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Methylphenidate Hydrochloride Modified-Release in Adults with Attention Deficit Hyperactivity Disorder: A Randomized Double-Blind Placebo-Controlled Trial

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. Electronic supplementary material The online version of this article (doi:10.1007/s12325-013-0085-5) contains supplementary material, which is available to authorized users.


INTRODUCTION
Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder commonly identified and well characterized in children and adolescents, with a worldwide pooled prevalence rate of approximately 5% [1]. The core symptoms of ADHD include attention deficit, hyperactivity, and impulsive disturbances which are often associated with impaired executive functioning [2]. ADHD has been considered as a childhood/adolescent disorder. However, recent epidemiologic studies have highlighted its persistence into adulthood with a prevalence rate of 2-5% of the adult population [3][4][5]. To date, many adults remain underdiagnosed and/or untreated due to poor diagnosis and suboptimal transition of medical services from childhood/adolescence to adulthood. Adult ADHD is known to be associated with a wide range of clinical and psychosocial challenges including history of school failure, occupational impairment, family problems, substance abuse, traffic violations, and arrests [6,7]. Furthermore, ineffective treatment of ADHD imposes a socio-economic burden due to elevated healthcare costs, less productivity, and more accidents [8,9]. Treatment options for ADHD include pharmacotherapy, employing either stimulants or non-stimulants, in addition to psychoeducation and cognitive behavioral therapy.
Stimulants like methylphenidate (MPH) and dexamphetamine have always been the first-line therapeutic options for the treatment of both childhood and adult ADHD based on their efficacy and safety data [6,7,10].
Methylphenidate hydrochloride modifiedrelease (MPH-LA) is an extended-release capsule containing a racemic mixture of d-and l-threo-MPH that is currently approved for use in children with ADHD aged 6 years and above in over 30 countries worldwide, including many in the European Union (EU).
According to the consensus statement by the European Network Adult ADHD [11], as well as the guidelines of the National Institute for Health and Clinical Excellence [12], pharmacotherapy should be the first-line treatment for adults with ADHD and MPH should be the treatment of first choice.
However, approval of such treatments for adult ADHD inside and outside the EU is extremely limited. Currently, only two medications are approved for treatment of adult ADHD patients in the EU, that is, atomoxetine and an extended-release (ER) MPH in Germany [13]. In the United States (US) and Switzerland, an extended-release formulation of the d-threo enantiomer of MPH (dexmethylphenidate HCl) is approved for use in adults with ADHD [11].
Growing recognition of the importance of diagnosis and treatment of ADHD in adults together with the current lack of approved drugs for this indication, represent an unmet medical need. In an effort to address this need, the current phase 3 clinical trial was designed to confirm the clinically effective and safe dose range and evaluate the maintenance effect of MPH-LA in adult patients with ADHD.

Study Design and Treatment
This was a 40-week, double-blind, randomized,   were required to discontinue the study due to a lack of therapeutic effect ( Fig. 1).

Study Participants
Adult patients (18- The study protocol was designed in accordance with the EU guideline on studies in ADHD which requires that ''two primary endpoints should be stipulated reflecting the symptomatic and the functional domain'' [14]. Ethics approval was received before the start of the study in compliance with global and local guidelines by ethic committees of the respective countries. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 and 2008. Informed consent was obtained from all patients for being included in the study.

