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Multiscale assessment of treatment efficacy in adults with ADHD: a randomized placebo-controlled, multi-centre study with extended-release methylphenidate.

ABSTRACT: This trial was performed to test the efficacy and safety of an extended-release formulation of methylphenidate (MPH ER).A total of 162 adults with ADHD according to DSM-IV were treated for 8 weeks with either two daily individually body weight-adjusted doses of MPH ER up to 1 mg/kg per day (N = 84) or placebo (N = 78). The primary efficacy outcome was the Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS) 8 weeks after randomization. Secondary efficacy measures were the ADHD Diagnostic Checklist (ADHD-DC), the Conners Adult Attention Deficit Disorder Scale (CAARS-S:L), the Clinical Global Impression (CGI) and the Sheehan Disability Scale (SDS).At week 8 a significantly higher decline of the total WRAADDS score was found in the MPH ER group as compared to the placebo group (P = 0.0003). The rates of responders were 50% in the MPH ER and 18% in the placebo group (P < 0.0001). Furthermore, similar effects were observed for the secondary efficacy variable: ADHD-DC score (P = 0.004), CAARS-S:L score (P = 0.008) and the SDS score (P = 0.017). 50% of the MPH ER group and 24.4% of the placebo group were improved "much" or "very much" according to the CGI rating (P = 0.0001). MPH ER treatment was well tolerated. At week 2 also the mean heart rate was significantly higher in the MPH ER group as compared to the placebo group (P = 0.01). No differences between the study groups were observed regarding mean blood pressure at any visit.This clinical trial demonstrated statistically significant and clinical relevant effects of MPH ER in adults with ADHD for several self- and investigator-rated ADHD psychopathology and also functional efficacy measures.

SUBMITTER: Retz W

PROVIDER: S-EPMC3279134 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Multiscale assessment of treatment efficacy in adults with ADHD: a randomized placebo-controlled, multi-centre study with extended-release methylphenidate.

Retz Wolfgang W Rösler Michael M Ose Claudia C Scherag André A Alm Barbara B Philipsen Alexandra A Fischer Roland R Ammer Richard R

The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry 20101214 1

<h4>Objectives</h4>This trial was performed to test the efficacy and safety of an extended-release formulation of methylphenidate (MPH ER).<h4>Methods</h4>A total of 162 adults with ADHD according to DSM-IV were treated for 8 weeks with either two daily individually body weight-adjusted doses of MPH ER up to 1 mg/kg per day (N = 84) or placebo (N = 78). The primary efficacy outcome was the Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS) 8 weeks after randomization. Secondary eff ...[more]

PMID: 21155632

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Project description:Backgroundα2-Adrenoceptor agonists are used adjunctively to psychostimulants in treating attention-deficit/hyperactivity disorder (ADHD) when psychostimulants alone do not sufficiently reduce symptoms. However, data on the pharmacokinetic profiles and safety of combination treatments in ADHD are needed.ObjectiveThe primary objective of this study was to evaluate the pharmacokinetic profiles of guanfacine extended release (GXR) and methylphenidate hydrochloride (MPH) extended release, alone and in combination.Study designThis was an open-label, randomized, three-period crossover, drug-drug interaction study.SettingThe study was conducted at a single clinical research center.ParticipantsThirty-eight healthy adults were randomized in this study.InterventionsSubjects were administered single oral doses of GXR (Intuniv(®); Shire Development LLC, Wayne, PA, USA) 4 mg, MPH (Concerta(®); McNeil Pediatrics, Titusville, NJ, USA) 36 mg, or GXR and MPH combined.Main outcome measuresGuanfacine, dexmethylphenidate (d-MPH), and l-methylphenidate (l-MPH) levels were measured with blood samples collected predose and up to 72 h postdose. Safety evaluations included treatment-emergent adverse events (TEAEs), vital signs, and electrocardiograms (ECGs).ResultsThirty-five subjects completed the study. Analyses of the 90 % confidence intervals (CIs) for the geometric mean ratios of the maximum plasma concentration (Cmax) and area under the concentration-time curve extrapolated to infinity (AUC∞) values for guanfacine and d-MPH following administration of GXR or MPH alone or combined met strict bioequivalence criteria (90 % CIs within the interval of 0.80-1.25). Overall, combining GXR and MPH did not alter the pharmacokinetic parameters of either medication. Sixteen subjects (42.1 %) had at least one TEAE. The most commonly reported TEAEs included headache and dizziness following GXR, MPH, and GXR and MPH combined. Two subjects had clinically significant abnormalities in ECG results following coadministration: both events were mild and resolved the same day.ConclusionsIn this short-term, open-label study of healthy adults, coadministration of GXR and MPH did not result in significant pharmacokinetic drug-drug interactions. No unique TEAEs were observed with coadministration of GXR and MPH compared with either treatment alone.

