Author: H. Lynn Starr, MD, McNeil Consumer & Specialty Pharmaceuticals, Fort Washington, PA

Two analyses from the Formal Observation of Concerta versus Strattera (FOCUS) trial—a comparison of osmotic methylphenidate (OROS® MPH/Concerta®, McNeil) and atomoxetine (Eli Lilly)—showed surprising symptom improvement and responder rate benefits over time with OROS® MPH in children with attention deficit/hyperactivity disorder (ADHD).

The FOCUS trial examined the efficacy and tolerability of both OROS® MPH, an extended-release, osmotic-delivery formulation of methylphenidate, and atomoxetine, a selective norepinephrine reuptake inhibitor (SNRI) developed as a non-stimulant therapy for ADHD, stated Dr. Starr. She noted that stimulant medications have long been recognized as a first-line therapy for ADHD. They have demonstrated symptom response rates as high as 70% to 90%. Clinical studies of have shown efficacy comparable with that of immediate-release methylphenidate.

The FOCUS trial enrolled 1,323 children (six to 12 years of age) with newly diagnosed ADHD, according to the criteria from the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) and with symptoms that had been inadequately managed by prior treatments.

The participants in this multicenter, randomized, prospective, three-week, open-label study were randomly assigned, in a 2:1 ratio, to receive OROS® MPH (n = 850) or atomoxetine (n = 473). OROS® MPH was initiated at 18 mg/day and titrated upward at the physician’s discretion. Atomoxetine was initiated at 0.5 mg/kg per day and was titrated similarly at the physician’s discretion. Assessment was performed via the ADHD Rating Scale (ADHD-RS) and the CGI-Improvement (CGI-I) scale. A parent/caregiver diary, the Parental Satisfaction Questionnaire (PSQ), was maintained as well.

The mean age of the children was 8.93 years, and 74% were boys. The baseline ADHD-RS score was 39.3, and the baseline CGI-S score was 4.69. Approximately 14% of children were rated as inattentive, 12% as hyperactive/impulsive, and 75% as combined. The mean dose after the third week was 32.7 mg for the OROS® MPH participants and 36.7 mg for the atomoxetine subjects.

At the end of the first week, the change in mean ADHD-RS scores from baseline with OROS® MPH exceeded that of atomoxetine by 2.8 points (P < .001). After the second week, that difference grew to 3.5 points (P < .001). At week three, it grew to 4.3 points (P < .001). The total change was approximately 20 points for OROS® MPH and 16 points for atomoxetine.

The percentage of responders (with a 40% or more reduction from baseline ADHD-RS score) was higher with OROS® MPH than with atomoxetine at the first week (29% vs. 21%), at the second week (48% vs. 37%), and at the third week (66% vs. 54%) (P< .0001).

The difference in CGI-I score responder rates (15.8% [68.6% with OROS® MPH, 52.8°% with atomoxetine]) was also significant in favor of OROS® MPH. The parental rating of treatment effects favored OROS® MPH quickly and significantly (P < .001), on the second day and at day 21, with strong improvements observed in both groups.
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The safety and tolerability of OROS® MPH and atomoxetine were similar. Most ADEs were mild and consistent with prior experience with the agents.

Dr. Starr concluded that although both agents achieved significant symptom improvement, “OROS® MPH consistently produced significantly greater improvement based on reduction in investigator-rated ADHD-RS scores.”

The findings were similar for responder analysis, with CGI-I ratings of “much improved” or “very much improved” in parental assessments.

Dr. Starr pointed out that whereas ADHD occurs in both boys and girls, most of what is known about ADHD is derived from studies of boys. Furthermore, it is thought that ADHD in school-aged girls might often remain unrecognized and untreated because symptoms in girls may be less overt.

“They [girls] are not as big a behavior problem, so it is easy to miss them,” she said.
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The inattentive ADHD subtype or combined type may be more prevalent than the hyperactive subtype. With a predominance of the inattentive subtype, girls tend to have greater cognitive and attentional impairment.

“We specifically wanted to see if these medications treat the inattentive as compared with the hyperactive subtypes,” she said in an interview.

Of 340 girls enrolled, 315 completed the study; 203 girls took OROS® MPH, and 112 took atomoxetine. Their response rates were similar to those of the boys. The OROS® MPH advantages over atomoxetine appeared for girls in all of the parameters measured for the overall group. A change was observed in the ADHD-RS (-20.2 vs. -16.5 points, P < .02), and improvements occurred in ADHD-RS inattentive subscale scores (-11 vs. -8.9 points, P < 0.05) and in the hyperactiv-ity/impulsivity subscale (-9.2 vs. -7.6 points, P < 0.05). Response rates were higher with OROS® MPH (55.2%) than with atomoxetine (30.3%) (P< .01).

Treatment-related ADEs occurred in similar proportions (24.3°% with OROS® MPH, 28.1°% with atomoxetine), and the rate of ADE-related withdrawals from the study was similar (6.4% for OROS® MPH vs. 6.6% for atomoxetine).

Insomnia was more common in the subjects receiving OROS® MPH (6.9% vs. 0.8% with atomoxetine, P = .014), and nausea was more common with atomoxetine (8.3%) than with OROS® MPH (1.8%) (P = .008).
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“We did not expect to see such an increasing difference in the symptom response rates, but that is what we found,” Dr. Starr stated. Girls in the OROS® MPH arm were 40% more likely to be responders.

With fewer overt symptoms in girls, how does one spot ADHD in them?

“It takes vigilant parents and teachers. When they are under-performing and not as focused as you’d like, you may have to raise the question,” Dr. Starr said.