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`Jo
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`v. final of the Amencan Academy of Childflm)
`G
`no. 6 (June 2003)
`eneral Collection
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`‘°
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`fouma/ oftbe American Academy of
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`CEIHLD 67
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`AD©LE§CCENT
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`*
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`A
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`In This Issue:
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`
`Guest Editor: Laurence L. Greenhill
`
`<
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`CBNECmefifimemmfl
`@fiwmwflmm
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`I
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`JOURNAL OF THE anERxcaN aanErw 0F CHILI
`nND RDOLESCENT PSYCHIATRY
`2803 VDLUHE 42 ISSUE 8
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`Page 1 of 13
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`KVK-TECH EXHIBIT 1037
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`KVK-TECH EXHIBIT 1037
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`AMERICAN ACADEMY OF
`CHILDéADOLESCENT
`PSYCHIATRY
`
`COUNCIL
`
`PRESIDENT
`
`Marilyn B. Benoit, M.D.
`
`PRESIDENT-ELECT
`Richard Sarles, M.D.
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`PAST PRESIDENT
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`CIariceJ. Kestenbaum, M.D.
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`SECRETARY
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`TREASURER
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`EXECUTIVE DIRECTOR
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`Karen Dineen Wagner, M.D., Ph.D.
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`MartinJ. DreII, M.D.
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`Virginia Q. Anthony
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`ASSEMBLY CHAIR
`Sandra Sexson, M.D.
`
`Thomas Anders, M.D.
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`Efrain Bleiberg, M.D.
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`Steven Cuffe, M.D.
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`David Fassler, M.D.
`
`J. Michael Houston, M.D.
`
`Louis Kraus, M.D.
`
`John O’Brien, M.D. Mary Schwab-Stone, M.D. Amy Ursano, M.D.
`
`John March, M.D., M.P.H.
`Susan Villani, M.D.
`
`Applications for membership may be obtained from:
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`3615 Wisconsin Avenue, N.W, Washington, DC. 20016
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`Page 2 of 13
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`Page 2 of 13
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`

`

`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, 1’H.D., JAMES J. MCGOUGH, M.D., THOMAS J. SPENCER, M.D., KELLY POSNER, P11.D.,
`SHARON WIGAL, I’II.D., CAROLY PATAKl, M.D., YUXIN ZHANG, I’ll.D., AND SIMON TULLOCH, MD.
`
`ABSTRACT
`
`Objectives: This investigation was conducted primarily to assess the safety and efficacy of SLI381 (Adderall XR‘“),
`developed as a once-daily treatment for children with attention-deficit/hyperactivity disorder (ADHD). Secondary objec-
`tives 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® 10 mg) given once daily to 51 children with ADHD. Weekly assessments in an analog classroom set-
`ting included blind ratings of attention and deportment and a pertormance 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 evi-
`dent for SLI381. SLI381 20 and 30 mg and Adderall all showed rapid improvements by 1.5 hours, but only the SLI381 20-
`and 30-mg doses showed continued activity at 10.5 and 12 hours for classroom behavior and math test pertormance
`versus placebo. Conclusions: These data provide support for the benefit of this novel, once-daily amphetamine prepa-
`ration 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 use-
`ful treatment option for many children with ADHD. J. Am. Acad. Child Adolesc. Psychiatry, 2003, 42(6):673—683. Key
`Words: attention-defieit/hyperactivity disorder, amphetamine, Adderall”, ADDERALL XFt‘“, 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 methyl-
`phenidate (Arnold et 31., 1978; Barkley, 1990; Bradley,
`1950; Connors, 1972; MTA Cooperative Group, 1999;
`
`Acreptcdjamtmy 14, 2003.
`Drs. MrCmrkm, McGaug/t, rmzl Dita/3i m‘r wit/1 I/lt‘ Department afi’syr/tirmy
`and Biobr/mviom/ Stimrcs. Division of C/Jild mzd/lrlo/esrent I’syr/iirltry, UCLA
`Nr'ztroptyr/Ji/ztric Institute, Lo: Ange/cs,- Drs. Bittirrnmtt and Spencer are with
`the Department of Psychiatry, Massachusetts Grnrml Hospital. Boston; Drs.
`Green/Jill and 1’0an are wit/7 t/u' Drpm-nm'tit r/fl’sydtinny, Calztm/n'zr University,
`New York; Dry. Swanson and Wigizi are will; the Cl/ila' Dentin/mm” Center,
`University of California at Irvine; Drs, Till/ad) and lining rm‘ wit/t S/tirr
`I’lmrm/zrrutimi Dentin/1mm! Inn, Rockuiilr, MD.
`7711': study um sup/mm! by agmntfi-am S/Jin’ Pharmaceutical Development Inc.
`Reprint requests to Dr. MtCmri’m, UCLA ertropsyr/Ii/Itric Institute, 760
`Wettwaod Plaza, Lo: Angela, CA 90024-1759; r-mztil: jmrrmrleen@mrt/-
`mt. rte/r1. edit.
`0890—8567/03/4206—0673©2003 by the American Academy of Child
`and Adolescent Psychiatry.
`DOI: 10.1097/0l.CHI.0000046863.56865.FE
`
`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 con-
`tinued need to develop strategies to optimize these treat-
`ments, especially as they are applied in community practice
`settings. Specifically, the short duration of action of avail—
`able stimulants necessitates multiple daily doses for many
`children to provide effective symptom management
`(l’elham et 31., 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 require-
`ments and less structured family routines, requiring addi—
`tional medication later in the day. The complexity of
`multiple daily dosing schedules contributes to reduced
`compliance and may increase the likelihood of drug diver—
`sion. Both practice patterns and poor compliance also
`serve to reduce the overall benefit of psychostimulant
`
`J. AM. ACAD. CHILD AIJOLESC. PSYCHIATRY. 42:6. JUNE 2005
`
`673
`
`Page 3 of 13
`
`This material was-copied
`atthe NLMand may be
`Subjett‘ LIE-,Cdpyrigbt‘ Laws
`
`Page 3 of 13
`
`

