Safety and Efficacy of Centanafadine Sustained-Release in Adults With Attention-Deficit Hyperactivity Disorder: Results of Phase 2 Studies.

PURPOSE: Two phase 2 studies evaluated the efficacy and tolerability of centanafadine sustained-release (SR) for adults with attention-deficit/hyperactivity disorder (ADHD). PATIENTS AND METHODS: In a phase 2a, flexible-dose, single-blind study, 41 male patients (aged 18‒55 years) with a diagnosis of ADHD (based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) were titrated with centanafadine-SR 200‒300, 400, or 500 mg/d for 2 weeks, and then were treated with the titrated dose for 2 weeks. In a phase 2b, randomized, double-blind, placebo-controlled, crossover study, 85 male and female patients (aged 18‒60 years) with a diagnosis of ADHD (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) were titrated to target doses of centanafadine-SR 400, 500, 600, or 800 mg/d over the course of 1 week, and then received their titrated dose for 3 weeks. The primary outcome in both studies was mean total ADHD Rating Scale-IV (ADHD-RS-IV) score. RESULTS: In the phase 2a study, mean ADHD-RS-IV total score decreased by 21.41 (standard deviation 10.74) from the start of active centanafadine-SR treatment to the end of week 4 (P<0.001). In the phase 2b study, centanafadine-SR treatment resulted in a statistically significant improvement in ADHD-RS-IV from baseline to week 3 compared with placebo (least-squares mean -16.5 vs -8.4; P<0.001; effect size 0.66), with significant efficacy demonstrated as early as week 1. Centanafadine-SR was generally well tolerated at doses ≤400 mg. Most treatment-emergent adverse events (TEAEs) were mild or moderate; decreased appetite, headache, and nausea were the most frequently reported. In the 2 studies, 13 of 120 patients discontinued centanafadine-SR due to TEAEs; however, only 1 patient who received ≤400 mg discontinued due to a TEAE. No serious TEAEs were reported at any dose. CONCLUSION: These results support the continued development of centanafadine-SR at doses up to 400 mg/d.

Review of Clinical Outcome Assessments in Pediatric Attention-Deficit/Hyperactivity Disorder.

PURPOSE: Various clinical outcome assessments (COAs) are used in clinical research to assess and monitor treatment efficacy in pediatric attention-deficit/hyperactivity disorder (ADHD) trials. It is unclear whether the concepts assessed are those that are important to patients and their caregivers. The concepts measured by commonly used COAs in this population have not been explicitly compared. METHODS: We conducted reviews of the qualitative literature to extract information on pediatric ADHD-related concepts reported by pediatric patients, parents, and teachers. Using these concepts, we developed a conceptual framework of pediatric ADHD using both the Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria and the additional symptoms and behavioral impacts identified in the literature. We searched for COAs that have been used in pediatric ADHD research and mapped their items based on their conceptual underpinning. RESULTS: Of the 27 COAs found in the empirical literature, 4 COAs assessed only DSM symptoms. The most comprehensive coverage of our conceptual framework was seen in the Swanson, Nolan, and Pelham Rating Scale-DSM-IV (SNAP-IV). Eighteen COAs were used in at least 1 clinical trial: ADHD-Rating Scale-IV (ADHD-RS-IV) was used most often (n=77), followed by SNAP-IV (n=50), Swanson, Kotkin, Agler, M-Flynn, and Pelham Scale (SKAMP; n=31), Weiss Functional Impairment Rating Scale (WFIRS; n=24), and Vanderbilt ADHD Diagnostic Rating Scale (VADRS; n=15). CONCLUSION: We identified symptoms and behavioral impacts from qualitative studies in pediatric ADHD that are not included in DSM-based criteria. Most COAs used in pediatric ADHD clinical trials measure only those symptoms listed in the DSM. While these COAs can measure symptom severity, they may not assess the full range of symptoms and impacts important to patients and their caregivers. Future research is needed to measure all concepts important to patients and caregivers within ADHD clinical trials.

A Randomized, Double-Blind, Placebo-Controlled Study of HLD200, a Delayed-Release and Extended-Release Methylphenidate, in Children with Attention-Deficit/Hyperactivity Disorder: An Evaluation of Safety and Efficacy Throughout the Day and Across Settings.

