Study Design and Treatment Regimens
Two randomized, double-blind, multicenter, parallel-group studies (one flexible-dose, one forced-dose) with placebo reference arms were conducted. Each study was conducted in accordance with the International Conference on Harmonisation of Good Clinical Practice and the Declaration of Helsinki. Study protocols and related information were approved by either a central review board or institution-specific review boards and appropriate regulatory agencies (US FDA, Therapeutic Product Directorate of Canada, Medical Products Agency of Sweden, Medical Research Council of Hungary, The Federal Institute for Drugs and Medical Devices [Bundesinstitut für Arzneimittel und Medizinprodukte] of Germany) before study initiation.
Flexible-Dose Study
The flexible-dose study [ClinicalTrials.gov: NCT01552915; Fig. S1A in the Electronic Supplementary Material (ESM)] was conducted at 70 US clinical sites between April 2012 and January 2014; it consisted of a screening and washout phase (up to 4 weeks), 8 weeks of double-blind (i.e., participants and investigators) treatment (dose optimization, 5 weeks; dose maintenance; 3 weeks), and a 1-week follow-up phase.
At the start of double-blind treatment, participants were randomized (2:2:1) using an interactive web-response system (IWRS) to once-daily lisdexamfetamine, OROS-MPH, or placebo, respectively. To maintain blinding, treatments were identical in appearance; participants were also instructed to take one capsule from two separate bottles. Participants randomized to lisdexamfetamine started treatment at 30 mg/day; those randomized to OROS-MPH started treatment at 18 mg/day. Dosages could be raised or lowered by single dose levels at each weekly visit until week 5, when the optimal dose based on tolerability and clinical response (an ADHD-RS-IV total score reduction of ≥30% and CGI-I score of 1 or 2, with tolerable side effects) was established. After week 5, the dose could not be changed. This maintenance dose was continued for 3 weeks (weeks 6–8). Participants unable to tolerate active treatment after week 5 were discontinued. A follow-up telephone call was made 7 (+2) days after the last dose to assess adverse events (AEs) or serious AEs (SAEs), and concomitant medications. Follow-up continued until safety concerns were resolved or the participant returned to their baseline state.
Forced-Dose Study
The forced-dose study (ClinicalTrials.gov: NCT01552902; Fig S1B, in the ESM) was conducted at 77 clinical sites in the USA, Canada, and Europe between April 2012 and May 2014; it consisted of a screening and washout phase (up to 4 weeks), a 6-week double-blind treatment phase (forced titration, 4 weeks; dose maintenance, 2 weeks), and a 1-week follow-up period.
At the start of double-blind treatment, participants were randomized (2:2:1) using an IWRS to once-daily treatment with lisdexamfetamine 70 mg/day, OROS-MPH 72 mg/day, or placebo, respectively. To maintain blinding, treatments were over-encapsulated and identical in appearance; participants were also instructed to take one capsule from two separate bottles. The initial lisdexamfetamine dose (30 mg/day) was increased weekly in 10-mg increments up to 50 mg/day (week 1, 30 mg/day; week 2, 40 mg/day; week 3, 50 mg/day) and then in a 20-mg increment (week 4) to a maximum of 70 mg/day. The initial OROS-MPH dose (18 mg/day) was increased weekly in 18-mg increments to a maximum of 72 mg/day during weeks 2 through 4. For the remaining 2 weeks of treatment, doses were maintained at lisdexamfetamine 70 mg/day and OROS-MPH 72 mg/day. Participants could discontinue at any time because of unacceptable tolerability, but dose reductions were not allowed. Follow-up safety assessments occurred via telephone 7 (+2) days after the last dose of study drug and continued until safety concerns resolved or returned to their baseline state.
Study Population
Both studies enrolled adolescent males and nonpregnant, nonlactating females (13–17 years). Eligible participants were required to weigh > 79.5 lb, have a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) primary ADHD diagnosis, a baseline ADHD-RS-IV total score ≥ 28, and screening and baseline blood pressure values that did not exceed the 90th percentile for age, sex, and height based on US Centers for Disease Control and Prevention (CDC) guidelines. If currently being treated, participants were required to not be completely satisfied with their current ADHD therapy, as judged by the investigator at the baseline assessment; this criterion reflects the ethical requirement to not discontinue treatment in individuals exhibiting a satisfactory response to their current therapy. The participant and the participant’s parent/legally authorized representative were required to provide informed assent and consent and to be willing and able to comply with study requirements.
