This Phase 1, open-label, single-dose, one-period, one-treatment PK study enrolled 12 children 6-12 y with ADHD. PK parameters for d- and l-amphetamine in plasma (Cmax, tmax, AUC0-8, and t1/2) were ...calculated and expressed as means, geometric means, and standard deviations. The primary endpoint was all objective PK measurements at 28 hours post-dose. PK was evaluated for 2 cohorts (6 pts ages 6-9 y and 6 pts aged 10-12 y). Safety was monitored continuously and assessed based on occurrence of adverse events.
A single dose of 10 mg (4 ml) AMPH EROS (2.5 mg/ml) administered under fasted conditions resulted in a rapid rise in mean plasma concentration in d-amphetamine, reaching maximum concentrations within 5 hours. The overall study population mean (SD) plasma AUC0-8 (d-amphetamine) was 1061.2 (309) h*ng/mL, and for l-amphetamine was 380.5 (112) h*ng/mL. The mean maximum concentration (Cmax) for the overall study population was 54.91 ng/mL and 17.1 (5.2) ng/mL for d- and l-amphetamine, respectively. The overall study population median time to maximum concentrations (Tmax) for d-amphetamine were reached at 3.4 hours, and for l-amphetamine at 4.1 hours. The elimination half-life (t1/2) for the entire study cohort was 10.6 (2.0) hours for d-amphetamine, and 12.5 (3.2) hours for l-amphetamine. Directionally, a higher mean Cmax, AUC0-8, AUCt, and median Tmax were observed in the younger (6 to 9-year-old) age group, and this result was consistent with both the d- and l-amphetamine enantiomers. The mean elimination t1/2 for both d- and l-amphetamine was higher in the older cohort (10-12 years) than in the 6 to 12-year-olds. Study drug was well-tolerated by the subjects in this study. Two TEAEs were reported in one subject TEAEs (diarrhea and rash on legs) occurred approximately 12 hours postdose.
This study confirmed that the PK profile of AMPH EROS in 6 to 12-year-olds provided a consistent, predictable extended-release profile in a highly titratable liquid formulation, and this finding was relatively consistent and directionally predictable between the age groups assessed, with higher maximum concentrations and AUCs and shorter elimination half-lives noted in the younger population, with no anomalous parameters demonstrated, and no untoward or unexpected safety issues noted.
Tris Pharma, Inc.
Objective:
DR/ER-MPH (formerly HLD200) is an evening-dosed delayed-release and extended-release methylphenidate approved for the treatment of ADHD in patients ≥6 years. Post hoc analyses of two ...pivotal Phase 3 trials: HLD200-107 (NCT02493777) and HLD200-108 (NCT02520388) evaluated emotional lability (EL) with DR/ER-MPH treatment.
Methods:
Differences in Conners Global Index—Parent (CGI-P) EL subscale scores and age- and gender-adjusted T-scores over an open-label titration phase (HLD200-107) and between treatment and placebo groups at endpoint (HLD200-108) were evaluated.
Results:
In HLD200-107 (N = 117) mean CGI-P EL subscale scores improved from 5.3 to 1.3 (p < .0001) after 6 weeks; in HLD200-108 significant improvements were observed in the treatment group (n = 81) versus placebo (n = 80; 3.11 vs. 4.08; p = .0053). T-scores showed an improvement with DR/ER-MPH treatment in both trials. Few emotional adverse events (AEs) were reported.
Conclusion:
DR/ER-MPH treatment resulted in statistically significant improvements in EL to the level of non-ADHD peers as contextualized by T-scores.
Attention-deficit/hyperactivity disorder (ADHD) is a neurobehavioral disorder defined by persistent inattention and/or hyperactivity and impulsivity. These symptoms occur more frequently and are more ...severe in individuals with ADHD compared with those at a similar developmental level without ADHD, and can be conceptualized as deficits in executive functioning (EF). EF includes domains of metacognition and inhibition, which influence the ability to regulate responses elicited by emotional stimuli. EF deficits can lead to emotional lability (EL), which is characterized by sudden changes in emotion and behaviors of inappropriately high intensity that may include sudden bouts of anger, dysphoria, sadness, or euphoria. EL is common and estimated to occur in about 3.3-10% of the population. Recent estimates of EL prevalence in children and adolescents with ADHD range from 38 to 75%. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition does not include EL in diagnostic criteria for ADHD, but does include ADHD-associated features of low frustration tolerance, irritability, or mood lability. The neurobiological basis of EL is not well understood, but brain imaging studies support dividing EF into "cool" cognitive networks encompassing attention and planning activities, and "hot" motivational networks involved in temporal discounting, reward processing, and reward anticipation. Dysfunction in "hot" networks is thought to be related to EL. EL symptoms are associated with more severe ADHD and co-morbidities, have significant impact on functioning, and may respond to treatment with medications frequently used to treat ADHD. Treatment outcomes and areas for future research are discussed.
