Objective:
To evaluate the treatment effect size throughout the day of amphetamine extended-release oral suspension (AMPH EROS; Tris Pharma, Inc., Monmouth Junction, NJ, USA) in a laboratory ...classroom study conducted in children aged 6–12 years with attention-deficit/hyperactivity disorder (ADHD).
Methods:
A
post hoc
analysis was performed to assess the overall effect size as well as the effect size at each time point from early morning through evening (1, 2, 4, 6, 8, 10, 12, and 13 hours postdose) for each efficacy measure evaluated in a 5-week, randomized, dose-optimized, double-blind, placebo-controlled, laboratory classroom assessment, efficacy, and safety study of AMPH EROS (
N
= 99). Change from baseline of the primary (Swanson, Kotkin, Agler, M-Flynn, Pelham SKAMP-C) and key secondary (secondary efficacy assessments included the SKAMP attention SKAMP-A, SKAMP-deportment subscale SKAMP-D, Permanent Product Measure of Performance-number of problems attempted PERMP-A, PERMP-number of problems correct PERMP-C) efficacy measures were analyzed using a linear mixed model repeated-measures analysis model. Comparisons among treatments were adjusted for multiple comparisons using the Bonferroni method. The effect size was estimated using Cohen's
d
, to determine “small,” (0.2), “medium,” (0.5), or “large” (0.8) magnitudes of treatment effects.
Results:
Large overall effect sizes were observed for all primary and key secondary efficacy assessments. Moreover, the SKAMP-C, PERMP-number of problems attempted, and PERMP-C scores showed large effect sizes at each time point evaluated across the day, from 1 to 13 hours postdose. The SKAMP-A and SKAMP-D scores showed a medium to large effect size at each time point.
Conclusions:
AMPH EROS demonstrated a large and consistent effect size across the day, including early in the morning, in the treatment of symptoms of ADHD in children aged 6–12 years. Trial Registration:
clinicaltrials.gov
identifier: NCT02083783
Attention-deficit/hyperactivity disorder (ADHD) is a neurobehavioral disorder characterized by pervasive impairment in symptoms of inattention, hyperactivity, and impulsivity. Psychopharmacologic ...treatment is targeted at the management of symptoms of ADHD, and evidence exists that ADHD persists into adulthood. Clinical practice guidelines recommend a combination of behavior therapy and psychostimulant medication for the treatment of ADHD in children, adolescents, and adults. Psychostimulants are often prescribed for ADHD in adults, and amphetamine long has been considered a mainstay of treatment for this population. As adult patients seek relief from ADHD symptoms early in the workday and into the early evening hours, with fewer required doses, extended-release formulations with an early onset of efficacy and an extended duration of effect are considered very desirable. The amphetamine-extended release tablet (AMPH ER TAB) was developed to provide a portable, easy-to-use amphetamine tablet dosage option that can be chewed or swallowed whole.
To evaluate the efficacy and safety of an Amphetamine Extended-Release Tablet (AMPH ER TAB) in adults with ADHD aged 18 to 60 years. Methods: In a 5-week forced dose-titration phase, eligible subjects were randomized to either oral double-blind AMPH ER TAB 5 mg starting dose or matching placebo, once daily in the morning beginning the day after the Baseline Visit. Subjects were titrated up (5 mg increments) each week. Safety and efficacy assessments were done weekly. After Visit 3, subjects received 20 mg for 14 (3) days before Visit 5 (V5). Subjects who could not tolerate study drugs discontinued. A Permanent Product Measure of Performance (PERMP) placement test was done at Screening or Baseline. At V5, efficacy assessments included the administration of serial PERMPs predose, 0.5, 1, 2, 4, 8, 10, 12, 13, and 14 hours postdose. The primary efficacy endpoint was the mean PERMP-T score across postdose time points during the Visit 5 serial PERMPs. Safety was monitored by AEs assessed at each visit, C-SSRS, vital signs, weight, and assessment of sleep, appetite, mood, and psychotic AEs.
The mean postdose PERMP-T score over all postdose time points at V5 was statistically significantly higher in the AMPH ER TAB group vs placebo (302.8 vs 279.6; P = .0043). Common adverse events were decreased appetite, insomnia, and dry mouth. The majority of TEAEs were mild to moderate in severity, and no SAEs were reported.
The AMPH ER TAB demonstrated efficacy in the treatment of symptoms of ADHD in adults, with an anticipated safety profile.
Tris Pharma, Inc.
This open-label, single-dose, randomized, two-period, two-treatment, two-sequence, crossover study evaluated the comparative bioavailability between amphetamine extended-release oral suspension ...(treatment A: AMPH EROS, Dyanavel XR 2.5 mg/mL, 18.8 mg amphetamine base per 7.5 mL) and extended-release mixed amphetamine salts (treatment B: ER MAS, Adderall XR 30 mg capsules, equivalent to 18.8 mg amphetamine base per capsule) after a single dose in healthy adult subjects, under fasted conditions.
