- Email: [email protected]
Analog Classroom Assessment of a Once-Daily Mixed Amphetamine Formulation, SLI381 (ADDERALL XR), in Children With ADHD
Analog Classroom Assessment of a Once-Daily Mixed Amphetamine Formulation, SLI381 (ADDERALL XR), in Children With ADHD 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.
ABSTRACT Objectives: This investigation was conducted primarily to assess the safety and efficacy of SLI381 (Adderall XR娃), developed as a once-daily treatment for children with attention-deficit/hyperactivity disorder (ADHD). Secondary objectives included examination of the time course, pharmacokinetic, and pharmacodynamic properties of SLI381. Method: This was a randomized, double-blind, crossover study of three doses of SLI381 (10, 20, and 30 mg), placebo, and an active control (Adderall威 10 mg) given once daily to 51 children with ADHD. Weekly assessments in an analog classroom setting included blind ratings of attention and deportment and a performance measure (math test) obtained every 1.5 hours over a 12-hour period. Results: SLI381 was well tolerated. All active treatment conditions displayed significant time course effects and were superior to placebo in improving efficacy measures. Dose-dependent improvements were evident for SLI381. SLI381 20 and 30 mg and Adderall all showed rapid improvements by 1.5 hours, but only the SLI381 20and 30-mg doses showed continued activity at 10.5 and 12 hours for classroom behavior and math test performance versus placebo. Conclusions: These data provide support for the benefit of this novel, once-daily amphetamine preparation in the treatment of ADHD. The longer duration of action of SLI381 has the potential to simplify psychostimulant dosing, thus reducing dose diversion and eliminating the need for in-school administration. SLI381 appears to be a useful treatment option for many children with ADHD. J. Am. Acad. Child Adolesc. Psychiatry, 2003, 42(6):673–683. Key Words: attention-deficit/hyperactivity disorder, amphetamine, Adderall威, ADDERALL XR娃, stimulant, children.
Psychostimulant medications comprise a mainstay of treatment for attention-deficit/hyperactivity disorder (ADHD), with a long history of research documenting the acute efficacy of both amphetamine and methylphenidate (Arnold et al., 1978; Barkley, 1990; Bradley, 1950; Connors, 1972; MTA Cooperative Group, 1999; Accepted January 14, 2003. Drs. McCracken, McGough, and Pataki are with the Department of Psychiatry and Biobehavioral Sciences, Division of Child and Adolescent Psychiatry, UCLA Neuropsychiatric Institute, Los Angeles; Drs. Biederman and Spencer are with the Department of Psychiatry, Massachusetts General Hospital, Boston; Drs. Greenhill and Posner are with the Department of Psychiatry, Columbia University, New York; Drs. Swanson and Wigal are with the Child Development Center, University of California at Irvine; Drs. Tulloch and Zhang are with Shire Pharmaceutical Development Inc., Rockville, MD. This study was supported by a grant from Shire Pharmaceutical Development Inc. Reprint requests to Dr. McCracken, UCLA Neuropsychiatric Institute, 760 Westwood Plaza, Los Angeles, CA 90024-1759; e-mail: [email protected]. 0890-8567/03/4206–0673䉷2003 by the American Academy of Child and Adolescent Psychiatry. DOI: 10.1097/01.CHI.0000046863.56865.FE
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 2 : 6 , J U N E 2 0 0 3
Pelham et al., 1990; Spencer et al., 1996; Swanson et al., 1978; Weiss et al., 1971). However, clinical experience and a variety of research data suggest that there is a continued need to develop strategies to optimize these treatments, especially as they are applied in community practice settings. Specifically, the short duration of action of available stimulants necessitates multiple daily doses for many children to provide effective symptom management (Pelham et al., 1987; Swanson et al., 1978). Some have suggested the brief duration of action may undercut the possible long-term benefit of stimulant treatment (Schachar and Sugarman, 2000). Clinically, children with ADHD often experience difficulty with evening homework requirements and less structured family routines, requiring additional medication later in the day. The complexity of multiple daily dosing schedules contributes to reduced compliance and may increase the likelihood of drug diversion. Both practice patterns and poor compliance also serve to reduce the overall benefit of psychostimulant 673
M C CRACKEN ET AL.
treatment of many children with ADHD (Brown et al., 1987; Kauffman et al., 1981; MTA Cooperative Group, 1999). Therefore, there is a need to develop drug delivery systems that can effectively treat ADHD symptoms with a single daily dose. In spite of the frequency of use of amphetamine-containing products for the treatment of ADHD, there is a surprising paucity of studies on the pharmacokinetic (PK) and behavioral time course of effects of low-dose amphetamine administration for ADHD (Brown et al., 1979, 1980; Pelham et al., 1999; Swanson et al., 1998). The current study describes the efficacy, tolerability, and detailed time course of SLI381 (Adderall XR娃), a unique drug delivery system containing the mixture of amphetamine salts contained in a currently approved treatment, Adderall威, on symptoms of ADHD in a sample of children with ADHD. Adderall is a racemic mixture of dextro- and levo-isomers of amphetamine composed of equal parts of amphetamine salts (d-amphetamine sulfate, d-amphetamine saccharate, d,l-amphetamine aspartate monohydrate, and d,l-amphetamine sulfate). The mixture yields a 3:1 ratio of dextro- to levo-isomers of amphetamine. A previous analog classroom pharmacodynamic study of Adderall documented the time course of behavioral and classroom performance effects across a dose range of 5 to 20 mg given once, with behavioral effects evident up to approximately 5 to 7 hours postdose for the highest dose condition (Swanson et al., 1998). Pelham et al. (1999) studied Adderall effects in a summer treatment program and found apparent benefits up to 7 hours after administration. James et al. (2001) recently described locomotor activity effects of amphetamine preparations up to 12 hours postdose, but they did not repeatedly probe disruptive behavior or academic performance. It is interesting that the Swanson et al. (1998) report also demonstrated the pattern of deterioration on placebo in performance across morning into afternoon assessments, highlighting the importance of providing appropriate control groups for time-response studies. This study was aimed to systematically evaluate the efficacy and tolerability of SLI381 as a treatment for ADHD, using an analog classroom observational procedure. SLI381 is designed to release two pulses of active medication, modeling the PK profile of Adderall administered twice daily with doses administered approximately 4 hours apart. A 20-mg dose of SLI381 is bioequivalent to Adderall 10 mg b.i.d., with a 4-hour interval (Michaels et al., 2001). In addition, the study adds to the literature on the behav674
ioral and cognitive effects of amphetamines in children with ADHD. METHOD The study was conducted at four academic sites under local university human subject protection committee approval. Subjects were recruited at the four sites through a combination of advertising and distribution of information about study participation at local outpatient clinics. All subjects provided written assent for study participation; parents provided written consent for their child’s enrollment. Families were compensated $50 for participation in each all-day analog classroom day. Subjects Potential subjects were screened to meet the following eligibility criteria: (1) age 6 to 12 years; (2) diagnosis of DSM-IV ADHD (combined or hyperactive-impulsive subtype as determined by a comprehensive clinician evaluation and selected modules of the Diagnostic Interview Schedule for Children, Version IV-Lifetime [DISC-IV]) (Shaffer et al., 2000) administered by a research staff member with suitable training; (3) no evidence of mental retardation; and (4) history of positive response to psychostimulant medication, or no prior stimulant treatment. Information pertaining to co-occurring psychopathology from the clinical evaluation was supplemented by the Comorbid Disorders Checklist (Hudziak et al., 1993), a parent-report questionnaire composed of DSM-III-R symptom items. All diagnoses were based on DSM-IV criteria. Subjects were excluded if they met criteria for any of the following: (1) comorbid psychiatric conditions including psychosis, pervasive developmental disorder, bipolar disorder; (2) severe obsessive-compulsive disorder, severe depressive or anxiety disorder (severe defined as any comorbid disorder with impairment necessitating concurrent treatment of any type); (3) a clinically significant medical condition (e.g., seizure disorder, hypertension, abnormal laboratory test result); (4) need for ongoing medical treatment; (5) intolerance of psychostimulants; (6) history of nonresponse to Adderall; or (7) history of a tic disorder. A total of 51 subjects met all eligibility criteria and provided consent for participation. The characteristics of the sample are listed in Table 1. Study Design Following screening and a 1-week washout period with discontinuation of previous stimulant medication, 51 eligible subjects were enrolled and assessed in an analog classroom setting on 7 consecutive Saturdays. The first prerandomization study day involved the openlabel administration of 20 mg of SLI381 to all subjects with repeated plasma sampling for PK analyses to assess individual tolerability to the drug, to acquire data on SLI381’s PK profile, and to familiarize subjects with the research environment and procedures. The study design which followed the first study day was randomized, double-blind, crossover, placebo- and active-controlled. Subjects who tolerated the initial study day and exposure to SLI381 were then randomly assigned in a crossover design to each of five treatment weeks: SLI381 10 mg (equivalent to Adderall 5 mg b.i.d. with a 4-hour dosing interval), SLI381 20 mg (equivalent to Adderall 10 mg b.i.d.), SLI381 30 mg (equivalent to Adderall 15 mg b.i.d.), Adderall 10 mg, and placebo, each administered daily at 7:30 A.M. A Latin square design was used to determine the randomization sequence for individual subjects for the first 5 weeks with approximately one fifth of the sample randomized to each of five treatment sequences. Randomization schedules
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 2 : 6 , J U N E 2 0 0 3
ANALOG CLASSROOM ASSESSMENT OF ADDERALL XR
TABLE 1 Demographic and Baseline Characteristics of Randomized Sample Characteristic Gender: n (%) Male Female Race: n (%) White Black Hispanic Asian/Pacific Islander Other Age (yr): mean ± SD Weight (lb): mean ± SD Height (in): mean ± SD ADHD diagnosis: n (%) Hyperactive-impulsive Combined Duration of prior stimulant treatment: mean ± SD (yr) ADHD treatment before study entry: n (%) Amphetamine only Methylphenidate only None listed
All Patients (N = 51) 44 (86.3) 7 (13.7) 25 (49.0) 8 (15.7) 12 (23.5) 3 (5.9) 3 (5.9) 9.5 ± 1.9 83.5 ± 28.9 54.6 ± 4.9 1 (2.0) 50 (98.0) 1.7 ± 1.7 17 (33.3) 30 (58.8) 4 (7.8)
Note: ADHD = attention-deficit/hyperactivity disorder. were generated by the sponsor of the study and distributed to the onsite research pharmacists. A sixth treatment week was included as a potential makeup week and as a week for additional PK sampling across all treatment groups, and treatment assignment was handled by a separate procedure. Those subjects who had not completed one of the five randomly assigned treatment conditions were assigned to the missed condition during the final week; those subjects who had completed all prior treatment weeks were randomly assigned to repeat one of the five treatment conditions. All subjects were invited to return for the final analog classroom session. During the final analog classroom day of the makeup week, PK sampling was again performed on all subjects. Pharmacokinetic Sampling When a subject arrived at the laboratory for study visits 1 and 7, an indwelling catheter was inserted into an antecubital vein for plasma sampling. PK samples were obtained at predose, 0.5, 1.5, 3, 4.5, 6, 7.5, 9, 10.5, 12, and 24 hours after administration of SLI381. Concentrations of d- and l-amphetamine were assayed using validated liquid chromatography-mass spectroscopy methodology at a central laboratory. Results of the PK analyses will be presented in a separate report. Analog Classroom Protocol Subjects were assessed in groups of children during consecutive analog classroom study days held on Saturdays at each site. The schedule and procedures for the analog classroom days were based on a modification of well-validated procedures used in previous timeresponse stimulant studies (Pelham et al., 1995; Swanson et al., 1978, 1998, 2000). On each classroom day, subjects were instructed to arrive at the laboratory at approximately 7:00 A.M.; they remained until 7:30 or 8:00 P.M. All subjects were administered study material capsules by study physicians at 7:30 A.M. The daily schedule consisted
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 2 : 6 , J U N E 2 0 0 3
of alternating classroom, play, meals or snacks, and research activities, with a classroom period scheduled every 1.5 hours, beginning immediately after morning dose administration and recurring at 1.5, 4.5, 6.0, 7.5, 9.0, 10.5, and 12.0 hours after administration. To allow extra recess time for study subjects, no classroom (efficacy assessment) period was scheduled at 3.0 hours. Each classroom period lasted a total of 45 minutes and was directed by two teachers for the group of 10 to 15 subjects. In addition, each classroom contained two observers who simultaneously rated the behaviors of one half of the study group, using a behavioral observation system described previously (Swanson et al., 1998, 2000). All classroom raters had completed reliability training for behavioral assessments. Outside of the classroom period, a separate group of research staff (counselors) directed and supervised subjects’ activities. To avoid confounding observation of medication effects, no behavioral or other treatment approaches were used during the analog classroom days. Dependent Measures Several primary and secondary efficacy measures were obtained during the study. Primary efficacy variables included the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) scale Attention and Deportment variables (Swanson et al., 2000), as completed by the classroom raters during each classroom period. Test-retest reliability and concurrent validity of the SKAMP are high (Wigal et al., 1998). In addition, academic performance was assessed using a Permanent Product Measure of Performance (PERMP), a 10-minute age-appropriate math test that was scored to yield absolute number of problems attempted and problems correct (Swanson et al., 2000). These measures have been shown to be sensitive to both dosage and time effects in prior stimulant research (Swanson et al., 1998). Secondary measures included a global behavior rating scale (Parent Global Assessment) that parents were instructed to complete at midweek during each of the six treatment weeks. Parents also completed a weekly Side Effect Rating Scale specific to stimulant treatment. Each analog classroom day, teachers completed the Teacher Side Effect Rating Scale and adverse events were noted by study physicians or research staff. Data Analysis Statistical analyses were conducted on the primary efficacy variables using a mixed-effects analysis of variance (ANOVA) model, with fixed-effect terms of treatment (placebo, SLI381 10, 20, 30 mg, and Adderall 10 mg), period (weeks 1 through 5), session (0.5, 1.5, 4.5, 6, 7.5, 9, 10.5, 12 hours postdose), and treatment-by-session interaction. In those cases in which the overall treatment-by-session effect was significant (p < .05), additional comparisons of individual treatments versus placebo were performed with pairwise comparisons of individual means. As no evidence for possible carryover effects were noted (which would reduce drug-placebo or dose-dependent improvements), no secondary analyses for carryover effects were performed. All p values reported are two-tailed.