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).
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).
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:
< 0.001), averaged over the classroom day (SKAMP CS:
< 0.001), and in the late afternoon/evening (PREMB-R PM:
= 0.003) in the intent-to-treat population (
= 117). Average PERMP-A (
= 0.006) and PERMP-C (
= 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.
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.
The ADHD Rating Scale (ADHD-RS) assesses 18 symptoms of inattention and hyperactivity/impulsivity and has been used in many clinical trials to evaluate the treatment effect of drugs on ADHD. The ...fifth edition of this scale (ADHD-RS-5) also assesses the impact of inattention and hyperactivity/impulsivity symptoms on six domains of functional impairment (FI): family relationships, peer relationships, completing/returning homework, academic performance at school, controlling behavior at school, and self-esteem. Here, we report the effect of viloxazine extended-release capsules (viloxazine ER), a novel nonstimulant treatment for ADHD in children and adolescents (ages 6-17 years), on FI from a post hoc analysis of four randomized, double-blind, placebo-controlled Phase 3 clinical trials (N=1354).
ADHD-RS-5 investigator ratings of ADHD symptoms and FIs were conducted at baseline and weekly post-baseline for 6-8 weeks in the four trials. Change from baseline (CFB) in ADHD-RS-5 FI scores (Total score sum of 12 FI items and Inattention and Hyperactivity/Impulsivity subscale scores sum of 6 corresponding FI items) and the 30% and 50% Responder Rates (ADHD-RS-5 FI Total score) were compared between viloxazine ER and placebo.
The reduction (improvement) in ADHD-RS-5 FI scores (Total and subscale scores) and the percentage of responders (30% and 50%) at Week 6 were significantly greater in each viloxazine ER dose group vs placebo. In the 100-400 mg/day viloxazine ER groups, improvements were found as early as Week 1 (100-mg/day) or Week 2 (200-, 400-mg/day) of treatment. Analysis of individual items of ADHD-related FIs demonstrated that the effect of viloxazine ER was observed across all domains of impairment.
Significant improvements observed in ADHD-related FIs are consistent with the reduction in inattention and hyperactivity/impulsivity symptoms demonstrated in the viloxazine ER Phase 3 pediatric trials. Therefore, viloxazine ER provides clinically meaningful improvement of ADHD symptoms and functioning in children and adolescents with ADHD, starting as early as Week 1-2 of treatment.
Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral disorder associated with a wide range of impairments. Psychostimulants are generally first-line pharmacotherapy, but ...symptom improvement is suboptimal in some patients. In these patients, clinicians frequently use a combination of psychostimulants and nonscheduled medications to manage ADHD, although published evidence supporting this practice was relatively scarce until recently.
Guanfacine extended release (GXR), a selective alpha2A-adrenoceptor agonist, is approved as a monotherapy and adjunctive therapy to psychostimulant medications for ADHD in patients 6–17 years of age. Drug-drug interaction studies have demonstrated that the adjunctive administration of GXR with a long-acting methylphenidate preparation or lisdexamfetamine dimesylate did not change exposure to the active components of either medication in a clinically meaningful way compared with either treatment alone.
Data supporting the potential efficacy of GXR adjunctive to psychostimulants were preliminarily observed in a 9-week, open-label, dose-escalation study and subsequent extension study (≤ 24 months) in subjects aged 6–17 years with suboptimal control of ADHD symptoms on psychostimulant monotherapy. In a subsequent 9-week, randomized, double-blind, placebocontrolled study of subjects aged 6–17 years with suboptimal response to a long-acting, extendedrelease, oral psychostimulant, adjunctive GXR (administered in the morning or evening) was associated with significantly greater symptom reduction than placebo and psychostimulant (ADHD Rating Scale IV ADHD-RS-IV total score, placebo-adjusted least squares mean reductions: GXR AM, −4.5,
P
= 0.002; GXR PM, −5.3,
P
< 0.001, based on Dunnett’s test). Across multiple studies, the safety and tolerability profile of GXR administered adjunctively to psychostimulants has been consistent with the known profiles of each medication. Additional studies should further explore the role of adjunctive GXR in clinical practice to help identify those patients most likely to benefit from such therapy.
