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2004;113;e206Pediatrics
DeCory, Sharon J. Hirshe Dirksen and Simon J. Hatch
L. Greenhill, Joseph Biederman, Scott Kollins, Annamarie Stehli Nguyen, Heleen H.
James M. Swanson, Sharon B. Wigal, Tim Wigal, Edmund Sonuga-Barke, Laurence
School (The Comacs Study)
in Children With Attention-Deficit/Hyperactivity Disorder in the Laboratory
A Comparison of Once-Daily Extended-Release Methylphenidate Formulations
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located on the World Wide Web at:
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of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2004 by the American Academy
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
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A Comparison of Once-Daily Extended-Release Methylphenidate
Formulations in Children With Attention-Deficit/Hyperactivity Disorder
in the Laboratory School (The Comacs Study)
James M. Swanson, PhD*; Sharon B. Wigal, PhD*; Tim Wigal, PhD*; Edmund Sonuga-Barke, PhD*;
Laurence L. Greenhill, MD‡; Joseph Biederman, MD§; Scott Kollins, PhD储;
Annamarie Stehli Nguyen, MPH*; Heleen H. DeCory, PhD¶; Sharon J. Hirshey Dirksen, PhD¶;
Simon J. Hatch, MD¶; and the COMACS Study Group
ABSTRACT. Objective. The objective of this study
was to evaluate differences in the pharmacodynamic
(PD) profile of 2 second-generation extended-release
(ER) formulations of methylphenidate (MPH): Metadate
CD (MCD; methylphenidate HCl, US Pharmacopeia) ex-
tended-release capsules, CII, and Concerta (CON; meth-
ylphenidate HCl) extended-release tablets, CII. Little em-
pirical information exists to help the clinician compare
the PD effects of the available ER formulations on atten-
tion and behavior. Previous studies have shown that the
near-equal doses of MCD and CON provide equivalent,
total exposure to MPH as measured by area under the
plasma concentration time curve, yet their pharmacoki-
netic (PK) plasma concentration versus time profiles are
different. We previously offered a theoretical PK/PD ac-
count of the similarities and differences among available
ER formulations based on the hypothesis that all formu-
lations produce effects related to MPH delivered by 2
processes: 1) an initial bolus dose of immediate-release
(IR) MPH that is expected to achieve peak plasma con-
centration in the early morning and have rapid onset of
efficacy within 2 hours of dosing, which for the MCD
capsule is delivered by 30% of the total daily dose as
uncoated beads and for the CON tablet is delivered by an
overcoat of 22% of the total daily dose; and 2) an ex-
tended, controlled delivery of ER MPH that is expected to
achieve peak plasma concentrations in the afternoon to
maintain efficacy for a programmed period of time after
the peak of the initial bolus, which for the MCD capsule
is delivered by polymer-coated beads and for the CON
tablet by an osmotic-release oral system. According to
this PK/PD model, clinical superiority is expected at any
point in time for the formulation with the highest MPH
plasma concentration.
Methods. This was a multisite, double-blind, double-
dummy, 3-way crossover study of 2 active treatments
(MCD and CON) and placebo (PLA). Children with con-
firmed diagnoses of attention-deficit/hyperactivity disor-
der were stratified to receive bioequivalent doses of
MCD and CON that were considered to be low (20 mg of
MCD and 18 mg of CON), medium (40 mg of MCD and
36 mg of CON), or high (60 mg of MCD and 54 mg of
CON), and in a randomized order each of the study
treatments was administered once daily in the morning
for 1 week. On the seventh day of each treatment week,
children attended a laboratory school, where surrogate
measures of response were obtained by using teacher
ratings of attention and deportment and a record of per-
manent product of performance on a 10-minute math test
at each of the 7 classroom sessions spread across the day
at 1.5-hour intervals. Safety was assessed by patient re-
ports of adverse events, parent ratings on a stimulant
side-effects scale, and measurement of vital signs.
Results. The analyses of variance revealed large, sta-
tistically significant main effects for the within-subject
factor of treatment for all 3 outcome measures (deport-
ment, attention, and permanent product). The interac-
tions of treatment ⴛ session were also highly significant
for all 3 outcome measures. Inspection of the PD profiles
for the treatment ⴛ session interactions suggested 4 pat-
terns of efficacy across the day: 1) PLA > MCD ⬃ CON
(PLA superiority) immediately after dosing; 2) MCD >
CON > PLA during the morning (MCD superiority);
3) MCD ⬃ CON > PLA during the afternoon (PD equiv-
alence of MCD and CON); and 4) CON > MCD ⬃ PLA in
the early evening (CON superiority). The effect of site
was significant, because some study centers had low and
some high scores for behavior in the lab classroom, but
both the low- and high-scoring sites showed similar PD
patterns across the day. The interaction of dose ⴛ treat-
ment was not significant, indicating that the pattern of
treatment effects was consistent across each dose level.