RESULTS
Fifty-one children were enrolled in the study. The mean age of the total sample was 9.5 (±1.9) years. The sample consisted of 44 boys and 7 girls. The subjects had a mean duration of prior psychostimulant medication treatment of 1.7 (±1.7) years. Of those children with a history of 675
M C CRACKEN ET AL.
stimulant treatment at the time of study screening, 30 (59%) were receiving methylphenidate and 17 (33%) were receiving an amphetamine-containing medication. Demographics and other characteristics of the sample are shown in Table 1. Of the 51 eligible children who attended the practice day, 2 children dropped out because of withdrawal of consent. Forty-nine children were randomized for the crossover treatment portion of the study. Of the 49 randomized subjects, 47 (92.2%) completed the 5 weeks of the doubleblind portion of the study (all treatment conditions), with 2 subjects withdrawing (1 because of stomachache and 1 after developing an exclusion criterion). A total of 44 (86.3%) children completed the entire protocol, including the extra or “makeup” week. Of the 3 children (5.9%) withdrawing during the final week, 2 withdrew because of an adverse event (1 subject while receiving placebo and 1 subject while receiving SLI381 20 mg); 1 additional subject withdrew because of withdrawal of consent. After each Saturday analog classroom session, medication was provided to parents in the form of six capsules for the coming week. Compliance during the study was assessed weekly by return of medication bottle and review with the parent. Nearly all patients (96%) were compliant with study treatment, defined as administration of 80% to 100% of prescribed study medication based on investigative site capsule counts. The overall mixed-model ANOVA for the intent-totreat population on all four of the primary efficacy variables, SKAMP Attention and Deportment and math problems attempted and problems correct, showed highly significant effects of treatment (SLI381 10, 20, 30 mg, Adderall 10 mg, versus placebo), period (week), session (time points during 12-hour assessment), and treatmentby-session interactions (Table 2). Inclusion of “week” in the model controls for influence of order, even though analog study sessions were performed 7 days apart, on the seventh and final day of each treatment condition, thereby avoiding carryover effects.
Given the highly significant treatment-by-session interaction (p < .0001), additional examination of SKAMP Attention and Deportment scores demonstrated the improvement associated with active treatments versus placebo (Fig. 1). As evident in Fig. 1, increasing doses of SLI381 were associated with larger and consistent improvements (decreases in ratings of inattentive and disruptive behaviors) in SKAMP ratings. Applying pairwise mean comparisons between SLI381 and placebo (Table 3), the SLI381 30-mg dose showed significant improvement (p < .01) over placebo at all postdose time points. SLI381 20 mg just missed attaining statistical significance for Attention problem ratings at 1.5 hours (p = .0513) and Deportment problem ratings at 12 hours (p = .0531), but ratings were significant (p < .01) at all other postdose time points. SLI381 10 mg demonstrated significant reductions in Attention problem ratings at 4.5, 6.0, 7.5, and 10.5 hours postdose, Deportment problem ratings from 4.5 to 9.0 hours postdose. Adderall 10 mg was associated with significant decreases in SKAMP ratings for Attention problems from 1.5 to 7.5 hours and for Deportment problems from 1.5 to 10.5 hours postdose. Descriptive data for all primary efficacy variables are displayed in Table 4. Analysis of the math problem variables also showed robust, apparently dose-dependent treatment effects versus placebo by session (see Fig. 2, Tables 3 and 4). All active treatments were associated with robust increases in problems attempted and problems solved versus placebo. SLI381 20- and 30-mg doses were associated with statistically significant increases in number attempted and number solved for all postdose time points through 12 hours. SLI381 10 mg demonstrated significant increases from 4.5 to 10.5 hours versus placebo. Adderall 10 mg was found to demonstrate increases versus placebo at 1.5, 6.0, 7.5, and 9.0 hours postdose for number attempted; for number solved significance was found at the 1.5, 4.5, 6.0, and 9.0 time points. Overall, study medications were well tolerated by the subjects. No serious side effects were reported or observed. Rates of specific adverse events by condition as reported by parents are shown in Table 5. Because of the modest sam-
TABLE 2 Results of Analysis of Variance of SKAMP and PERMP Scores
SKAMP Attention SKAMP Deportment PERMP no. Attempted PERMP no. Solved
Treatment
Period
Session
Treatment ⫻ Session
F4,1617 = 41.70; p < .0001 F4,1617 = 65.98; p < .0001 F4,1611 = 52.71; p < .0001 F4,1611 = 61.71; p < .0001
F4,1617 = 13.47; p < .0001 F4,1617 = 10.51; p < .0001 F4,1611 = 2.83; p < .0234 F4,1611 = 2.40; p < .0483
F7,1617 = 7.95; p < .0001 F7,1617 = 12.98; p < .0001 F7,1611 = 25.60; p < .0001 F7,1611 = 26.00; p < .0001
F28,1617 = 3.17; p < .0001 F28,1617 = 4.07; p < .0001 F28,1611 = 3.72; p < .0001 F28,1611 = 4.07; p < .0001
Note: SKAMP = Swanson, Kotkin, Agler, M-Flynn, and Pelham scale; PERMP = Permanent Product Measure of Performance.
676
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 2 : 6 , J U N E 2 0 0 3
ANALOG CLASSROOM ASSESSMENT OF ADDERALL XR
Fig. 1 Mean Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) scale Attention and Deportment problem ratings for each treatment condition for the intent-to-treat sample (N = 49) at each time point after administration. Note decreasing values represent improvement in inattentive and hyperactive-impulsive symptoms. Solid symbols indicate statistical significance (p < .05) by two-tailed pairwise comparisons versus placebo (see Table 3).
ple size, comparative analyses were not performed. Only anorexia displayed a dose-dependent pattern of increases for Adderall XR doses, with the incidence at the dose of 20 mg of SLI381 (equivalent to Adderall 10 mg b.i.d.) comparable with that seen with Adderall 10 mg q.d., the posi-
tive control. Adderall 10 mg was associated with comparable frequencies of reported side effects for abdominal pain and asthenia compared with the highest dose (SLI381 30 mg) condition. The reported frequency of headache was similar in all active treatment groups and the placebo group.
TABLE 3 Pairwise Mean Comparisons of SKAMP and PERMP Scores Between Active Treatment and Placebo Over the Analog Classroom Day at Each Assessment Session (Two-Tailed) Time (hr) Postdose (p Value) vs. Placebo 0.0 SKAMP Attention SLI381 30 mg SLI381 20 mg SLI381 10 mg Adderall 10 mg SKAMP Deportment SLI381 30 mg SLI381 20 mg SLI381 10 mg Adderall 10 mg PERMP no. attempted SLI381 30 mg SLI381 20 mg SLI381 10 mg Adderall 10 mg PERMP no. correct SLI381 30 mg SLI381 20 mg SLI381 10 mg Adderall 10 mg
1.5
4.5
6.0
7.5
9.0
10.5
12.0
0.6647 0.8912 0.0152 0.0072
0.0015 0.0513 0.5846 0.0025
<0.0001 0.0023 0.0269 0.0005
<0.0001 <0.0001 0.0003 0.0005
<0.0001 <0.0001 0.0001 0.0002
0.0001 0.0072 0.2442 0.8264
<0.0001 <0.0001 0.0062 0.3250
0.0034 0.0077 0.0626 0.3064
0.7640 0.1205 0.0845 0.0051
0.0002 0.0031 0.0725 <0.0001
<0.0001 <0.0001 0.0090 <0.0001
<0.0001 <0.0001 <0.0001 <0.0001
<0.0001 <0.0001 0.0001 <0.0001
<0.0001 <0.0001 0.0083 0.0004
<0.0001 0.0021 0.0724 0.0246
0.0062 0.0531 0.9878 0.7901
0.3952 0.0304 0.0019 0.0001
0.0030 0.0283 0.0920 0.0004
<0.0001 0.0006 0.0136 0.0850
<0.0001 <0.0001 0.0001 0.0015
<0.0001 <0.0001 0.0017 0.0157
<0.0001 0.0001 0.0230 0.0048
<0.0001 <0.0001 0.0101 0.7626
0.0017 0.0053 0.9938 0.7508
0.3114 0.0193 0.0009 <0.0001
0.0059 0.0333 0.1121 0.0007
<0.0001 <0.0001 0.0020 0.0353
<0.0001 <0.0001 <0.0001 0.0007
<0.0001 <0.0001 0.0029 0.0667
<0.0001 <0.0001 0.0128 0.0195
<0.0001 <0.0001 0.0025 0.3424
0.0001 0.0007 0.5420 0.9304
Note: SKAMP = Swanson, Kotkin, Agler, M-Flynn, and Pelham scale; PERMP = Permanent Product Measure of Performance.
