Improved Executive Function in Adults Diagnosed With Attention-Deficit/ Hyperactivity Disorder as Measured by the Brown Attention-Deficit Disorder Scale Following Treatment With SHP465 Mixed Amphetamine Salts Extended-Release: Post Hoc Analyses From 2 Randomized, Placebo-Controlled Studies.

OBJECTIVE: Assess executive function (EF) improvement with SHP465 mixed amphetamine salts (MAS) extended-release in adults with attention-deficit/hyperactivity disorder (ADHD) using responder analyses of the Brown Attention-Deficit Disorder Scale (BADDS). METHODS: Post hoc analyses examined data from placebo-controlled SHP465 MAS dose-optimization (12.5-75 mg) and fixed-dose (25-75 mg) studies. Treatment response was assessed using two definitions (BADDS total score at endpoint <50 [no EF impairment] vs. ≥50 [impaired]; BADDS total score at endpoint relative to the in-treatment 90% CI range for baseline total score [below the range = improved]). RESULTS: Response rates (SHP465 MAS vs. placebo) favored SHP465 MAS (all nominal p < .0001) in the dose-optimization (BADDS <50: 41.9% vs. 19.2%; below 90% CI range: 57.4% vs. 29.6%) and fixed-dose (BADDS <50: 51.9% vs. 16.7%; below 90% CI range: 70.6% vs. 32.3%) studies. CONCLUSION: Improvement in EF measured by BADDS response rates was approximately 2-fold greater with SHP465 MAS than placebo.

Functional impairment outcomes in clinical trials of different ADHD medications: post hoc responder analyses and baseline subgroup analyses.

Several recent phase 3 clinical trials of attention-deficit/hyperactivity disorder (ADHD) medications have used the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P). Here, we assess WFIRS-P response in individual patients in two pivotal trials of lisdexamfetamine dimesylate (LDX) and guanfacine extended release (GXR). We also analysed pooled WFIRS-P data from seven phase 3 studies of ADHD medications to shed light on factors associated with baseline functional impairment. The proportion of patients with a change in WFIRS-P score that exceeded the minimal important difference (MID) criteria for response was greater for LDX than placebo in the Family, Learning and School, and Risky Activities domains, and was greater for GXR than placebo in the Social Activities, Learning and School, and Family domains. Responders had significantly worse baseline scores in all WFIRS-P domains (all p < 0.001) than non-responders. In the pooled analyses, baseline WFIRS-P scores in all domains were significantly worse in participants with oppositional defiant disorder (ODD) than in those without ODD. Having combined type or hyperactive-impulsive type ADHD, being enrolled into a study in Europe, being male and being younger also had modest negative effects on baseline WFIRS-P scores. The present analysis of WFIRS-P response shows that previously reported group-level improvements in WFIRS-P functional impairment score translated into clinically relevant improvements in many individual participants. Functional impairment is a diverse and subjective construct that is influenced by multiple factors. Optimal management of individuals with ADHD should involve monitoring improvements in functioning and quality of life, as well as symptomatic improvement.

A Phase 3, Randomized Double-Blind Study of the Efficacy and Safety of Low-Dose SHP465 Mixed Amphetamine Salts Extended-Release in Children with Attention-Deficit/Hyperactivity Disorder.

Objectives: In a previous pivotal study of children and adolescents (aged 6-17 years) with attention-deficit/hyperactivity disorder (ADHD), dose-optimized SHP465 mixed amphetamine salts (MAS) extended-release (12.5-25 mg once daily) was superior to placebo in reducing ADHD symptoms. This study evaluated the efficacy, tolerability, and safety of 6.25 mg SHP465 MAS once daily (one-half the lowest approved dose for adolescents and adults) versus placebo in children aged 6-12 years with ADHD. Methods: Children (aged 6-12 years) with Diagnostic and Statistical Manual of Mental Disorders, Fifth edition-defined ADHD; baseline ADHD-Rating Scale, Fifth Edition, Child, Home Version total scores (ADHD-RS-5-HV-TS) ≥28; and baseline Clinical Global Impressions-Severity scores ≥4 were eligible. Participants received 6.25 mg SHP465 MAS once daily or placebo for 4 weeks. The primary (ADHD-RS-5-HV-TS change from baseline at week 4) and key secondary (Clinical Global Impressions-Improvement [CGI-I] score at week 4) efficacy end points were assessed using linear mixed-effects models for repeated measures. Safety and tolerability assessments included treatment-emergent adverse events (TEAEs) and vital sign changes. Results: Of 89 randomized participants, 83 completed the study (placebo, n = 41; SHP465 MAS, n = 42). At week 4, the least squares mean (95% confidence interval) treatment differences (SHP465 MAS-placebo) were not statistically significant for ADHD-RS-5-HV-TS change (-1.9 [-6.8 to 3.1], p = 0.451; effect size [ES] = 0.17) or CGI-I score (-0.1 [-0.5 to 0.3], nominal p = 0.597; ES = 0.12). The percentage of participants reporting TEAEs was 16.3% with placebo and 24.4% with SHP465 MAS. The most frequently reported TEAEs (placebo; SHP465 MAS) were headache (7.0%; 4.4%) and decreased appetite (4.7%; 2.2%). Minimal increases in blood pressure were observed with SHP465 MAS at the final on-treatment assessment. Conclusions: SHP465 MAS 6.25 mg once daily (one-half the lowest dose approved for adolescents and adults) was well tolerated in children aged 6-12 years but was not superior to placebo in reducing ADHD symptoms, suggesting that this dose of SHP465 MAS was subtherapeutic in this age group. The Clinical Trial Registration number: NCT03325881.