There were no statistically significant overall differences
among the 3 treatments for the frequency of treatment-
emergent adverse events, ratings of side effects, or vital
signs. Two additional PK/PD questions were addressed:
1. The a priori hypothesis called for a comparison of the
average of sessions (removing session as a factor) dur-
ing a time period that corresponds to the length of a
typical school day (from 1.5 through 7.5 hours after
dosing). For the planned contrast of the 2 treatment
conditions (MCD versus CON), the difference was
significant, confirming the a priori hypothesis of su-
periority of near-equal daily doses of MCD over CON
for this predefined postdosing period.
2. In the design of the study, the dose factor represented
the total daily dose, consisting of 2 components: the
initial bolus doses of IR MPH, which differ for the
near-equal total daily doses of MCD and CON, and
the reservoir doses of ER MPH, which were the same
for the 2 formulations. To evaluate the moderating
From the *University of California at Irvine Child Development Center,
Irvine, California; ‡New York State Psychiatric Institute, New York, New
York; §Massachusetts General Hospital, Cambridge, Massachusetts; 储Duke
Child and Family Study Center, Duke University Medical Center, Durham,
North Carolina; and ¶Celltech Americas, Inc, Rochester, New York.
Received for publication May 1, 2003; accepted Nov 3, 2003.
Reprint requests to (J.M.S.) University of California at Irvine Child Devel-
opment Center, 19722 MacArthur (Centerpointe), Irvine, CA 92612. E-mail:
jmswanso@uci.edu
PEDIATRICS (ISSN 0031 4005). Copyright © 2004 by the American Acad-
emy of Pediatrics.
e206 PEDIATRICS Vol. 113 No. 3 March 2004 http://www.pediatrics.org/cgi/content/full/113/3/e206
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effects of the bolus component of dose on outcome,
average effect size (ES) was calculated for the efficacy
outcomes at the time of expected peak PK concentra-
tion times of the initial bolus component for each
formulation at the 3 dose levels. The correlation (r)of
ES with IR MPH bolus dose was significant for each of
the 3 outcome measures (r ⬃ .9), indicating that the
magnitude of effects in the early morning may be
attributed to the dose administered by the IR MPH
bolus of each formulation. For the 2 dose conditions
with equal 12-mg IR MPH boluses (MCD 40 and CON
54), the ESs were large and indistinguishable (eg, de-
portment ES ⬃ 0.75 for both).
Conclusions. Once-daily doses of MCD and CON
produced statistically significantly different PD effects
on surrogate measures of behavior and performance
among children with attention-deficit/hyperactivity dis-
order in the laboratory school setting. As predicted by the
PK/PD model, superiority at any point in time was
achieved by the formulation with the highest expected
plasma MPH concentration. Pediatrics 2004;113:e206–e216.
URL: http://www.pediatrics.org/cgi/content/full/113/3/e206;
ADHD, methylphenidate, pharmacodynamic effects, chil-
dren, laboratory classroom, SKAMP, Metadate CD, Con-
certa.
ABBREVIATIONS. ADHD, attention-deficit/hyperactivity disor-
der; MPH, methylphenidate; PD, pharmacodynamic; IR, immedi-
ate release; PK, pharmacokinetic; SR, sustained release; FDA, US
Food and Drug Administration; ER, extended release; CON, Con-
certa; MCD, Metadate CD; TID, 3 times a day; BID, 2 times a day;
AUC, plasma concentration time curve; PLA, placebo; SKAMP,
Swanson, Kotkin, Atkins, M/Flynn, Pelham Scale; PERMP, per-
manent product; AE, adverse event; ANOVA, analysis of variance;
ES, effect size; ITT, intent to treat.
E
pidemiologic studies suggest that between 3%
and 6% of the school-aged population in the
United States meet the Diagnostic and Statistical
Manual of Mental Health Disorders, Fourth Edition cri-
teria for attention-deficit/hyperactivity disorder
(ADHD).
1
It is well established that ADHD symp
-
toms typically emerge early in life and remain prob-
lematic in two thirds to three quarters of children in
middle adolescence and that difficulties persist into
late teenage years in academic and social domains.
2
The use of methylphenidate (MPH) for the treat-
ment of ADHD provides significant short-term
symptomatic and classroom behavior improvement.
3
The pharmacodynamic (PD) effects of immediate-
release (IR) MPH match the pharmacokinetic (PK)
profile of a given dose, with a maximum effect ⬃1.5
to 2.0 hours after dosing and a half-life of ⬃2.0 to 3.0
hours.
4,5
Due to these PK and PD properties, multi
-
ple doses of IR MPH are usually required to maintain
effectiveness across the day.