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 2 : 6 , J U N E 2 0 0 3
677
M C CRACKEN ET AL.
TABLE 4 Descriptive Statistics of Primary Efficacy Variables (SKAMP and Math Test) Obtained During Randomized Treatment for the Intent-to-Treat Population (N = 49) Variable—SKAMP Attention Scores Time (hr) Postdose Treatment Placebo Mean SD Adderall 10 mg Mean SD Adderall XR 10 mg Mean SD Adderall XR 20 mg Mean SD Adderall XR 30 mg Mean SD
0.0
1.5
4.5
6.0
7.5
9.0
10.5
12.0
1.18 0.977
1.31 0.825
1.40 0.954
1.74 1.006
1.73 1.005
1.51 0.970
1.74 0.869
1.44 0.929
1.59 1.210
0.88 0.828
0.92 0.920
1.26 1.182
1.22 0.872
1.55 1.284
1.60 1.262
1.59 1.211
1.55 1.050
1.27 0.934
1.13 0.982
1.26 1.034
1.21 0.796
1.40 1.022
1.40 1.016
1.23 0.964
1.27 1.152
1.16 1.089
1.07 1.088
1.14 0.986
1.13 1.048
1.26 1.154
1.27 0.876
1.18 1.010
1.38 1.075
0.98 0.987
0.90 0.823
0.74 0.737
0.74 0.809
1.05 1.160
1.23 1.278
1.15 1.208
7.5
9.0
10.5
12.0
Variable—SKAMP Deportment Scores Time (hr) Postdose Treatment Placebo Mean SD Adderall 10 mg Mean SD Adderall XR 10 mg Mean SD Adderall XR 20 mg Mean SD Adderall XR 30 mg Mean SD
0.0
1.5
4.5
6.0
1.88 1.388
2.22 1.368
2.28 1.314
2.88 1.395
2.90 1.341
2.82 1.162
2.66 1.305
1.99 1.252
2.43 1.757
1.08 1.272
1.25 1.257
1.70 1.639
1.94 1.414
2.04 1.464
2.17 1.416
1.91 1.445
2.28 1.497
1.91 1.396
1.80 1.277
1.85 1.314
2.13 1.244
2.35 1.414
2.44 1.518
2.15 1.319
2.26 1.367
1.69 1.257
1.22 1.002
1.84 1.491
1.67 1.392
1.79 1.447
2.15 1.686
1.73 1.262
1.96 1.507
1.58 1.579
0.90 0.887
1.13 1.185
1.29 1.338
1.46 1.328
1.45 1.511
1.59 1.571
Variable—PERMP Number Attempted Time (hr) Postdose Treatment Placebo Mean SD Adderall 10 mg Mean SD 51.933 Adderall XR 10 mg Mean SD Adderall XR 20 mg Mean SD
0.0
1.5
4.5
6.0
7.5
9.0
10.5
12.0
89.43 56.22
88.61 58.240
85.61 64.935
69.16 49.278
60.39 42.865
60.18 46.917
58.05 41.789
73.48 51.943
59.37 38.428 49.482
118.86 65.036
100.21 56.710
95.83 61.995
81.16 52.505
84.4 59.880
62.21
73.37
63.71 45.384
102.62 58.454
106.12 63.856
102.62 60.219
87.85 57.539
79.80 50.216
78.95 49.375
72.43 44.755
68.36 46.393
102.87 61.162
111.48 62.649
120.87 64.498
107.87 65.574
89.27 55.667
90.07 50.611
91.77 59.364 — Continued
678
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 2 : 6 , J U N E 2 0 0 3
ANALOG CLASSROOM ASSESSMENT OF ADDERALL XR
TABLE 4 (Continued) Variable—PERMP Number Attempted Time (hr) Postdose Treatment Adderall XR 30 mg Mean SD
0.0
1.5
4.5
6.0
7.5
9.0
80.39 53.556
110.98 52.277
131.29 56.214
127.90 61.682
120.12 60.736
108.19 62.271
10.5 100.20 54.122
12.0 95.63 54.893
Variable—PERMP Number Corrected Time (hr) Postdose Treatment Placebo Mean SD Adderall 10 mg Mean SD Adderall XR 10 mg Mean SD Adderall XR 20 mg Mean SD Adderall XR 30 mg Mean SD
0.0
1.5
4.5
6.0
7.5
9.0
10.5
12.0
86.77 56.094
85.20 58.456
77.77 51.058
63.23 44.314
57.34 43.247
54.23 46.019
50.17 40.023
64.88 50.296
56.20 38.018
112.72 68.891
94.69 59.063
90.29 63.837
72.58 54.465
73.40 53.299
60.40 51.419
67.78 48.002
60.95 44.297
97.74 59.854
102.12 62.336
97.90 60.317
82.12 87.396
74.44 48.904
73.55 48.592
68.85 45.108
65.39 45.957
98.11 61.267
107.18 61.914
112.49 67.941
103.80 64.498
85.64 55.545
86.16 50.856
87.25 60.715
77.78 52.453
105.52 54.723
123.79 55.699
124.52 61.138
115.55 60.621
105.02 61.379
97.39 53.601
92.54 54.302
Note: SKAMP = Swanson, Kotkin, Agler, M-Flynn, and Pelham scale; PERMP = Permanent Prudent Measure of Performance.
Fig. 2 Mean math test (Permanent Product Measure of Performance [PERMP]) problems attempted and problems solved for each treatment condition for ITT sample (N = 49) at each time point after administration. Note higher values indicate improved academic performance. Solid symbols indicate statistical significance (p < .05) by twotailed pairwise comparisons versus placebo (see Table 3).
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 2 : 6 , J U N E 2 0 0 3
679
M C CRACKEN ET AL.
TABLE 5 Number (%) of Subject Adverse Events by Parent Report for Treatment Group, Body System, and Preferred Term Treatment Placebo (N = 49) Nervous Nervousness Insomnia Anxiety Emotional lability Depression Movement disorder Body as a whole Abdominal pain Headache Asthenia Digestive Anorexia
29 10 10 5 5 3
(59.2) (20.4) (20.4) (10.2) (10.2) (6.1)
Adderall 10 mg (N = 48) 22 17 11 10 4 2
(45.8) (35.4) (22.9) (20.8) (8.3) (4.2)
26 6 13 13 5 3
(54.2) (12.5) (27.1) (27.1) (10.4) (6.3)
SLI381 20 mg (N = 50) 28 16 11 9 11 1
(56.0) (32.0) (22.0) (18.0) (22.0) (2.0)
SLI381 30 mg (N = 49) 21 14 9 6 3 5
(42.9) (28.6) (18.4) (12.2) (6.1) (10.2)
12 (24.5) 12 (24.5) 8 (16.3)
16 (33.3) 12 (25.0) 11 (22.9)
14 (29.2) 12 (25.0) 8 (16.7)
18 (36.0) 15 (30.0) 12 (24.0)
17 (34.7) 12 (24.5) 11 (22.4)
11 (22.4)
22 (45.8)
13 (27.1)
20 (40.0)
27 (55.1)
DISCUSSION
The goal of this investigation was to assess the efficacy, tolerability, and time course of response of SLI381 (Adderall XR), a new drug delivery system for d-, l-amphetamine salts as a treatment for children with ADHD. SLI381 at three doses (10, 20, and 30 mg q.d.) was compared with a positive control, immediate-release Adderall 10 mg q.d., and placebo, in a randomized, double-blind, crossover design, using an analog classroom procedure with measurements of behavior and classroom performance obtained across a 12-hour observation period. The study design afforded repeated assessments of drug effect and revealed unique time courses of drug action. Overall, Adderall XR showed excellent efficacy and tolerability and displayed a time course of action that extended beyond that of immediate-release Adderall at the 10-mg q.d. dose used as a positive control in this study, and by comparison to prior reports of the pharmacodynamic time course for Adderall as assessed by similar measures (Swanson et al., 1998), even for doses as high as 20 mg q.a.m. For the three SLI381 conditions, a consistent pattern of dose-dependent improvement and extension of time of improvement were observed. Analyses of the effects of SLI381 20 mg (equivalent to 10 mg of Adderall b.i.d.) and 30 mg (equivalent to 15 mg of Adderall b.i.d.) showed both beneficial effects at the first postdose assessment (1.5 hours postdose) and maintenance of these improvements throughout 12 hours for the majority of assessments. For Adderall XR 10 mg, equivalent to 5 mg of Adderall administered b.i.d., improvement in SKAMP Attention and 680
SLI381 10 mg (N = 48)
Deportment ratings (as decreases in attention and behavior problems) were observed by 4.5 hours postdose, and math problems attempted and correct were increased. Because the study protocol did not include a 3-hour postdose assessment, it is not known exactly at what point between 1.5 and 4.5 hours the SLI381 10-mg dose may have attained statistical significance versus placebo. The pattern of dose-dependent improvements observed on all efficacy measures from low, medium, to high doses suggests that the SLI381 delivery system allows for predictable clinical effects during titration of medication. The continued efficacy of Adderall XR at later time points suggests that the delivery system may provide sufficient sustained benefit to enable once-daily administration for many children with ADHD. Although this study was not designed to determine optimal doses for individual subjects, it is interesting to note that treatment effect sizes generated from each of the four primary efficacy variables average approximately 1.0 for the SLI381 30-mg condition at 6 hours postdose, suggesting excellent overall efficacy. The strengths of the study include the methods of direct observation used to assess drug effect, the general comparability of classroom and play settings to those regularly experienced by the children in school, a larger sample size than in prior analog classroom studies, and use of techniques for behavior and performance assay which have been described in prior ADHD treatment research (Swanson et al., 2000) with extensive training used across the four research sites in the reliable implementation of use of analog classroom procedures. In particular, the J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 2 : 6 , J U N E 2 0 0 3
ANALOG CLASSROOM ASSESSMENT OF ADDERALL XR
SKAMP and math test measures have been shown to be both dosage- and time-sensitive in prior reports on stimulants. Our data suggest that the math test variables may in fact be most sensitive to drug efficacy in ADHD. The time course of each experimental treatment condition appeared to be unique by analysis of efficacy measures and by visual inspection of time-action curves (Figs. 1 and 2). Our placebo data replicate the deterioration in classroom behavior and performance across most of the 12-hour period, which was also observed over a shorter timeframe by Swanson et al. (1998). In our study, subjects assigned to placebo demonstrated deteriorating behavior and classroom performance across the day, with only modest recovery at the final session of the assessment period (see Figs. 1 and 2). By 10.5 hours postdose, subjects on placebo were attempting 35% fewer math problems and were correctly answering 43% less than at the first assessment session. At the 12-hour session, placebo children attempted 17% fewer math problems and were correct on 25% fewer than at the initial assessment. In contrast, each of the active treatments showed unique curves characterized by early improvements, followed by varying degrees of symptom return or worsening performance. For example, the extended benefit of SLI381 20- and 30-mg conditions on math measures (shown in Fig. 2) is still apparent at 12.0 hours after administration, with children in the SLI381 groups correctly completing 34% and 43% more math problems over placebo children (20- and 30-mg SLI381 groups, respectively). We also noted that all active treatment groups demonstrated higher ratings of behavior problems at the first time point assessment, but that robust improvement was evident at the next rating 1.5 hours after administration. This could suggest a possible morning “rebound” effect, although we are quite cautious in making any conclusions about this observation. The precise relationship of the pharmacokinetics of SLI381 in relation to its pharmacodynamic action in this study is beyond the scope of this article and will be the subject of a detailed separate report. Few studies have attempted to assess systematically the time-action effects of any psychostimulant for effects as prolonged as 12 hours postdose. James et al. (2001) showed statistically significant reductions in locomotor activity for up to 12 hours for some high-dose amphetamine preparations, but lacking repeated assessments of behavior and academic function, the observed locomotor activity reductions were of uncertain clinical significance. In our investigation, we have documented statistically significant differences between SLI381 20 mg and 30 mg versus placebo J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 2 : 6 , J U N E 2 0 0 3
on both behavioral and academic measures at 12 hours after administration. As these differences calculate to dimensionless effect sizes of between approximately 0.3 and 0.5, we would argue that they represent at least suggestive evidence of “clinically significant” (Kraemer, 1992) remaining treatment benefit from this extended-release preparation for ADHD as long as 12 hours after administration. Limitations
Although the analog classroom attempts to mimic many aspects of a regular school classroom, it admittedly represents a unique setting that may influence behavior (Barkley, 1991). The analog assessments included only ADHD subjects; no control or normal subjects were available for comparison. Furthermore, the level of staffing may have influenced behavior, although mean behavior problem ratings on the SKAMP were clearly elevated during the placebo condition, and treatment effects were robust. In addition, the classroom performance variable is restricted in its ability to reflect any child’s overall academic performance across multiple subjects, demands, and tasks. In this sense, our limited study outcome variables were chosen primarily to measure as sensitively as possible the time-action properties of the treatment conditions. Additional measures and assessments, such as actigraph measures of motor activity, peer assays, global teacher ratings, and other classroom performance measures, would be important to round out the profile of drug action on behavior and academic performance. Even larger samples than ours are needed to better explore differences between treatments in adverse events and other clinical outcomes. Additional studies with other age groups such as adolescents are needed to address concerns about age differences in dose-response relationships (Evans et al., 2001). Clinical Implications
To our knowledge, these data form the largest single direct observational study of the effects of an amphetamine-containing ADHD treatment, and they add significantly to the literature that supports the therapeutic benefit of this agent for the treatment of ADHD in children. The study was not designed to ascertain optimal dose levels for individual subjects, which are well known to vary considerably among individuals. Without optimal dose assessments for individual subjects, it is difficult to make extensive comparisons to other efficacy studies that have used flexible-dose, individually titrated protocols. As a fixed-dose study, it also was not intended to achieve minimal side 681
M C CRACKEN ET AL.