Efficacy of Guanfacine Extended Release in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder and Comorbid Oppositional Defiant Disorder.

OBJECTIVE: To assess the efficacy of the non-stimulant guanfacine extended release (GXR) on attention-deficit/hyperactivity disorder (ADHD) symptoms in children and adolescents, with and without comorbid oppositional defiant disorder (ODD). METHODS: Data were derived from 4 phase 3, randomized, placebo-controlled trials of dose-optimized GXR monotherapy, in which at least 10% of participants had a diagnosis of comorbid ODD. SPD503-312 and SPD503-316 were 10- to 13-week studies of GXR (1-7 mg/d). SPD503-314 and SPD503-307 were 8-week studies of GXR (1-4 mg/d). Efficacy was assessed using the ADHD Rating Scale IV (ADHD-RS-IV) total scores. RESULTS: In total, 1,084 participants were included (SPD503-312 and SPD503-316, n = 537; SPD503-314, n = 333; and SPD503-307, n = 214). GXR was associated with significant improvements in ADHD core symptoms at endpoint in participants with and without ODD (p < 0.01 in all studies). Placebo-adjusted least-squares mean (95% confidence interval) changes from baseline to endpoint in the ADHD-RS-IV total scores in participants with and without ODD were -8.6 (-14.4, -2.8) and -7.3 (-9.5, -5.0) in the pooled data from SPD503-312 and SPD503-316, -12.6 (-19.6, -5.7) and -8.7 (-11.8, -5.5) in SPD503-314, and -12.7 (-17.3, -8.1) and -11.8 (-19.3, -4.4) in SPD503-307, respectively. The corresponding effect sizes were 0.688 and 0.598 in SPD503-312 and SPD503-316, 0.876 and 0.729 in SPD503-314, and 0.962 and 0.842 in SPD503-307. CONCLUSION: The findings demonstrate the efficacy of GXR for treating ADHD in children and adolescents with comorbid ODD.

Post hoc Responder and Remission Analyses from Two Studies of SHP465 Mixed Amphetamine Salts Extended-Release Among Adults with Attention-Deficit/Hyperactivity Disorder.

Objectives: In two studies of adult attention-deficit/hyperactivity disorder (ADHD), SHP465 mixed amphetamine salts (MAS) extended-release significantly reduced ADHD-Rating Scale, 4th Edition total score (ADHD-RS-IV-TS) versus placebo (PBO). This report describes post hoc analyses of SHP465 MAS treatment response and remission rates from those studies. Methods: Adults with Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision-defined ADHD were randomized to SHP465 MAS (12.5-75 mg) or PBO in a 7-week dose-optimization study and to SHP465 MAS (25, 50, or 75 mg) or PBO in a 6-week fixed-dose study. Response was examined using three definitions (definition 1: ≥30% ADHD-RS-IV-TS reduction + Clinical Global Impressions-Improvement [CGI-I] rating of 1 or 2; definition 2: ≥50% ADHD-RS-IV-TS reduction + CGI-I rating of 1 or 2; definition 3: ADHD-RS-IV-TS ≤18). Remission was defined as ADHD-RS-IV-TS ≤12. The Kaplan-Meier analyses assessed time to response or remission. Results: The intent-to-treat populations included 136 SHP465 MAS and 132 PBO participants in the dose-optimization study and 302 SHP465 MAS and 103 PBO participants in the fixed-dose study. Percentages of participants meeting response criteria (SHP465 MAS vs. PBO) at the final treatment week in the dose-optimization and fixed-dose studies, respectively, were 66.0% versus 31.6% and 72.7% versus 28.3% (definition 1); 47.9% versus 27.6% and 60.6% versus 16.7% (definition 2); and 54.3% versus 30.3% and 52.6% versus 18.3% (definition 3). The remission criterion (SHP465 MAS vs. PBO) at the final treatment week was met by 37.2% versus 19.7% of participants in the dose-optimization study and 39.7% versus 10.0% of participants in the fixed-dose study. Times to response and remission favored SHP465 MAS over PBO in both studies (all nominal log-rank p < 0.0001). Conclusion: These post hoc analyses indicate that SHP465 MAS was associated with greater response and remission rates than PBO in adults with ADHD, with times to response and remission also nominally favoring SHP465 MAS.

Relationships Between Executive Function Improvement and ADHD Symptom Improvement With Lisdexamfetamine Dimesylate in Adults With ADHD and Executive Function Deficits: A Post Hoc Analysis.

OBJECTIVE: Executive function (EF) deficits are not generally considered synonymous with attention-deficit/hyperactivity disorder (ADHD). Evidence suggests stimulants improve ADHD symptoms and EF deficits in adults with ADHD, but the relationships between improvements in these domains have not been studied. METHODS: These post hoc analyses used data from a 10-week double-blind, placebo-controlled study of adults with ADHD and EF deficits treated with lisdexamfetamine dimesylate (30-70 mg) or placebo conducted from May 2010 to November 2010. Efficacy endpoints included change from baseline at week 10/early termination (ET) in self-report Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) Global Executive Composite (GEC) T-score and ADHD-Rating Scale with Adult Prompts total score (ADHD-RS-AP-TS). Relationships between ADHD symptom and EF changes were examined using recursive path analyses. RESULTS: Mediation proportions were 0.62 (indirect and total treatment effect coefficients [95% CI]: -6.85 [-9.83 to -3.86] and -11.12 [-14.88 to -7.37]) for self-report BRIEF-A GEC T-score change from baseline at week 10/ET on ADHD-RS-AP-TS change from baseline at week 10/ET and 0.93 (indirect and total treatment effect coefficients [95% CI]: -10.34 [-14.11 to -6.57] and -11.18 [-15.80 to -6.55]) for ADHD-RS-AP-TS change from baseline at week 10/ET on self-report BRIEF-A GEC T-score change from baseline at week 10/ET. CONCLUSIONS: Although these data suggest ADHD symptom and EF deficit improvement following lisdexamfetamine are interdependent, it is advantageous to use measures like the BRIEF-A to assess stimulant effects on the wide range of EF deficits associated with ADHD that are not captured by the ADHD-RS-AP alone. TRIAL REGISTRATION: Data used in this secondary analysis came from ClinicalTrials.gov identifier: NCT01101022.

