A total of 134 patients were screened, and 56 patients met criteria for ADHD (n = 20) and ADHD+D (n = 36). A total of 47 patients, 16 in the ADHD group and 31 in the ADHD+D group, completed the study. Figure displays the patient disposition. The patient population for this study was predominantly male (70%), and the median age was 12.6 years and 11.4 years for the ADHD and ADHD+D groups, respectively. Demographic characteristics, including weight, origin, and age, were similar between both groups, with the exception of height. The ADHD subtype was comparable between groups, with most patients diagnosed as predominantly combined (54%) or inattentive (43%) subtype. Whereas the K-BIT IQ composite mean baseline score was comparable between both groups, the ADHD group had a statistically significantly lower K-BIT matrices mean subtest standard score (99.9 ± 13.6) compared with the ADHD+D group (109.5 ± 10.3; p = .004). The K-TEA mean baseline scores were numerically similar between groups (p ≥ .118). The mean final prescribed dose was 1.29 mg/kg/day. Table presents the patient baseline demographics.
Disposition of Patients. Abbreviations: ADHD = attention-deficit/hyperactivity disorder; ADHD+D = ADHD with dyslexia; ATX = atomoxetine.
Extension Phase Baseline Patient Characteristics
The primary efficacy measure was the ADHDRS-IV total score. Similar statistically significant mean change improvement was demonstrated in both the ADHD and ADHD+D groups on ADHDRS-IV total score (-20.2 ± 2.8 and -17.7 ± 2.5, respectively; p < .001 for both groups) and the subscores for inattention (-11.0 ± 1.6 and -10.4 ± 1.4, respectively; p < .001 for both groups) and hyperactive/impulsivity (-8.5 ± 1.4 and -7.7 ± 1.2, respectively; p < .001 for both groups). There was no differentiation of response between the 2 groups on total score and the inattentive and hyperactive/impulsivity subscores (p = .503, p = .769, p = .660, respectively). Figure presents the ADHDRS-IV total score mean change over time, which further supports improvements in both groups at every time-point throughout the study (p < .001).
Figure 2 ADHDRS-IV Total Scores Over 16 Weeks of Treatment. Abbreviations: ADHD = attention deficit-hyperactivity disorder; ADHD+D = ADHD with dyslexia; ADHDRS-IV = ADHD Rating Scale-IV-Parent Version: Investigator Administered and Scored. * p < .001 for (more ...)
The secondary efficacy outcome measure of the LPS-C showed statistically significant adaptive function improvement and agreement between the investigator-rated and parent-rated versions of the scale. Mean change from baseline to endpoint was statistically significant for both groups, though there were no differences between groups.
One of the key secondary objectives in this study was to assess the effects of atomoxetine on K-TEA measures in patients with ADHD or ADHD+D after 16 weeks of treatment. Patients with ADHD and ADHD+D demonstrated statistically significant improvements in mean standard scores and age equivalencies in all K-TEA reading decoding, reading comprehension, reading composite, and spelling measures (p values < .05), with the following exception: The ADHD reading decoding standard score (p = .08) and the ADHD+D spelling standard scores (p = .14) were not statistically significantly improved (Table ). Baseline measures in the ADHD+D group for reading comprehension and reading composite and spelling measures were numerically lower compared to the ADHD group. The mean change improvements from baseline to endpoint in reading comprehension and reading composite measures were statistically significant for both groups, and there were no statistically significant differences between the groups. The baseline for mean age equivalency (measured in months) was numerically lower for the ADHD+D group for reading comprehension and reading composite compared to the ADHD group. At endpoint, the mean change improvements were statistically significant for both groups. When evaluating improvement by visit, the K-TEA mean reading composite standard score and age equivalency score, reading comprehension standard score, and reading decoding age equivalencies improvements were statistically significant after 4 weeks of treatment and continued to improve after 8 and 16 weeks of treatment for both the ADHD and ADHD+D groups. Improvements in mean reading comprehension standard scores and age equivalencies, and the spelling age equivalencies were statistically significant after 8 weeks of treatment and continued to improve until the end of study for both groups (p ≤ .021). No differences between groups were observed for any of the analyses.
