A thorough QT study of guanfacine.

OBJECTIVES: Guanfacine extended- release (GXR) is approved for the treatment of attention-deficit/hyperactivity disorder in children and adolescents. As part of the clinical development of GXR, and to further explore the effect of guanfacine on QT intervals, a thorough QT study of guanfacine was conducted (ClinicalTrials. gov identifier: NCT00672984). METHODS: In this double-blind, 3-period, crossover trial, healthy adults (n = 83) received immediaterelease guanfacine (at therapeutic (4 mg) and supra-therapeutic (8 mg) doses), placebo, and 400 mg moxifloxacin (positive control) in 1 of 6 randomly assigned sequences. Continuous 12-lead electrocardiograms were extracted, and guanfacine plasma concentrations were assessed pre-dose and at intervals up to 24 hours post-dose. QT intervals were corrected using 2 methods: subject-specific (QTcNi) and Fridericia (QTcF). Time-matched analyses examined the largest, baseline-adjusted, drug-placebo difference in QTc intervals. RESULTS: In the QTcNi analysis, the largest 1-sided 95% upper confidence bound (UCB) through hour 12 was 1.94 ms (12 hours postdose). For the 12-hour QTcF analysis, the largest 1-sided 95% UCB was 10.34 ms (12 hours post-supratherapeutic dose), representing the only 1-sided 95% UCB > 10 ms. Following the supra-therapeutic dose, maximum guanfacine plasma concentration was attained at 5.0 hours (median) post-dose. Assay sensitivity was confirmed by moxifloxacin results. Among guanfacine-treated subjects, most treatment-emergent adverse events were mild (78.9%); dry mouth (65.8%) and dizziness (61.8%) were most common. CONCLUSIONS: Neither therapeutic nor supra-therapeutic doses of guanfacine prolonged QT interval after adjusting for heart rate using individualized correction, QTcNi, through 12 hours postdose. Guanfacine does not appear to interfere with cardiac repolarization of the form associated with pro-arrhythmic drugs.

Physician burnout: the effect of time allotted for a patient visit on physician burnout among OB/GYN physicians.

The purpose of this study was to determine the correlation between time allotted for a new OB patient visit and the prevalence of symptoms of burnout among OB/GYNs in Pennsylvania, New Jersey, and Delaware, and to identify some optimal length of patient visit in order to decrease physician dissatisfaction. The survey was limited to the tri-state area of Pennsylvania, New Jersey, and Delaware. We hope the survey can be expanded to a national sample.

Morning and Evening Effects of Guanfacine Extended Release Adjunctive to Psychostimulants in Pediatric ADHD.

OBJECTIVE: To examine efficacy and safety of adjunctive guanfacine extended release (GXR) on morning and evening ADHD symptoms using the Conners' Global Index-Parent (CGI-P) and Before-School Functioning Questionnaire (BSFQ). METHOD: Participants 6 to 17 years with ADHD ( N = 461) and suboptimal psychostimulant response were maintained on current psychostimulants and randomized to dose-optimized GXR (≤4 mg/d) in the morning (GXR AM) or evening (GXR PM), or placebo. RESULTS: CGI-P scores improved with GXR (morning assessment, GXR AM, placebo-adjusted least squares [LS] mean = -1.7, GXR PM = -2.6; evening assessment, GXR AM = -2.4, GXR PM = -3.0; all ps < .01). Parent-rated BSFQ scores reflected improved morning functioning with GXR (GXR AM, placebo-adjusted LS mean = -5.1; GXR PM = -4.7; both ps < .01). Most adverse events were mild or moderate. CONCLUSION: Adjunctive GXR AM or GXR PM was associated with improvements in morning and evening ADHD symptoms in children and adolescents.

Guanfacine extended release adjunctive to a psychostimulant in the treatment of comorbid oppositional symptoms in children and adolescents with attention-deficit/hyperactivity disorder.

