Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

160th Annual Meeting of the American Psychiatric Association

San Diego, California / May 19-24, 2007

Here at the APA annual meeting, investigators presented efficacy, safety and tolerability data of an open-label extension of a prior phase III clinical trial. According to their results, adolescents with attention-deficit hyperactivity disorder (ADHD) can take mixed amphetamine salts (MAS) in an extended-release (XR) formulation as a long-term therapy for managing their illness.

Psychiatrists are becoming increasingly aware that ADHD is not exclusively a pediatric diagnosis. Specialists in the field have been concerned whether the medication being used will continue to be efficacious. Medication issues change as a patient matures and as such, physicians have also been concerned that those used to treat adolescents with ADHD continue to be safe.

Dr. Andrew Cutler, Courtesy Assistant Professor of Psychiatry, University of Florida, and President of CORE Research, Maitland, Florida, and co-investigators addressed these concerns in their study. “Although ADHD is most commonly diagnosed in young children, it occurs in all age groups,” he confirmed. It was observed that psychostimulant medications are long-established treatment strategies for ADHD and have been shown to be safe and effective across age groups. Long-term results of MAS XR are required due to the importance of the role of long-acting medication in treating adolescents with ADHD. According to Dr. Cutler, symptom control throughout the day and the potential for improved adherence with once-daily dosing are key reasons that both physicians and patients find this option helpful.

“These patients were on MAS XR for up to 24 months,” he reported. “We found that the treatment was safe and well tolerated for as long as 24 months. Even though we expect things like weight loss with stimulant medications, in this study the patients gained weight.” These findings might help psychiatrists manage adolescents with ADHD, because the literature shows the 30% to 80% of children with ADHD will continue to have this diagnosis into adolescence, he noted (Barkley et al. J Am Acad Child Adolesc Psychiatry 1990;29:546-57). Lead author Dr. Cutler followed 238 patients who were on flexible dosing of MAS XR, ranging from 10 mg/day to 60 mg/day, for up to 24 months. Previously, the patients had been in a four-week, double-blind trial (Part A). The investigators assessed the participants using the ADHD Rating Scale version IV (ADHD-RS-IV) on the total score, as well as on the inattentiveness and hyperactivity/impulsivity subscale scores. Interestingly, the patients who had previously been on placebo before switching to active treatment in the open-label phase improved at a rate similar to patients who had been on continuous MAS XR, noted Dr. Cutler.

Among the patients who averaged 14.6 years of age, 71.8% were boys and 28.2% were girls. The open-label study was for 18 months but was later extended to 24 months. Part A participants were divided into three groups:

• One cohort entered a six-month extension (Part B), then went on to the 18- to 24-month open-label study.

• Another cohort received active treatment during Part A and directly entered the 24-month open-label study.

• The last cohort received placebo during Part A then directly entered the 24-month open-label study.

The ADHD-RS-IV total scores of the 237 in the intent-to-treat (ITT) population improved significantly from the initial baseline among patients in the three groups. Among the patients originally in the Part A-placebo group, the total score significantly improved (-11.7 points, P<0.001). In the Part A-active treatment cohort, total score also improved, decreasing an average of 3.9 points (P=0.0001) (Figure 1). Conversely, there was an increase of 0.3 points from baseline to end point in the Part B-open-label group, a difference that was not statistically significant. The investigators observed a significant improvement (decrease in score) in the inattentiveness and hyperactivity/impulsivity subscales, Dr. Cutler told delegates. He explained, “These data add to a large database that says stimulants can be safe and effective over longer periods of time. People have some concerns about long-term treatment with stimulants, and ADHD is a condition that requires long-term treatment. The study gives us some degree of confidence that using MAS XR for up to two years is associated with a continuation of efficacy and that the drug appears to be well-tolerated. Cardiovascular adverse events, which are a particular worry, were not seen here.”

Figure 1. Mean ADHD-RS-IV Scores at End Point

Clinical Improvement

Dr. Richard Weisler, Associate Professor of Psychiatry, Duke University Medical Center and University of North Carolina-Chapel Hill, Raleigh, echoed Dr. Cutler’s concern about the persistence of ADHD beyond childhood and the hope that long-acting strategies might be associated with improved adherence in this population. Also discussed here at the APA was the scarcity of data regarding the use of psychostimulants to treat ADHD as patients move into adolescence. “Because ADHD is a chronic condition, treatments with demonstrated long-term efficacy and safety are needed,” emphasized the investigators. To that end, they analyzed the global improvement data in the study, as measured on the Clinical Global Impression Improvement (CGI-I) scale.

“Roughly the same percentage of patients benefited at 24 months as was seen in the original double-blind phase,” Dr. Weisler told listeners. “Those who were treated with placebo in the double-blind phase and switched to treatment in the extension took some time to catch up, but they did catch up and the results were the same for both sets of patients further out.”

In the analysis of the global improvement data, he and co-investigators found similarly encouraging results. Using the CGI-I scale, Dr. Weisler and colleagues categorized patients as “improved,” which was further subdivided into “very much improved” or “much improved,” and “not improved,” which in turn was subdivided into five other categories.