Objectives: HLD200, a once-daily, evening-dosed, delayed-release and extended-release methylphenidate (DR/ER-MPH), was designed to provide therapeutic effect beginning upon awakening and lasting into the evening. This pivotal, randomized, double-blind, multicenter, placebo-controlled, phase 3 trial assessed improvements in functional impairment across the day using multiple validated measures tailored for different settings and time of day in children (6-12 years) with attention-deficit/hyperactivity disorder (ADHD). Methods: Following a 6-week, open-label titration of DR/ER-MPH to an optimal dose (20, 40, 60, 80, or 100 mg/day) and dosing time (8:00 PM ±1.5 hours), participants were randomized to treatment-optimized DR/ER-MPH or placebo for 1 week. The primary endpoint was the model-adjusted average of postdose Swanson, Kotkin, Agler, M-Flynn, and Pelham Scale combined scores (SKAMP CS) over a 12-hour laboratory classroom day (8:00 AM to 8:00 PM). The key secondary endpoint was the Parent Rating of Evening and Morning Behavior-Revised, Morning (PREMB-R AM) subscale. Secondary/exploratory measures included the PREMB-R Evening (PREMB-R PM) subscale and Permanent Product Measure of Performance (Attempted [PERMP-A] and Correct [PERMP-C]). Safety endpoints included treatment-emergent adverse events (TEAEs). Results: After the treatment-optimization phase, the mean optimized dose was 66.2 mg and the most common prescribed dosing time was 8:00 PM. Double-blind DR/ER-MPH treatment significantly improved functional impairment versus placebo in the early morning (PREMB-R AM: p < 0.001), averaged over the classroom day (SKAMP CS: p < 0.001), and in the late afternoon/evening (PREMB-R PM: p = 0.003) in the intent-to-treat population (N = 117). Average PERMP-A (p = 0.006) and PERMP-C (p = 0.009) also indicated improved classroom performance with DR/ER-MPH versus placebo. In the double-blind phase, TEAEs did not differ between DR/ER-MPH and placebo groups and no serious TEAEs or TEAEs leading to discontinuation were reported. Conclusion: DR/ER-MPH was well tolerated and demonstrated significant improvements versus placebo in functional impairment throughout the day across different settings in children with ADHD.

Efficacy and Safety of Dasotraline in Children With ADHD: A Laboratory Classroom Study.

Objective: To evaluate the efficacy and safety of dasotraline for treatment of ADHD in children. Method: Children (ages 6-12 years; N = 112) with ADHD were randomized, double-blind, to 14 days of once-daily evening doses of dasotraline 4 mg or placebo. ADHD symptom severity was measured at baseline and Day 15 in seven, 30-min classroom sessions using the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) and the Permanent Product Measure of Performance (PERMP) math test. Results: Significant improvement was observed for dasotraline versus placebo in the SKAMP-combined score (-3.2 vs. +2.0; p < .001; effect size = 0.85) and SKAMP and PERMP subscale scores. The three most common adverse events for dasotraline (vs. placebo) were insomnia (19.6% vs. 3.6%), headache (10.7% vs. 8.9%), and decreased appetite (10.7% vs. 3.6%). Conclusion: In this laboratory classroom study, dasotraline 4 mg was found to be an efficacious and generally well-tolerated treatment for ADHD in children aged 6 to 12 years.

The Time Course of Effect of Multilayer-Release Methylphenidate Hydrochloride Capsules: A Randomized, Double-Blind Study of Adults With ADHD in a Simulated Adult Workplace Environment.

Objective: The aim of this study is to assess the onset and duration of efficacy of multilayer-release methylphenidate (PRC-063) over 16 hr compared with placebo in adults with ADHD using the simulated adult workplace environment. Method: After dose-optimization with PRC-063, participants entered a double-blind, placebo-controlled, crossover phase. Primary outcome measure was the Permanent Product Measure of Performance (PERMP) total score measured pre-dose and from 1 to 16 hr post-dose. Results: Of the 59 randomized participants, 45 participants completed the study. While receiving PRC-063, adults had greater mean PERMP total scores across all time points compared with placebo (268.7 ± 11.24 vs. 255.6 ± 10.87; p = .0064). Common adverse events were decreased appetite, headache, and insomnia. There was no significant impact on overall sleep quality (p = .9542). Conclusion: PRC-063 significantly improved PERMP scores with an onset within 1 hr post-dose, and maintained improvement throughout the 16 hr post-dose study period compared with placebo in adults with ADHD.

Laboratory School Protocol Mini-Review: Use of Direct Observational and Objective Measures to Assess ADHD Treatment Response Across the Lifespan.