effects. However, the detailed time course assessment it does provide confirms that Adderall XR possesses an extended pattern of clinical efficacy. Arnold (2000), Swanson et al. (1998), and others (Elia et al., 1991) have stated that head-to-head comparisons of amphetamine agents versus methylphenidate suggest nearly equivalent group effects, although Arnold (2000) has raised the question of differential benefits in some symptom domains. Given the availability of several new modified-release preparations for methylphenidate and now SLI381 for amphetamine salts, clinical choice is more complicated than ever before. In the absence of direct comparative studies, our study underscores the recommendation that both classes of stimulants (amphetamine and methylphenidate) be considered first-line agents and that nonresponse to one type of psychostimulant should be followed by a trial of the other class before other alternatives are prescribed, consistent with evolving treatment algorithms (American Academy of Pediatrics, 2001; Pliszka et al., 2000). Similarly, hospital and insurance formularies should include a variety of both types of agents. Our data suggest new drug delivery systems such as SLI381 (Adderall XR) represent a successful strategy to extend the benefits of psychostimulant treatment of ADHD without incurring added side effects, thereby avoiding some of the compliance issues raised by shorter-acting stimulant preparations (Brown et al., 1987; Firestone, 1982; Kauffman et al., 1981). Furthermore, these data demonstrate the clear and compelling therapeutic effects of stimulants, by documenting improvements in both classroom behavioral and performance measures. Acknowledging the striking interindividual differences in stimulant drug effect across children with ADHD, both for time of action and dosage, SLI381 appears to represent a promising new addition to the armamentarium of ADHD treatments. It has the potential to work throughout the day and into the early evening after a single morning administration, thus avoiding in-school administration for those children who need extended therapy. The side effect data from our study are also relevant to clinical practice. Though limited to brief observations over a 6-week period, our initial data suggest that extending drug exposure over a 12-hour period sufficient to yield clinical improvement does not markedly increase reported side effects. One larger study of SLI381 with longer exposure appeared to confirm our observation of apparent excellent tolerability of SLI381 (Biederman et al., 2002). The possibility exists that some degree of daily physio682
logical adaptation takes place which serves to moderate the adverse effects of amphetamine. These observations add to the excellent safety record of the psychostimulants. REFERENCES American Academy of Pediatrics, Committee on Quality Improvement and Subcommittee on Attention-Deficit/Hyperactivity Disorder (2001), Clinical practice guideline: treatment of the school-aged child with attentiondeficit/hyperactivity disorder. Pediatrics 108:1033–1044 Arnold LE (2000), Methylphenidate versus amphetamine: a comparative review. In: Ritalin: Theory and Practice, Greenhill LL, Osman BB, eds. New York: Mary Ann Liebert, pp 127–139 Arnold LE, Christopher J, Huestis RD, Smeltzer DJ (1978), Methylphenidate vs. dextroamphetamine vs. caffeine in minimal brain dysfunction. Arch Gen Psychiatry 35:463–473 Barkley RA (1990), Attention-Deficit Hyperactivity Disorder: A Handbook for Diagnosis and Treatment. New York: Guilford Barkley RA (1991), The ecological validity of laboratory and analogue assessment methods of ADHD symptoms. J Abnorm Child Psychol 19:149–179 Biederman J, Lopez FA, Boellner SW, Chandler MC (2002), A randomized, double-blind, placebo-controlled, parallel-group study of SLI381 (Adderall XR) in children with attention-deficit/hyperactivity disorder. Pediatrics 110:258–266 Bradley C (1950), Benzedrine and Dexedrine in the treatment of children’s behavior disorders. Pediatrics 5:24–37 Brown GL, Ebert MH, Mikkelsen EJ, Hunt RD (1979), Plasma levels of damphetamine in hyperactive children. Psychopharmacology 62:133–140 Brown GL, Ebert MH, Mikkelsen EJ, Hunt RD (1980), Behavior and motor activity response in hyperactive children and plasma amphetamine levels following a sustained release preparation. J Am Acad Child Psychiatry 19:225–239 Brown RT, Borden KA, Wynne ME, Spunt AL, Clingerman SR (1987), Compliance with pharmacological and cognitive treatments for attention deficit disorder. J Am Acad Child Adolesc Psychiatry 26:521–526 Connors CK (1972), Psychological effects of stimulant drugs in children with minimal brain dysfunction. Pediatrics 49:702–709 Elia J, Borcherding BG, Rapoport JL, Keysor CS (1991), Methylphenidate and dextroamphetamine treatments of hyperactivity: are there true nonresponders? Psychiatry Res 36:141–155 Evans SW, Pelham WE, Smith BH et al. (2001), Dose-response effects on ecologically valid measures of academic performance and classroom behavior in adolescents with ADHD. Exp Clin Psychopharmacol 9:163–175 Firestone P (1982), Factors associated with children’s adherence to stimulant medication. Am J Orthopsychiatry 52:447–457 Hudziak JJ, Helzer JE, Wetzel MW et al. (1993), The use of the DSM-III-R Checklist for initial diagnostic assessments. Compr Psychiatry 34:375–383 James RS, Sharp WS, Bastain TM et al. (2001), Double-blind, placebocontrolled study of single-dose amphetamine formulations in ADHD. J Am Acad Child Adolesc Psychiatry 40:1268–1276 Kauffman RE, Smith-Wright D, Reese CA, Simpson R, Jones F (1981), Medication compliance in hyperactive children. Pediatr Pharmacol 1:231–237 Kraemer HC (1992), Reporting the size of effects in research studies to facilitate assessment of practical or clinical significance. Psychoneuroendocrinology 17:527–536 Michaels MA, Weston IE, Zhang Y, Tulloch S (2001), Pharmacokinetics of SLI381, a two-component extended-release formulation of mixed amphetamine salts, administered in fasted and fed states and sprinkled on food. Poster presentation at 41st annual meeting of the New Clinical Drug Evaluation Unit, Phoenix, May 29 MTA Cooperative Group (1999), A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 56:1073–1086 Pelham WE Jr, Gnagy EM, Chronis AM et al. (1999), A comparison of morning-only and morning/late afternoon Adderall to morning-only, twicedaily, and three times-daily methylphenidate in children with attentiondeficit/hyperactivity disorder. Pediatrics 104:1300–1311
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 2 : 6 , J U N E 2 0 0 3
ANALOG CLASSROOM ASSESSMENT OF ADDERALL XR
Pelham WE Jr, Greenslade KE, Vodde-Hamilton M et al. (1990), Relative efficacy of long-acting stimulants on children with attention-deficit hyperactivity disorder: a comparison of standard methylphenidate, sustained-release methylphenidate, sustained-release dextroamphetamine, and pemoline. Pediatrics 86:226–237 Pelham WE Jr, Sturges J, Hoza J et al. (1987), Sustained release and standard methylphenidate effects on cognitive and social behavior in children with attention deficit disorder. Pediatrics 80:491–501 Pelham WE Jr, Swanson JM, Furman MB, Schwindt H (1995), Pemoline effects on children with ADHD: a time-response by dose-response analysis on classroom measures. J Am Acad Child Adolesc Psychiatry 34:1504–1513 Pliszka SR, Greenhill LL, Crismon ML et al. (2000), The Texas Children’s Medication Algorithm Project: report of the Texas Consensus Conference Panel on Medication Treatment of Childhood Attention-Deficit/Hyperactivity Disorder. Part I: strategies. J Am Acad Child Adolesc Psychiatry 39:908–919 Schachar R, Sugarman R (2000), Combining parent training and medication in the treatment of attention deficit hyperactivity disorder. In: Ritalin: Theory and Practice, Greenhill LL, Osman BB, eds. New York: Mary Ann Liebert, pp 87–112 Shaffer D, Fisher P, Lucas CP, Dulcan MK, Schwab-Stone ME (2000), NIMH Diagnostic Interview for Children Version IV (NIMH DISC-IV): descrip-
tion, differences from previous versions, and reliability of some common diagnoses. J Am Acad Child Adolesc Psychiatry 39:28–38 Spencer T, Biederman J, Wilens TE, Harding M (1996), Pharmacotherapy of ADHD across the lifecycle: a literature review. J Am Acad Child Adolesc Psychiatry 35:409–432 Swanson JM, Agler D, Fineberg E et al. (2000), University of California, Irvine, Laboratory School Protocol for Pharmacokinetic and Pharmacodynamic Studies. In: Ritalin: Theory and Practice, Greenhill LL, Osman BB, eds. New York: Mary Ann Liebert, pp 405–432 Swanson JM, Kinsbourne M, Roberts W, Zucker K (1978), A time-response analysis of the effect of stimulant medication on the learning ability of children referred for hyperactivity. Pediatrics 61:21–29 Swanson JM, Wigal S, Greenhill LL et al. (1998), Analog classroom assessment of Adderall威 in children with ADHD. J Am Acad Child Adolesc Psychiatry 37:519–526 Weiss G, Minde K, Douglas V (1971), Comparison of the effects of chlorpromazine, dextroamphetamine, and methylphenidate on the behavior and intellectual functioning of hyperactive children. Can Med J 104:20–25 Wigal SB, Gupta S, Guinta D, Swanson J (1998), Reliability and validity of the SKAMP rating scale in a laboratory school setting. Psychopharmacol Bull 34:47–53
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 2 : 6 , J U N E 2 0 0 3
683
ABSTRACT Objectives: This investigation was conducted primarily to assess the safety and efficacy of SLI381 (Adderall XR娃), developed as a once-daily treatment for children with attention-deficit/hyperactivity disorder (ADHD). Secondary objectives included examination of the time course, pharmacokinetic, and pharmacodynamic properties of SLI381. Method: This was a randomized, double-blind, crossover study of three doses of SLI381 (10, 20, and 30 mg), placebo, and an active control (Adderall威 10 mg) given once daily to 51 children with ADHD. Weekly assessments in an analog classroom setting included blind ratings of attention and deportment and a performance measure (math test) obtained every 1.5 hours over a 12-hour period. Results: SLI381 was well tolerated. All active treatment conditions displayed significant time course effects and were superior to placebo in improving efficacy measures. Dose-dependent improvements were evident for SLI381. SLI381 20 and 30 mg and Adderall all showed rapid improvements by 1.5 hours, but only the SLI381 20and 30-mg doses showed continued activity at 10.5 and 12 hours for classroom behavior and math test performance versus placebo. Conclusions: These data provide support for the benefit of this novel, once-daily amphetamine preparation in the treatment of ADHD. The longer duration of action of SLI381 has the potential to simplify psychostimulant dosing, thus reducing dose diversion and eliminating the need for in-school administration. SLI381 appears to be a useful treatment option for many children with ADHD. J. Am. Acad. Child Adolesc. Psychiatry, 2003, 42(6):673–683. Key Words: attention-deficit/hyperactivity disorder, amphetamine, Adderall威, ADDERALL XR娃, stimulant, children.