Randomization and Blinding
Randomization was performed at the beginning of the double-blind dose-confirmation phase and the double-blind maintenance of effect phase upon fulfillment of the inclusion/exclusion criteria mentioned above. Patients were randomized to one of the treatment arms using a validated Interactive Voice/Web Response System (IVRS/ IWRS). A unique, confidential randomization number was assigned to each patient and IVRS/ IWRS allocated medication accordingly, as assigned, throughout the respective treatment periods. An unbiased, confidential patient randomization list was produced by the IVRS/ IWRS provider using a validated system that automated the random assignment of patient numbers to randomization numbers. A separate medication randomization list was produced under the responsibility of Novartis Drug Supply Management using a validated system that automated the random assignment of medication numbers to medication packs containing each of the study drugs. The randomization scheme was reviewed and approved by a member of the Biostatistics Quality Assurance Group. All sites and personnel for clinical, medical, statistical, data management and monitoring were blinded, and randomization data were kept strictly confidential until the time of un-blinding after the conclusion of the study. The identity of the treatments has been concealed by the use of study drugs that are all identical in packaging, labeling, schedule of administration, appearance, taste, and odor, in line with Consort guidelines.
Prior to study enrollment, the investigator and the patient jointly decided the most appropriate time of administration of study medication.
The investigator promoted compliance by instructing the patient to take the study drug exactly as prescribed and by stating that compliance was necessary for the patient's safety and the validity of the study.
The patient was instructed to contact the investigator if he/she was unable for any reason to take the study drug as prescribed. After the start of the study, drug patients were not allowed to take psychotropic drugs or other medications that would have interfered with the study assessments. The use of rescue medication was not permitted during the study. Patients whose symptoms were not adequately controlled on study medication were discontinued from the study and treated at the discretion of the investigator.
Compliance was assessed by the investigator and/or study personnel at each visit using pill counts and information provided by the patient.

Efficacy and Safety Endpoints
The primary objectives of this study were to confirm the clinically effective and safe dose of MPH-LA in adults with ADHD and to evaluate the maintenance of effect of MPH-LA in this population. Symptomatic and functional domains were evaluated using the change from baseline to the end of the double-blind dose-confirmation phase (week 9) total score on the physician-rated DSM-IV ADHD RS (range 0-54) [15] and self-rated SDS (range 0-30) [16] as co-primary endpoints. SDS total is composed out of three sub-scores: work, family and social life sub-score. DSM-IV ADHD RS consisted of 18 items directly adapted from the ADHD symptom list according to the DSM-IV, wherein the clinician recorded the frequency of each symptom as reported by the patient for the past week. SDS is a five-item, self-rated questionnaire which measured the extent to which a patient's disability due to an illness or health problem (e.g., anxiety disorder, painful conditions, depression) interferes with three sub-scores assessing work/school, social life/ leisure, and family life/home responsibilities.
Patients were asked to indicate how much their symptoms have disrupted their regular activities over the past week in each of these areas using a scale for each item ranging from 0 ('not at all') to 10 ('extremely'). The SDS scale has been Treatment failures were withdrawn from the study if they fulfilled both of the lack of therapeutic effect discontinuation criteria: (1) 30% or more worsening from baseline of this study phase on DSM-IV ADHD rating scale score AND; (2) less than 30% remaining improvement from the phase 1 baseline score on DSM-IV ADHD rating scale. The denominator for calculating percentage of treatment failures was the number of patients randomized at the start of maintenance of effect phase.
The key secondary endpoint was the proportion of patients with clinical improvement at the end of the initial doubleblind dose-confirmation phase on the physicianrated Clinical Global Impression-Improvement Scale (CGI-I) [17]. CGI-I scale was used to assess the overall change in illness relative to the baseline. The CGI-I scale consisted of seven ratings ranging from 1 ('very much improved') to 7 ('very much worse'). Improvement on CGI-I scale was defined as a visit rating of 1 ('very much improved') or 2 ('much improved').
Other secondary efficacy measurements included the improvement from baseline to end of the double-blind dose-confirmation phase on the physician-rated Clinical Global Impression-Severity scale (CGI-S) [17], the observer-rated Conner's Adult ADHD Rating Scale-Observer (CAARS-O:S) [18], and on the Adult Self-Report Scale (ASRS) total scores [19].
CGI-S scale was used to rate globally, the severity of symptoms on a 7-point scale, give approximately 96% power. Assuming a 20% dropout rate in this initial dose-confirmation phase, a total of 700 randomized patients were required.
Assuming a responder rate of 80% and a dropout rate of 15% during the real-life doseoptimization phase, approximately 380 patients were expected to be re-randomized to placebo and MPH-LA with an allocation ratio of 1:3.
Allowing 40% dropout rate in the double-blind maintenance of effect phase, a total of approximately 230 patients were expected to complete the 6-month double-blind maintenance of effect phase. Assuming a two-sided alpha-level of 0.0083, this number of patients could detect a 30% difference in treatment failure  were not available for LOCF for the third primary efficacy endpoint. The analyses were performed on the intent-to-treat population. The significance levels for the three primary and the key secondary endpoints were determined by a gate-keeping procedure based on the graphical approach to sequentially rejective multiple test procedures [23]. For other secondary endpoints, CGI-S was analyzed using a logistic regression model, and CAARS-O:S and ASRS were evaluated by the ANCOVA model.   Fig. 4a; Table 3).
Similarly, functional improvement, as assessed by change from baseline in the SDS total score, was significantly greater for all MPH-LA dose levels compared to placebo (40 mg, P = 0.0003; 60 mg, P = 0.0176; 80 mg, P\0.0001; Fig. 4b; Table 3). Figure 5 shows