6
The initial sustained-
release (SR) formulations of MPH (eg, Ritalin SR),
developed to overcome the need for multiple daily
doses, were approved by the US Food and Drug
Administration (FDA) for the treatment of ADHD
decades ago, but they were not well accepted in
clinical practice, apparently due to a perception of
reduced clinical effectiveness, slower onset of action,
and greater variability of response compared with IR
MPH.
7
Recently, second-generation, once-daily, ex
-
tended-release (ER) formulations of MPH were de-
veloped that were shown to be as effective as multi-
ple doses of IR MPH.
8–10
After FDA approval, these
new products
11–14
were rapidly accepted into clinical
practice.
Differences among the second-generation ER for-
mulations of MPH exist; however, little empirical
information is available to guide the selection of the
most appropriate choice among the available new
formulations for use in a particular clinical situation.
A PK/PD model proposed by Swanson et al
8,10
offers
a theoretical account of the similarities and differ-
ences among these new ER formulations based on
the hypothesis that all formulations produce effects
related to the dose of MPH delivered by 2 processes:
1) an initial bolus delivery of IR MPH that is ex-
pected to achieve peak plasma concentrations in the
early morning and have rapid onset of efficacy
within 2 hours of dosing and 2) an extended, con-
trolled delivery of ER MPH that is expected to
achieve higher plasma concentrations in the after-
noon than in the morning to maintain efficacy for a
programmed period of time after the peak of the
initial bolus. According to this PK/PD model, clini-
cal superiority at any point in time would be ex-
pected for the ER MPH formulation with the highest
MPH plasma concentration.
The objective of the current study was to compare
the clinical effect of 2 second-generation ER formu-
lations of MPH: Concerta (CON) and Metadate CD
(MCD). CON was designed to replace 3-times-a-day
(TID) regimens of IR MPH and consists of an insol-
uble OROS tablet formulation with 22% of the dose
in an IR overcoat and 78% in a controlled-release
bilayer core inside a membrane, which also contains
a water-sensitive polymer that expands and results
in drug delivery by an osmotic process.
8,13
MCD was
designed to replace 2-times-a-day (BID) regimes of
IR MPH and consists of a capsule formulation con-
taining 30% of the dose in IR MPH beads and 70% of
the dose in ER MPH beads coated with a controlled-
release polymer to deliver MPH gradually over a
12-hour time frame.
9,14
Both CON
11
and MCD
12
have
been shown individually in randomized, controlled
clinical trials to be safe and effective for the treatment
of ADHD in school-aged children, and both are
available in near-equal daily doses considered to be
in the low (20 mg of MCD and 18 mg of CON),
medium (40 mg of MCD and 36 mg of CON), and
high (60 mg of MCD and 54 mg of CON) ranges of
clinical doses of MPH.
These near-equal daily doses of MCD and CON
were compared recently in a crossover study in
healthy adult volunteers.
15
When compared for total
exposure to MPH, measured as area under the
plasma concentration time curve (AUC), and maxi-
mum plasma concentration (C
max
), the dose pairs
met current FDA criteria for single-dose bioequiva-
lence. However, despite these similarities, the
plasma concentration versus time profiles produced
by these 2 formulations were shown to be clearly
different: Plasma concentrations of MPH were sig-
nificantly higher for MCD than for CON for up to 6
hours after dosing, and by contrast, plasma concen-
trations of MPH were significantly higher for CON at
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8, 10, and 12 hours after dosing. These differences
can be ascribed to differences in the formulation of
the products that affect both the amount and the
timing of release of both the IR and ER components.
For example, MCD releases 50% more IR MPH in the
initial bolus delivery process than CON (6 vs 4 mg at
the low daily dose, 12 vs 8 mg at the medium daily
dose, and 18 vs 12 mg at the high daily dose) but the
same amount of ER MPH (for both MCD and CON,
14 mg at the low, 28 mg at the medium, or 42 mg at
the high daily doses).
We adopted a nonequivalence design for a direct
(head-to-head) comparison of the PD effects of MCD
and CON administered at bioequivalent daily doses.
The use of a nonequivalence comparison is contro-
versial; therefore, an inactive (placebo [PLA]) condi-
tion was included to allow comparisons with the
literature on efficacy and safety of the respective
MPH formulations. We used the University of Cali-
fornia at Irvine Laboratory School Protocol
16
to con
-
trol for timing and context of assessment across the
day and used surrogate measures of efficacy to eval-
uate the comparative efficacy of MCD and CON at
specific time points across the entire day in the lab-
oratory school. We performed a full analysis of the
main effects of the study that are relevant to the PD
response (dose: low, medium, and high; treatment:
MCD, CON, and PLA; time: 7 sessions) as well as
their interaction (dose ⫻ treatment ⫻ time). In addi-
tion, we tested an a priori hypothesis that provided
the rationale for the study to evaluate the average
effects measured over a specified period (1.5- to 7.5-
hour postdosing) corresponding to the typical school
day.