INTRODUCTION: The time of onset and the duration of treatment effect are important considerations in the choice of the medication to be prescribed in treating children, adolescents, and adults with ADHD. Early onset of effect may facilitate preparation for school, improved behavior during the trip to school, and attention during morning classes. Sustained treatment effect through afternoon and evening hours can be important because impairments associated with ADHD are not limited to the naturalistic classroom. Laboratory school protocols (LSPs) provide a simulated, rigorously controlled classroom setting environment and have proven valuable for providing pharmacokinetic and pharmacodynamic information about medications, and other treatments used in managing ADHD in school-aged children and across the lifespan. METHODS: This paper is an invited mini-review of LSPs of stimulant medication, which includes data from multiple, randomized, double-blind, and placebo-controlled medication trials for ADHD. Assessment endpoints included the permanent product measure of performance (PERMP), Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) rating scale in the preschool assessment laboratory (PAL), child/adolescent, and adult workplace environment (AWE) studies. These measures allow the study of improvement in attention and behavior in individuals with ADHD. RESULTS: Analog classroom settings (LSP or AWE) have been used to assess immediate and modified-release stimulant formulations of medications to treat ADHD in multiple age groups. Results based on both subjective (e.g., SKAMP ratings) and objective (e.g., PERMP) measures are used as clinical outcomes in testing drugs currently in development for ADHD. CONCLUSION: The LSP and its extension to PAL and AWE settings continue to be used to assess the time-course of effect of ADHD medications because they provide valuable information in their respective structured, controlled environments.

Optimization of Methylphenidate Extended-Release Chewable Tablet Dose in Children with ADHD: Open-Label Dose Optimization in a Laboratory Classroom Study.

OBJECTIVE: To examine methylphenidate extended-release chewable tablets (MPH ERCT) dose patterns, attention-deficit/hyperactivity disorder (ADHD) symptom scores, and safety during the 6-week, open-label (OL) dose-optimization period of a phase 3, laboratory classroom study. METHODS: Boys and girls (6-12 years) diagnosed with ADHD were enrolled. MPH ERCT was initiated at 20 mg/day; participants were titrated in 10-20 mg/day increments weekly based on efficacy and tolerability (maximum dose, 60 mg/day). Dose-optimization period efficacy assessments included the ADHD Rating Scale (ADHD-RS-IV), analyzed by week in a post hoc analysis using a mixed-effects model for repeated measures with final optimized dose (20, 30/40, or 50/60 mg), visit, final optimized dose and visit interaction, and baseline score as terms. Adverse events (AEs) and concomitant medications were collected throughout the study. RESULTS: Mean MPH ERCT daily dose increased weekly from 29.4 mg/day after the first dose adjustment at week 1 (n = 90) to 42.8 mg/day after the final adjustment at week 5 (n = 86). Final optimized MPH ERCT dose ranged from 20 to 60 mg/day. Mean final optimized MPH ERCT dose ranged from 40.0 mg/day in 6-8 year-old participants to 44.8 mg/day for 11-12 year-old participants. There was a progressive decrease in mean (standard deviation) ADHD-RS-IV total score from 40.1 (8.72) at baseline to 12.4 (7.88) at OL week 5, with similar improvement patterns for hyperactivity/impulsivity and inattentiveness subscale scores. Participants optimized to MPH ERCT 50/60 mg/day had a significantly higher mean (standard error) ADHD-RS-IV score at baseline compared with participants optimized to MPH ERCT 20 mg/day (42.4 [1.34] vs. 35.1 [2.55]; p = 0.013). Treatment-emergent AEs were reported by 65/90 (72.2%) participants in the dose-optimization period. CONCLUSIONS: Dose-optimization period results describing relationships between change in ADHD symptom scores and final optimized MPH ERCT dose will be valuable for clinicians optimizing MPH ERCT dose.

A Double-Blind, Placebo-Controlled, Phase II Study to Determine the Efficacy, Safety, Tolerability and Pharmacokinetics of a Controlled Release (CR) Formulation of Mazindol in Adults with DSM-5 Attention-Deficit/Hyperactivity Disorder (ADHD).