Psychostimulant medications comprise a mainstay of treatment for attention-deficit/hyperactivity disorder (ADHD), with a long history of research documenting the acute efficacy of both amphetamine and methylphenidate (Arnold et al., 1978; Barkley, 1990; Bradley, 1950; Connors, 1972; MTA Cooperative Group, 1999; Accepted January 14, 2003. Drs. McCracken, McGough, and Pataki are with the Department of Psychiatry and Biobehavioral Sciences, Division of Child and Adolescent Psychiatry, UCLA Neuropsychiatric Institute, Los Angeles; Drs. Biederman and Spencer are with the Department of Psychiatry, Massachusetts General Hospital, Boston; Drs. Greenhill and Posner are with the Department of Psychiatry, Columbia University, New York; Drs. Swanson and Wigal are with the Child Development Center, University of California at Irvine; Drs. Tulloch and Zhang are with Shire Pharmaceutical Development Inc., Rockville, MD. This study was supported by a grant from Shire Pharmaceutical Development Inc. Reprint requests to Dr. McCracken, UCLA Neuropsychiatric Institute, 760 Westwood Plaza, Los Angeles, CA 90024-1759; e-mail: [email protected]. 0890-8567/03/4206–0673䉷2003 by the American Academy of Child and Adolescent Psychiatry. DOI: 10.1097/01.CHI.0000046863.56865.FE
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 2 : 6 , J U N E 2 0 0 3
Pelham et al., 1990; Spencer et al., 1996; Swanson et al., 1978; Weiss et al., 1971). However, clinical experience and a variety of research data suggest that there is a continued need to develop strategies to optimize these treatments, especially as they are applied in community practice settings. Specifically, the short duration of action of available stimulants necessitates multiple daily doses for many children to provide effective symptom management (Pelham et al., 1987; Swanson et al., 1978). Some have suggested the brief duration of action may undercut the possible long-term benefit of stimulant treatment (Schachar and Sugarman, 2000). Clinically, children with ADHD often experience difficulty with evening homework requirements and less structured family routines, requiring additional medication later in the day. The complexity of multiple daily dosing schedules contributes to reduced compliance and may increase the likelihood of drug diversion. Both practice patterns and poor compliance also serve to reduce the overall benefit of psychostimulant 673
M C CRACKEN ET AL.
treatment of many children with ADHD (Brown et al., 1987; Kauffman et al., 1981; MTA Cooperative Group, 1999). Therefore, there is a need to develop drug delivery systems that can effectively treat ADHD symptoms with a single daily dose. In spite of the frequency of use of amphetamine-containing products for the treatment of ADHD, there is a surprising paucity of studies on the pharmacokinetic (PK) and behavioral time course of effects of low-dose amphetamine administration for ADHD (Brown et al., 1979, 1980; Pelham et al., 1999; Swanson et al., 1998). The current study describes the efficacy, tolerability, and detailed time course of SLI381 (Adderall XR娃), a unique drug delivery system containing the mixture of amphetamine salts contained in a currently approved treatment, Adderall威, on symptoms of ADHD in a sample of children with ADHD. Adderall is a racemic mixture of dextro- and levo-isomers of amphetamine composed of equal parts of amphetamine salts (d-amphetamine sulfate, d-amphetamine saccharate, d,l-amphetamine aspartate monohydrate, and d,l-amphetamine sulfate). The mixture yields a 3:1 ratio of dextro- to levo-isomers of amphetamine. A previous analog classroom pharmacodynamic study of Adderall documented the time course of behavioral and classroom performance effects across a dose range of 5 to 20 mg given once, with behavioral effects evident up to approximately 5 to 7 hours postdose for the highest dose condition (Swanson et al., 1998). Pelham et al. (1999) studied Adderall effects in a summer treatment program and found apparent benefits up to 7 hours after administration. James et al. (2001) recently described locomotor activity effects of amphetamine preparations up to 12 hours postdose, but they did not repeatedly probe disruptive behavior or academic performance. It is interesting that the Swanson et al. (1998) report also demonstrated the pattern of deterioration on placebo in performance across morning into afternoon assessments, highlighting the importance of providing appropriate control groups for time-response studies. This study was aimed to systematically evaluate the efficacy and tolerability of SLI381 as a treatment for ADHD, using an analog classroom observational procedure. SLI381 is designed to release two pulses of active medication, modeling the PK profile of Adderall administered twice daily with doses administered approximately 4 hours apart. A 20-mg dose of SLI381 is bioequivalent to Adderall 10 mg b.i.d., with a 4-hour interval (Michaels et al., 2001). In addition, the study adds to the literature on the behav674
ioral and cognitive effects of amphetamines in children with ADHD. METHOD The study was conducted at four academic sites under local university human subject protection committee approval. Subjects were recruited at the four sites through a combination of advertising and distribution of information about study participation at local outpatient clinics. All subjects provided written assent for study participation; parents provided written consent for their child’s enrollment. Families were compensated $50 for participation in each all-day analog classroom day. Subjects Potential subjects were screened to meet the following eligibility criteria: (1) age 6 to 12 years; (2) diagnosis of DSM-IV ADHD (combined or hyperactive-impulsive subtype as determined by a comprehensive clinician evaluation and selected modules of the Diagnostic Interview Schedule for Children, Version IV-Lifetime [DISC-IV]) (Shaffer et al., 2000) administered by a research staff member with suitable training; (3) no evidence of mental retardation; and (4) history of positive response to psychostimulant medication, or no prior stimulant treatment. Information pertaining to co-occurring psychopathology from the clinical evaluation was supplemented by the Comorbid Disorders Checklist (Hudziak et al., 1993), a parent-report questionnaire composed of DSM-III-R symptom items. All diagnoses were based on DSM-IV criteria. Subjects were excluded if they met criteria for any of the following: (1) comorbid psychiatric conditions including psychosis, pervasive developmental disorder, bipolar disorder; (2) severe obsessive-compulsive disorder, severe depressive or anxiety disorder (severe defined as any comorbid disorder with impairment necessitating concurrent treatment of any type); (3) a clinically significant medical condition (e.g., seizure disorder, hypertension, abnormal laboratory test result); (4) need for ongoing medical treatment; (5) intolerance of psychostimulants; (6) history of nonresponse to Adderall; or (7) history of a tic disorder. A total of 51 subjects met all eligibility criteria and provided consent for participation. The characteristics of the sample are listed in Table 1. Study Design Following screening and a 1-week washout period with discontinuation of previous stimulant medication, 51 eligible subjects were enrolled and assessed in an analog classroom setting on 7 consecutive Saturdays. The first prerandomization study day involved the openlabel administration of 20 mg of SLI381 to all subjects with repeated plasma sampling for PK analyses to assess individual tolerability to the drug, to acquire data on SLI381’s PK profile, and to familiarize subjects with the research environment and procedures. The study design which followed the first study day was randomized, double-blind, crossover, placebo- and active-controlled. Subjects who tolerated the initial study day and exposure to SLI381 were then randomly assigned in a crossover design to each of five treatment weeks: SLI381 10 mg (equivalent to Adderall 5 mg b.i.d. with a 4-hour dosing interval), SLI381 20 mg (equivalent to Adderall 10 mg b.i.d.), SLI381 30 mg (equivalent to Adderall 15 mg b.i.d.), Adderall 10 mg, and placebo, each administered daily at 7:30 A.M. A Latin square design was used to determine the randomization sequence for individual subjects for the first 5 weeks with approximately one fifth of the sample randomized to each of five treatment sequences. Randomization schedules
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 2 : 6 , J U N E 2 0 0 3
ANALOG CLASSROOM ASSESSMENT OF ADDERALL XR
TABLE 1 Demographic and Baseline Characteristics of Randomized Sample Characteristic Gender: n (%) Male Female Race: n (%) White Black Hispanic Asian/Pacific Islander Other Age (yr): mean ± SD Weight (lb): mean ± SD Height (in): mean ± SD ADHD diagnosis: n (%) Hyperactive-impulsive Combined Duration of prior stimulant treatment: mean ± SD (yr) ADHD treatment before study entry: n (%) Amphetamine only Methylphenidate only None listed
All Patients (N = 51) 44 (86.3) 7 (13.7) 25 (49.0) 8 (15.7) 12 (23.5) 3 (5.9) 3 (5.9) 9.5 ± 1.9 83.5 ± 28.9 54.6 ± 4.9 1 (2.0) 50 (98.0) 1.7 ± 1.7 17 (33.3) 30 (58.8) 4 (7.8)
Note: ADHD = attention-deficit/hyperactivity disorder. were generated by the sponsor of the study and distributed to the onsite research pharmacists. A sixth treatment week was included as a potential makeup week and as a week for additional PK sampling across all treatment groups, and treatment assignment was handled by a separate procedure. Those subjects who had not completed one of the five randomly assigned treatment conditions were assigned to the missed condition during the final week; those subjects who had completed all prior treatment weeks were randomly assigned to repeat one of the five treatment conditions. All subjects were invited to return for the final analog classroom session. During the final analog classroom day of the makeup week, PK sampling was again performed on all subjects. Pharmacokinetic Sampling When a subject arrived at the laboratory for study visits 1 and 7, an indwelling catheter was inserted into an antecubital vein for plasma sampling. PK samples were obtained at predose, 0.5, 1.5, 3, 4.5, 6, 7.5, 9, 10.5, 12, and 24 hours after administration of SLI381. Concentrations of d- and l-amphetamine were assayed using validated liquid chromatography-mass spectroscopy methodology at a central laboratory. Results of the PK analyses will be presented in a separate report. Analog Classroom Protocol Subjects were assessed in groups of children during consecutive analog classroom study days held on Saturdays at each site. The schedule and procedures for the analog classroom days were based on a modification of well-validated procedures used in previous timeresponse stimulant studies (Pelham et al., 1995; Swanson et al., 1978, 1998, 2000). On each classroom day, subjects were instructed to arrive at the laboratory at approximately 7:00 A.M.; they remained until 7:30 or 8:00 P.M. All subjects were administered study material capsules by study physicians at 7:30 A.M. The daily schedule consisted
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 2 : 6 , J U N E 2 0 0 3
of alternating classroom, play, meals or snacks, and research activities, with a classroom period scheduled every 1.5 hours, beginning immediately after morning dose administration and recurring at 1.5, 4.5, 6.0, 7.5, 9.0, 10.5, and 12.0 hours after administration. To allow extra recess time for study subjects, no classroom (efficacy assessment) period was scheduled at 3.0 hours. Each classroom period lasted a total of 45 minutes and was directed by two teachers for the group of 10 to 15 subjects. In addition, each classroom contained two observers who simultaneously rated the behaviors of one half of the study group, using a behavioral observation system described previously (Swanson et al., 1998, 2000). All classroom raters had completed reliability training for behavioral assessments. Outside of the classroom period, a separate group of research staff (counselors) directed and supervised subjects’ activities. To avoid confounding observation of medication effects, no behavioral or other treatment approaches were used during the analog classroom days. Dependent Measures Several primary and secondary efficacy measures were obtained during the study. Primary efficacy variables included the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) scale Attention and Deportment variables (Swanson et al., 2000), as completed by the classroom raters during each classroom period. Test-retest reliability and concurrent validity of the SKAMP are high (Wigal et al., 1998). In addition, academic performance was assessed using a Permanent Product Measure of Performance (PERMP), a 10-minute age-appropriate math test that was scored to yield absolute number of problems attempted and problems correct (Swanson et al., 2000). These measures have been shown to be sensitive to both dosage and time effects in prior stimulant research (Swanson et al., 1998). Secondary measures included a global behavior rating scale (Parent Global Assessment) that parents were instructed to complete at midweek during each of the six treatment weeks. Parents also completed a weekly Side Effect Rating Scale specific to stimulant treatment. Each analog classroom day, teachers completed the Teacher Side Effect Rating Scale and adverse events were noted by study physicians or research staff. Data Analysis Statistical analyses were conducted on the primary efficacy variables using a mixed-effects analysis of variance (ANOVA) model, with fixed-effect terms of treatment (placebo, SLI381 10, 20, 30 mg, and Adderall 10 mg), period (weeks 1 through 5), session (0.5, 1.5, 4.5, 6, 7.5, 9, 10.5, 12 hours postdose), and treatment-by-session interaction. In those cases in which the overall treatment-by-session effect was significant (p < .05), additional comparisons of individual treatments versus placebo were performed with pairwise comparisons of individual means. As no evidence for possible carryover effects were noted (which would reduce drug-placebo or dose-dependent improvements), no secondary analyses for carryover effects were performed. All p values reported are two-tailed.