Lisdexamfetamine Dimesylate for Preschool Children with Attention-Deficit/Hyperactivity Disorder.

Objectives: Describe the safety and tolerability of lisdexamfetamine dimesylate (LDX) and provide data on clinical effects for efficacy-related endpoints and pharmacokinetics in preschool-aged children with attention-deficit/hyperactivity disorder (ADHD). Methods: This phase 2, multicenter, open-label, dose-optimization study (ClinicalTrials.gov registry: NCT02402166) was conducted at seven U.S. sites between April 15, 2015, and June 30, 2016. Children (4-5 years of age) meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for ADHD and having ADHD Rating Scale-IV Preschool version (ADHD-RS-IV-PS) total scores ≥28 (boys) or ≥24 (girls) were eligible. Open-label LDX (8-week duration) was initiated at 5 mg and titrated to 30 mg until achieving an optimal dose. Assessments included treatment-emergent adverse events (TEAEs), vital sign changes, ADHD-RS-IV-PS total score changes, and pharmacokinetic evaluations. Results: Among 24 participants, the most frequently reported TEAE was decreased appetite (8/24; 33%). At week 8/early termination, mean (standard deviation) systolic and diastolic blood pressure and pulse changes from baseline were -1.1 (7.31) and 1.5 (6.93) mmHg and -0.8 (12.75) bpm, respectively. The mean (95% confidence interval) change from baseline ADHD-RS-IV-PS total score at the final on-treatment assessment was -26.1 (-32.2 to -20.0). Pharmacokinetic parameters of d-amphetamine, a major active metabolite of LDX, were characterized: d-amphetamine exposure increased with LDX dose; mean tmax and t1/2, respectively, ranged from 4.00 to 4.23 hours and 7.18 to 8.46 hours. Conclusions: In preschool-aged children with ADHD, LDX was generally well tolerated and reduced ADHD symptoms, consistent with observations in children 6-17 years of age. Based on these findings, a starting LDX dose as low as 5 mg in phase 3 studies in preschool-aged children is supported.

Assessment of Amphetamine Withdrawal Symptoms of Lisdexamfetamine Dimesylate Treatment for Adults With Binge-Eating Disorder.

OBJECTIVE: To determine whether physical dependence developed during lisdexamfetamine dimesylate treatment, as evidenced by presence of withdrawal symptoms after treatment cessation in adults with binge-eating disorder (BED) treated for up to 38 weeks. METHODS: Three studies enrolled adults with DSM-IV-TR-defined BED. In two 12-week, randomized, double-blind, placebo-controlled studies conducted from November 2012 to September 2013, participants were treated with placebo or dose-optimized lisdexamfetamine (50 or 70 mg). In a double-blind, placebo-controlled, randomized-withdrawal maintenance-of-efficacy study conducted from January 2014 to April 2015, participants categorized as responders after 12 weeks of open-label lisdexamfetamine (50 or 70 mg) were randomized to continued lisdexamfetamine or placebo for 26 weeks. The Amphetamine Cessation Symptom Assessment (ACSA), a 16-item self-report instrument (total score: 0-64), assessed withdrawal experiences. Mean ± SD ACSA scores and medians are presented for study completers. RESULTS: In the short-term efficacy studies, mean ± SD ACSA aggregate scores for placebo and lisdexamfetamine (pooled data) were 7.0 ± 7.60 (n = 275) and 4.9 ± 6.41 (n = 271), respectively, on the day of the last dose at week 12/early termination (ET) and 4.8 ± 6.82 (n = 234) and 5.5 ± 7.50 (n = 221) on day 7 after the last dose. In the maintenance-of-efficacy study, mean ± SD ACSA aggregate scores for placebo and lisdexamfetamine were 4.8 ± 6.67 (n = 44) and 4.7 ± 7.78 (n = 85) on the day of the last dose at week 38/ET and 3.9 ± 5.75 (n = 37) and 5.2 ± 7.93 (n = 71) on day 7 after the last dose. CONCLUSIONS: Study results suggest that abrupt lisdexamfetamine termination was not associated with amphetamine withdrawal symptoms at the exposure durations and therapeutic doses analyzed. TRIAL REGISTRATION: Clinicaltrials.gov identifiers: NCT01718483, NCT01718509, and NCT02009163.

