS mean (SE) effect sizes were 0.5 (0.15), 0.8 (0.16), 0.7 (0.16), 0.7 (0.16), 0.7 (0.16), and 0.6 (0.16) at 2, 4, 8, 10, 12, and 14 hours, respectively. Medium-to-large effect sizes (0.5-0.8) were generally maintained from 2 to 14 hours for all PERMP assessments. Overall LS mean (SE) ADHD-RS-IV total and subscale effect sizes were -1.2 (0.19), -1.2 (0.19), and -1.0 (0.17), respectively. Remission was achieved in 67.6% of participants receiving LDX. Treatment-emergent adverse events (≥ 5% with LDX) during the 4-week dose-optimization phase were decreased appetite, dry mouth, headache, insomnia, upper respiratory tract infection, irritability, nausea, anxiety, and feeling jittery. During the crossover week on LDX, there were no TEAEs ≥ 5%. CONCLUSIONS: In adults studied in the AWE, medium-to-large model-based effect sizes were maintained from 2 to 14 hours postdose, on a performance-based measure of productivity, suggesting participants experienced improvement in sustained attention throughout the day and into the evening hours. Lisdexamfetamine dimesylate demonstrated a safety profile consistent with long-acting stimulants.

Efficacy and safety of lisdexamfetamine dimesylate in adolescents with attention-deficit/hyperactivity disorder.

OBJECTIVE: To examine lisdexamfetamine dimesylate (LDX) efficacy and safety versus placebo in adolescents with attention-deficit/hyperactivity disorder (ADHD). METHOD: Adolescents (13 through 17) with at least moderately symptomatic ADHD (ADHD Rating Scale IV: Clinician Version [ADHD-RS-IV] score ≥28) were randomized to placebo or LDX (30, 50, or 70 mg/d) in a 4-week, forced-dose titration, double-blind study. Primary and secondary efficacy measures were the ADHD-RS-IV, Clinical Global Impressions-Improvement (CGI-I), and Youth QOL-Research Version (YQOL-R). Safety assessments included treatment-emergent adverse events (TEAEs), vital signs, laboratory findings, physical examinations, and ECG. RESULTS: Overall, 314 participants were randomized; 309 were in efficacy analyses and 49 withdrew (11 due to TEAEs). Least squares mean (SE) change from baseline at endpoint in ADHD-RS-IV total scores were -18.3 (1.25), -21.1 (1.28), -20.7 (1.25) for 30, 50, and 70 mg/d LDX, respectively; -12.8 (1.25) for placebo (p ≤ .0056 versus placebo for each). Differences in ADHD-RS-IV total scores favored all LDX doses versus placebo at all weeks (p ≤ .0076). On the CGI-I, 69.1% of participants were rated very much/much improved at endpoint with LDX all doses versus placebo (39.5%) (p < .0001). YQOL-R changes at endpoint scores for LDX groups versus placebo were not significant. Commonly reported LDX (all doses combined) TEAEs (≥5%) were decreased appetite, headache, insomnia, decreased weight, and irritability. Small mean increases in pulse and blood pressure and no clinically meaningful trends in ECG changes were noted with LDX. CONCLUSIONS: LDX at all doses was effective versus placebo in treating adolescent ADHD and demonstrated a safety profile consistent with previous LDX studies. CLINICAL TRIALS REGISTRY INFORMATION: Efficacy and Safety of Lisdexamfetamine Dimesylate (LDX) in Adolescents With Attention-Deficit/Hyperactivity Disorder (ADHD); http://www.clinicaltrials.gov; NCT00735371.

Open-label administration of lisdexamfetamine dimesylate improves executive function impairments and symptoms of attention-deficit/hyperactivity disorder in adults.

INTRODUCTION/OBJECTIVE: Executive function (EF) impairment in attention-deficit/hyperactivity disorder (ADHD) may account for behavioral symptoms such as poor concentration, impaired working memory, problems in shifting among tasks, and prioritizing and planning complex sets of tasks or completing long-term projects at work or school. Poor self-regulation and control of emotional behaviors frequently are seen in patients with ADHD. This study assessed EF behaviors in adults with ADHD at baseline and after 4 weeks of treatment with lisdexamfetamine dimesylate (LDX). METHODS: Executive function behavior was assessed using the Brown Attention-Deficit Disorder Scale (BADDS) during the 4-week open-label dose-optimization phase prior to a 2-period, randomized, double-blind, placebo-controlled crossover study of LDX (30-70 mg/day). The ADHD Rating Scale IV (ADHD-RS-IV) with adult prompts assessed ADHD symptoms. Change in EF behavioral symptoms was evaluated based on week 4 BADDS total and cluster scores; analyses of shifts from baseline among subjects with BADDS scores < 50, 50 to 59, 60 to 69, and ≥ 70; and scores less than or greater than baseline 90% confidence range (eg, reliably improved or worsened, respectively). Treatment-emergent adverse events (TEAEs) were described. RESULTS: At week 4, BADDS total and cluster scores were reduced (ie, improved; all P < 0.0001 vs baseline [n = 127]). The ADHD-RS-IV with adult prompts scores also improved (all P < 0.0001 vs baseline). At week 4, 62.7% of subjects had a BADDS total score of < 50, and 78.9% were reliably improved; 1.4% were reliably worsened. Common TEAEs (≥ 5%) during the dose-optimization phase were decreased appetite (36.6%), dry mouth (30.3%), headache (19.7%), insomnia (18.3%), upper respiratory tract infection (9.9%), irritability (8.5%), nausea (7.7%), anxiety (5.6%), and feeling jittery (5.6%). CONCLUSION: Clinically optimized doses of LDX (30-70 mg/day) significantly improved EF behaviors in adults with ADHD. Treatment-emergent adverse events with LDX were consistent with those observed with long-term stimulant use.