`

`MCCRACKICN li'l' A1,.
`
`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 deliv—
`ery systems that can effectively treat ADHD symptoms
`with a single daily dose.
`In spite of the frequency of use of amphetamine-con—
`taining 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 amphet—
`atnine administration for ADHD (Brown et a1, 1979, 1980;
`I’elham et al., 1999; Swanson et al., 1998). The current
`study describes the efficacy, tolerability, and detailed time
`course of SL1381 (Adderall XRT”), a unique drug delivery
`system containing the mixture of amphetamine salts con-
`tained in a currently approved treatment, Adderall®, on
`symptoms ofADHD in a sample ofchildren with ADHD.
`Adderall is a racemic mixture of dextro— and levo-isomers
`
`of amphetamine composed of equal parts of ampheta—
`mine salts (d—amphetamine sulfate, d—amphetamine sac—
`charate, oil—amphetamine aspartate monohydrate, and
`£1, [-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 approx—
`imately 5 to 7 hours postdose for the highest dose con—
`dition (Swanson et a1., 1998). Pelham et a1. (1999) studied
`Adderall effects in a summer treatment program and
`found apparent benefits up to 7 hours after administra-
`tion. James er al. (2001) recently described locomotor
`activity effects of amphetamine preparations up to 12
`hours postdose, but they did not repeatedly probe dis—
`ruptive behavior or academic performance. It is interest—
`ing that the Swanson er 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 effi-
`cacy and tolerability ofSl,1381 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 SL1381 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 behav—
`
`ioral and cognitive effects of amphetamines in children
`with ADHD.
`
`METHOD
`
`The study was conducted at four academic sites under local Lllll-
`versity human subject protection committee approval. Subjects were
`recruited at the four sites through a combination ofadvertising and
`distribution of information about study participation at local outpa-
`tient clinics. All subjects provided written assent for study participa—
`tion; parents provided written consent for their child‘s enrollment.
`Families were compensated $50 for participation in each all-day ana»
`log classroom day.
`
`Subjects
`
`Potential subjects were screened to meet the following eligibility
`criteria: (1) age 6 to 12 years; (2) diagnosis ofDSM—IVADHD (com-
`bined or hyperactive-impulsive subtype as determined by a compre-
`hensive clinician evaluation and selected modules of the Diagnostic
`Interview Schedule for Children, Version IV—Lifetime [DISC—1V1)
`(Shaffer et al., 2000) administered by a research staff member with
`suitable training; (3) no evidence of mental retardation; and (4) his-
`tory of positive response to psycltostimnlant medication, or no prior
`stimulant treatment. Information pertaining to co-occurring psy-
`chopathology from the clinical evaluation was supplemented by the
`Comorbid Disorders Checklist (Hudziak et al., 1993), a pflfem‘FCPOYt
`questionnaire composed ofDSM—III—R symptom items. All diagnoses
`were based on DS/W—IVcriteria. Subjects were excluded if they met
`criteria for any of the following: (1) comorbid psychiatric conditions
`including psychosis, pervasive developmental disorder, bipolar disor—
`der; (2) severe obsessive—compulsive disorder, severe depressive or anx-
`iety disorder (severe defined as any comorbid disorder with impairment
`necessitating concurrent treatment of any type); (3) a clinically sig-
`nificant medical condition (eg, seizure disorder, hypertension, abnor-
`mal laboratory test result); (4) need for ongoing medical treatment;
`(5) intolerance of psychostimulants; (6) history of nonresponse to
`Adderall; or (7) history ofa tie disorder. A total of 51 subjects met all
`eligibility criteria and provided consent for participation. The char—
`acteristics of the sample are listed in Table 1.
`
`Study Design
`
`Following screening and a 1—week washout period with discontin-
`ttation 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 open—
`label administration of 20 mg ofSLl381 to all subjects with repeated
`plasma sampling for [K analyses to assess individual tolerability to the
`drug, to acquire data on SLI381’s I’K profile, and to familiarize sub-
`jects 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 SL138] 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),
`SL138] 20 mg (equivalent to Adderall 10 mg b.i.d.). SL138] 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 random-
`ized to each of five treatment sequences. Randomization schedules
`
`1. AM. ACAI). CHILD ADOLESC. PSYCHlATRY, 42:6, jUNE 2003
`
`674
`
`Page4 of 13
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`This material was-copied
`attire NLM and may be
`Subject US» Copyright. Laws
`
`Page 4 of 13
`
`

