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 - 55th Annual Meeting of the American Academy of Child & Adolescent Psychiatry

Chicago, Illinois / October 28-November 2, 2008

Among school-aged children, attention-deficit/hyperactivity disorder (ADHD) is the most prevalent neurobehavioural disorder in many countries (Faraone et al. World Psychiatry 2003;2:104-13). According to the Centers for Disease Control and Prevention, in 2003, an estimated 4.4 million children from ages 4 to 17 were diagnosed with ADHD by a healthcare professional and 7.8% of school-aged children were reported to have parentally reported ADHD (National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, 2005. http://www.cdc.gov/ncbddd/adhd/default.htm).

ADHD impairs function both at school and home. In a recent survey of 500 parents of children and adolescents with ADHD, 56% of parents (of children) and 49% of parents (of adolescents) reported that their child’s ADHD medication stopped providing symptom relief before 6:00 p.m. (Findling et al. CHADD 2007, Alexandria, VA). These study results emphasize the need for once-daily ADHD treatment medications that offer longer duration of symptom control and coverage throughout the school day and during after-school hours, including homework activity.

Improved Efficacy

Lisdexamfetamine dimesylate (LDX) is a therapeutically inactive molecule, also called a prodrug, that is converted after oral ingestion into a naturally occurring amino acid (l-lysine) and active d-amphetamine, which is responsible for its therapeutic effect (Biederman et al. Biol Psychiatry 2007;62:970-6). This prodrug is a therapeutically inactive molecule that requires endogenous enzymatic cleavage in the gastrointestinal tract to produce d-amphetamine, making it unlikely to be sought out for inhalation or injection. In a study conducted in a laboratory school setting, LDX resulted in significant improvements across a broad range of ADHD symptoms in school-aged children (from 6 to 12 years) throughout and to the end of the classroom day. Results from this 13-hour analogue classroom study demonstrated that LDX improved attention and behaviour after a morning dose and continued for each time point measured (1.5 hours through 13 hours) throughout the 13-hour treatment day.

As explained by study investigator Dr. Sharon Wigal, Clinical Professor and Director of Clinical Trials, University of California, Irvine, “LDX is a longer-acting agent that helps to treat ADHD symptoms throughout the school day as well as through after-school and homework hours.”

The study was a six-week, randomized, double-blind, placebo-controlled, two-period crossover (one week each) conducted at seven sites in the US. Dosages of LDX (30, 50, 70 mg/day) were tested in 129 children aged 6 to 12 years with ADHD. The study included an open-label, dose-optimization phase (four weeks) and an analogue classroom phase (two weeks). In the classroom setting, trained raters observed and coded subject behaviours and then translated these ratings into the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Rating Scale, an ADHD symptom measurement scale. SKAMP assesses subject attention (SKAMP-A, items 1-4), subject deportment (SKAMP-D, items 5-8), quality of work (items 9-11), and subject compliance (items 12, 13).

As measured by SKAMP-D, LDX efficacy was statistically significant at each post-dose time point in comparison with placebo. Duration of efficacy (the key secondary objective) was also measured by SKAMP-D and demonstrated that statistically significant LDX efficacy continued through 13 hours’ post-dose (P<0.005) (Figure 1).

Another secondary efficacy objective was the Permanent Product Measure of Performance (PERMP), a five-page math test comprising 400 problems measuring academic productivity. LDX demonstrated significant improvement in math problems attempted (PERMP-A) and answered correctly (PERMP-C) beginning at 1.5 hours’ post-dose and for up to 13 hours’ post-dose.

Dr. Wigal told delegates that this study examined beginning and end points with LDX treatment, and she noted that the drug worked both earlier and longer to control ADHD symptoms. She remarked, “Patients have received tremendous benefits from LDX treatment, and those benefits are life-changing. Parents are often astonished at the change in their child’s behaviour.” Parent-rated Medication Satisfaction Questionnaire (MSQ) responses from the classroom study revealed parent satisfaction ratings to be very satisfied (76.1%, n=86) or moderately satisfied (23.0%, n=26) with LDX.

