Methylphenidate hydrochloride modified-release in adults with attention deficit hyperactivity disorder: a randomized double-blind placebo-controlled trial

Michael Huss, Ylva Ginsberg, Torbjorn Tvedten, Torben Arngrim, Alexandra Philipsen, Katherine Carter, Chien-Wei Chen, Vinod Kumar, Michael Huss, Ylva Ginsberg, Torbjorn Tvedten, Torben Arngrim, Alexandra Philipsen, Katherine Carter, Chien-Wei Chen, Vinod Kumar

Abstract

Introduction: Treatment options for adults with attention deficit hyperactivity disorder (ADHD) are limited. The study was conducted to confirm the clinically effective and safe dose of methylphenidate hydrochloride modified-release (MPH-LA) in adults with ADHD and evaluate the maintenance of effect of MPH-LA.

Methods: The study consisted of three treatment phases. The double-blind dose-confirmation phase: 9-week double-blind period (3-week titration period, 6-week fixed dose) with randomization to MPH-LA 40, 60, or 80 mg/day or placebo. The real-life dose-optimization phase: a 5-week re-titration period to optimal dose; and the double-blind maintenance of effect phase, a 6-month double-blind randomized placebo-controlled maintenance of effect phase. The three co-primary endpoints were change in Diagnostic and Statistical Manual of Mental Disorders-IV ADHD Rating Scale (DSM-IV ADHD RS) and Sheehan Disability Scale (SDS) total scores from baseline to end of 9-week confirmation phase and the percentage of treatment failures during the 6-month maintenance of effect phase.

Results: 725 of 863 screened patients were randomized to 40 (N = 181), 60 (N = 182), or 80 mg (N = 181) MPH-LA or placebo (N = 181), and 584 (80.6%) completed. 489 (83.7%) of completers were re-randomized to the double-blinded maintenance of effect phase and 235 (48.1%) of them completed. Improvement from baseline in DSM-IV ADHD RS (P < 0.0001 for all comparisons) and SDS (40 mg, P = 0.0003; 60 mg, P = 0.0176; 80 mg, P < 0.0001) total scores was significantly greater vs. placebo for all MPH-LA doses. Treatment failure rate was significantly lower with MPH-LA (21.3%) versus placebo (49.6%) during the 6-month maintenance of effect phase. Safety profile was consistent with the profile for MPH-LA in children; percentage of serious adverse events was comparable between all MPH-LA arms (1.3%) and placebo (1.5%), while percentage of adverse events was higher in MPH-LA arms.

Conclusion: MPH-LA provided and maintained significant symptomatic and functional improvement in adult ADHD patients.

Trial registration: ClinicalTrials.gov NCT01259492.

Figures

Fig. 1
Fig. 1
Study design. Study design including the three study phases and extension study: the double-blind dose-confirmation phase, the real-life dose-optimization phase, the double-blind maintenance of effect phase, and the long-term safety extension. d day
Fig. 2
Fig. 2
Patient disposition. FAS full analysis set, GCP good clinical practice, MPH-LA methylphenidate hydrochloride modified-release
Fig. 3
Fig. 3
Response rate on DSM-IV ADHD RS total score at the end of the 9-week double-blind dose-confirmation phase. Responders = patients with at least 30% improvement from baseline to end of the 9-week double-blind dose-confirmation phase. *P values refer to two-sided P value based on the difference between MPH-LA group and placebo. #Full analysis set (all randomized/re-randomized patients who took at least one dose of study medication) for the double-blind dose-confirmation phase. DSM-IV ADHD RS Diagnostic and Statistical Manual of Mental Disorders-IV ADHD Rating Scale, MPH-LA methylphenidate hydrochloride modified-release
Fig. 4
Fig. 4
Primary efficacy endpoints: improvement in DSM-IV ADHD RS (a) and SDS total scores (b) from baseline to the end of the double-blind dose-confirmation phase. DSM-IV ADHD RS Diagnostic and Statistical Manual of Mental Disorders-IV ADHD Rating Scale, MPH-LA methylphenidate hydrochloride modified-release, SDS Sheehan Disability Scale
Fig. 5
Fig. 5
Progression of improvement on DSM-IV ADHD RS total score from baseline to the end of the double-blind dose-confirmation phase by week. *LOCF, last observation carried forward using the final visit for each patient with data in the 6-week fixed-dose phase of double-blind dose-confirmation phase. DSM-IV ADHD RS Diagnostic and Statistical Manual of Mental Disorders-IV ADHD Rating Scale, MPH-LA methylphenidate hydrochloride modified-release
Fig. 6
Fig. 6
Primary efficacy endpoint: percentage of treatment failures during the double-blind maintenance of effect phase. Treatment failures: patient with ≥30% worsening from baseline during the 6-month double-blind maintenance of effect phase and <30% remaining improvement from phase 1 baseline on DSM-IV ADHD RS. Treatment failures were analyzed using a logistic regression model with treatment as the factor and baseline as covariate. Missing post-baseline scores were imputed based on last observation carried forward (LOCF) or based on the multiple imputation approach if data were not available for LOCF. Significance level = 0.05. DSM-IV ADHD RS Diagnostic and Statistical Manual of Mental Disorders-IV ADHD Rating Scale, MPH-LA methylphenidate hydrochloride modified-release

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