`

`TABLE 1
`
`Demographic and Baseline Characteristics of Randomized Sample
`Characteristic
`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 a 1.9
`83.5 :t 28.9
`54.6 1 4.9
`
`Gender: 71 (%)
`Male
`Female
`Race: 72 (We)
`White
`Black
`Hispanic
`Asian/Pacific Islander
`Other
`Age (yr): mean i SD
`Weight (lb): mean i SD
`Height (in): mean 1 SD
`ADHD diagnosis: n (0%))
`Hyperactive-impulsive
`Combined
`Duration of prior stimulant
`treatment: mean i SD (yr)
`ADHD treatment before study
`entry: 71 (”/u)
`17 (33.3)
`Amphetamine only
`30 (58.8)
`MCthylpbenidate only
`
`
`4None listed (7.8)
`
`(2.0)
`1
`50 (98.0)
`
`1.7 i 1.7
`
`Note: ADHD = atrention-deficit/hyperactivity disorder.
`
`were generated by the sponsor of the study and distributed to the on-
`site 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 sep—
`arate 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 live
`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 antccubital 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 ofSL1381. Concentrations
`of d- and l-amphetamine were assayed using validated liquid
`Chromatography—mass spectroscopy methodology at a central labora—
`tory. 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 sched-
`ule and procedures for the analog classroom days were based on a
`modification of well—validated procedures used in previous time—
`response stimulant studies (Pelham ct al., 1995; Swanson et 211., 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 8200 PM. All subjects were administered study material cap-
`sules by study physicians at 7:30 AM. The daily schedule consisted
`
`ANALOG CLASSROOM ASSESSMliN'l' OP ADDERALI. XR
`
`of alternating classroom, play, meals or snacks, and research activi—
`ties, 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 (efiicacy 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,
`rising a behavioral observation system described previously (Swanson
`et al., 1998, 2000). All classroom raters had completed reliability train—
`ing 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 dur—
`ing 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 l’elham (SKAMI’) 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 ofthe SKAMP are high (Wigal et al., 1998).1n
`addition, academic performance was assessed using :1 Permanent Product
`Measure of Performance (PERMP). a 10—minute age—appropriate math
`test that was scored [0 yield absolute number of problems attempted
`and problems correct (Swanson er al., 2000). These measures have
`been shown to be sensitive to both dosage and time effects in prior
`stimulant research (Swanson et .11., 1998).
`Secondary measures included a global behavior rating scale (Parent
`Global Assessment) that parents were instructed to complete at mid—
`week during each of the six treatment weeks. Parents also completed
`a weeldy Side Effect Rating Scale specific to stimulant treatment. l‘iach
`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 vari—
`ables using a mixed—effects analysis ofvariance (ANOVA) model, with
`fixed-effect terms of treatment (placebo, SL1381 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 inter-
`action. In those cases in which the overall treatment—by—session effect
`was significant (p < .05), additional comparisons of individual treat-
`ments 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 improve—
`ments), no secondary analyses for carryover effects were performed.
`All]; 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 (:17) years. Of those children with a history of
`
`}. AM. ACAD. CHILD ADOLESC. I‘SYCHlA'l'RY. 42:6, jUNE 2003
`
`675
`
`Page 5 of 13
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`atthe NLM and may be
`Subject US {iopyright Laws
`
`Page 5 of 13
`
`

