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Cost-effectiveness of extended-release methylphenidate in children and adolescents with attention-deficit/hyperactivity disorder sub-optimally treated with immediate release methylphenidate.

ABSTRACT: Attention-Deficit/Hyperactivity Disorder (ADHD) is a common psychiatric disorder in children and adolescents. Immediate-release methylphenidate (IR-MPH) is the medical treatment of first choice. The necessity to use several IR-MPH tablets per day and associated potential social stigma at school often leads to reduced compliance, sub-optimal treatment, and therefore economic loss. Replacement of IR-MPH with a single-dose extended release (ER-MPH) formulation may improve drug response and economic efficiency.To evaluate the cost-effectiveness from a societal perspective of a switch from IR-MPH to ER-MPH in patients who are sub-optimally treated.A daily Markov-cycle model covering a time-span of 10 years was developed including four different health states: (1) optimal response, (2) sub-optimal response, (3) discontinued treatment, and (4) natural remission. ER-MPH options included methylphenidate osmotic release oral system (MPH-OROS) and Equasym XL/Medikinet CR. Both direct costs and indirect costs were included in the analysis, and effects were expressed as quality-adjusted life years (QALYs). Univariate, multivariate as well as probabilistic sensitivity analysis were conducted and the main outcomes were incremental cost-effectiveness ratios.Switching sub-optimally treated patients from IR-MPH to MPH-OROS or Equasym XL/Medikinet CR led to per-patient cost-savings of €4200 and €5400, respectively, over a 10-year treatment span. Sensitivity analysis with plausible variations of input parameters resulted in cost-savings in the vast majority of estimations.This study lends economic support to switching patients with ADHD with suboptimal response to short-acting IR-MPH to long-acting ER-MPH regimens.

SUBMITTER: van der Schans J

PROVIDER: S-EPMC4449164 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Cost-effectiveness of extended-release methylphenidate in children and adolescents with attention-deficit/hyperactivity disorder sub-optimally treated with immediate release methylphenidate.

van der Schans Jurjen J Kotsopoulos Nikos N Hoekstra Pieter J PJ Hak Eelko E Postma Maarten J MJ

PloS one 20150529 5

<h4>Background</h4>Attention-Deficit/Hyperactivity Disorder (ADHD) is a common psychiatric disorder in children and adolescents. Immediate-release methylphenidate (IR-MPH) is the medical treatment of first choice. The necessity to use several IR-MPH tablets per day and associated potential social stigma at school often leads to reduced compliance, sub-optimal treatment, and therefore economic loss. Replacement of IR-MPH with a single-dose extended release (ER-MPH) formulation may improve drug re ...[more]

PMID: 26024479

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Project description:Guanfacine extended release (GXR) and atomoxetine (ATX) are nonstimulant treatments for attention-deficit/hyperactivity disorder (ADHD). As nonstimulant treatments are often used after stimulants in ADHD, GXR was assessed relative to prior stimulant treatment in a randomized controlled trial (RCT), in which ATX was included as a reference arm, and in the open-label phase of a randomized-withdrawal study (RWS). Participants were 6-17 years old with ADHD Rating Scale version IV (ADHD-RS-IV) scores ≥32 and Clinical Global Impressions - Severity scores ≥4. RCT participants received dose-optimized GXR (1-7 mg/day), ATX (10-100 mg/day), or placebo for 10-13 weeks. RWS participants received dose-optimized GXR (1-7 mg/day) for 13 weeks. Participants' last stimulant medication prior to enrolment, and reasons for stopping this medication, were collected at baseline. Change from baseline ADHD-RS-IV score and the proportion of responders were assessed by prior stimulant exposure. Of 163 RCT and 296 RWS participants who had previously received stimulant treatment, 142 and 224, respectively, had received methylphenidate (MPH); due to the low number of participants and the heterogeneity of non-MPH treatments, we only report data for prior MPH treatment. The most frequent reasons for stopping MPH were lack of effectiveness or side effects. Placebo-adjusted ADHD-RS-IV changes from baseline were significant in participants receiving GXR (prior MPH, -9.8, P<0.001, effect size [ES] 0.85; stimulant-naïve, -7.6, P<0.001, ES 0.65). In ATX-treated participants, significant placebo-adjusted differences were seen in stimulant-naïve (-5.0, P=0.022, ES 0.43) but not prior MPH-treated (-1.8, P>0.05, ES 0.15) participants. More participants met responder criteria with GXR versus placebo, regardless of prior treatment. GXR response was unaffected by prior stimulant treatment; ATX produced improvement only in stimulant-naïve participants relative to placebo. These findings may be relevant to clinical decision-making regarding sequencing of ADHD treatments.