Post-Hoc Analyses of the Effects of Baseline Sleep Quality on SHP465 Mixed Amphetamine Salts Extended-Release Treatment Response in Adults with Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: Sleep problems are common in adults with attention-deficit/hyperactivity disorder (ADHD). The presence of sleep problems at the time of presentation for ADHD treatment could impact the level of improvement in ADHD symptoms or executive function occurring with ADHD pharmacotherapy. Therefore, we examined the influence of baseline sleep quality on the effects of SHP465 mixed amphetamine salts (MAS) extended-release. METHODS: Adults (18-55 years) with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision-defined ADHD and baseline ADHD Rating Scale IV (ADHD-RS-IV) total scores ≥ 24 were randomized to once-daily SHP465 MAS (12.5-75 mg) or placebo in a 7-week, double-blind, dose-optimization study. Post-hoc analyses evaluated SHP465 MAS treatment effects on ADHD symptoms, using the ADHD-RS-IV, and executive function, using the Brown Attention-Deficit Disorder Scale (BADDS), based on baseline sleep quality as defined by Pittsburgh Sleep Quality Index (PSQI) scores [sleep quality impaired (PSQI total score > 5; PSQI component scores 2 or 3) versus not impaired (PSQI total score ≤ 5; PSQI component scores 0 or 1)]. Analyses were conducted in the intent-to-treat population. RESULTS: Of 280 enrolled participants, 272 were randomized (placebo, n = 135; SHP465 MAS, n = 137). The intent-to-treat population consisted of 268 participants (placebo, n = 132; SHP465 MAS, n = 136), and 170 participants (placebo, n = 76; SHP465 MAS, n = 94) completed the study. Treatment differences nominally favored SHP465 MAS over placebo in both sleep impairment groups regarding ADHD-RS-IV total score changes (all nominal p < 0.05), except for those with impairment defined by sleep efficiency (p = 0.2696), and regarding BADDS total score changes (all nominal p < 0.05), except for those with impairment defined by sleep duration (p = 0.1332) and sleep efficiency (p = 0.8226). There were no statistically significant differences in SHP465 MAS treatment effects between sleep impairment groups. CONCLUSIONS: Improvements in ADHD symptoms and executive function occurred with dose-optimized SHP465 MAS, regardless of baseline impairment in some aspects of sleep in adults with ADHD, with no significant differences observed as a function of sleep impairment. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier-NCT00150579.

Effects of Food on the Bioavailability of Amphetamine in Healthy Adults After Administration of SHP465 Mixed Amphetamine Salts Extended-Release Capsules.

BACKGROUND AND OBJECTIVE: SHP465 mixed amphetamine salts extended release is a once-daily, single-entity, mixed amphetamine salts capsule product for attention-deficit/hyperactivity disorder. The objective of this study was to evaluate amphetamine pharmacokinetics following SHP465 mixed amphetamine salts under three administration conditions. METHODS: Healthy adults (n = 16) enrolled in an open-label, randomized, three-period crossover study with three single-dose 50-mg SHP465 mixed amphetamine salts treatments (fasting ≥ 10 h before administration [reference]; high-fat meal consumption 30 min before administration; sprinkling capsule contents on applesauce) separated by ≥ 7-day washouts. Blood samples for evaluating d- and l-amphetamine pharmacokinetics were collected pre-dose and up to 60 h post-dose. Assessments included maximum plasma concentration, time to maximum plasma concentration, and area under the plasma concentration-time curve from 0 to infinity. Exponentiated least-squares mean ratios with 90% confidence intervals for test treatments relative to the reference treatment were calculated, with the absence of an effect indicated by the 90% confidence intervals falling within the 80-125% range. RESULTS: Least-squares mean (90% confidence interval) ratios for maximum plasma concentration and area under the plasma concentration-time curve from 0 to infinity indicated neither consuming a high-fat meal (d-amphetamine: 85.33 [80.44, 90.50] and 91.11 [86.69, 95.75], respectively; l-amphetamine: 85.22 [80.18, 90.59] and 88.74 [83.89, 93.87]) nor sprinkling the capsule contents on applesauce (d-amphetamine: 95.76 [90.28, 101.57] and 95.77 [91.13, 100.65]; l-amphetamine: 96.90 [91.16, 103.00] and 94.78 [89.60, 100.26]) altered amphetamine exposure. Consuming a high-fat meal prolonged median time to maximum plasma concentration for d- and l-amphetamine by 5.0 and 4.5 h, respectively, relative to reference treatment. CONCLUSIONS: These findings demonstrate SHP465 mixed amphetamine salts capsules can be swallowed whole with or without food or the capsule contents can be sprinkled on applesauce.

A randomized, double-blind, 3-way crossover, analog classroom study of SHP465 mixed amphetamine salts extended-release in adolescents with ADHD.

OBJECTIVES: To evaluate the duration of efficacy, safety, and tolerability of SHP465 mixed amphetamine salts (MAS) extended-release versus placebo and immediate-release MAS (MAS IR) in adolescents with attention-deficit/hyperactivity disorder (ADHD). METHODS: This phase 2, randomized, 3-period, 3-treatment crossover study compared SHP465 MAS (25/50 mg) with placebo and MAS IR (12.5 mg) in 13-17-year-old adolescents with ADHD having ADHD Rating Scale, Version IV (ADHD-RS-IV) total scores ≥24. A laboratory classroom served as a controlled environment during 16-hour observations, with efficacy assessed on the last day of each 7-day treatment period. The primary efficacy analysis compared SHP465 MAS with placebo on Permanent Product Measure of Performance (PERMP) total score averaged over the 16-hour postdose period using a mixed linear model. Comparisons were also conducted between MAS IR and placebo (for assay sensitivity) and between SHP465 MAS and MAS IR. PERMP problems attempted and answered correctly and ADHD symptoms based on ADHD-RS-IV; participant self-report; Swanson, Kotkin, Agler, M-Flynn, and Pelham Scale; and Revised Conner's Parent Rating Scale scores were also evaluated. Safety and tolerability assessments included treatment-emergent adverse events and vital signs. RESULTS: The intent-to-treat population included 84 participants. Least squares mean (95% CI) PERMP total score treatment differences significantly favored SHP465 MAS (combined 25/50 mg) over placebo for the average of all postdose assessment time points (41.26 [32.24, 50.29]; P < 0.0001) and each postdose assessment time point (all P < 0.0001). Similar results were observed for MAS IR versus placebo (all postdose assessment time points averaged: nominal P < 0.0001; each postdose assessment time point: all nominal P < 0.004). The safety and tolerability of SHP465 MAS were consistent with previous reports. CONCLUSIONS: SHP465 MAS significantly improved PERMP total scores versus placebo from 2 to 16 hours postdose in adolescents with ADHD. The safety and tolerability profile of SHP465 MAS was consistent with previous reports of SHP465 MAS in individuals with ADHD.