METHODS
Clinical Materials
MCD 20-mg capsules (lot CL-02088) were obtained from Eu-
rand Americas, Inc (Vandalia, OH). CON tablets (18, 36, and 54
mg; lots 0116991, 0111487, and 0116969, respectively) were ob-
tained from Alza Corporation (Mountain View, CA) and overen-
capsulated in size-0 hard-gelatin capsules by PCI Clinical Services
(Philadelphia, PA). The resulting overencapsulated CON tablets
were tested according to the US Pharmacopeia dissolution condi-
tions for MPH tablets. A statistical F2 comparison of the dose
fraction in solution at each sampling time point showed a compa-
rable dissolution profile to unencapsulated CON tablets from the
same commercial lot (F2 ⬎ 70 for all doses), indicating no signif-
icant effect of overencapsulation on the in vitro release of MPH
(Celltech Pharmaceuticals Inc, unpublished data, 2002). PLAs for
MCD and overencapsulated CON were manufactured by PCI
Clinical Services.
Treatments were packaged according to a double-dummy de-
sign. Each treatment pack contained a 1-week supply of study
treatment, with each day’s supply consisting of 1 large capsule to
accommodate the size of any dose level of CON (containing CON
or PLA) and, depending on dose level, between 1 and 3 smaller
MCD-sized capsules (containing MCD or PLA).
Patients
Children (6 –12 years old) were recruited who had clinical
diagnoses of a Diagnostic and Statistical Manual of Mental Health
Disorders, Fourth Edition subtype of ADHD (inattentive type, hy-
peractive-impulsive type, or combined type) and were being
treated with MPH in doses of 10 to 60 mg/day (5–20 mg per
administration, 1–3 times a day). The physician at each center
chose his/her own patient-recruitment method (ie, chart review or
advertisement). The clinical diagnosis of ADHD was confirmed by
a structured parent interview using the National Institute of Men-
tal Health Diagnostic Interview Schedule for Children (version
4.0). Children were deemed otherwise healthy by means of a
medical history, physical examination, vital-sign measurements
(blood pressure, heart rate, respiration, and temperature), and
clinical laboratory assessments (hematology and urinalysis). In
addition, children had to demonstrate the ability to swallow PLA
study-treatment capsules whole and without difficulty.
Exclusion criteria included an intelligence quotient ⬍80 or the
inability to follow or understand study instructions; pregnancy; a
history of seizure or tic disorder; a family history of seizure or
Gilles de La Tourette’s syndrome; congenital cardiac abnormality,
a history of cardiac disease including myocardial infarction within
3 months of study entry, glaucoma, or hyperthyroidism; a history
of substance abuse or a caretaker with a history of substance
abuse; concurrent chronic or acute illness or other condition that
might confound the study rating measures; a documented allergy
or intolerance to MPH; the use of an investigational drug within 30
days of study entry; and the use of concomitant medication that
could interfere with the assessment of efficacy and safety of the
study treatments. Children provided signed assent, and their legal
guardians signed an institutional review board–approved consent
form to participate in the study.
Study Design
This was a double-blind, PLA-controlled, crossover study com-
paring 3 treatment conditions: MCD, CON, and PLA. The study
was conducted at 10 centers in the United States in accordance
with the principle of the Declaration of Helsinki and its amend-
ments and the International Committee on Harmonization E6
guidelines on Good Clinical Practice. The study protocol and
assent and consent forms were approved by the institutional
review board for each study site before initiation of the study.
Eligible patients were assigned to a dose level according to their
preexisting dosing requirement for MPH (see Table 1) and re-
mained at this level for the study duration. Children treated with
low doses (ⱕ20 mg/day) of MPH were randomized to receive
MCD 20, CON 18, or PLA; those treated with medium doses (⬎20
to 40 mg/day) were randomized to receive MCD 40, CON 36, or
PLA; and children treated with high doses (⬎40 mg/day) were
randomized to receive MCD 60, CON 54, or PLA. Within each
stratum, patients were assigned to 1 of the 6 treatment sequences
of MCD, CON, and PLA to balance for the order of administration
of the treatments. Each of the 3 treatments was administered for 7
days (in the assigned sequence) without an intervening washout
period.