BACKGROUND: Mazindol is under investigation for the treatment of attention-deficit/hyperactivity disorder (ADHD) because of its alertness-enhancing properties. A novel controlled-release (CR) formulation of mazindol was developed to allow once-daily dosing. OBJECTIVE: The aim of this study was to evaluate the efficacy of mazindol CR in adults with ADHD. DESIGN: We conducted a randomized, double-blind, placebo-controlled 6-week trial. METHODS: Subjects diagnosed with ADHD using the Mini-International Neuropsychiatric Structured Interview (MINI) and with an ADHD Rating Scale, Diagnostic and Statistical Manual of Mental Disorders 5th Edition (ADHD-RS-DSM5) score ≥ 28 were randomized to receive placebo or 1-3 mg/day of mazindol for 6 weeks. The primary endpoint was the reduction from baseline in the ADHD-RS-DSM5 score on Day 42. Secondary endpoints were response rates defined by change in ADHD-RS-DSM5 (≥ 30 or ≥ 50% reduction) and dichotomized Clinical Global Impression-Improvement (CGI-I) score (1 or 2). An exploratory endpoint of functional impairment, as measured by the Target Impairment Scale, examined individualized deficits in specific settings. Safety, tolerability, and pharmacokinetics were assessed. RESULTS: Eighty-five participants were randomized (n = 43 active, 42 placebo); 75 completed. Weekly ADHD-RS-DSM5 measurements after mazindol differed from placebo beginning at Day 7, with a least squares mean difference (active-placebo) of - 13.2 at Day 42 and an effect size of 1.09. For the 30% or more reduction in ADHD-RS-DSM5 (minimal response), a significant difference (active-placebo) was seen starting at Day 7 and continuing to Day 42. For the CGI-I (1 or 2) and for the 50% or more reduction in ADHD-RS-DSM5 (measures of excellent response), the differences began at Day 14 and continued to Day 42. Functional impairment was significantly different in the proportion achieving at least a 50% reduction in target impairment score (42.9% mazindol vs 11.9% placebo) by Day 42. Dry mouth, nausea, fatigue, heart rate (HR) increased, decreased appetite, and constipation were more prevalent for mazindol versus placebo. Overall, mazindol CR had minimal effects on blood pressure and small effects on HR. CONCLUSION: Mazindol CR was efficacious in the treatment of adults with ADHD, with a large effect size, and was well tolerated, supporting the progression to phase III. (Clinicaltrials.gov Registration No. NCT02808104).

Reliability and Validity of the Daily Parent Rating of Evening and Morning Behavior Scale, Revised.

OBJECTIVE: Children with ADHD frequently manifest behavioral difficulties in the morning prior to school. We sought to assess the reliability and validity of the Daily Parent Rating of Evening and Morning Behavior Scale, Revised (DPREMB-R) morning score as a measure of morning behaviors impaired by ADHD. METHOD: We used data from a clinical trial of HLD200 treatment in pediatric participants with ADHD to address our objectives. RESULTS: The DPREMB-R morning score showed significant internal homogeneity, test-retest reliability ( r = .52-.45), and good concurrent validity ( r = .50-.71). CONCLUSION: The DPREMB-R morning score could be a useful instrument for assessing treatment efficacy in the morning before school.

Efficacy and Safety of Amphetamine Extended-Release Oral Suspension in Children with Attention-Deficit/Hyperactivity Disorder.

OBJECTIVES: To determine the efficacy and safety of amphetamine extended-release oral suspension (AMPH EROS) in the treatment of attention-deficit/hyperactivity disorder (ADHD) in a dose-optimized, randomized, double-blind, parallel-group study. METHODS: Boys and girls aged 6 to 12 years diagnosed with ADHD were enrolled. During a 5-week, open-label, dose-optimization phase, patients began treatment with 2.5 or 5 mg/day of AMPH EROS; doses were titrated until an optimal dose (maximum 20 mg/day) was reached. During the double-blind phase, patients were randomized to receive treatment with either their optimized dose (10-20 mg/day) of AMPH EROS or placebo for 1 week. Efficacy was assessed in a laboratory classroom setting on the final day of double-blind treatment using the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Rating Scale and Permanent Product Measure of Performance (PERMP) test. Safety was assessed measuring adverse events (AEs) and vital signs. RESULTS: The study was completed by 99 patients. The primary efficacy endpoint (change from predose SKAMP-Combined score at 4 hours postdose) and secondary endpoints (change from predose SKAMP-Combined scores at 1, 2, 6, 8, 10, 12, and 13 hours postdose) were statistically significantly improved with AMPH EROS treatment versus placebo at all time points. Onset of treatment effect was present by 1 hour postdosing, the first time point measured, and duration of efficacy lasted 13 hours postdosing. PERMP data mirrored the SKAMP-Combined score data. AEs (>5%) reported during dose optimization were decreased appetite, insomnia, affect lability, upper abdominal pain, mood swings, and headache. CONCLUSION: AMPH EROS was effective in reducing symptoms of ADHD and had a rapid onset and extended duration of effect. Reported AEs were consistent with those of other extended-release amphetamine products.

The Qualitative Interview Study of Persistent and Nonpersistent Substance Use in the MTA: Sample Characteristics, Frequent Use, and Reasons for Use.

