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Characteristics of ADHD Symptom Response/Remission in a Clinical Trial of Methylphenidate Extended Release.

ABSTRACT: Clinical trials in attention-deficit/hyperactivity disorder (ADHD) have typically measured outcome using clinician ratings on the Attention-Deficit/Hyperactivity Disorder Rating Scale, Fourth Edition (ADHD-RS-IV) and the Clinical Global Impression-Improvement (CGI-I) scale. Remission has been defined as an endpoint score of less than or equal to 18 on the ADHD-RS-IV (or a mean score of 1). Responders have been defined as patients who achieve a CGI-I score of much or very much improved (1 or 2). There is a lack of agreement in the literature on what percent change in symptoms on the ADHD-RS-IV should be used to define improvement or remission. This study uses data from a clinical trial of a methylphenidate extended release (MPH-MLR; Aptensio XR®) phase III clinical trial to attempt to determine the percent change of symptoms that best corresponds with improvement and remission. Symptom remission at endpoint (ADHD-RS-IV total score ?18) was most closely aligned with a ?46% reduction in ADHD-RS-IV total score. Clinical improvement was most closely aligned with a ?40% reduction in ADHD-RS-IV total score. The three different measures of outcome were strongly aligned during double blind and open label treatment, and were independent of subtype status. Our data suggest that at least 40% improvement in symptoms is needed to achieve a robust response at endpoint.

SUBMITTER: Weiss M

PROVIDER: S-EPMC6517933 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Characteristics of ADHD Symptom Response/Remission in a Clinical Trial of Methylphenidate Extended Release.

Weiss Margaret M Childress Ann A Nordbrock Earl E Adjei Akwete L AL Kupper Robert J RJ Mattingly Greg G

Journal of clinical medicine 20190405 4

Clinical trials in attention-deficit/hyperactivity disorder (ADHD) have typically measured outcome using clinician ratings on the Attention-Deficit/Hyperactivity Disorder Rating Scale, Fourth Edition (ADHD-RS-IV) and the Clinical Global Impression-Improvement (CGI-I) scale. Remission has been defined as an endpoint score of less than or equal to 18 on the ADHD-RS-IV (or a mean score of 1). Responders have been defined as patients who achieve a CGI-I score of much or very much improved (1 or 2). ...[more]

PMID: 30959790

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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: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

Characteristics of ADHD Symptom Response/Remission in a Clinical Trial of Methylphenidate Extended Release.

Publications

Characteristics of ADHD Symptom Response/Remission in a Clinical Trial of Methylphenidate Extended Release.

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