The Laboratory School
The patients were assessed in the laboratory school on days 7,
14, and 21. The standard laboratory classroom staff included a
TABLE 1. Dosage Stratification
Previous MPH Daily Dose Stratification Dose
Low dose
ⱕ15 mg of IR MPH or ⱕ20 mg of ER MPH (eg, 5 mg
BID/TID or 20 mg of MPH SR)
MCD 20 mg vs CON 18 mg vs PLA (dose level 1)
Medium dose
⬎10 to ⱕ30 mg IR MPH or ⬎20 to ⱕ40 mg of ER MPH
(eg, 10 mg BID/TID or 40 mg of MPH SR)
MCD 40 mg vs CON 36 mg vs PLA (dose level 2)
High dose
⬎30 mg IR MPH or ⬎40 mg of ER MPH (to a maximum
of 60 mg) (eg, 15 mg BID/TID or 60 mg of MPH SR)
MCD 60 mg vs CON 54 mg vs PLA (dose level 3)
e208 COMPARISON OF ER MPH FORMULATIONS IN CHILDREN WITH ADHD
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clinical teacher, an activity teacher, and 2 trained observers to rate
each child, but adjustments were made depending on the number
of students in a classroom (from 4 to 18). In addition, playground
counselors and medical staff supervised nonclassroom activities,
which included recording of vital signs and participation in group
games in a playground or gym.
The laboratory school days lasted for ⬃13 hours and included
7 sessions: 1 preparation classroom period immediately after dos-
ing, 5 classroom periods separated by 1.5-hour intervals across the
typical school day, and 1 classroom period 4.5 hours later at the
end of the day. A 1.5-hour cycle of activities was used to control
for timing and setting of the assessments as prescribed by in the
University of California at Irvine Laboratory School Protocol (see
Table 2).
16
The 2 trained observers assessed subjects during each
classroom session on the Swanson, Kotkin, Atkins, M/Flynn, Pel-
ham Scale (SKAMP),
17
consisting of 6 deportment items (interact
-
ing with other children, interacting with adults, remaining quiet,
staying seated, complying with the teacher’s directions, and fol-
lowing the classroom rules) and 7 attention items (getting started,
sticking with tasks, attending to an activity, making activity tran-
sitions, completing assigned tasks, performing work accurately,
and being neat and careful while writing or drawing). In addition,
during each classroom session, a written 10-minute math test was
administered to provide an objective measure from its permanent
product (PERMP), defined as the number of problems answered
correctly.
18
The outcome measures obtained at each of the 7 classroom
periods were intended to document differences in the PD profiles
of the 3 treatments (MCD, CON, and PLA) that were predicted by
the PK/PD model.
10
The first session (at time 0) was scheduled to
occur before the bolus dose of IR MPH delivered by MCD or by
CON was absorbed and thus before it was expected to produce an
effect. The following 3 sessions before lunch (1.5, 3.0, and 4.5 hours
after dosing) were scheduled when the larger bolus dose delivered
by MCD (via IR MPH beads) and the greater proportion of ER
MPH delivered during this time (via ER MPH beads) were ex-
pected to produce higher plasma concentrations than the bolus
dose delivered by CON (via the IR MPH overcoat) and the ER
MPH delivered by CON. The next 2 sessions after lunch (6.0 and
7.5 hours after dosing) were scheduled to occur during the school
day afternoon when the combinations of IR and ER MPH deliv-
eries by MCD and CON were expected to yield approximately the
same plasma concentrations. The last session was delayed until
12.0 hours after dosing and scheduled in the early evening when
the ER component of CON was expected to produce higher
plasma concentrations than the ER component of MCD.
Safety
Safety was assessed by adverse event (AE) reports by the
patient, parent, or guardian. The reported AEs were characterized
(by the investigator at each site) as mild, moderate, or severe: a
mild AE would require minimal or no treatment; a moderate AE
would result in a low level of inconvenience or concern; and a
severe AE would interrupt a patient’s usual daily activity and may
require drug or other therapy. In addition, each week, the parent
or guardian completed the Barkley Side Effect Rating Scale,
19
which delineates 17 side effects commonly reported during treat-
ment with stimulant medication. The parent/guardian assessed
the presence and severity of these side effects during the past
week, rating each item on a scale of 0 (absent) to 9 (severe). The
children’s temperatures were measured at the start of each class-
room day, and blood pressure and heart rate were measured
before or after each classroom session.
Statistical Analyses
For factorial analyses, the SAS analysis of variance (ANOVA)
program for the General Linear Model was used. A mixed model
was specified to perform a standard evaluation of 2 within-subject
factors (treatment and session) and 3 between-subject factors
(dose, site, and sequence) and their interactions. Not all sequences
were assigned to each of the combinations of site and dose, so
interactions of sequence with site and dose were not included in
the ANOVA model. For the PD analyses described here, we se-
lected the SAS General Linear Model option that utilizes data from
just those subjects with complete data (ie, those cases without
missing data). To maintain an overall significance level at P ⬍ .05
across the 3 outcome measures, a Bonferroni correction for mul-
tiple tests was made, and a P value ⬍ .016 for any individual
outcome measure was required for significance.