OBJECTIVE: The purpose of this study was to assess the effect of guanfacine extended release (GXR) adjunctive to a psychostimulant on oppositional symptoms in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). METHODS: A multicenter, double-blind, placebo-controlled dose-optimization study of GXR (1-4 mg/d) or placebo administered morning (a.m.) or evening (p.m.) adjunctive to psychostimulant was conducted in subjects ages 6-17 with suboptimal response to psychostimulant alone. Suboptimal response was defined as treatment with a stable dose of psychostimulant for ≥4 weeks with ADHD Rating Scale IV total score ≥24 and Clinical Global Impressions-Severity of Illness score ≥3, as well as investigator opinion. Primary efficacy and safety results have been reported previously. Secondary efficacy measures included the oppositional subscale of the Conners' Parent Rating Scale-Revised: Long Form (CPRS-R:L); these are reported herein. RESULTS: Significant reductions from baseline to the final on-treatment assessment on the oppositional subscale of the CPRS-R:L were seen with GXR plus psychostimulant compared with placebo plus psychostimulant, both in the overall study population (placebo-adjusted least squares [LS] mean change from baseline to the final on-treatment assessment: GXR a.m.+psychostimulant, -2.4, p=0.001; GXR p.m.+psychostimulant, -2.2, p=0.003) as well as in the subgroup of subjects with significant baseline oppositional symptoms (GXR a.m.+psychostimulant, -3.6, p=0.001; GXR p.m.+psychostimulant, -2.7, p=0.013). Treatment-emergent adverse events were reported by 77.3%, 76.3%, and 63.4% of subjects in the GXR a.m., GXR p.m., and placebo groups, respectively, in the overall study population. CONCLUSIONS: GXR adjunctive to a psychostimulant significantly reduced oppositional symptoms compared with placebo plus a psychostimulant in subjects with ADHD and a suboptimal response to psychostimulant alone.

Randomized, double-blind trial of guanfacine extended release in children with attention-deficit/hyperactivity disorder: morning or evening administration.

OBJECTIVE: To examine the efficacy and tolerability of guanfacine extended release (GXR) administered in the morning or evening in children with attention-deficit/hyperactivity disorder (ADHD). METHOD: In this multicenter, double-blind, placebo-controlled, dose-optimization study, children 6 to 12 years of age with ADHD were randomized to receive GXR (1-4 mg/d) in the morning and placebo in the evening (GXR am), placebo in the morning and GXR in the evening (GXR pm), or twice-daily placebo. The primary efficacy measure was the ADHD Rating Scale-IV (ADHD-RS-IV). RESULTS: A total of 333 child participants received study drug in the following cohorts: GXR am (n = 107), GXR pm (n = 114), or placebo (n = 112). Mean (standard deviation) changes from baseline to week 8 (visit 10 or last observation carried forward) in ADHD-RS-IV total scores were significant for both GXR treatment groups combined (GXR all-active: -20.0 [12.97]) and separately (GXR am: -19.8 [12.95]; GXR pm: -20.1 [13.04]) compared with placebo (-11.0 [12.93]; p < .001 for all). Most spontaneously-elicited treatment-emergent adverse events were mild or moderate in severity; the most common was somnolence (GXR all-active: 44.3%; GXR am: 46.7%; GXR pm: 42.1%; placebo: 12.5%). CONCLUSIONS: GXR administered either in the morning or evening was associated with significant and clinically meaningful improvements in ADHD symptoms. The levels of response and tolerability observed with GXR were similar regardless of time of dosing (morning versus evening), indicating that once-daily GXR monotherapy is effective whether administered in the morning or evening. Clinical trial registration information-Tolerability and Efficacy of AM and PM Once Daily Dosing With Extended-release Guanfacine Hydrochloride in Children 6-12 With Attention-Deficit/Hyperactivity Disorder (ADHD) (The ADHD Tempo Study.

A controlled trial of extended-release guanfacine and psychostimulants for attention-deficit/hyperactivity disorder.

OBJECTIVE: To examine efficacy, tolerability, and safety of guanfacine extended release (GXR; ≤4 mg/d) adjunctive to a long-acting psychostimulant for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents 6 to 17 years of age with suboptimal, but partial, response to psychostimulant alone. METHOD: In this multicenter, 9-week, double-blind, placebo-controlled, dose-optimization study, subjects (N = 461) continued their stable dose of psychostimulant given in the morning and were randomized to receive GXR in the morning (GXR AM), GXR in the evening (GXR PM), or placebo. Efficacy measures included ADHD Rating Scale IV (ADHD-RS-IV) and Clinical Global Impressions of Severity of Illness (CGI-S) and Improvement (CGI-I) scales. Safety measures included adverse events (AEs), vital signs, electrocardiograms, and laboratory evaluations. RESULTS: At endpoint, GXR treatment groups showed significantly greater improvement from baseline ADHD-RS-IV total scores compared with placebo plus psychostimulant (GXR AM, p = .002; GXR PM, p < .001). Significant benefits of GXR treatment versus placebo plus psychostimulant were observed on the CGI-S (GXR AM, p = .013; GXR PM, p < .001) and CGI-I (GXR AM, p = .024; GXR PM, p = .003). At endpoint, small mean decreases in pulse, systolic, and diastolic blood pressure were observed in GXR treatment groups versus placebo plus psychostimulant. No new safety signals emerged following administration of GXR with psychostimulants versus psychostimulants alone. Most AEs were mild to moderate in severity. CONCLUSIONS: Morning or evening GXR administered adjunctively to a psychostimulant showed significantly greater improvement over placebo plus psychostimulant in ADHD symptoms and generated no new safety signals. Clinical trial registration information-Efficacy and Safety of SPD503 in Combination With Psychostimulants; http://www.clinicaltrials.gov; NCT00734578.

