Dataset Information

Pharmacokinetics, Safety, and Tolerability of SHP465 Mixed Amphetamine Salts After Administration of Multiple Daily Doses in Children Aged 4-5 Years with Attention-Deficit/Hyperactivity Disorder.

ABSTRACT:

Background

Given the limited treatment options for younger children with attention-deficit/hyperactivity disorder (ADHD), a clinical study for SHP465 treatment was warranted.

Objectives

We aimed to evaluate the pharmacokinetics, safety, and tolerability of SHP465 mixed amphetamine salts (MAS) 6.25 mg after multiple once-daily doses in children aged 4-5 years with ADHD.

Methods

In this open-label multicenter study, SHP465 MAS 6.25 mg once daily was administered for 28 days to children aged 4-5 years with ADHD; baseline ADHD Rating Scale-5 total score ≥ 28 (boys) or ≥ 24 (girls) and Clinical Global Impression-Severity scale score ≥ 4. Blood samples were collected in the pharmacokinetic-rich group predose on day 1 week 1 and day 7 week 4 (predose, postdose at 2, 5, 8, 12, 16, 24, and 48 hours); and in the pharmacokinetic-sparse group predose on day 1 weeks 1, 2, and 3 and 24 hours postdose on day 7 week 4 . Key pharmacokinetic parameters included maximum plasma drug concentration (C_max), plasma trough drug concentration, time to C_max during a dosing interval (t_max), area under the concentration-time curve from time 0 to time of last collected sample, area under the concentration-time curve over the dosing interval (24 h) at steady state (AUC_tau,ss), first-order rate constant associated with the terminal phase of elimination, terminal half-life (t_1/2), total clearance of drug from plasma after oral administration, and apparent volume of distribution at steady state. Safety endpoints included treatment-emergent adverse events and vital signs.

Results

Mean ± standard deviation age and body mass index of 24 participants (66.7% male) were 4.8 ± 0.41 years and 17.2 ± 3.18 kg/m², respectively. The most common ADHD was the combined presentation (91.7%); ratings were 50% markedly ill and 45.8% moderately ill on the Clinical Global Impression-Severity scale. Plasma d-amphetamine and l-amphetamine steady state was attained by predose on treatment day 8, consistent with the half-life. Peak steady-state plasma concentration (median t_max) for both d-amphetamine and l-amphetamine occurred at 7.92 h postdose on day 7 week 4 and thereafter declined monoexponentially, with a geometric mean t_1/2 of 10.4 and 12.3 h for d-amphetamine and l-amphetamine, respectively. For both d-amphetamine and l-amphetamine, C_max and AUC_tau,ss were comparable between children aged 4 years (n = 3) and children aged 5 years (n = 8) regardless of sex. In total, 14 treatment-emergent adverse events were reported by 45.8% (11/24) of participants. Five treatment-emergent adverse events, reported for four (16.7%) participants, were considered treatment related; affect lability occurred in two (8.3%) participants, and insomnia, accidental overdose, and increased blood pressure each occurred in one (4.2%) participant.

Conclusions

In children aged 4-5 years with ADHD, following multiple once-daily administrations of SHP465 MAS 6.25 mg, the pharmacokinetic profile of plasma d-amphetamine and l-amphetamine was generally consistent among participants. Between-individual variability of plasma d-amphetamine and l-amphetamine steady-state exposure was low to moderate. SHP465 MAS was generally well tolerated in this study.

Trial registration

ClinicalTrials.gov, NCT03327402 (31 October, 2017).

SUBMITTER: Ilic K

PROVIDER: S-EPMC8732812 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.

Project description: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.

Project description: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.

Project description: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.

Project description: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).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.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.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.

