The methods used in this study for the overall study population have been described previously . This was a multicenter, randomized, double-blind, forced-dose titration, parallel-group study, conducted in accordance with the Guideline for Good Clinical Practice from the World Health Organization and the Declaration of Helsinki and its amendments.
Biederman et al previously described full inclusion/exclusion criteria . Briefly, children aged 6 to 12 years who met DSM-IV-TR criteria for a primary diagnosis of ADHD  and had a ADHD Rating Scale IV (ADHD-RS-IV) [19, 20] score of ≥ 28 at baseline after washout were eligible for inclusion, regardless of medication used for ADHD at screening.
The study comprised a 1-week screening period; a 1-week washout period of prior psychoactive medications; and 4-weeks of double-blind treatment. During screening, participants received an initial ADHD-RS-IV evaluation. Participants receiving medication for ADHD at enrollment were allowed to continue their medication during the screening evaluation. After screening, the parents/caregivers of eligible participants were instructed to discontinue their prior ADHD medications, if they had not already done so.
Baseline assessments were made after the 1-week washout. Participants were randomized in a 1:1:1:1 ratio (using a block-randomization schedule) to receive double-blind, oral administration of LDX 30 mg/day for 4 weeks, 50 mg/day (30 mg/day for week 1, 50 mg/day for weeks 2 to 4), 70 mg/day (30 mg/day for week 1, 50 mg/day for week 2, 70 mg/day for weeks 3 and 4), or placebo for 4 weeks.
Efficacy Outcome Measures
The primary efficacy outcome was the change in mean ADHD-RS-IV total score from baseline to treatment endpoint, defined as the last postrandomization week for which a score was obtained. ADHD-RS-IV total score assessments were based on investigator interviews with the caregiver and child regarding symptom severity during the preceding week.
Secondary efficacy measures included ADHD-RS-IV total scores at screening, baseline, and endpoint; percent change in ADHD-RS-IV total score; the Conners' Parent Rating Scale-Revised (CPRS-R: Short Form) ; and the investigator-rated Clinical Global Impressions (CGI) scale . The CGI-Severity (CGI-S) assessment was conducted at the baseline visit and the CGI-Improvement (CGI-I) assessment was conducted at subsequent visits.
Efficacy was assessed in the overall efficacy population, all participants who had ADHD-RS-IV scores recorded at baseline and at least one other postrandomization time point.
Post Hoc Efficacy Analyses
This post hoc efficacy analysis assessed treatment effects of LDX and placebo in participants receiving MPH prior to entering the present study, who had available screening data and significant ADHD symptoms prior to discontinuing their MPH regimen. Efficacy was further evaluated according to mean daily MPH dose received (≥ 1 mg/kg vs < 1 mg/kg) during prior treatment.
Rates of symptomatic remission and clinical response were evaluated throughout the study in participants receiving prior MPH therapy and the efficacy population.
Steele et al  suggested that treatment response be considered as an improvement in symptom scores from baseline of 25% to 30%. However, reductions from baseline do not take into account potential differences in baseline severity of disease. Participants with severe symptoms at baseline may be considered responders but still exhibit symptoms. Hence, a clinical response definition that includes a percent reduction in symptoms and a measure of global clinical improvement, such as the CGI-I, may be a better measure of clinical response to treatment. Moreover, other studies have shown that a 1-level change on the CGI-I was consistent with an estimated 10- to 15-point or 25% to 30% change from baseline in ADHD-RS-IV total score .
In the primary analysis , Biederman et al reported on the ADHD-RS-IV (primary outcome measure) and CGI-I (secondary outcome measure) as continuous measures. In this present analysis, clinical response to LDX treatment was defined as a dual criteria of ≥ 30% reduction in ADHD-RS-IV total score from baseline and a CGI-I score of 1 or 2 at endpoint based on data from previous reports defining response [23, 25]; symptomatic remission was defined as ADHD-RS-IV total score of ≤ 18 . Conversely, nonremitters on prior MPH were defined as participants with an ADHD-RS-IV total score > 18 while receiving MPH prior to entering the study. Number-needed-to-treat (NNT) for 1 participant to achieve a therapeutic clinical response or symptomatic remission at treatment endpoint was calculated to translate the efficacy data into more clinically meaningful terms.
Safety assessments, in enrolled participants who received at least 1 dose of study medication, have been reported previously . Briefly, these included adverse events (AEs), electrocardiograms (ECGs), blood pressure (BP), heart rate, and laboratory assessments. Treatment-emergent AEs (TEAEs) were coded using the Medical Dictionary for Regulatory Activities version 7.1 . TEAEs referred to events with onset after the first date of treatment and no later than 3 days following termination of treatment. No separate assessments were performed in nonremitters on prior MPH due to low sample numbers and no reason to expect differences in safety/tolerability in these participants.
ADHD-RS-IV total and CPRS-R ADHD Index scores were summarized as mean (standard deviation [SD]). Mean change in ADHD-RS-IV total score for the overall population was assessed using 2-way analysis of covariance. Dunnett test for multiple mean comparisons with least-squares adjustment was used to compare change from baseline in the 3 active treatment groups versus placebo. NNT to achieve 1 clinical responder or 1 symptomatic remitter was calculated as the reciprocal of the difference in proportions of clinical responders or symptomatic remitters on active treatment and placebo at treatment endpoint.