`

`MCCRACKEN ICT AL.
`
`stimulant treatment at the time of study screening, 30
`(59%) were receiving methylphenidate and 17 (3300)
`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 con—
`sent. Forty—nine children were randomized for the crossover
`treatment portion of the study. Of the 49 randomized sub—
`jects, 47 (92.2%) completed the 5 weeks of the double-
`blind portion of the study (all treatment conditions), with
`2 subjects withdrawing (1 because ofstomachache and I
`after developing an exclusion criterion). A total of 44
`(86.300) children completed the entire protocol, includ—
`ing 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 SL138] 20 mg); 1 additional
`subject withdrew because of withdrawal of consent.
`After each Saturday analog classroom session, med—
`ication was provided to patents in the form of six cap—
`sules for the coming week. Compliance during the study
`was assessed weekly by return of medication bottle and
`review with the patent. Nearly all patients (96%) were
`compliant with study treatment, defined as administra-
`tion of 80% to 100% of prescribed study medication
`based on investigative site capsule counts.
`The overall mixed-model ANOVA for the intent-to—
`
`treat population on all four of the primary efficacy vari-
`ables, SKAMP Attention and Deportment and math
`problems attempted and problems correct, showed highly
`significant effects of treatment (81.1381 10, 20, 30 mg,
`Adderall 10 mg, versus placebo), period (week), session
`(time points during 12—hour assessment), and treatment-
`by-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 inter—
`action (p < .0001), additional examination of SKAMP
`Attention and Deportment scores demonstrated the im-
`provement associated with active treatments versus placebo
`(Fig. I). As evident in Fig. 1, increasing doses of SL138]
`were associated with larger and consistent improvements
`(decreases in ratings of inattentive and disruptive behav-
`iors) in SKAMP ratings. Applying pairwise mean corn-
`parisons between SL1381 and placebo (Table 3), the SL1381
`30-mg dose showed significant improvement ()3 < .01)
`over placebo at all postdose time points. SL138] 20 mg
`just missed attaining statisrical 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.
`SL1381 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 sig-
`nificant decreases in SKAMP ratings for Attention prob—
`lems from 1.5 to 7.5 hours and for Department 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 ver—
`sus placebo by session (see Fig. 2, Tables 3 and 4). All active
`treatments were associated with robust increases in prob—
`lems attempted and problems solved versus placebo. SL138]
`20- and 30-mg doses were associated with statistically sig—
`nificant increases in number attempted and number solved
`for all postdose time points through 12 hours. SL138] 10
`mg demonstrated significant increases from 4.5 to 10.5
`hours versus placebo. Adderall 10 mg was found to demon-
`strate increases versus placebo at 1.5, 6.0, 7.5, and 9.0 hours
`postdose for number attempted; for number solved sig—
`niIicance 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 sain-
`
`TABLE 2
`Results ofAnalysis of Variance of SKAMI’ and I’ERMP Scores
`Trcatm en t
`Period
`Session
`
`Treatment >< Session
`
`SKAMI’ Attention
`SKAMI’ Department
`I’ERMI’ no. Attempted
`PERM I’ no. Solved
`
`174.1617 = 4170;11 < .000]
`174.1017 = 13.47;]; < .0001
`F/MGU = 6598;]2 < .0001
`£10017 = 10-51;]; < .0001
`174.1611 = 52.71;p < .0001
`thu = 2.83; p < .0234
`[11.1011 = 2-40;]) < .0483
`F4.1011= 61.71”) < .0001
`
`F28,]6l7 = 317;]: <.0001
`117.1517 = 7.95;)? < .0001
`Fzs.1s17 = 4.07:1) < .000]
`mey = 12.98; p < .0001
`F28,]6]l = 3.72;[) < .000]
`F7.1s11 = 25.60;p < .0001
`FJEJGH = 4.07;p < .000]
`F7.1011 = 26-00;p < .0001
`
`Note: SKAMI’ = Swanson, Kotkin, Agler, M—Flynn, and I’elham scale; I’ERMI’ = Permanent Product Measure of Performance.
`
`676
`
`I. AM. ACAI). CHILI) ADOLESC. PSYCHIATRY, 42:6. jUNli 2003
`
`Page 6 of 13
`
`This mate-rial was copied
`attire NLM and may be
`Subject Uiflapyright Laws
`
`Page 6 of 13
`
`