Project description:ImportanceAdult attention-deficit/hyperactivity disorder (ADHD) is prevalent but often unrecognized, in part because it tends to co-occur with other disorders such as substance use disorders. Cocaine use disorder is one such disorder with high co-occurrence of ADHD.ObjectiveTo examine whether treatment of co-occurring ADHD and cocaine use disorder with extended-release mixed amphetamine salts is effective at both improving ADHD symptoms and reducing cocaine use.Design, setting, and participantsThirteen-week, randomized, double-blind, 3-arm, placebo-controlled trial of participants meeting DSM-IV-TR criteria for both ADHD and cocaine use disorder conducted between December 1, 2007, and April 15, 2013, at 2 academic health center substance abuse treatment research sites. One hundred twenty-six adults diagnosed as having comorbid ADHD and cocaine use disorder were randomized to extended-release mixed amphetamine salts or placebo. Analysis was by intent-to-treat population.InterventionsParticipants received extended-release mixed amphetamine salts (60 or 80 mg) or placebo daily for 13 weeks and participated in weekly individual cognitive behavioral therapy.Main outcomes and measuresFor ADHD, percentage of participants achieving at least a 30% reduction in ADHD symptom severity, measured by the Adult ADHD Investigator Symptom Rating Scale; for cocaine use, cocaine-negative weeks (by self-report of no cocaine use and weekly benzoylecgonine urine screens) during maintenance medication (weeks 2-13) and percentage of participants achieving abstinence for the last 3 weeks.ResultsMore patients achieved at least a 30% reduction in ADHD symptom severity in the medication groups (60 mg: 30 of 40 participants [75.0%]; odds ratio [OR] = 5.23; 95% CI, 1.98-13.85; P < .001; and 80 mg: 25 of 43 participants [58.1%]; OR = 2.27; 95% CI, 0.94-5.49; P = .07) compared with placebo (17 of 43 participants [39.5%]). The odds of a cocaine-negative week were higher in the 80-mg group (OR = 5.46; 95% CI, 2.25-13.27; P < .001) and 60-mg group (OR = 2.92; 95% CI, 1.15-7.42; P = .02) compared with placebo. Rates of continuous abstinence in the last 3 weeks were greater for the medication groups than the placebo group: 30.2% for the 80-mg group (OR = 11.87; 95% CI, 2.25-62.62; P = .004) and 17.5% for the 60-mg group (OR = 5.85; 95% CI, 1.04-33.04; P = .04) vs 7.0% for placebo.Conclusions and relevanceExtended-release mixed amphetamine salts in robust doses along with cognitive behavioral therapy are effective for treatment of co-occurring ADHD and cocaine use disorder, both improving ADHD symptoms and reducing cocaine use. The data suggest the importance of screening and treatment of ADHD in adults presenting with cocaine use disorder.Trial registrationclinicaltrials.gov Identifier:NCT00553319.

Project description:ObjectiveWe sought to determine the dose-response effects of extended-release (ER) dexmethylphenidate (d-MPH) and ER mixed amphetamine salts (MAS) on objective measures of sleep.MethodsThis was an 8-week, double-blind, placebo-controlled, randomized, two period, crossover study of youth with attention-deficit hyperactivity disorder (ADHD) as confirmed by the Kiddie Schedule for Affective Disorders for School-Age Children-Present and Lifetime version (K-SADS-PL). Children aged 10-17 years were recruited from clinical practice, colleague referrals, and flyers. Participants were randomized to initially receive either d-MPH or MAS. During each 4-week drug period, children received three dose levels (10, 20, and 25/30 mg) in ascending order, with placebo substituted for active medication in a randomized fashion during 1 week of the study. After 4 weeks, participants were switched to the alternative medication for another 4 weeks of treatment. The main outcome measure was sleep duration as measured by actigraphy. Children, parents, and researchers were blinded to drug, dose, and placebo status.ResultsSixty-five participants met the inclusion criteria and were enrolled in the study. Of these, 37 participants with sufficient sleep data for analysis were included. Sleep schedule measures showed a significant effect for dose on sleep start time (F(1,36) = 6.284; p < 0.05), with a significantly later sleep start time when children were receiving 20- or 30-mg doses, compared with placebo (p < 0.05). A significant dose effect was found on actual sleep duration (F(1,36) = 8.112; p < 0.05), with significantly shorter actual sleep duration for subjects receiving 30 mg compared with those receiving placebo (p < 0.05). There were no significant differences on sleep duration or sleep schedule between the two stimulant medications. The trial is complete and closed to follow-up.ConclusionsHigher stimulant doses were associated with reduced sleep duration and later sleep start times, regardless of medication class.Trial registrationClinicalTrials.gov: NCT00393042.