Lisdexamfetamine dimesylate for the treatment of attention deficit hyperactivity disorder in adults with a history of depression or history of substance use disorder.

OBJECTIVE: To evaluate the efficacy and safety of lisdexamfetamine dimesylate in participants with attention deficit hyperactivity disorder and a history of depression and/or substance use disorder. History of these comorbidities was recorded from medical history forms completed by the study clinicians. DESIGN/SETTING: An exploratory, post-hoc analysis was conducted using data from a randomized, double-blind, placebo-controlled, forced-dose titration study of lisdexamfetamine dimesylate. PARTICIPANTS: Adults with attention deficit hyperactivity disorder. MEASUREMENTS: Changes in Attention Deficit Hyperactivity Disorder Rating Scale IV total scores and Clinical Global Impressions-Improvement scale were used to evaluate the efficacy of lisdexamfetamine dimesylate. The incidence of treatment-emergent adverse events was also evaluated. RESULTS: The intention-to-treat population included 36 participants with a history of depression and 17 participants with a history of substance use disorder. Mean changes in Attention Deficit Hyperactivity Disorder Rating Scale IV and Clinical Global Impressions-Improvement from baseline to endpoint for these subpopulations were similar to those of participants without a history of depression and/or history of substance use disorder. Lisdexamfetamine dimesylate was generally well tolerated in all subgroups. CONCLUSION: The response to lisdexamfetamine dimesylate and the treatment-emergent adverse event profiles of participants with a history of depression and/or a history of substance use disorder were similar to those of participants with no history of these disorders. Larger studies that prospectively enroll participants with attention deficit hyperactivity disorder and these comorbid disorders are needed to more conclusively evaluate the safety and efficacy of stimulant treatment in these populations.

Triple-bead mixed amphetamine salts (SPD465), a novel, enhanced extended-release amphetamine formulation for the treatment of adults with ADHD: a randomized, double-blind, multicenter, placebo-controlled study.

INTRODUCTION: The efficacy and safety of triple-bead mixed amphetamine salts (MAS), an oral, once-daily, enhanced extended-release amphetamine formulation designed for a duration of action up to 16 hours, were evaluated in adults with attention-deficit/hyperactivity disorder (ADHD). METHOD: In this phase 3, 7-week, randomized, double-blind, multicenter, placebo-controlled, parallel-group, dose-optimization study of 272 adults with ADHD (DSM-IV-TR criteria), subjects (aged 18 to 55 years) were randomly assigned to triple-bead MAS (starting dose 12.5 mg) or placebo. The primary outcome measure was change in ADHD Rating Scale-IV (ADHD-RS-IV). Secondary outcome measures included Clinical Global Impressions (CGI) scale, Time-Sensitive ADHD Symptom Scale (TASS) (measuring extended duration), Brown Attention-Deficit Disorder Scale (BADDS) (measuring executive function), Adult ADHD Impact Module (AIM-A) (measuring quality of life [QOL]), and ADHD-RS-IV hyperactivity-impulsivity and inattentiveness subscales. Adverse events (AEs), vital signs, electrocardiograms (ECGs), and laboratory data were collected. The trial was conducted from January 2005 to June 2005. RESULTS: Triple-bead MAS resulted in significantly greater improvement versus placebo in mean ADHD-RS-IV total score change (p < .0001), CGI-Improvement (p < .0001), TASS total score at 13-16 hours postdose (p = .002), BADDS total score (p < .0001), all AIM-A domains (p < or = .01), and ADHD-RS-IV subscales (p < .01), demonstrating extended duration of efficacy and improvements in executive function and QOL. The most common treatment-emergent AEs included insomnia, dry mouth, decreased appetite and weight, and headache. Most treatment-emergent AEs were mild or moderate in severity. CONCLUSIONS: Triple-bead MAS was significantly more effective than placebo in treating adult ADHD. The extended duration of action up to 16 hours and significant improvements in executive function and QOL address unique treatment needs of adults with ADHD. Treatment-emergent AEs with triple-bead MAS were consistent with amphetamine treatment.