`

`ANALOG CLASSROOM ASSESSMENT O]2 ADDISRAH. XR
`
`
`
`
`
`SKAMPScore
`
`i Attention
`
`: Department
`
`SL1381
`
`Placebo
`
`SLI381
`
`SL138]
`
`Time (hr) Post Dose
`
`Fig. 1 Mean Swanson, Kotkin, Agler, M—lilynn, and Pelham (SKAMP) scale Attention and Department problem
`ratings for each treatment condition for the intent»toAtreat sample (N = 49) at each time point after administra-
`tion. Note decreasing values represent improvement in inattentive and hyperactive—impnlsive symptoms. Solid sym-
`bols indicate statistical significance (p < .05) by two-tailed pairwise comparisons versus placebo (see Table 3).
`
`tive control. Adderal] 10 mg was associated with compara—
`ple size, comparative analyses were not performed. Only
`ble frequencies of reported side effects for abdominal pain
`anorexia displayed a dose—dependent pattern of increases
`and asthenia compared with the highest dose (SL1381 30
`for Adderall XR doses, with the incidence at the dose of 20
`mg) condition. The reported frequency of headache was
`mg of SL158] (equivalent to Adderall 10 mg bid.) com—
`similar in all active treatment groups and the placebo group.
`parable with that seen with Adderall 10 mg q.d., the posi-
`TABLE 3
`
`Pairwise Mean Comparisons of SKAMP and PERMP Scores Between Active Treatment and Placebo Over the Analog
`Classroom Day at Each Assessment Session ('lvv()—111iletl)
`Time (hr) Postdose (/2 Value) vs. Placebo(w
`12.0
`0.0
`1.5
`4.5
`6.0
`7.5
`9.0
`10.5
`___________P___.——————————-———
`SKAMI’ Attention
`
`SL138] 30 mg
`SL138] 20 mg
`SL138] 10 mg
`Adderall 10 mg
`SKAMP Department
`SL138] 30 mg
`SL138] 20 mg
`SL138] 10 mg
`Adderflll 10 [mg
`PERMP no. attempted
`SL138] 30 mg
`SL138] 20 mg
`SL138] 10 mg
`Adderall 10 mg
`PERMP no. correct
`
`0.6647
`0.8912
`0.0152
`0.0072
`
`0.7640
`0.1205
`0.0845
`0.0051
`
`0.3952
`0.0304
`0.0019
`0.000]
`
`0.0015
`0.0513
`0.5840
`0.0025
`
`0.0002
`0.003]
`0.0725
`<0.0001
`
`0.0030
`0.0283
`0.0920
`0.0004
`
`<0.0001
`0.0023
`0.0269
`0.0005
`
`<0.0001
`<0.0001
`0.0090
`<0.0001
`
`<0.0001
`0.0006
`0.0136
`0.0850
`
`<0.0001
`<0.0001
`0.0003
`0.0005
`
`<0.0001
`<0.0001
`<0.0001
`<0.0001
`
`<0.0001
`<0.0001
`0.000]
`0.0015
`
`<0.0001
`<0.0001
`0.0001
`0.0002
`
`<0.0001
`<0.0001
`0.0001
`<0.0001
`
`<0.0001
`<0.0001
`0.0017
`0.0157
`
`0.0001
`0.0072
`0.2442
`0.8264
`
`<0.0001
`<0.0001
`0.0083
`0.0004
`
`<0.0001
`0.0001
`0.0250
`0.0048
`
`<0.0001
`<0.0001
`0.0062
`0.3250
`
`<0.0001
`0.002]
`0.0724
`0.0240
`
`<0.0001
`<0.0001
`0.0101
`0.7626
`
`0.0001
`<0.0001
`<0.0001
`<0.0001
`<0.0001
`<0.0001
`0.0059
`0.3114
`SL138] 30 mg
`0.0007
`<0.0001
`<0.0001
`<0.0001
`<0.0001
`<0.0001
`0.0333
`0.0193
`SL138] 20 mg
`0.5420
`0.0025
`0.0128
`0.0029
`<0.0001
`0.0020
`0.1121
`0.0009
`SL138] 10 mg
`0.9304
`
`
`
`
`
`0.00070.03530.0007<0.0001Atlderal] 10 mg 0.3424 0.0667 0.0195
`
`
`
`0.0034
`0.0077
`0.0626
`0.3064
`
`0.0062
`0.0531
`0.9878
`0.790]
`
`0.0017
`0.0053
`0.9938
`0.7508
`
`Note: SKAMP = Swanson, Kotkin, Agler, M—Flynn, and Pelham scale; PERMP = Permanent Product Measure of Performance.
`
`J. AM. ACAI). CHILI) ADOLESC. PSYCHIATRY. 42:6.JUN1‘12003
`
`677
`
`Page 7 of 13
`
`T11 is mate-ti a l was copied
`at the N LM 5 rid may be
`Subject USCamtrignt Laws
`
`Page 7 of 13
`
`