Long-term safety and efficacy of guanfacine extended release in children and adolescents with ADHD.

Data are reported from SPD503-318, a phase 3, open-label, safety study of guanfacine extended release (GXR) in European children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Participants received dose-optimized GXR (1-7 mg/day) for up to 2 years. Of 215 enrolled participants, 214 were included in the safety population and 133 completed the study. Participants' mean age was 11.7 years and 73.8% were male. Overall, 177 participants (82.7%) experienced a treatment-emergent adverse event (TEAE). TEAEs reported in at least 10% of participants were somnolence (36.0%), headache (28.5%), fatigue (20.1%), and nasopharyngitis (11.7%). Serious TEAEs were reported in 4.7% of participants and TEAEs leading to discontinuation were reported in 3.3% of participants. There were no deaths. Mean z-scores for BMI were stable throughout the study. The incidence of sedative TEAEs (somnolence, sedation, and hypersomnia) peaked during week 3 and decreased thereafter. Small changes from baseline to the final assessment in mean supine pulse [- 5.5 bpm (standard deviation, 12.98)] and blood pressure [systolic, 0.6 mmHg (9.32); diastolic, 0.2 mmHg (9.17)] were reported. ADHD symptoms initially decreased and remained significantly lower than baseline at study endpoint. At the final assessment, the mean change in ADHD-RS-IV total score from baseline was - 19.8 (standard error of mean, 0.84; nominal p < 0.0001). In conclusion, GXR was well tolerated and more than 60% of participants completed the 2-year study.

Cognitive Function of Children and Adolescents with Attention-Deficit/Hyperactivity Disorder in a 2-Year Open-Label Study of Lisdexamfetamine Dimesylate.

BACKGROUND: SPD489-404 was the first 2-year safety study of lisdexamfetamine dimesylate in the treatment of attention-deficit/hyperactivity disorder in children and adolescents. In accordance with advice from the European Medicines Agency, assessment of cognitive function was a predefined safety outcome in SPD489-404. OBJECTIVE: The objective of this study was to assess cognitive function over 2 years in study SPD489-404, using the Cambridge Neuropsychological Test Automated Battery (CANTAB). METHODS: Participants aged 6-17 years received dose-optimised open-label lisdexamfetamine dimesylate (30, 50 or 70 mg/day) for 104 weeks. Cognition was assessed using four CANTAB tasks; Delayed Matching to Sample (DMS), Spatial Working Memory (SWM), Stop Signal Task (SST) and Reaction Time (RTI). Key and additional variables were pre-specified for each CANTAB task; groupwise mean percentage changes in key variables from baseline of > 5% were considered potentially clinically significant. RESULTS: All 314 enrolled participants received lisdexamfetamine dimesylate and were included in the safety population, and 191 (60.8%) completed the study. No potentially clinically significant deteriorations from baseline were observed in any key CANTAB variable over the 2 years of the study. Based on predefined thresholds, potentially clinically significant improvements from baseline were observed at 6 months (DMS median reaction time, mean per cent change, - 6.6%; SWM total between-search errors, - 22.8%; SST stop signal reaction time, -18.9%), and at the last on-treatment assessment (DMS median reaction time, - 6.5%; SWM total between-search errors, - 32.6%; SST stop signal reaction time, - 25.7%). CONCLUSIONS: Lisdexamfetamine dimesylate treatment for 2 years was not associated with deterioration of cognitive function in children and adolescents with attention-deficit/hyperactivity disorder. Although improvements in some cognitive measures were observed, lack of a control group makes interpretation of the findings difficult. Further studies of the impact of stimulants on cognition are required. CLINICALTRIALS. GOV IDENTIFIER: NCT01328756.

SHP465 Mixed Amphetamine Salts in the Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents: Results of a Randomized, Double-Blind Placebo-Controlled Study.

