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Once-Daily Adderall XR(R) Provides All-Day Symptom Control for Children With Attention-Deficit/Hyperactivity Disorder

NEWPORT, KY -- June 30, 2003 -- children with attention-deficit/hyperactivity disorder (ADHD) experienced significant control of their ADHD symptoms when using once-daily Adderall XR(R) (mixed salts of a single-entity amphetamine product), according to a study published in the June 2003 issue of the Journal of the Academy of Child and Adolescent Psychiatry (JAACAP).

Many of these children experienced significant symptom control through 12 hours.

Investigators from the University of California at Los Angeles (UCLA) and three other sites conducted the study comparing Adderall XR to placebo and active control medication, Adderall(R). Shire Pharmaceuticals Group plc, makers of Adderall XR and Adderall, sponsored the clinical trial.

The study documents that all doses of Adderall XR showed significant benefits during the day and superior symptom improvement compared to placebo treatment. Adderall XR dosed at 20 and 30 milligrams (mg), administered once a day, showed significant symptom improvement at the first assessment of medication effectiveness (1.5 hours after taking the medication). These doses also showed continuous activity and ability to control ADHD patients' symptoms through 12 hours.

"The longer duration of action of Adderall XR is essential to simplifying ADHD patient treatment and eliminating the need for in-school administration, while ensuring effective and well-tolerated control of the serious and life-disrupting symptoms of ADHD," said lead study author James T. McCracken, M.D., professor in the Division of Child and Adolescent Psychiatry, Neuropsychiatric Institute, the Department of Psychiatry and Biobehavioral Sciences at the University of California Los Angeles.

ADHD is the most commonly diagnosed psychiatric disorder in children and adolescents and as many as 66% of children may still exhibit symptoms into adulthood, according to the National Institute of Mental Health. Approximately 3% to 7% of all school-aged U.S. children, some 2 million, have been diagnosed with ADHD. ADHD symptoms can have a detrimental effect on a child's quality of life beyond academics, including maintaining friendships, focusing on sports and other after-school activities and relating well within their own families.

"Children with ADHD who take morning doses of short-acting medication often experience difficulty with evening homework and less structured family routines without additional medication later in their day," said Dr. McCracken. "The complexity of scheduling multiple daily doses can be hard for patients to comply with, which, in turn, may interfere with the effectiveness of their treatment. Medications, such as Adderall XR, that significantly control ADHD symptoms all day long with just one morning dose greatly enhance patients' ability to be fully functional and engaged at school, play and home."

Investigators assessed the children weekly on Saturdays in an analog classroom setting, a well-validated procedure for ADHD studies. The participants had alternating classroom, play, meals or snacks and research activities from 7 a.m. to 7:30 or 8:00 p.m. On those days, researchers used measures sensitive to both medication dosage and time since first dose to assess symptom control at regular intervals (every 1.5 hours except at the 3.0 hour time point, when the children had recess).

Children's attention and behavior (deportment) were observed using appropriate measures of the validated Swanson, Kotkin, Alger, M-Flynn and Pelham (SKAMP) Scale. Academic performance was evaluated using the Permanent Product Measure of Performance (PERMP), a 10-minute age-appropriate math test.

Using the SKAMP scale to observe attention and behavior, Dr. McCracken and his colleagues found that the 30 mg dose showed overall significant improvement compared to placebo at all 14 time measures (p <.01). The 20 mg dose showed significant improvements in 12 of the 14 measures (p <.01). For the other two time point measures, there was a trend toward significance for the 20 mg dose at 1.5 hours for attention (p=.0513) and at 12.0 hours for behavior (p=.0531). The 10 mg dose of Adderall XR showed significant improvement at 4.5, 6.0, 7.5 and 10.5 hours in attention ratings and from 4.5 to 9.0 hours in behavior ratings.

With no 3-hour assessment, the exact point is not known (between 1.5 hours and 4.5 hours) when the 10-mg dose achieved statistical significance. Using the PERMP math tests, the researchers also found robust improvements in academic performance. The 20 and 30 mg doses of Adderall XR had significant increases at all 14 time points through 12.0 hours in both math problems attempted, (p<.05 and p<.01, respectively) and problems solved (p<.05 and p<.01, respectively). The 10 mg Adderall XR dose demonstrated significance from 4.5 to 10.5 hours in both math problems attempted (p <.05) and solved (p <.05).