OBJECTIVE: To evaluate participants' perceptions about frequent use and reasons for substance use (SU) in the qualitative interview study, an add-on to the multimodal treatment study of ADHD (MTA). METHOD: Using the longitudinal MTA database, 39 ADHD cases and 19 peers with Persistent SU, and 86 ADHD cases and 39 peers without Persistent SU were identified and recruited. In adulthood, an open-ended interview was administered, and SU excerpts were indexed and classified to create subtopics (frequent use and reasons for use of alcohol, marijuana, and other drugs). RESULTS: For marijuana, the Persistent compared with Nonpersistent SU group had a significantly higher percentage of participants describing frequent use and giving reasons for use, and the ADHD group compared with the group of peers had a significantly higher percentage giving "stability" as a reason for use. CONCLUSION: Motivations for persistent marijuana use may differ for adults with and without a history of ADHD.

Efficacy and Safety of a Chewable Methylphenidate Extended-Release Tablet in Children with Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: This phase 3, laboratory classroom study assessed the efficacy and safety of methylphenidate hydrochloride extended-release chewable tablets (MPH ERCT) compared with placebo in children with attention-deficit/hyperactivity disorder (ADHD). METHODS: Following a 6-week, open-label, dose-optimization period, children 6-12 years of age (n = 90) with ADHD were randomly assigned to double-blind MPH ERCT at the final optimized dose (20-60 mg/day) or placebo. After 1 week of double-blind treatment, efficacy was assessed predose and 0.75, 2, 4, 8, 10, 12, and 13 hours postdose in a laboratory classroom setting. The primary efficacy measure was the average of postdose Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Rating Scale-Combined scores, analyzed using a mixed-model, repeated-measures analysis. Secondary efficacy measures included Permanent Product Measure of Performance (PERMP) total number of problems attempted and total number of problems correct. Safety assessments included adverse event (AE) monitoring and the Columbia-Suicide Severity Rating Scale (C-SSRS). RESULTS: MPH ERCT treatment statistically significantly reduced the average of all postdose SKAMP-Combined scores versus placebo (least-squares mean difference [95% confidence interval], -7.0 [-10.9, -3.1]; p < 0.001). Statistically significant treatment differences in SKAMP-Combined scores were observed at 2 hours postdose through 8 hours postdose (p-values <0.001). Statistically significant differences between MPH ERCT and placebo in PERMP total number of problems attempted and total number of problems correct were observed at 0.75 hours postdose through 8 hours postdose (p-values ≤0.049). Common AEs in the open-label period (≥5%) were decreased appetite, upper abdominal pain, mood swings, irritability, insomnia, upper respiratory tract infection (URTI), dysgeusia, and headache; URTI was the only AE reported by >1 subject receiving MPH ERCT in the double-blind period (placebo: URTI, contusion, wound, and initial insomnia). No suicidal ideation or behavior was reported on the C-SSRS at baseline or at any postbaseline assessment. CONCLUSIONS: MPH ERCT 20-60 mg significantly improved ADHD symptoms compared with placebo at 2 hours postdose through at least 8 hours postdose. MPH ERCT was generally safe and well tolerated, with a safety profile consistent with other MPH ER formulations. ClinicalTrials.gov Identifier: NCT01654250. www.clinicaltrials.gov/ct2/show/NCT01654250 .

Efficacy, Safety, and Tolerability of a Novel Methylphenidate Extended-Release Oral Suspension (MEROS) in ADHD.

OBJECTIVE: To test whether an optimal dose of Quillivant XR (methylphenidate extended-release oral suspension [MEROS]) would significantly reduce symptoms of ADHD in children. METHOD: A randomized, double-blind, placebo-controlled, cross-over, efficacy, safety, and tolerability study of MEROS in 45 children aged 6 to 12 years (open-label dose-optimization phase, followed by double-blind cross-over period). RESULTS: MEROS was significantly more efficacious than placebo during double-blind cross-over laboratory classroom days (Swanson, Kotkin, Agler, M-Flynn, and Pelham Rating Scale and Permanent Product Measure of Performance). During the open-label phase, improvements were observed in scores of ADHD Rating Scale-IV, and Clinical Global Impression-Severity and -Improvement Scales. No occurrences of suicidal ideation or behavior were recorded; the most common open-label treatment-emergent adverse events were typical of stimulant use: decreased appetite, insomnia, and abdominal pain. CONCLUSION: MEROS was efficacious in the treatment of children aged 6 to 12 years with ADHD, with a safety profile similar to that of other extended-release methylphenidate pharmacotherapies.