`

`MCCRACKICN 111‘ 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 (llr) Postdose
`
`
`
`
`
`
`
`
`
` 'l'rcatment 0.0 1.5 4.5 6.0 7.5 9.0 10.5 12.0
`
`1.18
`0.977
`
`1.59
`1.210
`
`1.55
`1.050
`
`1.27
`1.152
`
`1.31
`0.825
`
`0.88
`0.828
`
`1.27
`0.934
`
`1.16
`1.089
`
`1.40
`0.954
`
`0.92
`0.920
`
`1.13
`0.982
`
`1.07
`1.088
`
`1.74
`1.006
`
`1.26
`1.182
`
`1.26
`1.034
`
`1.14
`0.986
`
`1.73
`1.005
`
`1.22
`0.872
`
`1.21
`0.796
`
`1.13
`1.048
`
`1.51
`0.970
`
`1.55
`1.284
`
`1.40
`1.022
`
`1.26
`1.154
`
`1.74
`0.869
`
`1.60
`1.262
`
`1.40
`1.016
`
`1.27
`0.876
`
`1.44
`0.929
`
`1.59
`1.211
`
`1.23
`0.964
`
`1.18
`1.010
`
`Placebo
`Mean
`SD
`Adtlerall 10 mg
`Mean
`81)
`Adderall XR 10 mg
`Nlean
`SD
`Addcrall XR 20 mg
`Mean
`SD
`Adderall XR 30 mg
`1.15
`1.23
`1.05
`0.74
`0.74
`0.90
`0.98
`1.38
`Mean
`
`1.075 1.208 0.987 0.823 0.737 0.809 1.160 1.278
`
`
`
`
`
`
`SD
`Variable—SKAMP Department Scores
`
`Time (lrr) Postdose
`6.0
`7.5
`
`Treatment
`
`0.0
`
`1.5
`
`4.5
`
`9.0
`
`10.5
`
`12.0
`
`1.88
`1.388
`
`2.22
`1.368
`
`2.28
`1.314
`
`2.88
`1.395
`
`2.90
`1.341
`
`2.82
`1.162
`
`2.04
`1.464
`
`2.66
`1.305
`
`2.17
`1.416
`
`1.99
`1.252
`
`1.91
`1.445
`
`Placebo
`Mean
`SD
`Adderall 10 mg
`Mean
`SD
`Adderall XR 10 mg
`1V4czln
`SD
`Addcrall XR 20 mg
`Mean
`SD
`Adtlcrall XR 30 mg
`Mean
`1.96
`1.58
`0.90
`1.13
`1.29
`1.46
`1.45
`1.59
`
`SD
`1.507
`1.579
`0.887
`1.185
`1.338
`1.328
`1.511
`1.571
`
`Variable—PERMP Number Attempted
`
`Time (hr) Postdose
`
`'li'catmcnt
`0.0
`1.5
`6,0
`7,5
`Placebo
`Mean
`81)
`Addcrall 10 mg
`Nlean
`51)
`51933
`Addcrall XR 10 mg
`Mean
`51)
`Addcrall XR 20 mg
`Mean
`68.36
`102.87
`111.48
`120.87
`107.87
`89.27
`90.07
`91.77
`SD
`46.393
`61.162
`62.649
`64.498
`65.574
`55.667
`50.611
`59.364
`
`— Continual
`
`1.08
`1.272
`
`1.91
`1.396
`
`1.69
`1.257
`
`1
`
`88.61
`58.240
`
`118.86
`65.036
`
`1.25
`1.257
`
`1.80
`1.277
`
`1.22
`1.002
`
`4.5
`
`85.61
`64.935
`
`100.21
`56.710
`
`2.43
`1.757
`
`2.28
`1.497
`
`2.26
`1.367
`
`89.43
`56.22
`
`59.37
`38