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.

MEDICAL FRONTIERS - 162nd Annual Meeting of the American Psychiatric Association

San Francisco, California / May 16-21, 2009

In the setting of attention-deficit/hyperactivity disorder (ADHD), one approach to the delivery of stimulant therapy over an extended period is the use of an inactive prodrug which is gradually metabolized in the body to an active form. Lisdexamfetamine dimesylate (LDX) is converted to L-lysine and active dextroamphetamine. It has previously been shown to be a well-tolerated formulation, with a safety profile typical of long-acting stimulant drugs, and to provide therapeutic benefit for up to 12 hours.

Findings in a Laboratory School Setting

Dr. Sharon Wigal, Clinical Professor of Pediatrics and Director of Clinical Trials, University of California, Irvine, presented the results of an effect size analysis of a phase III, randomized, placebo-controlled, two-way crossover study of its efficacy for 1.5 to 13 hours. The study was conducted in a laboratory school, and children were monitored and scored throughout the school day by trained observers. The laboratory school environment permitted a highly structured approach to monitoring and assessment of the patients, noted Dr. Wigal. “This allowed us to standardize types of treatment, know exactly the time of dosing, pretty much dose simultaneously, and know with great confidence the actual time points of [behaviour] measurement across the day.”

The first phase of the study consisted of an open-label dose-optimization phase in which patients were optimized to a daily dose of 30 mg (58 patients), 50 mg (50 patients) or 70 mg (21 patients). Patients were then assigned to either placebo or their optimized dose for one week, followed by a one-week crossover. Baseline ADHD Rating Scale IV (RS-IV) scores were high, with a mean of 42.4, meaning that the children had a high degree of impairment.

The primary objective was assessment of the onset of efficacy using the Swanson, Kotkin, Agler, M-Flynn, and Pelham Deportment (SKAMP-D) scale. The main secondary objective was to assess the duration of efficacy compared to placebo. There were several other secondary end points and an assessment of treatment-emergent adverse events.

Dr. Wigal presented results in the form of effect size data (the difference between drug effects and placebo effects divided by their pooled standard deviation), which allows direct comparison between studies. They also provided information, not just on the statistical significance of the data points, but also on the magnitude of the drug’s effect at each point. Effect size scores of 0.2, 0.5 and 0.8 are considered to be small, medium and large, respectively.

The SKAMP-D results showed a clinically relevant effect size at 1.5 hours, followed by a large effect to 10 hours. By 13 hours, although the children are beginning to act out again, there was still a significant benefit from the drug, mentioned Dr. Wigal, noting that the effect size of SKAMP-A, which measures attention, was greater than that of the SKAMP-D by 0.42.

The maintenance of attention is further borne out by high effect sizes in the objective Permanent Product Measure of Performance (PERMP) scales, which consist of an analysis of the number attempted (PERMP-A) and the number correct (PERMP-C) in a math test of 400 questions. The PERMP scores remained above 1 at 13 hours. “So it may be [at 13 hours] that the kids are able to attend well, but their behaviour is not really going along with that,” suggested Dr. Wigal. There was some evidence of a dose effect in this study, she noted. The mean treatment effect size over the classroom day on the SKAMP-D was large at -1.73 (standard error [SE] 0.18) (Figure 1).

Although 85% of patients reported adverse events during the dose optimization phase of this study, most were mild or moderate. No severe adverse events were reported. The most common adverse events were decreased appetite, insomnia, headache, irritability, affect lability and upper abdominal pain. Nine patients discontinued due to adverse events.

According to Dr. Wigal, it would be beneficial to have a treatment option available with such a long duration of action. “This is the first such drug to document 13 hours of effect,” she concluded.

Figure 1.

“Real World” Therapy in a Summer Treatment Program

The relative effectiveness of behavioural therapy, pharmacotherapy and combinations of these is still the subject of controversy. Furthermore, most trials have been conducted in controlled laboratory conditions; there is a lack of data in naturalistic settings.

A small, dose-optimized, double-blind, randomized and counterbalanced order trial compared the effectiveness of treatment with LDX to behavioural intervention therapy in a “real-world” setting. The patients were 25 children (20 males, five females) aged 6 to 12 years (mean 8.8 years) enrolled in a behavioural Summer Treatment Program (STP). During weeks 4 to 6 of the STP, patients were randomized to active treatment, behaviour therapy only (BEH) or combination treatment (COM). Drug doses were given at approximately 8:30 am, although there was some variation in timing due to the naturalistic nature of the study, according to Dr. Thomas W. Frazier, Center for Pediatric Behavioral Health, Children’s Hospital, Cleveland, Ohio, which was also the time at which STP commenced. Counselors used the SKAMP Rating Scale at 0.5, 1, 3, 5, 7 and 9 hours’post-dose on days 1 through 4. On day 3 each week, parents participated in evening training sessions designed to reinforce positive behaviours at home. During these sessions, counselors performed SKAMP assessments at 10.5 and 12.5 hours’ post-dose. Seventeen of the 25 patients achieved full participation in all daytime and day 3 evening sessions. Parents rated specific behaviours at 10.5 and 12.5 hours’ post-dose on days 1, 2 and 4 each week, using the Clinical Global Impression of Severity (CGI-S) scale.