The investigators conclude that this pattern of greater improvement with increasing strengths suggests predictable clinical effects should the medication need to be prescribed at higher doses.

In the study, investigators enrolled 51 children who underwent one week of a washout period to discontinue their current ADHD treatment, if any. In the first week, all children received 20 mg doses of Adderall XR(R) for individual assessment of tolerability, including blood samples to measure how their bodies processed the drug, known as pharmacokinetics (PK). Then, one week later, at the beginning of the five-week crossover period, investigators randomly assigned the remaining 49 children to one of the trial groups: Adderall XR 10, 20 or 30 mg, Adderall 10 mg or placebo, all given once daily by 7:30 a.m. During each of the subsequent four weeks, the children were given one of the treatments not already taken, a sequence randomly assigned at the beginning of the study. Titrating to the optimal dose was not one of the objectives of the study design. A subsequent week of treatment was included as a potential makeup week and for an additional PK analysis. Neither investigators nor participants knew which treatments a child received until the study ended.

A separate article, based on the same study, published in the June JAACAP relating to the PK of these medications, found that participants taking extended release Adderall XR experienced prompt absorption of the medication into the bloodstream, similar to those receiving immediate-release Adderall. Importantly, the prompt absorption was observed after the children received a standard breakfast, demonstrating rapid onset of effect in the presence of food. This study, the first to describe pharmacokinetic properties of both Adderall XR and Adderall, assessed concentrations of the two formulations at the same assessment times for attention, behavior, and the math tests, as well as 24 hours after the initial dosing.

Overall, the participants tolerated the study medications well and no serious side effects were reported. The most common side effects reported by parents were common for medications in this class and included nervousness, loss of appetite, stomachache, headache and difficulty sleeping. The children averaged in age 9.5 years and included 44 boys and seven girls. All participants met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR(TM)) criteria for ADHD. For those taking prior medication treatment, they averaged 1.7 years on that medication. Of those receiving such medication at the study start, 30 (59%) received methylphenidate and 17 (33%) received an amphetamine-containing medication.

About ADHD
ADHD is a significant mental health concern that impacts the patients, their families and their social circles. Children with ADHD often are inattentive, impulsive, and hyperactive -- difficulties serious enough to interfere with their ability to function normally in home, academic or social settings. These symptoms continue beyond the school day, affecting all aspects of the child's life. ADHD is a neurological brain disorder that manifests as a persistent pattern of inattention and/or hyperactivity-impulsivity that is more frequent and severe than is typically observed in individuals at a comparable level of development. Hyperactivity is seen less frequently as the patient ages, however inattention and impulsivity often remain.

Although there is no cure for ADHD, physicians, parents, teachers, nurses and advocates are finding ways to help people with the condition learn to adapt to their academic, social and work settings. ADHD usually can be successfully managed with a combination of treatments, including educational approaches, psychological and behavioral therapies and medication. Medication should be considered part of an overall multi-modal treatment plan for ADHD.


REFERENCE
Analog Classroom Assessment of a Once-Daily Mixed Amphetamine Formulation, SLI381 (Adderall XR, in Children With ADH, James T. McCracken, M.D., Joseph Biederman, M.D., Laurence L. Greenhill, M.D., James M. Swanson, Ph.D., James J. McGough, M.D., Thomas J. Spencer, M.D., Kelly Posner, Ph.D., Sharon Wigal, Ph.D., Caroly Pataki, M.D., Yuxin Zhang, Ph.D., and Simon Tulloch, M.D., J Am Acad Child Adolesc Psychiatry. 2003 42:6, June.

Pharmacokinetics of SLI381 (Adderall XR), an Extended-Release Formulation of Adderall James J. McGough, M.D., Joseph Biederman, M.D., Laurence L. Greenhill, M.D., James T. McCracken, M.D., Thomas J. Spencer, M.D., Kelly Posner, Ph.D., Sharon Wigal, Ph.D., Jeffrey Gornbein, Dr. P.H., Simon Tulloch, M.D., and James M. Swanson, Ph.D., J Am Acad Child Adolesc Psychiatry. 2003. 42:6, June.


SOURCE: Shire US Inc.

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