20
We evaluated multiple comparisons of the 3 treatments by
estimating effect sizes (ESs), which were calculated by dividing
the difference between the active treatment mean and the PLA
treatment means by the square root of the mean square error term
from the ANOVA (ie, the pooled estimate of the standard devia-
tion). We also compared treatments by using paired sample t tests.
In addition, we evaluated an a priori hypotheses about treat-
ment effects averaged over the laboratory classroom sessions oc-
curring during the typical school day (the 5 classroom sessions
occurring from 1.5 to 7.5 hours after dosing) and compared treat-
ments by using paired sample t tests. For the nonequivalence
design, the sample size to achieve statistical power (⬎0.9) was set
based on this a priori hypothesis of an expected small difference
(an ES of ⬃0.225) between MCD and CON on a single outcome
measure (the average ratings of deportment).
RESULTS
Subjects
A total of 214 patients were screened for partici-
pation into the study, and 184 patients were stratified
across the 3 dose levels based on their previously
established clinical doses of MPH. Table 3 summa-
rizes patient demographic information for the intent-
to-treat (ITT) sample. Most of the patients met the
criteria for ADHD combined type. Approximately
25% had a comorbid condition; anxiety and opposi-
tional defiant disorder were the most frequently re-
ported comorbidities. At prescreening, ⬃91% of the
patients were on once-a-day dosing regimens; of the
remainder, 7.6% were taking IR MPH BID, and 1.6%
were taking IR MPH TID. In addition, 1.0% of pa-
tients were taking d-MPH (Focalin). Of the 184 sub-
jects entering the study, 157 received all 3 levels of
treatment and participated in all 7 classroom ses-
sions. Of these subjects, the number at the 10 sites
varied (at sites 1–10, n ⫽ 4, 13, 6, 4, 7, 24, 10, 26, 26,
TABLE 2. Daily Schedule of Assessments During Laboratory Classroom Day
Study Hour* Preparation ⫺0.75 0 (Dose) 1.5 3.0 4.5 6.0 7.5 9 12
Time [6:45 am] [7:30 am] [9:00 am] [10:30 am] [12:00 pm] [1:30 pm] [3:00 pm] [4:30 pm] [7:30 pm]
Vital signs† X X X X XXXX
SKAMP deportment X X X X X X X
SKAMP attention X X X X X X X
PERMP X X X X X X X
Complete Barkley
Scale (parent/
guardian)
X
Assess AEs X
* The chronological (clock) time was ⫾15 minutes this time, but the time between assessments was 1.5 hours.
† The subject’s temperature was obtained only during the initial vital-signs collection for the day.
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and 37, respectively), as did the number in the 3-dose
strata (at doses 1–3, n ⫽ 57, 53, and 47, respectively).
The demographic characteristics of the sample of
patients that completed all 3 treatments (n ⫽ 157)
were not different than those reported for the full
sample.
Overall ANOVAs
The overall ANOVAs revealed large main effects
for all 3 outcome measures for the within-subject
factors of treatment (deportment: F[2, 260] ⫽ 64.41,
P ⬍ .0001; attention: F[2, 260] ⫽ 26.50, P ⬍ .0001;
PERMP: F[2, 260] ⫽ 21.84, P ⬍ .0001]) and session
(deportment: F[6, 780] ⫽ 16.75, P ⬍ .0001; attention:
F[6, 780] ⫽ 27.76, P ⬍ .0001; PERMP: F[6, 780] ⫽
25.11, P ⬍ .0001). The interaction of treatment ⫻
session was also highly significant for all 3 outcome
measures (deportment: F[12, 1560] ⫽ 20.02, P ⬍
.0001; attention: F[12, 1560] ⫽ 20.40, P ⬍ .0001;
PERMP: F[12, 1560] ⫽ 16.94, P ⬍ .0001).
These significant interactions suggest that the
treatments differed but the pattern depended on the
time of the assessment (ie, the session) and called for
a simple-effect analysis of the treatments effects at
each of the 7 assessment times separately. As shown
in Fig 1, this revealed 4 general patterns of treatment
efficacy that were consistent across the 3 measures: 1)
immediately after dosing, the PLA treatment was
better than either active treatment; 2) during the
morning when MCD was better than CON and both
active treatments were better than PLA; 3) during the
afternoon when MCD and CON were, for the most
part, similar in efficacy, but both active treatments
were still superior to PLA; and 4) in the early evening
when CON but not MCD was superior to PLA in
some measures. ES estimates for MCD and CON at
each session for each of the 3 outcome measures are
shown in Fig 1. For each outcome measure, the max-
imum ES occurred during the morning sessions for
MCD and during the afternoon sessions for CON.