K-TEA Mean Baseline-to-Endpoint Scores
Another key secondary objective evaluated performance on the WMTB-C. For the ADHD group, the mean component and standard scores for central executive function (CE) were statistically significantly improved from baseline to endpoint (p ≤ .032; Table ). Likewise, the listening recall mean score, a subtest of the CE, was statistically significantly greater from baseline to endpoint (p = .02). Patients with ADHD+D demonstrated statistically significant improvements on the phonological loop (PL) standard score (p = .03) as well as the PL non-word list recall subtest (p = .004). No baseline-to-endpoint improvements were noted for the visuo-spatial sketchpad (VSP) standard or component scores for either group.
WMTB-C Mean Standard and Component Baseline-to-Endpoint Scores
A by-visit analysis of the least squares (LS) mean changes for the WMTB-C revealed a statistically significantly greater improvement at the last week for patients with ADHD over the ADHD+D group on the CE standard (p = .003) and component scores (p = .012; Figure ). Subtests of the CE function tests for the ADHD group revealed statistically significant improvements on the listening recall after 8 and 16 weeks of treatment (p ≤ .04) and backward digit recall mean scores at the end of treatment (p = .002). The ADHD group also gained improvements on the PL subtests for non-word list recall after 8 weeks of treatment, which continued to improve until the end of treatment (p < .04). Conversely, patients with ADHD+D demonstrated statistically significant improvement on the PL total standard and component score after only 4 weeks of treatment and continued to improve at every visit throughout the study. PL subtests for the ADHD+D group showed statistically significant gains for the ADHD+D group after 8 weeks of treatment that continued to the end of treatment for word list recall (p < .02) and non-word list recall (p < .01) tests, and statistically significant improvement on the PL digit recall subtest was realized by the end of the study (p < .04). Finally, the baseline-to-endpoint analyses did not reveal significant changes for the VSP component or standard scores for either group. However, the repeated measure analyses (by visit) of the VSP component and standard scores demonstrated statistically significant improvement for patients in the ADHD+D group but only at the end of 16 weeks of treatment (p < .03).
Figure 3 WMTB-C Component Scores Over 16 Weeks of Treatment. Abbreviations: WMTB-C = Working Memory Test Battery for Children; ADHD = attention deficit-hyperactivity disorder; ADHD+D = ADHD with dyslexia; PL = phonological loop; CE = central executive; VSP = visuo-spatial (more ...)
Pearson correlations between the ADHDRS-IV and K-TEA and WMTB-C were calculated. Only the ADHDRS-IV total score, and hyperactivity and inattentive subscores were statistically significantly correlated to the K-TEA Reading Comprehension standard score, though the correlation coefficients were weak (r = .33, r = .31, and r = .28, respectively). There were no statistically significant correlations between the ADHDRS-IV total score or subscores and any other K-TEA measures or to any WMTB-C components.
There were no serious adverse events reported. A total of 4 (7.1%) patients of the 56 randomized to the trial discontinued due to adverse events, which included nausea, mood swings, and abdominal pain. Adverse events occurring in at least 5% of all patients in the study were somnolence (n = 19), nausea (n = 17), decreased appetite (n = 12), headache (n = 11), nasopharyngitis (n = 7), upper abdominal pain (n = 11), vomiting (n = 9), cough (n = 4), upper respiratory tract infection (n = 3), constipation (n = 3), irritability (n = 5), psychomotor hyperactivity (n = 3), fatigue (n = 6), and abdominal pain (n = 3). There were no differences between groups in the occurrence of any reported adverse event. Likewise, ECGs, laboratory analytes, vital signs, height, and weight evaluations revealed no clinically significant changes from baseline to endpoint.