The agent was generally well tolerated. The most frequent treatment-emergent adverse events (TEAEs) were decreased appetite, headache and insomnia.

Consistency Across Individual Symptoms

A post-hoc analysis of primary ADHD rating scales of two pivotal pediatric studies of LDX aimed to assess whether consistent efficacy could be demonstrated on individual symptoms of ADHD as measured by different instruments. Both trials enrolled children with ADHD between the ages of 6 and 12. Placebo-adjusted changes in baseline were analyzed in each study to describe consistency of LDX on individual ADHD symptoms calculated by different scales in different settings.

In one study, symptoms were evaluated indirectly via reported behaviour in informal settings (home, school, and social situations) over weekly increments, whereas in the other study, investigators measured symptoms directly over 12 hours in a structured analogue classroom setting. In the two different clinical trial environments, LDX demonstrated consistent effects on a broad range of ADHD behaviours and symptoms.

According to study investigator Dr. Ann Childress, President, Center for Psychiatry and Behavioral Medicine, Inc., Las Vegas, and volunteer Assistant Professor of Psychiatry, University of Nevada School of Medicine, “In this analysis, LDX showed significant improvements with both sets of scores in each study. LDX is consistent across a number of ratings and environments.”

Study 1 analyzed data from a four-week, phase III, randomized, double-blind, placebo-controlled, forced-dose titration, parallel-group trial of LDX (30, 50, 70 mg/day) (Biederman et al. Clin Ther 2007;29:450-63). The primary efficacy assessment was clinician-rated Attention-Deficit/Hyperactivity Disorder Rating Scale Version IV (ADHD-RS-IV). Study 2 involved a multicentre, randomized, double-blind, placebo- and active-controlled crossover classroom analogue study that compared the efficacy and safety of LDX (30, 50, 70 mg/day) with placebo and used mixed amphetamine salts extended-release (MAS XR 10, 20, 30 mg/day) as a reference arm (Biederman et al. 2007). The primary efficacy measure was the change from baseline on SKAMP-D items.

In study 1, LDX treatment was associated with a significantly greater ADHD-RS-IV total score reduction (predose least squares [LS] mean reduction of 24.0 for LDX vs. 6.2 for placebo, P<0.0001) from baseline at end point compared with placebo. LDX treatment (30, 50, 70 mg) demonstrated significant improvement compared with placebo on all ADHD-RS-IV inattention (LS mean change -1.4 to -1.2 for LDX vs. -0.4 to -0.3 for placebo) and hyperactivity/impulsivity items (LS mean change -1.5 to -1.1 for LDX vs. -0.5 to -0.3 for placebo).

In study 2, at two hours’ post-dose and lasting to hour 12 post-dose, LDX resulted in significant improvements in SKAMP-A (attention, items 1-4) and SKAMP-D (deportment, items 5-8), based on LS mean change from first measurement scores compared with placebo: deportment per item mean score 0.8 vs. 1.7, respectively; inattention per item mean s
ectively (Figure 2).

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When asked how these clinical outcomes had been observed in the behaviour of children with ADHD, Dr. Childress remarked, “What we have literally seen in children diagnosed with ADHD is that one week, a boy can be out of control running down the halls, and the next week, the same boy treated with LDX is able to sit quietly and do his math. LDX treatment is really consistent across different settings on a wide range of ADHD symptoms and behaviours.”

LDX was generally well tolerated. In study 1, common TEAEs were decreased appetite, insomnia, upper abdominal pain, headache, and irritability. In study 2, common TEAEs included insomnia, decreased appetite, and anorexia.

Dosage Adjustment Capability

Consistent improvement of ADHD symptoms, as measured by investigator and parental ratings, were observed in the first study to evaluate the efficacy and safety of LDX administered in an expanded range of dosage strengths. LDX was tested at 20, 30, 40, 50, 60 and 70 mg/day in children aged 6 to 12 years with ADHD diagnosed by DSM-IV-TR. The newly approved dosages in the US are 20, 40 and 60 mg/day dosages.