To determine whether amphetamine extended-release oral suspension (AMPH EROS) has an onset of effect at 30 minutes postdose in children with attention-deficit/hyperactivity disorder (ADHD).
This ...randomized, double-blind, two-treatment, two-sequence, placebo-controlled crossover pilot study enrolled subjects aged 6-12 years with ADHD and ADHD-Rating Scale-5 scores of ≥90th percentile for sex and age. An optimized dose of 5-20 mg/day of AMPH EROS was determined during a 1-week open-label dose optimization phase based on medication history, symptom control, and tolerability. Subjects completed a practice laboratory classroom then received 1 day of double-blind active drug or placebo each in random sequence during two double-blind laboratory classroom days. Subjects completed the first double-blind laboratory classroom, returned to open-label drug for 5 days, and then crossed over on day 6 during a second double-blind laboratory classroom. Double-blind dose was fixed at AMPH EROS 15, 17.5, or 20 mg. The primary end point was change from predose in the Swanson, Kotkin, Agler, M-Flynn, Pelham-Combined (SKAMP-C) Rating Scale score at 30 minutes postdose on two double-blind days. The key secondary end points were change from predose in the SKAMP-C score at 3 hours postdose for AMPH EROS compared with placebo and change from baseline Permanent Product Measure of Performance (PERMP) scores at 30 minutes and 3 hours postdose compared with placebo. Safety assessments included vital signs and adverse events (AEs).
Eighteen subjects were enrolled in the study (14 males and 4 females) with a mean age of 9 years. At both 30 minutes and 3 hours postdose, changes from baseline in SKAMP-C for AMPH EROS versus placebo were statistically significant (p < 0.01 and p = 0.0002, respectively). PERMP scores were not statistically significantly improved at 30 minutes postdose for AMPH EROS relative to the placebo group. PERMP scores were statistically significantly improved at 3 hours postdose for AMPH EROS relative to the placebo group (PERMP problems attempted treatment difference least-squares LS mean SE = 60.3 12.93, p = 0.0003; PERMP problems correct treatment difference LS mean SE = 61.6 13.16, p = 0.0003). AEs (>10%) during the open-label phase included upper respiratory tract infection, fatigue, upper abdominal pain, headache, decreased appetite, and affect lability.
AMPH EROS was effective in reducing ADHD symptoms at 30 minutes postdose as indicated by SKAMP-C score improvement, although improvements in PERMP scores at 30 minutes were not statistically significant. AEs were mild or moderate and consistent with those of other extended-release amphetamines.
Lisdexamfetamine dimesylate (LDX) is indicated for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children 6 to 12 years of age and in adults. In a previous laboratory school ...study, LDX demonstrated efficacy 2 hours postdose with duration of efficacy through 12 hours. The current study further characterizes the time course of effect of LDX.
Children aged 6 to 12 years with ADHD were enrolled in a laboratory school study. The multicenter study consisted of open-label, dose-optimization of LDX (30, 50, 70 mg/d, 4 weeks) followed by a randomized, placebo-controlled, 2-way crossover phase (1 week each). Efficacy measures included the SKAMP (deportment primary and attention secondary) and PERMP (attempted/correct) scales (secondary) measured at predose and at 1.5, 2.5, 5, 7.5, 10, 12, and 13 hours postdose. Safety measures included treatment-emergent adverse events (AEs), physical examination, vital signs, and ECGs.
A total of 117 subjects were randomized and 111 completed the study. Compared with placebo, LDX demonstrated significantly greater efficacy at each postdose time point (1.5 hours to 13.0 hours), as measured by SKAMP deportment and attention scales and PERMP (P < .005). The most common treatment-emergent AEs during dose optimization were decreased appetite (47%), insomnia (27%), headache (17%), irritability (16%), upper abdominal pain (16%), and affect lability (10%), which were less frequent in the crossover phase (6%, 4%, 5%, 1%, 2%, and 0% respectively).
In school-aged children (6 to 12 years) with ADHD, efficacy of LDX was maintained from the first time point (1.5 hours) up to the last time point assessed (13.0 hours). LDX was generally well tolerated, resulting in typical stimulant AEs.
Official Title: A Phase IIIb, Randomized, Double-Blind, Multi-Center, Placebo-Controlled, Dose-Optimization, Cross-Over, Analog Classroom Study to Assess the Time of Onset of Vyvanse (Lisdexamfetamine Dimesylate) in Pediatric Subjects Aged 6-12 With Attention-Deficit/Hyperactivity Disorder. ClinicalTrials.gov Identifier: NCT00500149 http://clinicaltrials.gov/ct2/show/NCT00500149.
PDF