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:This phase 3, laboratory classroom study assessed the efficacy and safety of methylphenidate hydrochloride extended-release chewable tablets (MPH ERCT) compared with placebo in children with attention-deficit/hyperactivity disorder (ADHD).Following a 6-week, open-label, dose-optimization period, children 6-12 years of age (n?=?90) with ADHD were randomly assigned to double-blind MPH ERCT at the final optimized dose (20-60?mg/day) or placebo. After 1 week of double-blind treatment, efficacy was assessed predose and 0.75, 2, 4, 8, 10, 12, and 13 hours postdose in a laboratory classroom setting. The primary efficacy measure was the average of postdose Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Rating Scale-Combined scores, analyzed using a mixed-model, repeated-measures analysis. Secondary efficacy measures included Permanent Product Measure of Performance (PERMP) total number of problems attempted and total number of problems correct. Safety assessments included adverse event (AE) monitoring and the Columbia-Suicide Severity Rating Scale (C-SSRS).MPH ERCT treatment statistically significantly reduced the average of all postdose SKAMP-Combined scores versus placebo (least-squares mean difference [95% confidence interval], -7.0 [-10.9, -3.1]; p?<?0.001). Statistically significant treatment differences in SKAMP-Combined scores were observed at 2 hours postdose through 8 hours postdose (p-values <0.001). Statistically significant differences between MPH ERCT and placebo in PERMP total number of problems attempted and total number of problems correct were observed at 0.75 hours postdose through 8 hours postdose (p-values ?0.049). Common AEs in the open-label period (?5%) were decreased appetite, upper abdominal pain, mood swings, irritability, insomnia, upper respiratory tract infection (URTI), dysgeusia, and headache; URTI was the only AE reported by >1 subject receiving MPH ERCT in the double-blind period (placebo: URTI, contusion, wound, and initial insomnia). No suicidal ideation or behavior was reported on the C-SSRS at baseline or at any postbaseline assessment.MPH ERCT 20-60?mg significantly improved ADHD symptoms compared with placebo at 2 hours postdose through at least 8 hours postdose. MPH ERCT was generally safe and well tolerated, with a safety profile consistent with other MPH ER formulations. ClinicalTrials.gov Identifier: NCT01654250. www.clinicaltrials.gov/ct2/show/NCT01654250 .