RESULTS
Fifty-one children were enrolled in the study. The mean age of the total sample was 9.5 (±1.9) years. The sample consisted of 44 boys and 7 girls. The subjects had a mean duration of prior psychostimulant medication treatment of 1.7 (±1.7) years. Of those children with a history of 675
M C CRACKEN ET AL.
stimulant treatment at the time of study screening, 30 (59%) were receiving methylphenidate and 17 (33%) were receiving an amphetamine-containing medication. Demographics and other characteristics of the sample are shown in Table 1. Of the 51 eligible children who attended the practice day, 2 children dropped out because of withdrawal of consent. Forty-nine children were randomized for the crossover treatment portion of the study. Of the 49 randomized subjects, 47 (92.2%) completed the 5 weeks of the doubleblind portion of the study (all treatment conditions), with 2 subjects withdrawing (1 because of stomachache and 1 after developing an exclusion criterion). A total of 44 (86.3%) children completed the entire protocol, including the extra or “makeup” week. Of the 3 children (5.9%) withdrawing during the final week, 2 withdrew because of an adverse event (1 subject while receiving placebo and 1 subject while receiving SLI381 20 mg); 1 additional subject withdrew because of withdrawal of consent. After each Saturday analog classroom session, medication was provided to parents in the form of six capsules for the coming week. Compliance during the study was assessed weekly by return of medication bottle and review with the parent. Nearly all patients (96%) were compliant with study treatment, defined as administration of 80% to 100% of prescribed study medication based on investigative site capsule counts. The overall mixed-model ANOVA for the intent-totreat population on all four of the primary efficacy variables, SKAMP Attention and Deportment and math problems attempted and problems correct, showed highly significant effects of treatment (SLI381 10, 20, 30 mg, Adderall 10 mg, versus placebo), period (week), session (time points during 12-hour assessment), and treatmentby-session interactions (Table 2). Inclusion of “week” in the model controls for influence of order, even though analog study sessions were performed 7 days apart, on the seventh and final day of each treatment condition, thereby avoiding carryover effects.
Given the highly significant treatment-by-session interaction (p < .0001), additional examination of SKAMP Attention and Deportment scores demonstrated the improvement associated with active treatments versus placebo (Fig. 1). As evident in Fig. 1, increasing doses of SLI381 were associated with larger and consistent improvements (decreases in ratings of inattentive and disruptive behaviors) in SKAMP ratings. Applying pairwise mean comparisons between SLI381 and placebo (Table 3), the SLI381 30-mg dose showed significant improvement (p < .01) over placebo at all postdose time points. SLI381 20 mg just missed attaining statistical significance for Attention problem ratings at 1.5 hours (p = .0513) and Deportment problem ratings at 12 hours (p = .0531), but ratings were significant (p < .01) at all other postdose time points. SLI381 10 mg demonstrated significant reductions in Attention problem ratings at 4.5, 6.0, 7.5, and 10.5 hours postdose, Deportment problem ratings from 4.5 to 9.0 hours postdose. Adderall 10 mg was associated with significant decreases in SKAMP ratings for Attention problems from 1.5 to 7.5 hours and for Deportment problems from 1.5 to 10.5 hours postdose. Descriptive data for all primary efficacy variables are displayed in Table 4. Analysis of the math problem variables also showed robust, apparently dose-dependent treatment effects versus placebo by session (see Fig. 2, Tables 3 and 4). All active treatments were associated with robust increases in problems attempted and problems solved versus placebo. SLI381 20- and 30-mg doses were associated with statistically significant increases in number attempted and number solved for all postdose time points through 12 hours. SLI381 10 mg demonstrated significant increases from 4.5 to 10.5 hours versus placebo. Adderall 10 mg was found to demonstrate increases versus placebo at 1.5, 6.0, 7.5, and 9.0 hours postdose for number attempted; for number solved significance was found at the 1.5, 4.5, 6.0, and 9.0 time points. Overall, study medications were well tolerated by the subjects. No serious side effects were reported or observed. Rates of specific adverse events by condition as reported by parents are shown in Table 5. Because of the modest sam-
TABLE 2 Results of Analysis of Variance of SKAMP and PERMP Scores
SKAMP Attention SKAMP Deportment PERMP no. Attempted PERMP no. Solved
Treatment
Period
Session
Treatment ⫻ Session
F4,1617 = 41.70; p < .0001 F4,1617 = 65.98; p < .0001 F4,1611 = 52.71; p < .0001 F4,1611 = 61.71; p < .0001
F4,1617 = 13.47; p < .0001 F4,1617 = 10.51; p < .0001 F4,1611 = 2.83; p < .0234 F4,1611 = 2.40; p < .0483
F7,1617 = 7.95; p < .0001 F7,1617 = 12.98; p < .0001 F7,1611 = 25.60; p < .0001 F7,1611 = 26.00; p < .0001
F28,1617 = 3.17; p < .0001 F28,1617 = 4.07; p < .0001 F28,1611 = 3.72; p < .0001 F28,1611 = 4.07; p < .0001
Note: SKAMP = Swanson, Kotkin, Agler, M-Flynn, and Pelham scale; PERMP = Permanent Product Measure of Performance.
676
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 2 : 6 , J U N E 2 0 0 3
ANALOG CLASSROOM ASSESSMENT OF ADDERALL XR
Fig. 1 Mean Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) scale Attention and Deportment problem ratings for each treatment condition for the intent-to-treat sample (N = 49) at each time point after administration. Note decreasing values represent improvement in inattentive and hyperactive-impulsive symptoms. Solid symbols indicate statistical significance (p < .05) by two-tailed pairwise comparisons versus placebo (see Table 3).
ple size, comparative analyses were not performed. Only anorexia displayed a dose-dependent pattern of increases for Adderall XR doses, with the incidence at the dose of 20 mg of SLI381 (equivalent to Adderall 10 mg b.i.d.) comparable with that seen with Adderall 10 mg q.d., the posi-
tive control. Adderall 10 mg was associated with comparable frequencies of reported side effects for abdominal pain and asthenia compared with the highest dose (SLI381 30 mg) condition. The reported frequency of headache was similar in all active treatment groups and the placebo group.
TABLE 3 Pairwise Mean Comparisons of SKAMP and PERMP Scores Between Active Treatment and Placebo Over the Analog Classroom Day at Each Assessment Session (Two-Tailed) Time (hr) Postdose (p Value) vs. Placebo 0.0 SKAMP Attention SLI381 30 mg SLI381 20 mg SLI381 10 mg Adderall 10 mg SKAMP Deportment SLI381 30 mg SLI381 20 mg SLI381 10 mg Adderall 10 mg PERMP no. attempted SLI381 30 mg SLI381 20 mg SLI381 10 mg Adderall 10 mg PERMP no. correct SLI381 30 mg SLI381 20 mg SLI381 10 mg Adderall 10 mg
1.5
4.5
6.0
7.5
9.0
10.5
12.0
0.6647 0.8912 0.0152 0.0072
0.0015 0.0513 0.5846 0.0025
<0.0001 0.0023 0.0269 0.0005
<0.0001 <0.0001 0.0003 0.0005
<0.0001 <0.0001 0.0001 0.0002
0.0001 0.0072 0.2442 0.8264
<0.0001 <0.0001 0.0062 0.3250
0.0034 0.0077 0.0626 0.3064
0.7640 0.1205 0.0845 0.0051
0.0002 0.0031 0.0725 <0.0001
<0.0001 <0.0001 0.0090 <0.0001
<0.0001 <0.0001 <0.0001 <0.0001
<0.0001 <0.0001 0.0001 <0.0001
<0.0001 <0.0001 0.0083 0.0004
<0.0001 0.0021 0.0724 0.0246
0.0062 0.0531 0.9878 0.7901
0.3952 0.0304 0.0019 0.0001
0.0030 0.0283 0.0920 0.0004
<0.0001 0.0006 0.0136 0.0850
<0.0001 <0.0001 0.0001 0.0015
<0.0001 <0.0001 0.0017 0.0157
<0.0001 0.0001 0.0230 0.0048
<0.0001 <0.0001 0.0101 0.7626
0.0017 0.0053 0.9938 0.7508
0.3114 0.0193 0.0009 <0.0001
0.0059 0.0333 0.1121 0.0007
<0.0001 <0.0001 0.0020 0.0353
<0.0001 <0.0001 <0.0001 0.0007
<0.0001 <0.0001 0.0029 0.0667
<0.0001 <0.0001 0.0128 0.0195
<0.0001 <0.0001 0.0025 0.3424
0.0001 0.0007 0.5420 0.9304
Note: SKAMP = Swanson, Kotkin, Agler, M-Flynn, and Pelham scale; PERMP = Permanent Product Measure of Performance.
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 2 : 6 , J U N E 2 0 0 3
677
M C CRACKEN ET AL.