OBJECTIVE: The aim of this study was to evaluate the efficacy, safety, and tolerability of SHP465 mixed amphetamine salts (MAS) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). METHODS: This randomized, double-blind dose-optimization study enrolled children and adolescents (6-17 years) meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision ADHD criteria and having baseline ADHD Rating Scale IV (ADHD-RS-IV) total scores ≥28. Participants were randomized 1:1 to placebo or dose-optimized SHP465 MAS (12.5-25 mg) for 4 weeks. Total score change (baseline to week 4) on the ADHD-RS-IV (primary endpoint) and the Clinical Global Impressions-Improvement (CGI-I) scale score at week 4 (key secondary endpoint) were assessed using linear mixed-effects models for repeated measures. Safety and tolerability assessments (secondary endpoints) included treatment-emergent adverse events (TEAEs) and vital sign changes. RESULTS: Of 264 randomized participants (placebo, n = 132; SHP465 MAS, n = 132), 234 (placebo, n = 118; SHP465 MAS, n = 116) completed the study. The least squares mean (95% confidence interval) treatment difference significantly favored SHP465 MAS over placebo for ADHD-RS-IV total score change from baseline to week 4 (-9.9 [-13.0, -6.8]; p < 0.001; effect size = 0.80) and CGI-I score at week 4 (-0.8 [-1.1, -0.5]; p < 0.001; effect size = 0.65). TEAE frequency was 46.6% (61/131) with placebo and 67.4% (89/132) with SHP465 MAS; no serious TEAEs were reported. TEAEs reported at a frequency of ≥5% and ≥2 times the placebo rate were decreased appetite, insomnia, irritability, nausea, and decreased weight. Mean ± standard deviation increases (baseline to final on-treatment assessment) were higher with SHP465 MAS than placebo for pulse (5.7 ± 11.78 vs. 0.7 ± 10.79), systolic blood pressure (3.8 ± 9.15 vs. 2.1 ± 8.72), and diastolic blood pressure (4.0 ± 8.23 vs. 0.5 ± 7.45). CONCLUSIONS: SHP465 MAS demonstrated superiority over placebo in improving ADHD symptoms and global functioning in children and adolescents with ADHD. The safety and tolerability profile of SHP465 MAS was consistent with that of SHP465 MAS in adults and other long-acting psychostimulants in children and adolescents.

An open-label positron emission tomography study to evaluate serotonin transporter occupancy following escalating dosing regimens of (R)-(-)-O-desmethylvenlafaxine and racemic O-desmethylvenlafaxine.

SEP-227162 [R(-)-O-desmethylvenlafaxine] is an enantiomer of the venlafaxine metabolite O-desmethylvenlafaxine (ODV, Pristiq™, Wyeth). This study compared the serotonin transporter (SERT) occupancy achieved by SEP-227162 and ODV, at daily doses of 25, 50, 100, and 150 mg using [11 C]DASB positron emission tomography (PET). Sixteen healthy male subjects participated in one of four dose groups (N = 4 per group) during which they were administered two doses of the study drug (SEP-227162 or ODV). For each study drug, total daily doses of 25, 50, 100, and150 mg were studied. Subjects underwent three PET scans with [11 C]DASB. A baseline, off-medication, scan was performed prior to dosing and a [11 C]DASB PET scan was performed after 72 hr at each dose level. [11 C]DASB binding potential (BPND ) was calculated using the simplified reference tissue method. SERT occupancy was calculated as the change in BPND (ΔBPND ) from baseline scan to the on-medication scan relative to the baseline BPND value. SEP-227162 and ODV significantly reduced regional distribution volumes and region BPND values in a dose-dependent manner. Across all doses ODV produced significantly greater SERT occupancy than SEP-227162 (ANOVA F = 21.8, df = 1,23, p < .001). The total daily dose required to provide 50% SERT occupancy was 24.8 mg for SEP-227162 and 14.4 mg for ODV. In vitro data suggests a ratio of 3.3:1 for binding at human SERT for SEP-227162 relative to ODV. Our study suggests a ratio of 1.7:1, highlighting the value of in vivo imaging in the drug development process.

Efficacy and Safety of SHP465 Mixed Amphetamine Salts in the Treatment of Attention-Deficit/Hyperactivity Disorder in Adults: Results of a Randomized, Double-Blind, Placebo-Controlled, Forced-Dose Clinical Study.