Attention-deficit/hyperactivity disorder-specific quality of life with triple-bead mixed amphetamine salts (SPD465) in adults: results of a randomized, double-blind, placebo-controlled study.

OBJECTIVE: To assess the quality of life (QOL) in adults with attention-deficit/hyperactivity disorder (ADHD) given triple-bead mixed amphetamine salts (MAS), a long-acting amphetamine formulation designed for a duration of action of up to 16 hours. METHOD: 274 adults with ADHD (DSM-IV-TR criteria) were randomly assigned to 7 weeks of double-blind treatment with an optimal dose of triple-bead MAS (12.5 mg to 75 mg) (N = 137) or placebo (N = 137). As a secondary objective of this study, QOL was assessed on the basis of self-reported Adult ADHD Impact Module (AIM-A) scores, describing ADHD-specific QOL in 6 domains and global QOL (questions 1-4). To assess safety, data were collected on adverse events, vital signs, electrocardiograms, laboratory tests, and sleep quality. The trial was conducted from January 2005 to June 2005. RESULTS: Statistically significant improvement between triple-bead MAS and placebo was observed in all 6 ADHD-specific AIM-A subscales. In addition, statistically significant improvement in global QOL between triple-bead MAS and placebo was seen, based on AIM-A question 1 (p = .0006) and question 4 (p = .0001). Patients' age, gender, race, and prior use of stimulant medication were not found to significantly affect AIM-A subscale scores. The most common treatment-emergent adverse events with triple-bead MAS (insomnia, dry mouth, decreased appetite, headache, and weight decreased) were consistent with amphetamine treatment, and their incidence generally decreased with time. CONCLUSIONS: Adults with ADHD showed significantly improved QOL for both ADHD-specific and global measures with triple-bead MAS in comparison to placebo, based on AIM-A scores. Treatment-emergent adverse events were mostly mild to moderate in intensity and were consistent with amphetamine treatment. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00150579.

Bioavailability of triple-bead mixed amphetamine salts compared with a dose-augmentation strategy of mixed amphetamine salts extended release plus mixed amphetamine salts immediate release.

OBJECTIVE: To compare the single-dose pharmacokinetics of triple-bead mixed amphetamine salts (MAS), an oral, once-daily, enhanced extended-release amphetamine formulation, with MAS extended release (MAS XR) (Adderall XR) + MAS immediate release (MAS IR) administered 8 h later. METHODS: This was a phase I, randomized, open-label, single-dose, single-center, two-period, crossover study in healthy adult volunteers designed to evaluate the bioavailability of triple-bead MAS over the course of a full day. Subjects were randomized to triple-bead MAS 37.5 mg or MAS XR 25 mg + MAS IR 12.5 mg administered 8 h later (MAS XR + MAS IR). The reference treatment was designed to mimic the clinical practice of providing extended coverage by supplementing a morning dose of MAS XR with a dose of MAS IR 8 h later in order to increase the duration of action. Plasma was assayed for d-amphetamine and l-amphetamine. Treatment-emergent adverse events (TEAEs), vital signs, electrocardiograms (ECGs), and laboratory data were also collected for safety evaluation. RESULTS: Exposure to d- and l-amphetamine was equivalent between triple-bead MAS and MAS XR + MAS IR based on maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time 0 to infinity (AUC(0-infinity)). For Cmax, least-squares mean ratios comparing triple-bead MAS with MAS XR + MAS IR were 101.0% and 90.9% for d-amphetamine and l-amphetamine, respectively, and for AUC(0-infinity) were 104.4% and 95.3% for d-amphetamine and l-amphetamine, respectively. Median time to maximum observed plasma concentration (Tmax) values for d-amphetamine and l-amphetamine were 8.0 h for triple-bead MAS and 10.0 h for MAS XR + MAS IR. There were no clinically meaningful differences between the study formulations for TEAEs or laboratory values. One subject experienced an ECG abnormality (asymptomatic premature ventricular contractions) leading to early termination from the study. CONCLUSIONS: In healthy adults, the exposure observed with triple-bead MAS 37.5 mg was bioequivalent to MAS XR 25 mg supplemented by MAS IR 12.5 mg administered 8 h later. These data demonstrate that a single morning dose of triple-bead MAS provides equivalent plasma concentrations to those observed with a dose-augmentation strategy of MAS XR in the morning followed by MAS IR in the afternoon, while minimizing peak-to-trough fluctuations. Triple-bead MAS was also generally well-tolerated in this study.