Project description:ObjectiveTo evaluate measures of sleep (exploratory endpoints) in two pivotal studies of a multilayer bead extended-release methylphenidate (MPH-MLR) treatment of attention-deficit/hyperactivity disorder in children.MethodsStudy 1 evaluated the time course of response to MPH-MLR (n = 26) patients in an analog classroom setting through four phases: screening (≤28 days), open label (OL) dose optimization (4 weeks), double-blind (DB) crossover (2 weeks; placebo vs. optimized dose), and follow-up call. Study 2 was a forced-dose parallel evaluation of MPH-MLR (n = 230) in four phases: screening (≤28 days), DB (1 week; placebo or MPH-MLR 10, 15, 20, or 40 mg/day), OL dose optimization (11 weeks), and follow-up call. Sleep was evaluated by parents using the Children's or Adolescent Sleep Habits Questionnaire (CSHQ or ASHQ) during the DB and OL phases. DB analysis: Study 1 (crossover), analysis of variance; Study 2, analysis of covariance. OL analysis: paired t-test.ResultsDB: treatments were significantly different in Study 1 only for CSHQ Sleep Onset Delay (MPH-MLR, 1.90 vs. placebo, 1.34; p = 0.0046, placebo was better), and Study 2 for CSHQ Parasomnias (treatment, p = 0.0295), but no MPH-MLR treatment was different from placebo (pairwise MPH-MLR treatment to placebo, all p ≥ 0.170). OL: CSHQ total and Bedtime Resistance, Sleep Duration, Sleep Anxiety, Night Wakings, Parasomnias, and Sleep-disordered Breathing subscales decreased (improved, Study 1) significant only for CSHQ Night Wakings (p < 0.05); in Study 2 CSHQ total and Bedtime Resistance, Sleep Duration, Night Wakings, Parasomnias, and Daytime Sleepiness, and ASHQ total, Bedtime, Sleep Behavior, and Morning Waking all significantly improved (p < 0.05).ConclusionsIn both studies, there was minimal negative impact of MPH-MLR on sleep during the brief DB phase and none during the longer duration OL phase. Some measures of sleep improved with optimized MPH-MLR dose.

Project description:ObjectiveCurrent extended-release (ER) formulations of psychostimulants used for treatment of attention-deficit/hyperactivity disorder (ADHD) provide an extended duration of ADHD symptom control; however, the onset of efficacy can be protracted and variable, leaving the early morning untreated. The primary objective was to characterize the single-dose pharmacokinetics and tolerability of HLD200, an evening-dosed, delayed-release (DR) and ER formulation of methylphenidate (MPH), in healthy adults and in adolescents and children with ADHD.MethodsThe pharmacokinetics and tolerability of a single, oral evening dose of HLD200 (54 mg) were evaluated in two single-center open-label studies: the first in healthy adults (n = 12) and the second in adolescents (n = 18) and children (n = 11) with ADHD. Primary pharmacokinetic endpoints were the rate and extent of MPH absorption (Cmax and area under the curve [AUC]) and time to peak concentration (Tmax). These parameters were calculated using noncompartmental analysis.ResultsHLD200 produced a pharmacokinetic profile characterized by an 8- to 10-hour delay in MPH release, followed by a period of extended controlled release, resulting in an ascending absorption profile that coincided with the early morning and afternoon. Mean values (coefficient of variation [CV]%) of weight-adjusted pharmacokinetic parameters were similar in adults and in adolescents and children with ADHD: Cmax ([ng/mL]/[mg/kg]) was 9.1 (35.2), 8.8 (34.5), and 7.4 (30.1); AUC0-t ([ng · h/mL]/[mg/kg]) was 126.5 (35.5), 129.4 (34.8), and 129.7 (27.3); and Tmax (hours) was 15.6 (11.1), 17.1 (14.5), and 17.7 (14.1), respectively. Intersubject variability in the mean time to achieve ascending plasma MPH concentrations of 2, 3, 4, and 5 ng/mL was low (CV: 7.8%-17.7%).ConclusionsEvening-dosed HLD200 produces the intended DR and ER pharmacokinetic profile that provides a consistent predictable delay in initial MPH release until the early morning, followed by extended release across the day. The body weight-adjusted pharmacokinetics of HLD200 were similar between adults and adolescents and children with ADHD.

Dataset Information

Cost-effectiveness of extended-release methylphenidate in children and adolescents with attention-deficit/hyperactivity disorder sub-optimally treated with immediate release methylphenidate.

Publications

Cost-effectiveness of extended-release methylphenidate in children and adolescents with attention-deficit/hyperactivity disorder sub-optimally treated with immediate release methylphenidate.

Similar Datasets

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