Counselor-rated SKAMP scores rated from 9:00 am to 5:30 pm deteriorated in the BEH group vs. the LDX and COM groups as the day progressed. Mean SKAMP scores collected from 9:00 am to 9:00 pm for the 17 patients with full attendance at evening parent sessions indicated that children who received LDX or COM maintained benefit throughout the day, while children given only BEH deteriorated by 11:30 am (P<0.001). The effect size of active treatment alone compared to BEH was subs
e 2).

Figure 2.

<img3283|center>

CGI-S scores rated by the parents on three evenings each week revealed that at 7:00 pm, the LDX and COM groups were better able to follow instructions than the BEH group (P=0.03), although there were no differences between groups in their ability to calm themselves or to tolerate frustration. By 9:00 pm, no behavioural differences were observed between groups.

Investigators concluded that LDX or COM provided sustained benefit for up to 12.5 hours’ post-dose in various natural settings, while children were more able to follow instructions at home to 10.5 hours following dosage. Active therapy, whether used alone or in combination with behaviour therapy, was superior to behaviour treatment alone. “The behavioural component helps, ” commented Dr. Frazier. “It’s just that the medication over and above the behavioural component seems to be even more helpful for certain behaviours… following instructions is a great example, because this is a very important behaviour to parents as the night goes on, because you have to get kids into their nighttime routine… Real-world behaviours that we asked parents to rate, like following instructions, can be meaningfully improved with LDX treatment.”

Long-acting Psychostimulants and Sleep Disturbance

While it may be desirable to provide long-acting stimulant therapy to children with ADHD, there are some concerns surrounding the issue of sleep disturbance with this type of medication. A single-centre, double-blind, placebo-controlled, parallel-group study examined the effects of LDX on both subjective and objective measures of sleep in a group of 24 children with ADHD. Following a three-week, open-label, dose-optimization phase, patients were randomized to either placebo or their previously-determined optimized dose of LDX for the four-week treatment phase. CGI-S baseline scores established that patients were moderately to markedly ill.

During the study, the primary end point, latency to persistent sleep as measured by polysomnography, was not increased compared to placebo. Furthermore, there were no statistically significant differences in the secondary end points of wake time after sleep onset (WASO) or total sleep time (TST), also measured by polysomnography. However, there was a statistically significant (P<0.0001) decrease in the number of awakenings after sleep onset (NAASO) for the active-treatment group compared to the placebo group. “We didn’t expect it,” remarked Dr. John Giblin, Clinical Study Centers LLC, Little Rock, Arkansas, “but we did show that these kids had increased sleep efficiency; they didn’t wake up so many times during the night and didn’t stay awake so long during the middle of the night.”

Speculating on the reason for this, Dr. Giblin suggested, “I think that maybe these kids have some low baseline noise going on all the time, enough to stimulate them to wake up during the night, and then once they wake up, they’re awake, and maybe [as a result of treatment] they’ve accomplished what they need to accomplish during the day, they’ve had an efficient day, and then they get an efficient night’s sleep.” It should be noted, though, that the NAASO at baseline in the LDX gro
gher than that seen in the placebo group (Figure 3).

Figure 3.

<img3274|center>

Actigraphy, however, revealed no significant change between groups in terms of sleep efficiency, TST or WASO. Subjective impressions of the children’s sleep habits as reported by parents using the Child Sleep Habits Questionnaire (CSHQ) revealed no differences between treated children and those on placebo. Although 43 adverse events were reported during the course of this study, none were sleep-related and no serious adverse events occurred. Treatment-emergent adverse events were consistent with typical amphetamine side effects. All patients completed the study.

Dr. Giblin noted, “These kids all showed great improvement on the medicine once we titrated them to the right dose.” Larger sleep studies may help clarify the effects of LDX on sleep in patients with ADHD, eliminating some possibly anomalous baseline numbers that were seen in this study and providing stronger actigraphy data, which showed some evidence of statistically non-significant trends indicating possible further beneficial effects on sleep from LDX in this trial.

Summary

An issue with psychostimulant therapy for ADHD frequently reported by parents is that the effect of the drug wears off by early evening. Randomized controlled trials in both controlled and naturalistic settings have demonstrated that LDX has a substantial effect size in controlling symptoms of the disorder, and that it remains clinically effective to 13 hours. Furthermore, there is no evidence that it has any deleterious effects on sleep quality.

Note: At press time, lisdexamfetamine dimesylate is not available in Canada.