The between-subject factor of dose was significant
for SKAMP attention (F[2, 130] ⫽ 5.10, P ⫽ .0074) but
not for SKAMP deportment (F[2, 130] ⫽ 1.54, P ⫽
.2191) or PERMP (F[2, 130] ⫽ 4.16, P ⫽ .0178). The
interaction of dose ⫻ treatment was not significant at
P ⬍ .016 for any of the 3 outcome measures.
The between-subject factor of site was highly sig-
nificant (P ⬍ .001) for all 3 outcome measures (de-
portment: F[9, 130] ⫽ 9.32; attention: F[9, 130] ⫽
14.93; PERMP: F[9, 130] ⫽ 3.55), and for the 2 sub-
jective outcome measures from the SKAMP, the
site ⫻ treatment ⫻ session interactions were also
significant (deportment: F[108, 1560]⫽ 2.19, P ⬍
.0001; attention: F[108, 1560] ⫽ 1.34, P ⬍ .0126). These
significant interactions complicate the interpretation
of the overall treatment main effects and the treat-
ment ⫻ session interaction effects (described above)
and called for analyses of simple effects.
Fig 1. SKAMP deportment, SKAMP attention, and PERMP scores
over time after treatment with MCD (‚), CON (E), or PLA (䡺).
The data represent the mean ⫾ standard error of the mean for all
dose levels combined. Both MCD and CON were statistically
significantly better than PLA at hours 1.5–7.5 for all 3 assessments
(P ⬍ .016). Asterisks indicate the times at which MCD was statis-
tically significantly better than CON; daggers, the times at which
CON was statistically significantly better than MCD and PLA;
double daggers, the times at which PLA was statistically signifi-
cantly better than both MCD and CON. The corresponding ESs for
MCD and CON at each session are shown in the table.
TABLE 3. Summary of Demographics by All Treatments (ITT)
Treatment Group
MCD
(N ⫽ 174)
CON
(N ⫽ 181)
PLA
(N ⫽ 183)
Age, mean (SD) 9.7 (1.8) 9.6 (1.8) 9.6 (1.8)
Gender, n (%)
Male 128 (73.6) 134 (74.0) 135 (73.8)
Female 46 (26.4) 47 (26.0) 48 (26.4)
Race, n (%)
White 121 (69.5) 124 (68.5) 126 (69.2)
African American 20 (11.5) 21 (11.6) 21 (11.5)
Asian 3 (1.7) 3 (1.7) 3 (1.6)
Hispanic 21 (12.1) 23 (12.7) 23 (12.6)
Other 9 (5.2) 10 (5.5) 10 (5.5)
Subtype of ADHD, n (%)
Inattentive 23 (13.2) 23 (12.7) 24 (13.1)
Hyperactive/impulsive 8 (4.6) 9 (5.0) 9 (4.9)
Combined 143 (82.2) 149 (82.3) 150 (82.0)
SD indicates standard deviation.
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Simple-Effect ANOVAs
Inspection of main effects revealed low ratings for
SKAMP deportment and ATTENTION at 3 sites,
with average ratings per item ⬍1.0. For the posthoc
simple-effects analysis, we grouped the sites into
“low-scoring sites” (n ⫽ 87) and “high-scoring sites”
(n ⫽ 70) subgroups and analyzed them in separate
ANOVAs to determine how this characteristic of site
moderated effects of treatment. In the simple-effects
analyses, the between-subject factor of site was sig-
nificant for all 3 outcome measures, but the site ⫻
treatment interactions were not significant for any of
the 3 measures in the analyses of either the high- and
low-scoring subgroups, indicating that the treatment
effect was consistent despite the difference in the
overall ratings of these subgroups of sites. In sepa-
rate analyses of these subgroups, the effect of treat-
ment remained significant in both the high-scoring
(deportment: F[2, 92] ⫽ 30.96, P ⬍ .0001; attention:
F[2, 92] ⫽ 12.61, P ⬍ .0001; PERMP: F[2, 92] ⫽ 9.94,
P ⬍ .0001) and low-scoring (deportment: F[2, 134] ⫽
25.90, P ⬍ .0001; attention: F[2, 134] ⫽ 31.65, P ⬍
.0001; PERMP: F[2, 134] ⫽ 23.43, P ⬍ .0001) sub-
groups. Also, session remained significant in both
the high-scoring (deportment: F[6, 276] ⫽ 10.18, P ⬍
.0001; attention: F[6, 276] ⫽ 22.04, P ⬍ .0001; PERMP:
F[6, 276] ⫽ 16.48, P ⬍ .0001) and low-scoring (de-
portment: F[6, 402] ⫽ 3.71, P ⫽ .0013; attention: F[6,
402] ⫽ 8.74, P ⬍ .0001; PERMP: F[6, 402] ⫽ 13.28, P ⬍
.0001) subgroups. Finally, the interaction of treat-
ment ⫻ session also remained significant for the
high-scoring (deportment: F[12, 552] ⫽ 10.58, P ⬍
.0001; attention: F[12, 552] ⫽ 11.62, P ⬍ .0001;
PERMP: F[12, 552] ⫽ 9.79, P ⬍ .0001) and low-scor-
ing (deportment: F[12, 804] ⫽ 8.17, P ⬍ .0001; atten-
tion: F[12, 804] ⫽ 15.61, P ⬍ .0001; PERMP: F[12, 804]
⫽ 10.66, P ⬍ .0001) subgroups. As shown in Table 4,
the low-scoring subgroup showed smaller treatment
effects than the high-scoring subgroup, and the in-
clusion of the low-scoring subgroup (with unex-
pected low ratings in the laboratory classroom set-
ting) attenuates but does not contradict the overall
analyses.