Safety Assessments
Overall   No clinically meaningful differences were observed between treatment groups with respect to laboratory findings, vital signs or ECGs (Table 7b); none of the patients had a QT, QTcB or QTcF C500 ms during the study. One death (51-year-old male patient) was reported 21 days after patient completed the study (21 days after receiving last dose of study medication) due to aortic dissection rupture.
The patient had a history of aortic aneurysm not requiring any medical intervention according to the investigator, and was under the observation of another physician. The investigator did not suspect any relationship to drug.

Main Findings
In this large 40-week, randomized, doubleblind, placebo-controlled trial, the efficacy and failure. The fact that all these patients were exposed to MPH-LA for 5-14 weeks before being   ADHD symptoms persist into adulthood in 40-80% of children with ADHD and the prevalence of ADHD in adults is 2-5% [24,27,28]. With the increasing recognition of ADHD in adults [29,30] and few countries with drugs approved for this indication, efficacy and safety data from well-controlled clinical trials such as the present study are essential for meeting this unmet medical need. Beyond being a wellcontrolled trial, this is the first phase 3 study in adult patients with ADHD, designed to comply with the European Medicines Agency 'Guideline on the clinical investigation of medicinal products for the treatment of ADHD'. The guideline, released in 2010, calls for the inclusion of co-primary endpoints to evaluate both the symptomatic and functional domains in ADHD trials [14]. Therefore, the DSM-IV ADHD RS and the SDS were included as co-primary outcome measures. This is also the first study with MPH in adults with ADHD including a withdrawal design to evaluate maintenance of effect for 6 months, thus providing evidence supporting the management of adult ADHD patients requiring long-term treatment.

Research in Context
From a design perspective, the inclusion of coprimary endpoints to evaluate symptomatic and functional improvement in adult ADHD, together with a third primary endpoint to measure maintenance of treatment effect through a 6-month maintenance of effect phase     AEs adverse events, MPH-LA methylphenidate hydrochloride modified-release, SAEs serious adverse events * Safety analysis set for the real-life dose-optimization phase Table 5 continued AEs adverse events, MPH-LA methylphenidate hydrochloride modified-release, SAEs serious adverse events * Safety analysis set for the double-blind dose-confirmation phase

Limitations
A limitation of the study is the limited external validity, as the protocol did not allow the inclusion of patients with psychiatric co-morbidities. At least one co-morbid condition like anxiety, affective, substance use, or antisocial personality disorder is known to occur in nearly 80% of adults with ADHD [34][35][36]; however, patients with these conditions    [24,34,37].
As many clinicians prefer to use twice-daily dosing to extend coverage for their patients [11], the once-daily dosage regimen used in this study may be considered a limitation. However, the robust efficacy results of this study, particularly the significant patient-rated outcome for functional improvement, do not indicate that once-daily dosing with MPH-LA limited treatment benefit for the majority of patients.
Another limitation due to the design of the study was that the study was not powered to differentiate between the different dose levels, but powered to differentiate between the respective dose and placebo. However, during the second part of the study, which assessed ''optimal dose'' and individualized treatment, a comparable number of patients were optimized, upon the discretion of the  Compliance with ethics guidelines. The study protocol was designed in accordance with the EU guideline on studies in ADHD which requires that ''two primary endpoints should be stipulated reflecting the symptomatic and the functional domain'' [14]. Ethics approval was received before the start of the study in compliance with global and local guidelines by ethic committees of the respective countries. All procedures followed were in accordance with the ethical standards of Open Access. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.