TABLE 4 Descriptive Statistics of Primary Efficacy Variables (SKAMP and Math Test) Obtained During Randomized Treatment for the Intent-to-Treat Population (N = 49) Variable—SKAMP Attention Scores Time (hr) Postdose Treatment Placebo Mean SD Adderall 10 mg Mean SD Adderall XR 10 mg Mean SD Adderall XR 20 mg Mean SD Adderall XR 30 mg Mean SD
0.0
1.5
4.5
6.0
7.5
9.0
10.5
12.0
1.18 0.977
1.31 0.825
1.40 0.954
1.74 1.006
1.73 1.005
1.51 0.970
1.74 0.869
1.44 0.929
1.59 1.210
0.88 0.828
0.92 0.920
1.26 1.182
1.22 0.872
1.55 1.284
1.60 1.262
1.59 1.211
1.55 1.050
1.27 0.934
1.13 0.982
1.26 1.034
1.21 0.796
1.40 1.022
1.40 1.016
1.23 0.964
1.27 1.152
1.16 1.089
1.07 1.088
1.14 0.986
1.13 1.048
1.26 1.154
1.27 0.876
1.18 1.010
1.38 1.075
0.98 0.987
0.90 0.823
0.74 0.737
0.74 0.809
1.05 1.160
1.23 1.278
1.15 1.208
7.5
9.0
10.5
12.0
Variable—SKAMP Deportment Scores Time (hr) Postdose Treatment Placebo Mean SD Adderall 10 mg Mean SD Adderall XR 10 mg Mean SD Adderall XR 20 mg Mean SD Adderall XR 30 mg Mean SD
0.0
1.5
4.5
6.0
1.88 1.388
2.22 1.368
2.28 1.314
2.88 1.395
2.90 1.341
2.82 1.162
2.66 1.305
1.99 1.252
2.43 1.757
1.08 1.272
1.25 1.257
1.70 1.639
1.94 1.414
2.04 1.464
2.17 1.416
1.91 1.445
2.28 1.497
1.91 1.396
1.80 1.277
1.85 1.314
2.13 1.244
2.35 1.414
2.44 1.518
2.15 1.319
2.26 1.367
1.69 1.257
1.22 1.002
1.84 1.491
1.67 1.392
1.79 1.447
2.15 1.686
1.73 1.262
1.96 1.507
1.58 1.579
0.90 0.887
1.13 1.185
1.29 1.338
1.46 1.328
1.45 1.511
1.59 1.571
Variable—PERMP Number Attempted Time (hr) Postdose Treatment Placebo Mean SD Adderall 10 mg Mean SD 51.933 Adderall XR 10 mg Mean SD Adderall XR 20 mg Mean SD
0.0
1.5
4.5
6.0
7.5
9.0
10.5
12.0
89.43 56.22
88.61 58.240
85.61 64.935
69.16 49.278
60.39 42.865
60.18 46.917
58.05 41.789
73.48 51.943
59.37 38.428 49.482
118.86 65.036
100.21 56.710
95.83 61.995
81.16 52.505
84.4 59.880
62.21
73.37
63.71 45.384
102.62 58.454
106.12 63.856
102.62 60.219
87.85 57.539
79.80 50.216
78.95 49.375
72.43 44.755
68.36 46.393
102.87 61.162
111.48 62.649
120.87 64.498
107.87 65.574
89.27 55.667
90.07 50.611
91.77 59.364 — Continued
678
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 2 : 6 , J U N E 2 0 0 3
ANALOG CLASSROOM ASSESSMENT OF ADDERALL XR
TABLE 4 (Continued) Variable—PERMP Number Attempted Time (hr) Postdose Treatment Adderall XR 30 mg Mean SD
0.0
1.5
4.5
6.0
7.5
9.0
80.39 53.556
110.98 52.277
131.29 56.214
127.90 61.682
120.12 60.736
108.19 62.271
10.5 100.20 54.122
12.0 95.63 54.893
Variable—PERMP Number Corrected Time (hr) Postdose Treatment Placebo Mean SD Adderall 10 mg Mean SD Adderall XR 10 mg Mean SD Adderall XR 20 mg Mean SD Adderall XR 30 mg Mean SD
0.0
1.5
4.5
6.0
7.5
9.0
10.5
12.0
86.77 56.094
85.20 58.456
77.77 51.058
63.23 44.314
57.34 43.247
54.23 46.019
50.17 40.023
64.88 50.296
56.20 38.018
112.72 68.891
94.69 59.063
90.29 63.837
72.58 54.465
73.40 53.299
60.40 51.419
67.78 48.002
60.95 44.297
97.74 59.854
102.12 62.336
97.90 60.317
82.12 87.396
74.44 48.904
73.55 48.592
68.85 45.108
65.39 45.957
98.11 61.267
107.18 61.914
112.49 67.941
103.80 64.498
85.64 55.545
86.16 50.856
87.25 60.715
77.78 52.453
105.52 54.723
123.79 55.699
124.52 61.138
115.55 60.621
105.02 61.379
97.39 53.601
92.54 54.302
Note: SKAMP = Swanson, Kotkin, Agler, M-Flynn, and Pelham scale; PERMP = Permanent Prudent Measure of Performance.
Fig. 2 Mean math test (Permanent Product Measure of Performance [PERMP]) problems attempted and problems solved for each treatment condition for ITT sample (N = 49) at each time point after administration. Note higher values indicate improved academic performance. Solid symbols indicate statistical significance (p < .05) by twotailed pairwise comparisons versus placebo (see Table 3).
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 2 : 6 , J U N E 2 0 0 3
679
M C CRACKEN ET AL.
TABLE 5 Number (%) of Subject Adverse Events by Parent Report for Treatment Group, Body System, and Preferred Term Treatment Placebo (N = 49) Nervous Nervousness Insomnia Anxiety Emotional lability Depression Movement disorder Body as a whole Abdominal pain Headache Asthenia Digestive Anorexia
29 10 10 5 5 3
(59.2) (20.4) (20.4) (10.2) (10.2) (6.1)
Adderall 10 mg (N = 48) 22 17 11 10 4 2
(45.8) (35.4) (22.9) (20.8) (8.3) (4.2)
26 6 13 13 5 3
(54.2) (12.5) (27.1) (27.1) (10.4) (6.3)
SLI381 20 mg (N = 50) 28 16 11 9 11 1
(56.0) (32.0) (22.0) (18.0) (22.0) (2.0)
SLI381 30 mg (N = 49) 21 14 9 6 3 5
(42.9) (28.6) (18.4) (12.2) (6.1) (10.2)
12 (24.5) 12 (24.5) 8 (16.3)
16 (33.3) 12 (25.0) 11 (22.9)
14 (29.2) 12 (25.0) 8 (16.7)
18 (36.0) 15 (30.0) 12 (24.0)
17 (34.7) 12 (24.5) 11 (22.4)
11 (22.4)
22 (45.8)
13 (27.1)
20 (40.0)
27 (55.1)
DISCUSSION
The goal of this investigation was to assess the efficacy, tolerability, and time course of response of SLI381 (Adderall XR), a new drug delivery system for d-, l-amphetamine salts as a treatment for children with ADHD. SLI381 at three doses (10, 20, and 30 mg q.d.) was compared with a positive control, immediate-release Adderall 10 mg q.d., and placebo, in a randomized, double-blind, crossover design, using an analog classroom procedure with measurements of behavior and classroom performance obtained across a 12-hour observation period. The study design afforded repeated assessments of drug effect and revealed unique time courses of drug action. Overall, Adderall XR showed excellent efficacy and tolerability and displayed a time course of action that extended beyond that of immediate-release Adderall at the 10-mg q.d. dose used as a positive control in this study, and by comparison to prior reports of the pharmacodynamic time course for Adderall as assessed by similar measures (Swanson et al., 1998), even for doses as high as 20 mg q.a.m. For the three SLI381 conditions, a consistent pattern of dose-dependent improvement and extension of time of improvement were observed. Analyses of the effects of SLI381 20 mg (equivalent to 10 mg of Adderall b.i.d.) and 30 mg (equivalent to 15 mg of Adderall b.i.d.) showed both beneficial effects at the first postdose assessment (1.5 hours postdose) and maintenance of these improvements throughout 12 hours for the majority of assessments. For Adderall XR 10 mg, equivalent to 5 mg of Adderall administered b.i.d., improvement in SKAMP Attention and 680
SLI381 10 mg (N = 48)
Deportment ratings (as decreases in attention and behavior problems) were observed by 4.5 hours postdose, and math problems attempted and correct were increased. Because the study protocol did not include a 3-hour postdose assessment, it is not known exactly at what point between 1.5 and 4.5 hours the SLI381 10-mg dose may have attained statistical significance versus placebo. The pattern of dose-dependent improvements observed on all efficacy measures from low, medium, to high doses suggests that the SLI381 delivery system allows for predictable clinical effects during titration of medication. The continued efficacy of Adderall XR at later time points suggests that the delivery system may provide sufficient sustained benefit to enable once-daily administration for many children with ADHD. Although this study was not designed to determine optimal doses for individual subjects, it is interesting to note that treatment effect sizes generated from each of the four primary efficacy variables average approximately 1.0 for the SLI381 30-mg condition at 6 hours postdose, suggesting excellent overall efficacy. The strengths of the study include the methods of direct observation used to assess drug effect, the general comparability of classroom and play settings to those regularly experienced by the children in school, a larger sample size than in prior analog classroom studies, and use of techniques for behavior and performance assay which have been described in prior ADHD treatment research (Swanson et al., 2000) with extensive training used across the four research sites in the reliable implementation of use of analog classroom procedures. In particular, the J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 2 : 6 , J U N E 2 0 0 3
ANALOG CLASSROOM ASSESSMENT OF ADDERALL XR
SKAMP and math test measures have been shown to be both dosage- and time-sensitive in prior reports on stimulants. Our data suggest that the math test variables may in fact be most sensitive to drug efficacy in ADHD. The time course of each experimental treatment condition appeared to be unique by analysis of efficacy measures and by visual inspection of time-action curves (Figs. 1 and 2). Our placebo data replicate the deterioration in classroom behavior and performance across most of the 12-hour period, which was also observed over a shorter timeframe by Swanson et al. (1998). In our study, subjects assigned to placebo demonstrated deteriorating behavior and classroom performance across the day, with only modest recovery at the final session of the assessment period (see Figs. 1 and 2). By 10.5 hours postdose, subjects on placebo were attempting 35% fewer math problems and were correctly answering 43% less than at the first assessment session. At the 12-hour session, placebo children attempted 17% fewer math problems and were correct on 25% fewer than at the initial assessment. In contrast, each of the active treatments showed unique curves characterized by early improvements, followed by varying degrees of symptom return or worsening performance. For example, the extended benefit of SLI381 20- and 30-mg conditions on math measures (shown in Fig. 2) is still apparent at 12.0 hours after administration, with children in the SLI381 groups correctly completing 34% and 43% more math problems over placebo children (20- and 30-mg SLI381 groups, respectively). We also noted that all active treatment groups demonstrated higher ratings of behavior problems at the first time point assessment, but that robust improvement was evident at the next rating 1.5 hours after administration. This could suggest a possible morning “rebound” effect, although we are quite cautious in making any conclusions about this observation. The precise relationship of the pharmacokinetics of SLI381 in relation to its pharmacodynamic action in this study is beyond the scope of this article and will be the subject of a detailed separate report. Few studies have attempted to assess systematically the time-action effects of any psychostimulant for effects as prolonged as 12 hours postdose. James et al. (2001) showed statistically significant reductions in locomotor activity for up to 12 hours for some high-dose amphetamine preparations, but lacking repeated assessments of behavior and academic function, the observed locomotor activity reductions were of uncertain clinical significance. In our investigation, we have documented statistically significant differences between SLI381 20 mg and 30 mg versus placebo J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 2 : 6 , J U N E 2 0 0 3
on both behavioral and academic measures at 12 hours after administration. As these differences calculate to dimensionless effect sizes of between approximately 0.3 and 0.5, we would argue that they represent at least suggestive evidence of “clinically significant” (Kraemer, 1992) remaining treatment benefit from this extended-release preparation for ADHD as long as 12 hours after administration. Limitations
Although the analog classroom attempts to mimic many aspects of a regular school classroom, it admittedly represents a unique setting that may influence behavior (Barkley, 1991). The analog assessments included only ADHD subjects; no control or normal subjects were available for comparison. Furthermore, the level of staffing may have influenced behavior, although mean behavior problem ratings on the SKAMP were clearly elevated during the placebo condition, and treatment effects were robust. In addition, the classroom performance variable is restricted in its ability to reflect any child’s overall academic performance across multiple subjects, demands, and tasks. In this sense, our limited study outcome variables were chosen primarily to measure as sensitively as possible the time-action properties of the treatment conditions. Additional measures and assessments, such as actigraph measures of motor activity, peer assays, global teacher ratings, and other classroom performance measures, would be important to round out the profile of drug action on behavior and academic performance. Even larger samples than ours are needed to better explore differences between treatments in adverse events and other clinical outcomes. Additional studies with other age groups such as adolescents are needed to address concerns about age differences in dose-response relationships (Evans et al., 2001). Clinical Implications
To our knowledge, these data form the largest single direct observational study of the effects of an amphetamine-containing ADHD treatment, and they add significantly to the literature that supports the therapeutic benefit of this agent for the treatment of ADHD in children. The study was not designed to ascertain optimal dose levels for individual subjects, which are well known to vary considerably among individuals. Without optimal dose assessments for individual subjects, it is difficult to make extensive comparisons to other efficacy studies that have used flexible-dose, individually titrated protocols. As a fixed-dose study, it also was not intended to achieve minimal side 681
M C CRACKEN ET AL.