Participants were excluded if they had a current controlled or uncontrolled comorbid Axis I or II psychiatric diagnosis (except oppositional defiant disorder, which was allowed), with significant symptoms requiring treatment or contraindicating lisdexamfetamine or OROS-MPH treatment. Comorbid psychiatric diagnoses were established using the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present and Lifetime Version–Diagnostic Interview [13]. Participants were excluded if they were considered a suicide risk by the investigator, had previously made a suicide attempt, or were currently demonstrating active suicidal ideation. Additional exclusion criteria were underweight (less than the third percentile) or overweight (> 97th percentile) based on CDC body mass index (BMI) standards for age and sex; a medical or psychiatric condition that could confound safety assessments or increase participant risk; personal or family cardiovascular history or a clinically significant electrocardiogram (ECG) finding; history of suspected substance abuse or dependence (excluding nicotine) or a lifetime history of amphetamine, cocaine, or stimulant abuse and/or dependence; concomitant use of medications with central nervous system effects that could potentially affect study performance; documented allergy or hypersensitivity to amphetamine or methylphenidate; prior failed response to methylphenidate or amphetamine therapy (because it is not ethical to include individuals who do not have a reasonable expectation of deriving benefit from treatment); participation in another clinical study within 30 days before screening.
Efficacy Endpoints
Efficacy was assessed using the ADHD-RS-IV [14] and CGI-I [15]. The ADHD-RS-IV was administered to the parent (while the participant was present) at baseline and at all study visits by a clinician experienced in evaluating adolescent ADHD. The primary efficacy measure was the change in ADHD-RS-IV total score from baseline to end of study (EOS; week 8 in the flexible-dose study, week 6 in the forced-dose study).
ADHD severity was assessed using the CGI−Severity (CGI-S) scale, which rates symptoms from 1 (not ill) to 7 (extremely ill) [15]. The CGI-S was administered at baseline, week 5, and week 8/early termination (ET) in the flexible-dose study and at baseline and week 6/ET in the forced-dose study. Improvement in ADHD severity was assessed using the CGI-I, which rates change from baseline on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). The CGI-I (key secondary endpoint) was administered at all post-baseline visits.
Safety and Tolerability Endpoints
Adverse events were assessed at each visit and categorized by severity, relatedness to treatment, and seriousness. Vital sign assessments included systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse, and weight. Blood pressure and pulse were assessed after the participant had been seated for ≥ 5 min. ECGs were performed after 5 min of rest. The Columbia-Suicide Severity Rating Scale (C-SSRS), a semistructured interview that assesses suicide-related thoughts and behaviors [16], was administered at screening and all post-screening visits.
Statistical Analyses
Statistical analysis of the primary and key secondary efficacy endpoints was conducted in the full analysis set (FAS: all participants taking at least one study drug dose and having at least one post-baseline primary efficacy assessment). Sample size estimates were based on the primary efficacy endpoint. To detect an ES of ≥ 0.35 between lisdexamfetamine and OROS-MPH (90% power at a two-sided significance level of 0.05 using a two-sample t test), a total of 456 participants (placebo 92; lisdexamfetamine 182; OROS-MPH 182) for the flexible-dose study and 542 participants (placebo 108; lisdexamfetamine 217; OROS-MPH 217) for the forced-dose study were planned for randomization after accounting for estimated discontinuation rates of 5 and 20%, respectively.
Change in ADHD-RS-IV total score from baseline to EOS was assessed using a linear mixed-effects model for repeated measures, without imputation for missing data. Treatment, visit, and the treatment × visit interaction were included as factors; baseline score was a covariate; the interaction of baseline score with visit was included in the model. The primary contrast was the comparison of ADHD-RS-IV total score in the lisdexamfetamine versus OROS-MPH groups at EOS [null hypothesis (H
o): there is no difference between the effects of lisdexamfetamine and OROS-MPH on ADHD-RS-IV total score change from baseline]. For CGI-I analyses, scores were dichotomized as improved [very much improved (CGI-I = 1) or much improved (CGI-I = 2)] or not improved (minimally improved through very much worse; CGI-I = 3–7). The percentage of participants considered improved on the dichotomized CGI-I was assessed using a Cochran–Mantel–Haenszel test stratified by baseline CGI-S; missing data were imputed using last observation carried forward.
A fixed-sequence test procedure was applied to the primary and key secondary endpoints for the lisdexamfetamine versus OROS-MPH comparisons. If the H
o for the primary efficacy endpoint was not rejected at the 0.05 significance level, the p-value from the key secondary efficacy analysis result could not be considered statistically significant. Because of this testing hierarchy, only nominal unadjusted p values are reported for assessments of active treatment versus placebo (active treatment–placebo); these values are intended for descriptive purposes only.
Safety and tolerability endpoints were assessed in the safety analysis set (all participants taking at least one study drug dose) and summarized descriptively. Conservative threshold criteria for vital sign outlier analyses, determined based on prior lisdexamfetamine studies and recommendations of professional organizations, were used to capture trends of potential clinical importance. CDC growth charts were used to determine z scores for weight and BMI changes.