Project description:BackgroundThe effects of stimulant treatment on sleep in adults with attention-deficit/hyperactivity disorder (ADHD) are complex and varied, with some individuals experiencing worsening of sleep but others experiencing improvement.MethodsData from previously reported trials of the clinical efficacy and safety of the long-acting methylphenidate formulation PRC-063 (Adhansia XR® in the USA; Foquest® in Canada) in adults with ADHD were used to evaluate patient-reported sleep outcomes, as captured using the Pittsburgh Sleep Quality Index (PSQI) and adverse events of insomnia. The trials comprised 4 weeks of randomized, forced-dose PRC-063 treatment at a dose of 0 (placebo), 25, 45, 70, or 100 mg/day followed by an optional 6 months of open-label PRC-063 treatment at an individually optimized dose of 25-100 mg/day.ResultsAt the end of double-blind treatment, PRC-063 (all doses combined; N = 297) showed no significant difference versus placebo (N = 78) in least squares mean change in global PSQI score from baseline (- 0.7 vs. - 1.3; P = 0.0972) or in scores for each of the seven subscales of the PSQI. For patients enrolled in the open-label extension (N = 184), mean ± standard deviation global PSQI score improved from 7.8 ± 3.55 at the end of double-blind treatment to 5.8 ± 3.11 at 1 month and 5.4 ± 3.21 at 6 months (P < 0.0001). A greater proportion of patients were good sleepers (global PSQI score ≤ 5) at the end of the open-label extension (57.3%) than at baseline (20.9%) or at the end of double-blind treatment (26.0%). In a logistic regression analysis, baseline global PSQI score (odds ratio 1.491; P < 0.0001), but not randomized study treatment (P = 0.1428), was a significant predictor of poor sleep (global PSQI score > 5) at the end of double-blind treatment. Adverse event rates for insomnia (15.8 vs. 3.8%) and initial insomnia (6.1 vs. 1.3%) during double-blind treatment were higher for PRC-063 (all doses combined) than for placebo. Two patients receiving PRC-063 in the double-blind study and one patient in the open-label study were withdrawn because of insomnia adverse events.ConclusionsOur findings indicate that, on average, PRC-063 had no significant impact on overall sleep quality in adults with ADHD. Although insomnia was observed as an adverse event, when sleep was measured over time as an outcome in its own right for patients receiving dose-optimized PRC-063 open-label, more patients showed improvement in sleep than deterioration. CLINICALTRIALS.Gov identiferNCT02139124 and NCT02168127.