OBJECTIVE: The objective of this randomized, double-blind, placebo-controlled study was to evaluate the efficacy and safety of SHP465 mixed amphetamine salts (MAS) in adults with attention-deficit/hyperactivity disorder (ADHD). METHODS: Eligible adults [aged 18-55 years; meeting the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ADHD criteria; baseline ADHD Rating Scale with Adult Prompts (ADHD-RS-AP) total scores ≥28] were randomized 1:1:1 to placebo or forced-dose SHP465 MAS (12.5 or 37.5 mg/day) for 4 weeks. The ADHD-RS-AP total score change from baseline to week 4 (primary endpoint) and Clinical Global Impressions-Improvement score at week 4 (key secondary endpoint) were assessed using linear mixed-effects models for repeated measures. Other efficacy endpoints were changes from baseline to week 4 on the ADHD-RS-AP hyperactivity/impulsivity and inattentiveness subscales and the percentage of participants categorized as improved on the dichotomized Clinical Global Impressions-Improvement. Safety and tolerability assessments were treatment-emergent adverse events, vital sign and weight changes, Columbia-Suicide Severity Rating Scale responses, and electrocardiogram results. RESULTS: Of 369 screened participants, 275 were randomized (placebo, n = 91; 12.5 mg/day of SHP465 MAS, n = 92; 37.5 mg/day of SHP465 MAS, n = 92) and 236 completed the study (placebo, n = 80; 12.5 mg/day of SHP465 MAS, n = 80; 37.5 mg/day of SHP465 MAS, n = 76). Least-squares mean (95% confidence interval) treatment differences at week 4 significantly favored SHP465 MAS over placebo for the ADHD-RS-AP total score change from baseline [12.5 mg/day: -8.1 (-11.7, -4.4), effect size = 0.67; 37.5 mg/day: -13.4 (-17.1, -9.7), effect size = 1.11; both p < 0.001] and Clinical Global Impressions-Improvement score [12.5 mg/day: -0.8 (-1.1, -0.4), effect size = 0.68; 37.5 mg/day: -1.2 (-1.6, -0.9), effect size = 1.11; both p < 0.001]. Treatment differences for the change from baseline at week 4 favored 12.5 and 37.5 mg/day of SHP465 MAS, respectively, over placebo on the ADHD-RS-AP hyperactivity/impulsivity (both nominal p < 0.001; effect size = 0.56 and 0.91) and inattentiveness (both nominal p < 0.001; effect size = 0.70 and 1.19) subscales. At the final on-treatment assessment, the percentage of participants categorized as improved on Clinical Global Impressions-Improvement was higher with both SHP465 MAS doses than with placebo (both nominal p < 0.001). Treatment-emergent adverse events reported (>5%) with SHP465 MAS were decreased appetite, dry mouth, insomnia, headache, anxiety, initial insomnia, irritability, and bruxism. Severe treatment-emergent adverse events and treatment-emergent adverse events leading to discontinuation, respectively, were reported by 8 and 12 participants (placebo, n = 2 and 0; 12.5 mg/day SHP465 MAS, n = 1 and 7; 37.5 mg/day SHP465 MAS, n = 5 and 5). At the final on-treatment assessment, mean ± standard deviation increases from baseline were observed with 12.5 and 37.5 mg/day of SHP465 MAS for pulse (3.3 ± 10.52 and 7.1 ± 11.48 bpm) and blood pressure (systolic 0.2 ± 7.24 and 1.7 ± 9.99 mmHg; diastolic 1.0 ± 7.46 and 2.8 ± 7.90 mmHg) and decreases were observed for weight (-0.97 ± 1.523 and -1.65 ± 2.333 kg), body mass index (-0.33 ± 0.519 and -0.56 ± 0.777 kg/m2), and Fridericia corrected QT interval (-3.0 ± 10.72 and -1.6 ± 13.70 ms). No participant in any treatment group had a positive response for on-study Columbia-Suicide Severity Rating Scale assessments. CONCLUSIONS: SHP465 MAS was superior to placebo in reducing ADHD symptoms, with a safety profile consistent with other long-acting stimulants. ClinicalTrials.gov Registry Number: NCT02604407.

Extended Release Guanfacine in Pediatric Anxiety Disorders: A Pilot, Randomized, Placebo-Controlled Trial.

OBJECTIVE: This is a feasibility study evaluating the safety, tolerability, and potential anxiolytic efficacy of the α2 agonist guanfacine extended-release (GXR) in children and adolescents with generalized anxiety disorder (GAD), separation anxiety disorder (SAD), or social phobia/social anxiety disorder. METHODS: Youth aged 6-17 years with a primary diagnosis of GAD, SAD, and/or social anxiety disorder were treated with flexibly dosed GXR (1-6 mg daily, n = 62) or placebo (n = 21) for 12 weeks. The primary aim of this study was to determine the safety and tolerability of GXR in youth with anxiety disorders, which involved the analysis of treatment-emergent adverse events (TEAEs), the emergence of suicidal ideation and behaviors, vital signs, and electrocardiographic/laboratory parameters. Exploratory efficacy measures included dimensional anxiety scales (Pediatric Anxiety Rating Scale [PARS] and Screen for Child Anxiety Related Emotional Disorders [SCARED]), as well as the Clinical Global Impression-Improvement (CGI-I) scale. As this was an exploratory study, no inferential statistical analyses were performed. RESULTS: GXR was safe and well tolerated. Treatment-related mean ± standard deviation changes in heart rate (GXR: 1.8 ± 12 beats per minute [bpm] decrease; placebo: 0.5 ± 11 bpm decrease), systolic blood pressure (GXR: 2.3 ± 11 mm Hg decrease; placebo: 1.7 ± 11 mm Hg decrease), or diastolic blood pressure (GXR: 1.3 ± 9 mm Hg decrease; placebo: 0.9 ± 7 mm Hg increase) were similar between treatment groups. TEAEs, including headache, somnolence/fatigue, abdominal pain, and dizziness, were consistent with the known safety profile of GXR. No differences were observed between treatment groups for PARS and SCARED scores, although at endpoint, a higher proportion of subjects receiving GXR versus placebo demonstrated CGI-I scores ≤2 (54.2% vs. 31.6%), as rated by the clinician investigator. CONCLUSIONS: GXR was well tolerated in pediatric subjects with GAD, SAD, and/or social anxiety disorder. ClinicalTrials.gov Identifier: NCT01470469.

Guanfacine extended release for children and adolescents with attention-deficit/hyperactivity disorder: efficacy following prior methylphenidate treatment.

