This study demonstrated an onset of action for LDX at 1.5 hours (the first postdose time point measured), with duration of efficacy up to 13 hours postdose as assessed during the crossover treatment period. The symptoms of ADHD may extend beyond the school day and continue into afterschool activities and family interactions. This trial is the first to demonstrate duration of efficacy up to 13 hours postdose compared with placebo for an approved oral ADHD stimulant medication and may provide an important treatment option for prolonged ADHD symptom control.
Although pharmacokinetic (PK) data were not collected in this study, data from other studies of adults  and children  may assist in describing this extended duration of action . In both studies, PK data at the 70 mg dose were reported. In healthy adult volunteers, the plasma concentrations showed intact LDX levels reaching their maximum concentration at 1.1 hours after ingestion and then declined to 0 by 5 hours postdose. However, mean plasma levels of d-amphetamine reached their maximum at 3.7 hours and did not approach 0 until 72 hours following the final dose. In fact, the active d-amphetamine was about 18 times that of the intact LDX when drug absorption was compared . In children, the PK data were collected only up to 12 hours postdose. Since the plasma level of d-amphetamine after administration of LDX 70 mg was 86.7 ng/mL at 12 hours , it is reasonable to infer that the d-amphetamine levels would continue to be apparent even beyond the 13-hour time period. Thus, the earlier onset and longer duration of efficacy or therapeutic activity summarized for the present study seem to follow the known PK profile of d-amphetamine and not of intact LDX.
The present study also showed that LDX had a marked and sustained effect on attention, behavior, and math scores, as assessed by the SKAMP and PERMP scales. The therapeutic effects associated with LDX were particularly noticeable with regard to symptoms of inattention, whereby LDX produced sustained efficacy compared with placebo across all time points measured using the SKAMP-A subscale. This study showed significant efficacy and separation from placebo at the first time point of 1.5 hours postdose for the SKAMP-D, SKAMP-A, SKAMP total, and PERMP scales, and at the 2.5-hour time point for SKAMP quality of work subscale. LDX-treated subjects in this study continued to show significant improvement in all SKAMP- and PERMP-measured scales when compared to treatment with placebo at all time points up to and including 13 hours postdose (the last time point assessed).
This study expanded and further refined findings from a previous laboratory school study, due to a larger sample size (129 vs 52), and additional time points assessed predose and 13-hour measurements (-0.5 to 13 hours in this study vs 1 to 12 hours) . In the previous study, treatment effects were observed beginning at 2 hours postdose and continued until 12 hours postdose. In addition, results for CGI-I were similar in these 2 studies, which had similar design and assessment schedules. In the previous study, 74% of LDX-treated subjects were rated as improved (ie, very much or much improved)  compared with 82% of subjects in this study who were rated as improved while on LDX during the crossover phase. Consistent with the previous study, LDX was generally well tolerated with most AEs reported as mild to moderate in severity . The AEs reported here were similar in nature to those reported in studies of other stimulants and included decreased appetite, insomnia, headache, irritability, upper abdominal pain, and affect lability [10, 13, 27–29]. The frequency of newly reported AEs was higher in the noncontrolled phase of this study than is typically observed in stimulant clinical trials for decreased appetite and insomnia. It is unclear why this increased incidence occurred during the open-label phase of this study. It is also unknown if it may be related to the prodrug release profile. However, it should be noted that during the subsequent crossover phase, reported incidence of AEs was generally comparable between LDX and placebo treatments. The rate of discontinuations related to TEAEs was consistent with those seen for other stimulants in similar settings [10, 30, 31].
Predose time points had high (worsened) SKAMP deportment and attention scores in the early morning hours in both groups. However, higher (worse) ratings were evident in the LDX group compared with the placebo group prior to dosing. While there may be multiple factors that contributed to the higher ratings, the group differences may be, in part, related to residual drug from the previous treatment day as has been seen in another study with an amphetamine-based long-acting stimulant . Recent studies of long-acting stimulants examining multiple daily dose PK parameters suggest that residual plasma drug levels from the previous day's dose are measurable before dosing [24, 33].
It is of interest that the onset of LDX efficacy for the SKAMP quality of work scale was an hour later than that seen for the other SKAMP subscales of attention and deportment. This subscale of the SKAMP provides ratings of completeness, correctness, and neatness of assigned work versus other components of attention and interactions with peers and adults during the observation periods. It is possible that the items of this subscale, which are often grouped as a component of SKAMP-A, required a longer interval to separate from placebo.
Modest increases in mean SBP, DBP, and pulse were observed, consistent with the known effects of psychostimulants: typically increases of 2 to 4 mm Hg in blood pressure and 3 to 6 bpm in heart rate are reported [21–23]. As noted earlier, the mean increase in pulse at 12.5 hours postdose for the subjects receiving 70 mg LDX was higher than typically seen. Interestingly, the mean increase in pulse seen at 8.0 hours was lower in this group and in line with pulse changes seen in the placebo group. The present study does not include assessment of PK parameters and, thus, such pharmacologic effects cannot be correlated with relevant blood levels. While 14 subjects had one or more abnormal QT/QTc intervals or abnormal QT/QTc change from baseline, none had an interval ≥ 480 msec, and no clinically meaningful trends were observed in ECG parameters.
Strengths of the study included the use of a controlled laboratory school setting, ratings by trained investigators, and dose optimization, which mimicked dose titration in clinical practice. The blinded design of the crossover phase allowed a more valid assessment of patients at their optimized dosage of LDX versus placebo. Reliability and validity of SKAMP and PERMP scales were other strengths as well as their inclusion as subjective and objective evaluations of efficacy, respectively.
Results should be viewed in light of study design limitations. Consistent with laboratory school study designs, the short treatment duration and assessment phases may provide an underestimate of the number and severity of TEAEs typically seen with lengthier treatment of ADHD. Typical of ADHD studies, subjects with severe comorbid psychiatric conditions were excluded. This may have selected for a study population that under-represents psychiatric comorbidities generally seen in ADHD populations . Where efficacy assessments made during the dose-optimization phase (ADHD-RS-IV and CGI-I) are reported, it should be kept in mind that this was an open-label phase of the study with limitations to interpretation inherent to the unblinded design. While efficacy of LDX compared with placebo was demonstrated up to and including the last time point assessed (13 hours postdose), no measurements beyond 13 hours postdose were captured. Further analysis and future studies will be needed to determine the efficacy of LDX in relieving ADHD symptoms at later time points. Other limitations that may affect the ability to generalize these findings include the uniformly high level of baseline severity of the study subjects, the lack of a group of subjects with inattentive type ADHD, and the under-representation of minority populations.