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

Richard H. Weisler, Michael Greenbaum, Valerie Arnold, Ming Yu, Brian Yan, Margo Jaffee, Brigitte Robertson

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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/m 2 ), 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.

Original languageEnglish (US)
Pages (from-to)685-697
Number of pages13
JournalCNS Drugs
Volume31
Issue number8
DOIs
StatePublished - Aug 1 2017

Fingerprint

Amphetamine
Attention Deficit Disorder with Hyperactivity
Salts
Placebos
Safety
Therapeutics
Sleep Initiation and Maintenance Disorders
Suicide
Clinical Studies
Bruxism
Weights and Measures
Impulsive Behavior
Vital Signs
Appetite
Least-Squares Analysis
Diagnostic and Statistical Manual of Mental Disorders
Headache
Registries
Pulse
Mouth

All Science Journal Classification (ASJC) codes

  • Clinical Neurology
  • Psychiatry and Mental health
  • Pharmacology (medical)

Cite this

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. / Weisler, Richard H.; Greenbaum, Michael; Arnold, Valerie; Yu, Ming; Yan, Brian; Jaffee, Margo; Robertson, Brigitte.

In: CNS Drugs, Vol. 31, No. 8, 01.08.2017, p. 685-697.

Research output: Contribution to journalArticle

@article{849c618f5be540189345dfed1d754eec,
title = "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",
abstract = "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/m 2 ), 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.",
author = "Weisler, {Richard H.} and Michael Greenbaum and Valerie Arnold and Ming Yu and Brian Yan and Margo Jaffee and Brigitte Robertson",
year = "2017",
month = "8",
day = "1",
doi = "10.1007/s40263-017-0455-7",
language = "English (US)",
volume = "31",
pages = "685--697",
journal = "CNS Drugs",
issn = "1172-7047",
publisher = "Adis International Ltd",
number = "8",

}

TY - JOUR

T1 - Efficacy and Safety of SHP465 Mixed Amphetamine Salts in the Treatment of Attention-Deficit/Hyperactivity Disorder in Adults

T2 - Results of a Randomized, Double-Blind, Placebo-Controlled, Forced-Dose Clinical Study

AU - Weisler, Richard H.

AU - Greenbaum, Michael

AU - Arnold, Valerie

AU - Yu, Ming

AU - Yan, Brian

AU - Jaffee, Margo

AU - Robertson, Brigitte

PY - 2017/8/1

Y1 - 2017/8/1

N2 - 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/m 2 ), 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.

AB - 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/m 2 ), 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.

UR - http://www.scopus.com/inward/record.url?scp=85023750497&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85023750497&partnerID=8YFLogxK

U2 - 10.1007/s40263-017-0455-7

DO - 10.1007/s40263-017-0455-7

M3 - Article

VL - 31

SP - 685

EP - 697

JO - CNS Drugs

JF - CNS Drugs

SN - 1172-7047

IS - 8

ER -