Sleep and Tolerability Study: Comparing the Effects of Adderall XR and Focalin XR

Study Overview
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Brief Summary
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The purpose of this study is to evaluate how children and adolescents with Attention Deficit/ Hyperactivity Disorder (ADHD) respond to treatment with three differing doses of stimulant medications used to treat ADHD, Adderall XR® and Focalin XR®. Another purpose of the study is to evaluate if there are differences in sleep and other side effects, such as changes in mood or loss of appetite, which can occur with stimulant medications. A third purpose is to determine if there are differences in the characteristics of individuals who respond better to either of the medications. This research is being done because the investigators do not know if one of these two commonly used treatments is better tolerated than the other. Children and adolescents with ADHD often have a hard time sitting still, playing quietly, finishing things they start, paying attention, waiting their turn, and not distracting others. These medications improve these symptoms, but sometimes affect sleep, appetite, or mood. It is hypothesized that at effective and frequently prescribed doses, Adderall will be associated with insomnia, more stimulant side effects, and decreased tolerability during an acute trial relative to Focalin.

Detailed Description
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ADHD is often treated with stimulant medications, which have demonstrated short-term efficacy in numerous trials. However, treatment is often discontinued prematurely. Although ADHD often persists through adolescence, approximately half of all children who are treated with a stimulant medication discontinue treatment within one year (Charach, Ickowicz et al. 2004). Presumably, tolerability and treatment compliance are highly related to the side effect profile of stimulant medications (Schachar, Jadad et al. 2002). Sleep problems, particularly insomnia, are frequently associated with ADHD and are often exacerbated by stimulant medications, particularly at higher doses. Other frequent stimulant side effects are decreased appetite and mood lability (dysphoria/euphoria). Little is known about the relative effects of different stimulant formulations and dosages (i.e amphetamine, methylphenidate, dexmethylphenidate) on sleep and tolerability. There is some preliminary data with short acting stimulants suggesting a higher prevalence of sleep and appetite problems with amphetamine relative to mph (Pelham, Aronoff et al. 1999). Several studies indicate that sleep and other stimulant side effects are dose related (Stein, Sarampote et al. 2003), although this has not been found in all studies. Moreover, it is unclear if there are differences between long-acting amphetamine and methylphenidate based stimulants in their side effect profile and tolerability. Thus, we will directly compare these two long acting stimulant medications on their side effect profile and tolerability, including measures of sleep, mood, and evening behavior (e.g., family conflicts). The recently developed extended release formulation of dexmethylphenidate will be compared to one of the most common treatments for ADHD, extended release formulation of mixed amphetamine salts. The subject population will be older children and adolescents (10-17) with ADHD who are most likely to be treated with moderate to higher dose levels of stimulant medications and can complete all self-report measures.

Official Title
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Sleep and Tolerability of Extended Release Dexmethylphenidate vs. Mixed Amphetamine Salts: A Double Blind, Placebo Controlled Study (SAT STUDY)

Conditions
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Attention Deficit Hyperactivity Disorder

Intervention / Treatment
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* Drug: Dexmethylphenidate
* Drug: Mixed Amphetamine Salts, ER
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Any ADHD subtype, determined by KSADS interview (Kaufman, Birmaher et al. 1997). Comorbidity will likewise be allowed, to ensure representation. Signed informed consent and assent Clinical Global Impressions - Severity for ADHD (CGI-S-ADHD) rating is greater than or equal to 4 Findings on physical exam, laboratory studies, vital signs, and ECG are judged to be normal for age Pulse and blood pressure are within 95% of age and gender mean Able to complete study instruments and swallow capsules Willing to commit to the entire visit schedule for the study, including at least one visit to UIC Medical Center. Exclusion Criteria: Previous diagnosis of mental retardation Non-responder to either medication at the doses offered in the study in an adequate trial Must not have experienced disabling adverse effects with either medication Concomitant psychotropic medications are required or medications which might have a CNS effect Any other medical condition which represents a contraindication for either treatment is present History of alcohol or drug abuse in the past 3 months, or a positive urinary toxic screen on initial evaluation that is not explained by a time-limited medical circumstance Females of childbearing age who are sexually active, do not use acceptable birth control (double protection method), and after counseling, are unwilling to do so History of allergic reactions to multiple medications A history of psychosis Diagnosis of bipolar disorder