At study end, CGI-I results showed that 49.4% of patients in the ITT population were “improved,” including 20 of the 28 patients (71.4%) who had been on placebo in the double-blind phase. Of the 113 participants who had been given MAS XR from the outset, 66 (58.4%) were considered “improved,” as were 31 of the 96 patients (32.3%) from the extension phase.

The investigators noted that most improvements occurred during the first six months of treatment and that improvements from baseline were maintained from month 9 to month 24. Interestingly, the best results were seen among those patients who rolled over from the placebo group. It came as a surprise to the investigators that more than 70% of patients of this cohort were considered “improved” at the end of the 24-month study, remarked Dr. Weisler (Figure 2). “The treatment was effective over the long haul,” he mentioned. “You didn’t have to keep increasing the dose. You could build up to an optimal dose and stay there, and it worked well for those patients.”
ments in CGI-I Scores

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Safety and Tolerability Data

The most common treatment-emergent adverse events consisted of respiratory disorder in 22.3%, headache in 20.6%, pharyngitis in 17.2%, anorexia in 16.4%, insomnia in 15.5% and weight loss in 14.7%. These were typically mild to moderate and transient, he remarked. The six serious adverse events that did occur were all considered unrelated to the extended-release formulation.

Regarding other safety and tolerability results, Dr. Weisler and co-investigators were particularly attentive to any cardiovascular effects associated with treatment with MAS XR due to a general concern about the effects of stimulant therapy (Spencer et al. Am Acad Child Adolesc Psychiatry 1996;35:409-32).

To that end, they assessed patients’ diastolic blood pressure (BP), systolic BP and pulse rate, and used the patients’ previously obtained measures as a way to assess any changes. They noted that the study participants had been exposed to MAS XR for an average of 413.2 days during this study. When the double-blind and six-month extension phases were considered, the cumulative exposure consisted of 508.5 days. The doses ranged from 10 mg to 60 mg/day,* with the most commonly dispensed dose consisting of 30 mg/day.

The cardiovascular safety data, which were obtained from all 238 enrolled patients, showed that from baseline to end point, all of the groups did experience some changes in diastolic BP values. Those who had been on placebo had an increase of 5.9 mm Hg, while those who had been on active treatment in the double-blind phase had no change, and those who had been in the six-month extension phase had a decrease of 0.8 mm Hg. Similarly, the systolic BP values increased an average of 5.3 mm Hg for those originally on placebo, 2.8 mm Hg for those continuously on active treatment in the double-blind phase, and 1.4 mm Hg for those who had participated in the six-month extension. The pulse rate values increased an average of 4.5 bpm in those originally on placebo and 1.1 bpm for those on study medication in the double-blind phase, while they decreased an average of 3.4 bpm for those in the six-month extension (Figure 3). Patients who were originally on placebo had a slight increase in systolic BP of approximately 5 mm Hg when first switched, noted Dr. Weisler. He pointed out another way that patients who started on placebo differed from those who had been on treatment throughout the studies. Compared to the latter group, a greater percentage of such patients had an increase in pulse rate of at least 25 bpm, a systolic BP increase of at least 20 mm Hg or diastolic BP increase of at least 10 mm Hg. However, after the first few weeks of treatment, patients’ BPs stabilized. Patients on active treatment to begin with eventually had a slight decrease in diastolic BP, he told delegates.

“The cardiovascular effects were relatively small and consistent with those associated with amphetamine use,” Dr. Weisler reported. “While mean changes in cardiovascular parameters were small during the study, the magnitude of change differed among the rollover groups.” He explained that it was not surprising that the greatest changes were seen in the group that had not received the drug during the preceding study period. This finding suggests that cardiovascular effects decrease over tim
-term treatment.

Figure 3. Mean Changes in Pulse and Heart Rate

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However, he did urge some caution in certain patients. “Patients with certain cardiac problems generally should not be treated with stimulant medication,” Dr. Weisler stressed. “These include structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease or other serious cardiac problems or abnormalities.” Therefore, children, adolescents or adults who are being considered for treatment with stimulant medications should undergo a careful history and physical exam to assess for the presence of cardiac disease. They should also receive further cardiac evaluation if diseases in this category are suggested by any findings that develop, he advised listeners.

Summary

The new findings regarding the use of MAS XR have shown it could have a useful role as a long-term therapy in managing adolescents with ADHD. The researchers based their findings on an investigation lasting 24 months, including a four-week, double-blind trial and a six-month extension as well as the current study. The efficacy data showed that improvements seen in the earlier trials were maintained in the ADHD-RS-IV total scores as well as on the inattentiveness and hyperactivity/impulsivity subscales. Similarly, the CGI-I scores showed sustained improvement in most patients from the double-blind phase and continued improvement in some patients from the extension phase. The safety and tolerability analyses showed that patients had no unexpected adverse effects, which were typically mild to moderate and transient. The cardiac safety findings showed some slight increases in BP and pulse rate. This finding is consistent with other data regarding stimulant medications used in the treatment of ADHD.

Because ADHD is a diagnosis that often persists into adolescence, MAS XR appears to be safe and efficacious for the long-term treatment of this condition in adolescents who live with ADHD.

*Note: In Canada, the maximum recommended dose for extended-release mixed amphetamine salts is 30 mg/day.