Efficacy of Methylphenidate Hydrochloride Extended-Release Capsules (Aptensio XR™) in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: A Phase III, Randomized, Double-Blind Study.

BACKGROUND: Psychostimulants remain first-line treatment options for the management of attention-deficit/hyperactivity disorder (ADHD). A multilayer extended-release bead methylphenidate capsule (provisional name Aptensio XR™, MPH-MLR) with unique release properties is being investigated for the treatment of ADHD. OBJECTIVE: The aim of this study was to assess the efficacy (primary) and safety and tolerability (secondary) of MPH-MLR compared with placebo in children and adolescents aged 6-18 years with ADHD. METHODS: This study was a parallel, double-blind, multicenter, placebo-controlled, forced-dose, phase III study in which patients were randomized to placebo or MPH-MLR 10, 15, 20, or 40 mg given once daily. There were four study phases: (1) 4-week screening/baseline; (2) 1-week, double-blind treatment (DBP); (3) 11-week, open-label, dose-optimization period; and (4) 30-day follow-up call. During the open-label dose-optimization period all patients started with MPH-MLR 10 mg, unless the investigator deemed it necessary to begin at a higher dose, and were titrated to an optimized dose (10, 15, 20, 30, 40, 50, 60 mg; all given once daily) based on response and adverse events (AEs). The primary endpoint was the change from baseline to end of DBP in ADHD Rating Scale, 4th Edition (ADHD-RS-IV) total score. Secondary endpoints included changes in ADHD-RS-IV subscales and Clinical Global Impression-Improvement Scale (CGI-I) at the end of the DBP. The primary analysis was an analysis of covariance including terms for treatment, site, and baseline ADHD-RS-IV total score. RESULTS: A total of 221 patients completed the DBP. The primary endpoint had a statistically significant difference among treatments (p = 0.0046) and sites (p = 0.0018), and baseline covariate made a significant contribution (p < 0.0001). As the MPH-MLR dose increased, the ADHD-RS-IV total score improved; the 20 and 40 mg doses were statistically different (p = 0.0145 and p = 0.0011, respectively) from placebo. Females responded differently than did males (p = 0.0238); there was a significant difference among treatments for males but not for females, partly because only one-third of subjects were female and partly because some females who received placebo had considerable improvement during the DBP. Similarly, the ADHD-RS-IV subscales and CGI-I scores at the end of the DBP also showed more improvement as the dose of MPH-MLR increased. During the open-label phase, ADHD-RS-IV total scores improved (mean change from baseline -22.5) and correlated as the dose of MPH-MLR increased; CGI-I scores also improved. No unexpected AEs were noted. CONCLUSIONS: Dose-related improvements in ADHD-RS-IV scores that exceeded those of placebo were observed in patients treated with MPH-MLR. No new safety signals were noted.

A randomized placebo-controlled double-blind study evaluating the time course of response to methylphenidate hydrochloride extended-release capsules in children with attention-deficit/hyperactivity disorder.

OBJECTIVE: The purpose of this study was to assess the time of onset and time course of efficacy over 12.0 hours of extended-release multilayer bead formulation of methylphenidate (MPH-MLR) compared with placebo in children 6-12 years of age with attention-deficit/hyperactivity disorder (ADHD) in a laboratory school setting. METHODS: This randomized double-blind placebo-controlled study included children 6-12 years of age with ADHD. Enrolled children went through four study phases: 1) Screening period (≤4 weeks) and a 2 day medication washout period; 2) open-label period with dose initiation of MPH-MLR 15 mg daily and individual dose optimization treatment period (2-4 weeks); 3) double-blind crossover period in which participants were randomized to sequences (1 week each) of placebo and the optimized MPH-MLR dose given daily; and 4) follow-up safety call. Analog classroom time course evaluations were performed at the end of each double-blind week. The primary efficacy end-point was the mean of the on-treatment/postdose Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP)-Total scores over time points collected 1.0-12.0 hours after dosing. End-points were evaluated using a mixed-effects analysis of covariance. RESULTS: The evaluable population included 20 participants. The least-squares mean postdose SKAMP-Total score was higher for placebo than for MPH-MLR (2.18 vs. 1.32, respectively; p=0.0001), indicating fewer symptoms with MPH-MLR therapy than with placebo. No difference in SKAMP-Total score between participants who received sequence 1 or sequence 2 was noted. From each of hours 1.0-12.0, least-squares mean SKAMP-Total score was significantly lower for those receiving MPH-MLR than for those receiving placebo (p≤0.0261). Neither serious adverse events nor new or unexpected safety findings were noted during the study. CONCLUSIONS: MPH-MLR showed a significant decrease in SKAMP scores compared with placebo in children with ADHD 6-12 years of age, indicating a decrease in ADHD symptoms. The estimated onset was observed within 1.0 hour, and duration was measured to 12.0 hours postdose. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01269463.