The crossover design allowed for intra-subject PK comparisons. Relative comparable bioavailability was determined by a statistical comparison of the AUC and Cmax parameters for both d- and l-amphetamine, where the geometric mean ratios for AUC and Cmax were within the 90% confidence limits (80.0%-125.0%) to determine comparable bioavailability between test products. Subjects in sequence 1 received treatment A followed by B; subjects in sequence 2 received treatment B followed by treatment A. PK samples were obtained at 0 (pre-dose) through 60 hours post-dose. The safety assessment was based on reported frequency and severity of adverse events.
Thirty (30) subjects were enrolled and 28 completed. The mean age of subjects was 35 years, with a mean BMI of 25.9 kg/m2. Most subjects were Male (63.3%) and Black (56.7%). The geometric mean ratios for Cmax and all AUC measurements were within the 80-125% bound indicating comparable bioavailability between both test products. Both test products were generally well-tolerated with no serious AEs reported.
The bioavailability of a single 7.5 mL dose of AMPH EROS 2.5 mg/mL was comparable to a single 30 mg capsule dose of ER MAS. AMPH EROS (both d- and l-amphetamine) showed equivalent peak and overall exposure to ER MAS under fasted conditions.
Tris Pharma, Inc.
Purpose: This single-dose pivotal study evaluated the pharmacokinetics of amphetamine extended-release oral suspension (AMPH EROS) under fasted and fed conditions and the relative bioavailability of ...AMPH EROS and immediate-release mixed amphetamine salts (IR MAS) in adults. Methods: This open-label, randomized, three-period, three-treatment, six-sequence crossover study enrolled 30 healthy adult participants who were randomly assigned to receive either 1 dose of AMPH EROS 18.8 mg under fed or fasted conditions or 30 mg of IR MAS under fasted conditions. Participants crossed over with a 7-day washout period between each of the three periods. Plasma samples were measured for Cmax, AUC0-t, AUC0-5, AUC5-t, and AUC0-∞ for comparative bioavailability. Results: The geometric mean ratios for Cmax, AUC0-t, and AUC0-∞ were within the 90% confidence limits 80.0%, 125.0% for comparable bioavailability. There was no food effect for AMPH EROS. Both the AMPH EROS and IR MAS formulations were generally well tolerated with no serious adverse events reported. Conclusions: The bioavailability of a single dose of AMPH EROS was comparable to two 15 mg doses of IR MAS, given 4 hr apart, with no food effect or safety concerns observed.
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.
In two Phase III studies, lisdexamfetamine dimesylate (LDX) reduced binge eating (BE) days/week in adults with moderate to severe binge eating disorder (BED) and was associated with improvement based ...on the Clinical Global Impressions-Improvement (CGI-I) scale. In this study, post hoc analyses examined the relationships between clinical observations and clinical rating scales in individuals with BED.
NCT01718483 (ClinicalTrials.gov/ct2/show/NCT01718483); NCT01718509 (ClinicalTrials.gov/ct2/show/NCT01718509).
Two 12-week, double-blind, placebo-controlled studies randomized (1:1) adults meeting
, Fourth Edition, Text Revision, BED criteria and with protocol-defined moderate to severe BED (study 1, N=383; study 2, N=390) to placebo or dose-optimized LDX (50 or 70 mg). Assessments included the number of BE days/week, CGI-Severity (CGI-S) and CGI-I scores, and Yale-Brown Obsessive Compulsive Scale modified for Binge Eating (Y-BOCS-BE) total scores. For these post hoc analyses, data were pooled across studies and treatment arms. Statistical assessments included Spearman correlations and equipercentile linking analyses (ELA). Reported
-values are nominal (descriptive and not adjusted for multiplicity).
At baseline, nominally significant correlations with CGI-S scores were reported for BE days/week (
=0.374;
<0.0001) and Y-BOCS-BE total scores (
=0.319;
<0.0001). Baseline ELA for CGI-S further characterized this relationship: a CGI-S score of 4 (moderately ill) corresponding to 3.504 BE days/week and a Y-BOCS-BE total score of 18.6. Nominally significant correlations with CGI-I scores were reported for changes from baseline at study endpoint for BE days/week (
=0.647;
<0.0001) and Y-BOCS-BE total scores (
=0.741;
<0.0001). ELA for CGI-I scores at study endpoint showed that a CGI-I score of 1 (very much improved) corresponds to a reduction from baseline of 4.504 BE days/week and 19.4 points for Y-BOCS-BE total score.
These post hoc analyses suggest that indices of global disease severity and improvement positively correlate with BE behavior and with obsessive and compulsive features of BED, measured by the Y-BOCS-BE, supporting the clinical relevance of BED treatment outcomes.
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