Project description:Evening-dosed HLD200 is a delayed-release and extended-release methylphenidate (DR/ER-MPH) formulation consisting of uniform, dual-layered microbeads with an inner drug-loaded core. DR/ER-MPH is designed to delay the initial release of drug by 8-10 hours, and thereafter, provide a controlled, extended drug release to target onset of effect upon awakening that lasts into the evening. This phase 3 study evaluated the safety and efficacy of DR/ER-MPH on symptoms and temporal at-home functional impairment in children with attention-deficit/hyperactivity disorder (ADHD).This 3-week, randomized, double-blind, multicenter, placebo-controlled, parallel-group, forced-dose titration trial evaluated DR/ER-MPH (40-80?mg/day) in children aged 6-12 years with ADHD. Primary efficacy endpoint was the ADHD rating scale-IV (ADHD-RS-IV), and the key secondary endpoints were the Before-School Functioning Questionnaire (BSFQ), and Parent Rating of Evening and Morning Behavior-Revised, morning (PREMB-R AM) and evening (PREMB-R PM). Safety measures included spontaneously reported treatment-emergent adverse events (TEAEs) and two TEAEs of special interest, appetite suppression and insomnia (with direct questioning on sleep disturbance).One hundred sixty-one participants were included in the intent-to-treat population (DR/ER-MPH, n?=?81; placebo, n?=?80). After 3 weeks, DR/ER-MPH achieved significant improvements versus placebo in ADHD symptoms (least-squares [LS] mean ADHD-RS-IV: 24.1 vs. 31.2; p?=?0.002), and at-home early morning (LS mean BSFQ: 18.7 vs. 28.4; p?<?0.001; LS mean PREMB-R AM: 2.1 vs. 3.6; p?<?0.001) and late afternoon/evening (LS mean PREMB-R PM: 9.4 vs. 12.2; p?=?0.002) functional impairment. Commonly reported TEAEs (?10%) were insomnia and decreased appetite.DR/ER-MPH was generally well tolerated and demonstrated significant improvements versus placebo in ADHD symptoms and at-home functional impairments in the early morning, late afternoon, and evening in children with ADHD.

Project description:OBJECTIVE:To examine methylphenidate extended-release chewable tablets (MPH ERCT) dose patterns, attention-deficit/hyperactivity disorder (ADHD) symptom scores, and safety during the 6-week, open-label (OL) dose-optimization period of a phase 3, laboratory classroom study. METHODS:Boys and girls (6-12 years) diagnosed with ADHD were enrolled. MPH ERCT was initiated at 20?mg/day; participants were titrated in 10-20?mg/day increments weekly based on efficacy and tolerability (maximum dose, 60?mg/day). Dose-optimization period efficacy assessments included the ADHD Rating Scale (ADHD-RS-IV), analyzed by week in a post hoc analysis using a mixed-effects model for repeated measures with final optimized dose (20, 30/40, or 50/60?mg), visit, final optimized dose and visit interaction, and baseline score as terms. Adverse events (AEs) and concomitant medications were collected throughout the study. RESULTS:Mean MPH ERCT daily dose increased weekly from 29.4?mg/day after the first dose adjustment at week 1 (n?=?90) to 42.8?mg/day after the final adjustment at week 5 (n?=?86). Final optimized MPH ERCT dose ranged from 20 to 60?mg/day. Mean final optimized MPH ERCT dose ranged from 40.0?mg/day in 6-8 year-old participants to 44.8?mg/day for 11-12 year-old participants. There was a progressive decrease in mean (standard deviation) ADHD-RS-IV total score from 40.1 (8.72) at baseline to 12.4 (7.88) at OL week 5, with similar improvement patterns for hyperactivity/impulsivity and inattentiveness subscale scores. Participants optimized to MPH ERCT 50/60?mg/day had a significantly higher mean (standard error) ADHD-RS-IV score at baseline compared with participants optimized to MPH ERCT 20?mg/day (42.4 [1.34] vs. 35.1 [2.55]; p?=?0.013). Treatment-emergent AEs were reported by 65/90 (72.2%) participants in the dose-optimization period. CONCLUSIONS:Dose-optimization period results describing relationships between change in ADHD symptom scores and final optimized MPH ERCT dose will be valuable for clinicians optimizing MPH ERCT dose.

Dataset Information

Multiscale assessment of treatment efficacy in adults with ADHD: a randomized placebo-controlled, multi-centre study with extended-release methylphenidate.

Publications

Multiscale assessment of treatment efficacy in adults with ADHD: a randomized placebo-controlled, multi-centre study with extended-release methylphenidate.

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