Atomoxetine improved attention in children and adolescents with attention-deficit/hyperactivity disorder and dyslexia in a 16 week, acute, randomized, double-blind trial.

OBJECTIVE: The purpose of this study was to evaluate atomoxetine treatment effects in attention-deficit/hyperactivity disorder (ADHD-only), attention-deficit/hyperactivity disorder with comorbid dyslexia (ADHD+D), or dyslexia only on ADHD core symptoms and on sluggish cognitive tempo (SCT), working memory, life performance, and self-concept. METHODS: Children and adolescents (10-16 years of age) with ADHD+D (n=124), dyslexia-only (n=58), or ADHD-only (n=27) received atomoxetine (1.0-1.4 mg/kg/day) or placebo (ADHD-only subjects received atomoxetine) in a 16 week, acute, randomized, double-blind trial with a 16 week, open-label extension phase (atomoxetine treatment only). Changes from baseline were assessed to weeks 16 and 32 in ADHD Rating Scale-IV-Parent-Version:Investigator-Administered and Scored (ADHDRS-IV-Parent:Inv); ADHD Rating Scale-IV-Teacher-Version (ADHDRS-IV-Teacher-Version); Life Participation Scale-Child- or Parent-Rated Version (LPS); Kiddie-Sluggish Cognitive Tempo (K-SCT) Interview; Multidimensional Self Concept Scale (MSCS); and Working Memory Test Battery for Children (WMTB-C). RESULTS: At week 16, atomoxetine treatment resulted in significant (p<0.05) improvement from baseline in subjects with ADHD+D versus placebo on ADHDRS-IV-Parent:Inv Total (primary outcome) and subscales, ADHDRS-IV-Teacher-Version Inattentive subscale, K-SCT Interview Parent and Teacher subscales, and WMTB-C Central Executive component scores; in subjects with Dyslexia-only, atomoxetine versus placebo significantly improved K-SCT Youth subscale scores from baseline. At Week 32, atomoxetine-treated ADHD+D subjects significantly improved from baseline on all measures except MSCS Family subscale and WMTB-C Central Executive and Visuo-spatial Sketchpad component scores. The atomoxetine-treated dyslexia-only subjects significantly improved from baseline to week 32 on ADHDRS-IV-Parent:Inv Inattentive subscale, K-SCT Parent and Teacher subscales, and WMTB-C Phonological Loop and Central Executive component scores. The atomoxetine-treated ADHD-only subjects significantly improved from baseline to Week 32 on ADHDRS-Parent:Inv Total and subscales, ADHDRS-IV-Teacher-Version Hyperactive/Impulsive subscale, LPS Self-Control and Total, all K-SCT subscales, and MSCS Academic and Competence subscale scores. CONCLUSIONS: Atomoxetine treatment improved ADHD symptoms in subjects with ADHD+D and ADHD-only, but not in subjects with dyslexia-only without ADHD. This is the first study to report significant effects of any medication on SCT. CLINICAL TRIALS REGISTRATION: This study was registered at: http://clinicaltrials.gov/ct2/home, NCT00607919.

NWP06, an extended-release oral suspension of methylphenidate, improved attention-deficit/hyperactivity disorder symptoms compared with placebo in a laboratory classroom study.

OBJECTIVE: The purpose of this study was to determine the efficacy of NWP06, a novel extended-release (ER) liquid formulation of methylphenidate (MPH), compared with placebo in the treatment of attention-deficit/hyperactivity disorder (ADHD) in children in a laboratory school. METHODS: A total of 45 subjects ages 6-12 years were enrolled in this dose-optimized, randomized, double-blind, placebo-controlled, crossover laboratory school study. Following open-label dose optimization, subjects received 2 weeks of double-blind treatment (1 week of NWP06 and 1 week of placebo). The treatment sequence (NWP06/placebo or placebo/NWP06) was randomly assigned with the last day of each week-long treatment occurring on the laboratory school test day. Efficacy measures included Swanson, Kotkin, Agler, M-Flynn and Pelham (SKAMP) Rating Scale-Combined and Permanent Product Measure of Performance (PERMP) mathematics tests measured at pre-dose and at 0.75, 2, 4, 8, 10, and 12 hours post-dose on each laboratory classroom day. Safety assessments included physical examination, screening electrocardiogram (ECG), vital signs, clinical laboratory tests, adverse event measures, and assessment of suicidality with the Columbia Suicide Severity Rating Scale. RESULTS: NWP06 resulted in significant (p<0.0001) improvements in the SKAMP-Combined score at 4 hours post-dose (mean=7.12) as compared with placebo (mean=19.58) in the completers (n=39). Significant separation from placebo occurred at each time point tested (0.75, 2, 4, 8, 10, 12 hours), with onset of action of NWP06 at 45 minutes post-dose and duration of efficacy extending to 12 hours post-dose. Adverse events (AEs) and changes in vital signs following NWP06 treatment were generally mild and consistent with the known safety profile of MPH. The most common AEs in the open-label phase were decreased appetite (55.6%), upper abdominal pain (42.2%), affect lability (26.7%), initial insomnia (22.2%), insomnia (17.8%), and headache (17.8%). CONCLUSIONS: NWP06 treatment effectively reduced symptoms of ADHD in children beginning at 45 minutes and continuing for 12 hours post-dose. NWP06 was well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00904670. http://www.clinicaltrials.gov/ct2/show/NCT00904670 .