Guanfacine extended release (GXR) and atomoxetine (ATX) are nonstimulant treatments for attention-deficit/hyperactivity disorder (ADHD). As nonstimulant treatments are often used after stimulants in ADHD, GXR was assessed relative to prior stimulant treatment in a randomized controlled trial (RCT), in which ATX was included as a reference arm, and in the open-label phase of a randomized-withdrawal study (RWS). Participants were 6-17 years old with ADHD Rating Scale version IV (ADHD-RS-IV) scores ≥32 and Clinical Global Impressions - Severity scores ≥4. RCT participants received dose-optimized GXR (1-7 mg/day), ATX (10-100 mg/day), or placebo for 10-13 weeks. RWS participants received dose-optimized GXR (1-7 mg/day) for 13 weeks. Participants' last stimulant medication prior to enrolment, and reasons for stopping this medication, were collected at baseline. Change from baseline ADHD-RS-IV score and the proportion of responders were assessed by prior stimulant exposure. Of 163 RCT and 296 RWS participants who had previously received stimulant treatment, 142 and 224, respectively, had received methylphenidate (MPH); due to the low number of participants and the heterogeneity of non-MPH treatments, we only report data for prior MPH treatment. The most frequent reasons for stopping MPH were lack of effectiveness or side effects. Placebo-adjusted ADHD-RS-IV changes from baseline were significant in participants receiving GXR (prior MPH, -9.8, P<0.001, effect size [ES] 0.85; stimulant-naïve, -7.6, P<0.001, ES 0.65). In ATX-treated participants, significant placebo-adjusted differences were seen in stimulant-naïve (-5.0, P=0.022, ES 0.43) but not prior MPH-treated (-1.8, P>0.05, ES 0.15) participants. More participants met responder criteria with GXR versus placebo, regardless of prior treatment. GXR response was unaffected by prior stimulant treatment; ATX produced improvement only in stimulant-naïve participants relative to placebo. These findings may be relevant to clinical decision-making regarding sequencing of ADHD treatments.

Extended-release guanfacine hydrochloride in 6-17-year olds with ADHD: a randomised-withdrawal maintenance of efficacy study.

BACKGROUND: Extended-release guanfacine hydrochloride (GXR), a selective α2A-adrenergic agonist, is a nonstimulant medication for attention-deficit/hyperactivity disorder (ADHD). This phase 3, double-blind, placebo-controlled, randomised-withdrawal study evaluated the long-term maintenance of GXR efficacy in children/adolescents with ADHD. METHODS: Children/adolescents (6-17 years) with ADHD received open-label GXR (1-7 mg/day). After 13 weeks, responders were randomised to GXR or placebo in the 26-week, double-blind, randomised-withdrawal phase (RWP). The primary endpoint was the percentage of treatment failure (≥50% increase in ADHD Rating Scale version IV total score and ≥2-point increase in Clinical Global Impression-Severity compared with RWP baseline, at two consecutive visits). The key secondary endpoint was time to treatment failure (TTF). TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01081145; EudraCT 2009-018161-12. RESULTS: A total of 528 participants enrolled; 316 (59.8%) entered the RWP. Treatment failure occurred in 49.3% of the GXR and 64.9% of the placebo group (p = 0.006). TTF was significantly longer in GXR versus placebo (p = 0.003). GXR was well tolerated. CONCLUSIONS: Guanfacine hydrochloride demonstrated long-term maintenance of efficacy compared with placebo in children/adolescents with ADHD. Implications of the placebo substitution design and findings with different ADHD medications are discussed.

Does Guanfacine Extended Release Impact Functional Impairment in Children with Attention-Deficit/Hyperactivity Disorder? Results from a Randomized Controlled Trial.

BACKGROUND: In clinical trials of medications to treat attention-deficit/hyperactivity disorder (ADHD) in children, effects on functional impairment have been less well-studied than changes in ADHD symptoms. OBJECTIVE: Data regarding functional impairment were analyzed from a multicenter, double-blind, placebo-controlled study of guanfacine extended release (GXR) in children with ADHD, using the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P). The correspondence of changes in WFIRS-P scores with symptomatic and global response to GXR treatment was also examined, with treatment response defined by scores on both the ADHD Rating Scale IV (ADHD-RS-IV) and the Clinical Global Impressions-Improvement Scale (CGI-I). METHODS: In this 8-week, double-blind, placebo-controlled, dose optimization study at 47 sites across the USA and Canada, children aged 6-12 years with a diagnosis of ADHD [Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria, and an ADHD-RS-IV score ≥28 and CGI-Severity of Illness Scale score ≥4 at baseline], were randomized 1:1:1 into three groups: GXR AM [GXR (1-4 mg/day) in the morning, placebo in the evening], GXR PM [placebo in the morning, GXR (1-4 mg/day) in the evening], or twice-daily placebo. Parents rated their children on the WFIRS-P at screening, baseline, the end of dose optimization, and at the final on-treatment assessment. RESULTS: The efficacy population was composed of 333 subjects (GXR AM: n = 107; GXR PM: n = 114; placebo: n = 112). At the final on-treatment assessment, there were significant improvements from baseline in the placebo-adjusted difference in least-squares (LS) mean (95 % confidence interval) WFIRS-P Total scores for both GXR treatment groups combined [GXR all-active: -0.16 (-0.25, -0.07), effect size (ES) = 0.448, P <0.001] and separately [GXR AM: -0.15 (-0.26, -0.05), ES = 0.417, P = 0.004; GXR PM: -0.18 (-0.28, -0.07), ES = 0.478, P = 0.001]. Significant improvements in WFIRS-P domain scores for Family, Learning and School (including Academic Performance and Behavior in School), Social, and Risky Behavior were found for both GXR cohorts compared with placebo. However, the Life Skills and Self-Concept domain scores of the WFIRS-P did not improve with GXR treatment. Post hoc stratification by responder status revealed that significant (P <0.001) improvements in WFIRS-P Total and all domain scores were associated with symptomatic treatment response in the GXR all-active group. CONCLUSIONS: GXR treatment in children with ADHD was associated with reductions in WFIRS-P functional impairment scores compared with placebo, regardless of time of GXR administration. Changes in WFIRS-P scores were congruent with clinical response, as determined by both ADHD symptom reduction and CGI-I scores. CLINICALTRIALS. GOV IDENTIFIER: NCT00997984.