Ages Eligible for Study
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Minimum Age: 9 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Focalin XR then Adderall XR<br>Subjects are given the Focalin XR first (dexmethylphenidate) for four weeks with a randomized placebo week followed by Adderall XR (mixed amphetamine salts) for four weeks with a randomized placebo week. | Drug: Dexmethylphenidate<br>* 10, 20, 25-30 mg.<br>* Other names: Focalin XR;Drug: Mixed Amphetamine Salts, ER<br>* 10, 20, 25-30<br>* Other names: Adderall XR;Drug: placebo<br>* randomized placebo week during each 4 week period<br>|
| Experimental: Adderall XR then Focalin XR<br>Subjects are given the Adderall XR (mixed amphetamine salts) for four weeks with a randomized placebo week followed by Focalin XR first (dexmethylphenidate) for four weeks with a randomized placebo week. | Drug: Dexmethylphenidate<br>* 10, 20, 25-30 mg.<br>* Other names: Focalin XR;Drug: Mixed Amphetamine Salts, ER<br>* 10, 20, 25-30<br>* Other names: Adderall XR;Drug: placebo<br>* randomized placebo week during each 4 week period<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sleep Start Time, and End Time as Determined by Actigraph and Sleep Diary Over 8 Weeks. | Actigraphs (AW64 series) were worn each night and were used to assess participant's sleep patterns in their natural home environment. These computerized wristwatch-like devices collect data generated by movements. They are minimally invasive and allow sleep to be recorded reliably without interfering with the family's routine. One-minute epochs were used to analyze actigraphic sleep sata. Bedtimes and wake times were reported for each participant using sleep logs, and these times were used as the start and end times for the analyses. For each 1-min epoch, the total sum of activity counts were computed. If they exceeded a threshold (threshold sensitivity value = mean score in active period/45), then the epoch was considered waking. If it fell below that threshold, then it was considered sleep. The data for Adderall XR and Focalin XR was combined to look at the cumulative effects that medication has on sleep. | 8-10 weeks | 
| Sleep Duration | Actigraphs (AW64 series) were worn each night and were used to assess participant's sleep patterns in their natural home environment. These computerized wristwatch-like devices collect data generated by movements. They are minimally invasive and allow sleep to be recorded reliably without interfering with the family's routine. One-minute epochs were used to analyze actigraphic sleep sata. Bedtimes and wake times were reported for each participant using sleep logs, and these times were used as the start and end times for the analyses. For each 1-min epoch, the total sum of activity counts were computed. If they exceeded a threshold (threshold sensitivity value = mean score in active period/45), then the epoch was considered waking. If it fell below that threshold, then it was considered sleep.The data for Adderall XR and Focalin XR was combined to look at the cumulative effects that medication has on sleep. | 8-10 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ADHD Parent Rating Scale-IV | Measures the severity of Total ADHD symptoms, Inattention and Hyperactivity/Impulsive symptoms. The Inattention and Hyperactivity/Impulsive symptoms can range from 0 to 27 each, with a higher score reflecting more severe ADHD symptoms. The total score is calculated by summing the inattention and Hyperactivity/Impulsive subscales. The total score can range from 0 to 54 with a higher score reflecting more severe ADHD symptoms. | completed weekly over 8-10 weeks | 
| Dopamine Active Transporter (DAT) 1 Gene Type Effects on ADHD Symptoms | Three variations of the DAT 1 gene were observed, the 9/9 allele, the 9/10 allele and the 10/10 allele. The ADHD Rating Scale (ADHD-RS) and Clinical Global Impressions - Severity (CGI-S) measures were used to evaluate how the DAT 1 gene allele type altered the efficacy of the medication. The DAT 1 genotype did not predict differential response to Focalin XR or Adderall XR so the dose levels of each drug was combined to examine how the genotype interacted with the dose level. The ADHD-RS evaluates the severity of the participant's ADHD symptoms and includes two subscales: Inattention and Hyperactivity/Impulsivity. Both subscale scores range from 0 to 27 with a higher score representing more severe symptoms. The subscales are summed to calculate the total score which can range from 0 to 54. The CGI-S scale summarizes the clinician's impression of the participant's symptom severity and ranges from 1-7 with 1 representing normal (not at all ill) and 7 representing extremely ill. | 8-10 weeks | 
| Clinical Global Impression - Severity | The CGI-S scale summarizes the clinician's impression of the participant's symptom severity and ranges from 1-7 with 1 representing normal (not at all ill) and 7 representing extremely ill. | 8-10 weeks | 
| Weiss Functional Impairment Rating Scale (WFIRS) | The WFIRS consists of 50 questions where respondents are asked to rate their child's functional impairment. The items of the WFIRS are scored on a four point Likert-type rating scale: 0 (never or not at all), 1 (sometimes or somewhat), 2 (often or much) or 3 (very often or very much) and aggregated to produce six domain scores: Family (ranges between 0-24), Learning or School (ranges between 0-33), Self-Concept (ranges between 0-15), Social Activities (ranges between 0-27), Life Skills (ranges between 0-36), and Risky Activities (ranges between 0-42). The subscales are scored by summing the responses in the subsection. The Total score is the sum of all the responses and it ranges between 0-150. The higher the score in each of the subscales the more impairment is recorded, this is also true for the total score. | 8-10 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Attention Deficit Hyperactivity Disorder, sleep, side effects, stimulants