Exercise: applications to childhood ADHD.

ADHD is the most common neurobehavioral disorder of childhood, presenting with pervasive and impairing symptoms of inattention, hyperactivity, impulsivity, or a combination. The leading hypothesis of the underlying physiology of this disorder of inattention and/or hyperactivity-impulsivity is based on catecholamine dysfunction. Pharmacotherapy research indicates that psychostimulants, which are catecholamine agonists, show the greatest efficacy for treating the core symptoms of ADHD. Exercise affects the same dopaminergic and noradrenergic systems that stimulant medications target and is a stressor, which elicits measurable physiological changes. The magnitude of these peripheral alterations is posited as a potential biomarker of ADHD. The hypothesis that exercise training alters the underlying physiology present in ADHD and other medical conditions as well as conceptual issues behind its potential clinical utility is reviewed.

An update on lisdexamfetamine dimesylate for the treatment of attention deficit hyperactivity disorder.

INTRODUCTION: The efficacy and safety of stimulants for the pharmacologic management of attention deficit hyperactivity disorder (ADHD) is well documented. The US Food and Drug Administration approval of additional classes of medication even within stimulant treatments expands the prescribing options for practitioners. The focus of this paper is the prodrug amphetamine stimulant, lisdexamfetamine (LDX) , which is an example of such an agent with a novel delivery system. AREAS COVERED: This review covers the proof-of-concept and later studies of LDX to describe its use to treat ADHD in pediatric and adult populations. A literature search and review of LDX were carried out using the PubMed database up to August 2012. EXPERT OPINION: Clinical studies of LDX in children and adults with ADHD demonstrate its tolerability and its efficacy in reducing ADHD symptoms. Future research should be less restrictive in order to address some of the unmet needs in ADHD treatment. The inclusion of patients with ADHD and co-occurring mental health disorders and/or medical conditions is typically not studied in clinical trials nor is the prior ADHD treatment exposure of study participants. The preschool age population also is understudied in recently approved ADHD treatments such as LDX. Finally, how to approach the treatment of participants or first-degree relatives with a medical history or presence of substance use disorder presents an ongoing clinical challenge.

Phase synchronization of oxygenation waves in the frontal areas of children with attention-deficit hyperactivity disorder detected by optical diffusion spectroscopy correlates with medication.

The beneficial effects of pharmacotherapy on children with attention-deficit hyperactivity disorder (ADHD) are well documented. We use near-infrared spectroscopy (NIRS) methodology to determine reorganization of brain neurovascular properties following the medication treatment. Twenty-six children with ADHD (ages six through 12) participated in a modified laboratory school protocol to monitor treatment response with lisdexamfetamine dimesylate (LDX; Vyvanse®, Shire US Inc.). All children refrained from taking medication for at least two weeks (washout period). To detect neurovascular reorganization, we measured changes in synchronization of oxy (HbO2) and deoxy (HHb) hemoglobin waves between the two frontal lobes. Participants without medication displayed average baseline HbO2 phase difference at about -7-deg. and HHb differences at about 240-deg.. This phase synchronization index changed after pharmacological intervention. Medication induced an average phase changes of HbO2 after first medication to 280-deg. and after medication optimization to 242-deg.. Instead first medication changed of the average HHb phase difference at 186-deg. and then after medication optimization to 120-deg. In agreement with findings of White et al., and Varela et al., we associated the phase synchronization differences of brain hemodynamics in children with ADHD with lobe specific hemodynamic reorganization of HbO2- and HHB oscillations following medication status.