According to study investigator Dr. Robert Findling, Professor of Psychiatry and Director, Child and Adolescent Psychiatry, University Hospitals, Case Medical Center, Cleveland, Ohio, “New doses of the drug are generally well received. These new doses add a finer grain adjustment in the dosage.”

Results from the prospective, open-label, multicentre, seven-week, dose-optimization study that assessed the efficacy and tolerability of LDX dosing in children showed that treatment resulted in significant improvement (P<0.0001) in ADHD symptoms as assessed by the investigator-rated ADHD-RS-IV total score. Overall per cent (SD) improvement in ADHD-RS-IV total score from baseline to end point (last valid post-baseline score) was -69.3% (23.3), P<0.0001. Significant improvements from baseline were observed for both the ADHD-RS-IV inattention and hyperactivity/impulsivity subscales at each visit and at end point (P<0.0001). Mean (SD) scores for (clinician-rated) Clinical Global Impressions-Improvement (CGI-I) and (parent-rated) Parental Global Assessment (PGA) were 1.5 (0.8) and 1.8 (0.8), respectively (ITT population, n=316). Based on these measures, most subjects improved.

Continual behaviour patterns of inattention and/or hyperactivity/impulsivity in children with ADHD are oftentimes accompanied by deficits in executive functioning and abnormalities in emotional expression (American Psychiatric Association. (Ed.) (2000). 4th ed., pp. 85-93, Mares et al. Can J Psychiatry 2007;52:527-34, Strine et al. Prev Chronic Dis 2006;3:1-10). Executive functions include a broad range of facilities that guide goal-oriented behaviour, which can be impaired in children with ADHD and can manifest as impaired organization, working memory and response inhibition (Mares et al. Can J Psychiatry 2007, Willcutt et al. Biol Psychiatry 2005;57:1336-46). Emotional expression refers to outward appearance of affect and may also be affected by ADHD.

Dr. Findling pointed out that the study data began to look at aspects of expressed emotions and executive functions related to ADHD. LDX resulted in significant improvement at end point in the Behavior Rating Inventory of Executive Function—Global Executive Composit
r Regulation Index (BRI), and Metacognition Index (MI) (Figure 3).

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Dr. Findling stated, “Since this is an open study, possible benefits exist in other domains than previously considered in this class of compound.” He added, “Our data send a hypothesis-generating signal that deserves further exploration. The study is not placebo-controlled and there have been no head-to-head studies, but this represents a nice leap forward.”

Most parents were satisfied with treatment and reported they would continue, as evidenced by the MSQ, which indicated that 76% of parents were very satisfied with LDX and 21.1% were moderately satisfied. Compared with previous ADHD treatment of children, 38.3% of parents ranked LDX as “much better,” 19.5% as “better,” 6.5% as “the same” and 2.3% as “worse.” When asked whether they would “probably not,” “possibly,” “probably” or “absolutely” continue to use LDX for their children’s ADHD symptoms, 72% of parents responded that they would “absolutely” continue using it.

TEAEs reported in ³10% of subjects were decreased appetite, decreased weight, irritability, insomnia, headache, upper abdominal pain, and initial insomnia. The agent was generally well tolerated, including at the expanded doses.

Dr. Findling commented, “Our study includes a large sample of children (n=316) and lets practitioners know what sorts of outcomes to expect. LDX looks effective and safe in a large population.”

Summary

In addition to its reduced potential for abuse, this first long-acting prodrug stimulant brings significant improvements in the treatment of ADHD. As demonstrated by the study results shown at the AACAP, LDX is an effective and well-tolerated treatment option that offers a longer duration of action, allowing for coverage throughout the school day as well as during after-school hours, consistent control of a wide range of ADHD symptoms and behaviours, and an expanded range of dosage strengths for greater flexibility in dose optimization.

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