effects. However, the detailed time course assessment it does provide confirms that Adderall XR possesses an extended pattern of clinical efficacy. Arnold (2000), Swanson et al. (1998), and others (Elia et al., 1991) have stated that head-to-head comparisons of amphetamine agents versus methylphenidate suggest nearly equivalent group effects, although Arnold (2000) has raised the question of differential benefits in some symptom domains. Given the availability of several new modified-release preparations for methylphenidate and now SLI381 for amphetamine salts, clinical choice is more complicated than ever before. In the absence of direct comparative studies, our study underscores the recommendation that both classes of stimulants (amphetamine and methylphenidate) be considered first-line agents and that nonresponse to one type of psychostimulant should be followed by a trial of the other class before other alternatives are prescribed, consistent with evolving treatment algorithms (American Academy of Pediatrics, 2001; Pliszka et al., 2000). Similarly, hospital and insurance formularies should include a variety of both types of agents. Our data suggest new drug delivery systems such as SLI381 (Adderall XR) represent a successful strategy to extend the benefits of psychostimulant treatment of ADHD without incurring added side effects, thereby avoiding some of the compliance issues raised by shorter-acting stimulant preparations (Brown et al., 1987; Firestone, 1982; Kauffman et al., 1981). Furthermore, these data demonstrate the clear and compelling therapeutic effects of stimulants, by documenting improvements in both classroom behavioral and performance measures. Acknowledging the striking interindividual differences in stimulant drug effect across children with ADHD, both for time of action and dosage, SLI381 appears to represent a promising new addition to the armamentarium of ADHD treatments. It has the potential to work throughout the day and into the early evening after a single morning administration, thus avoiding in-school administration for those children who need extended therapy. The side effect data from our study are also relevant to clinical practice. Though limited to brief observations over a 6-week period, our initial data suggest that extending drug exposure over a 12-hour period sufficient to yield clinical improvement does not markedly increase reported side effects. One larger study of SLI381 with longer exposure appeared to confirm our observation of apparent excellent tolerability of SLI381 (Biederman et al., 2002). The possibility exists that some degree of daily physio682
logical adaptation takes place which serves to moderate the adverse effects of amphetamine. These observations add to the excellent safety record of the psychostimulants. REFERENCES American Academy of Pediatrics, Committee on Quality Improvement and Subcommittee on Attention-Deficit/Hyperactivity Disorder (2001), Clinical practice guideline: treatment of the school-aged child with attentiondeficit/hyperactivity disorder. Pediatrics 108:1033–1044 Arnold LE (2000), Methylphenidate versus amphetamine: a comparative review. In: Ritalin: Theory and Practice, Greenhill LL, Osman BB, eds. New York: Mary Ann Liebert, pp 127–139 Arnold LE, Christopher J, Huestis RD, Smeltzer DJ (1978), Methylphenidate vs. dextroamphetamine vs. caffeine in minimal brain dysfunction. Arch Gen Psychiatry 35:463–473 Barkley RA (1990), Attention-Deficit Hyperactivity Disorder: A Handbook for Diagnosis and Treatment. New York: Guilford Barkley RA (1991), The ecological validity of laboratory and analogue assessment methods of ADHD symptoms. J Abnorm Child Psychol 19:149–179 Biederman J, Lopez FA, Boellner SW, Chandler MC (2002), A randomized, double-blind, placebo-controlled, parallel-group study of SLI381 (Adderall XR) in children with attention-deficit/hyperactivity disorder. Pediatrics 110:258–266 Bradley C (1950), Benzedrine and Dexedrine in the treatment of children’s behavior disorders. Pediatrics 5:24–37 Brown GL, Ebert MH, Mikkelsen EJ, Hunt RD (1979), Plasma levels of damphetamine in hyperactive children. Psychopharmacology 62:133–140 Brown GL, Ebert MH, Mikkelsen EJ, Hunt RD (1980), Behavior and motor activity response in hyperactive children and plasma amphetamine levels following a sustained release preparation. J Am Acad Child Psychiatry 19:225–239 Brown RT, Borden KA, Wynne ME, Spunt AL, Clingerman SR (1987), Compliance with pharmacological and cognitive treatments for attention deficit disorder. J Am Acad Child Adolesc Psychiatry 26:521–526 Connors CK (1972), Psychological effects of stimulant drugs in children with minimal brain dysfunction. Pediatrics 49:702–709 Elia J, Borcherding BG, Rapoport JL, Keysor CS (1991), Methylphenidate and dextroamphetamine treatments of hyperactivity: are there true nonresponders? Psychiatry Res 36:141–155 Evans SW, Pelham WE, Smith BH et al. (2001), Dose-response effects on ecologically valid measures of academic performance and classroom behavior in adolescents with ADHD. Exp Clin Psychopharmacol 9:163–175 Firestone P (1982), Factors associated with children’s adherence to stimulant medication. Am J Orthopsychiatry 52:447–457 Hudziak JJ, Helzer JE, Wetzel MW et al. (1993), The use of the DSM-III-R Checklist for initial diagnostic assessments. Compr Psychiatry 34:375–383 James RS, Sharp WS, Bastain TM et al. (2001), Double-blind, placebocontrolled study of single-dose amphetamine formulations in ADHD. J Am Acad Child Adolesc Psychiatry 40:1268–1276 Kauffman RE, Smith-Wright D, Reese CA, Simpson R, Jones F (1981), Medication compliance in hyperactive children. Pediatr Pharmacol 1:231–237 Kraemer HC (1992), Reporting the size of effects in research studies to facilitate assessment of practical or clinical significance. Psychoneuroendocrinology 17:527–536 Michaels MA, Weston IE, Zhang Y, Tulloch S (2001), Pharmacokinetics of SLI381, a two-component extended-release formulation of mixed amphetamine salts, administered in fasted and fed states and sprinkled on food. Poster presentation at 41st annual meeting of the New Clinical Drug Evaluation Unit, Phoenix, May 29 MTA Cooperative Group (1999), A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 56:1073–1086 Pelham WE Jr, Gnagy EM, Chronis AM et al. (1999), A comparison of morning-only and morning/late afternoon Adderall to morning-only, twicedaily, and three times-daily methylphenidate in children with attentiondeficit/hyperactivity disorder. Pediatrics 104:1300–1311
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 2 : 6 , J U N E 2 0 0 3
ANALOG CLASSROOM ASSESSMENT OF ADDERALL XR
Pelham WE Jr, Greenslade KE, Vodde-Hamilton M et al. (1990), Relative efficacy of long-acting stimulants on children with attention-deficit hyperactivity disorder: a comparison of standard methylphenidate, sustained-release methylphenidate, sustained-release dextroamphetamine, and pemoline. Pediatrics 86:226–237 Pelham WE Jr, Sturges J, Hoza J et al. (1987), Sustained release and standard methylphenidate effects on cognitive and social behavior in children with attention deficit disorder. Pediatrics 80:491–501 Pelham WE Jr, Swanson JM, Furman MB, Schwindt H (1995), Pemoline effects on children with ADHD: a time-response by dose-response analysis on classroom measures. J Am Acad Child Adolesc Psychiatry 34:1504–1513 Pliszka SR, Greenhill LL, Crismon ML et al. (2000), The Texas Children’s Medication Algorithm Project: report of the Texas Consensus Conference Panel on Medication Treatment of Childhood Attention-Deficit/Hyperactivity Disorder. Part I: strategies. J Am Acad Child Adolesc Psychiatry 39:908–919 Schachar R, Sugarman R (2000), Combining parent training and medication in the treatment of attention deficit hyperactivity disorder. In: Ritalin: Theory and Practice, Greenhill LL, Osman BB, eds. New York: Mary Ann Liebert, pp 87–112 Shaffer D, Fisher P, Lucas CP, Dulcan MK, Schwab-Stone ME (2000), NIMH Diagnostic Interview for Children Version IV (NIMH DISC-IV): descrip-
tion, differences from previous versions, and reliability of some common diagnoses. J Am Acad Child Adolesc Psychiatry 39:28–38 Spencer T, Biederman J, Wilens TE, Harding M (1996), Pharmacotherapy of ADHD across the lifecycle: a literature review. J Am Acad Child Adolesc Psychiatry 35:409–432 Swanson JM, Agler D, Fineberg E et al. (2000), University of California, Irvine, Laboratory School Protocol for Pharmacokinetic and Pharmacodynamic Studies. In: Ritalin: Theory and Practice, Greenhill LL, Osman BB, eds. New York: Mary Ann Liebert, pp 405–432 Swanson JM, Kinsbourne M, Roberts W, Zucker K (1978), A time-response analysis of the effect of stimulant medication on the learning ability of children referred for hyperactivity. Pediatrics 61:21–29 Swanson JM, Wigal S, Greenhill LL et al. (1998), Analog classroom assessment of Adderall威 in children with ADHD. J Am Acad Child Adolesc Psychiatry 37:519–526 Weiss G, Minde K, Douglas V (1971), Comparison of the effects of chlorpromazine, dextroamphetamine, and methylphenidate on the behavior and intellectual functioning of hyperactive children. Can Med J 104:20–25 Wigal SB, Gupta S, Guinta D, Swanson J (1998), Reliability and validity of the SKAMP rating scale in a laboratory school setting. Psychopharmacol Bull 34:47–53
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 2 : 6 , J U N E 2 0 0 3
683