In the overall analyses, the dose ⫻ treatment in-
teractions were not significant at P ⬍ .016 (our estab-
lished significance level with a Bonferroni correction
for multiple tests), but the dose ⫻ treatment interac-
tions were significant at the unadjusted significance
level of P ⬍ .05 for attention (F[4, 260] ⫽ 2.46, P ⫽
.0460) and PERMP (F[4, 260] ⫽ 3.08, P ⫽ .0168).
Based on this trend, we performed the simple-effects
analyses separately for the 3 dose levels, which re-
vealed that the same patterns of treatment effects
were present in each of the subgroups stratified by
clinical dose (see Fig 2).
In the design of the study, the dose factor refers to
the total daily dose, consisting of 2 components that
were described earlier (ie, the initial bolus doses of IR
MPH, which differ for the near-equal total daily
doses of MCD and CON, and the reservoir doses of
ER MPH, which were the same for the 2 formula-
tions). To evaluate the moderating effects of the bo-
lus dose on outcome, we related the size of the drug
effects (ESs) to the initial bolus components of each
formulation at the 3 dose stratifications (low: CON
18 ⫽ 4 mg and MCD 20 ⫽ 6 mg; medium: CON 36 ⫽
8mg,MCD40⫽ 12 mg; high: CON 54 ⫽ 12 mg and
MCD 60 ⫽ 18 mg). Because the initial bolus domi-
nates the PK levels at 1.5 and 3.0 hours after dosing,
we calculated a correlation of the average ES at these
2 times with IR MPH bolus dose. As shown in Fig 3,
the correlations were high and significant for all 3
outcome measures (deportment: 0.932; attention:
0.865; PERMP: 0.912), indicating that despite the se-
lection of dose based on clinical titration, the ESs
obtained in the early morning were directly related
to the absolute dose administered in the IR MPH
bolus of each formulation (ie, the dose delivered by
the IR beads of MCD and by the overcoat of CON).
Test of the “a Priori” Hypothesis
To test the a priori hypothesis, for each subject a
summary score was established for the primary out-
come measure (SKAMP deportment) based on the
sessions during a time period corresponding to the
length of a typical school day (ie, sessions 2– 6, which
occurred from 1.5 through 7.5 hours after dosing).
This averaging process removes session as a factor,
and thus it does not evaluate the time course. This
process increases the precision of measurement for a
priori or posthoc tests,
21,22
and similar strategies
have been used to investigate differences between 2
active treatments that may be small but clinically
meaningful.
23,24
An ANOVA of the summary out
-
come measure revealed a significant main effect of
treatment (F[2, 162] ⫽ 64.07, P ⬍ .0001) as well as site
(F[9, 81] ⫽ 7.68, P ⬍ .0001) and site ⫻ treatment (F[18,
162] ⫽ 2.97, P ⫽ .0001). For the planned contrast of
the 2 treatment conditions (MCD versus CON) on
SKAMP deportment, the difference was significant
(mean difference ⫽ 1.62, t[156] ⫽ 5.33, P ⬍ .0001),
confirming the a priori hypothesis of superiority of
near-equal daily doses of MCD over CON for this
postdosing period. In ANOVAs of the summary
TABLE 4. ES Estimates for the Low- and High-Scoring Sites
ES at Each Hour Postdose
0 1.5 3.0 4.5 6 7.5 12
High-scoring sites
SKAMP deportment
MCD ⫺0.33 1.2 1.3 1.0 1.0 0.64 0.12
CON ⫺0.26 0.82 0.75 0.67 0.87 0.62 0.41
SKAMP attention
MCD ⫺0.67 0.87 0.90 0.66 0.84 0.38 0.13
CON ⫺0.62 0.55 0.60 0.38 0.83 0.48 0.11
PERMP (no. correct)
MCD ⫺0.31 0.62 0.62 0.54 0.61 0.40 ⫺0.02
CON ⫺0.35 0.51 0.42 0.39 0.54 0.49 0.22
Low-scoring sites
SKAMP deportment
MCD ⫺0.19 0.56 0.63 0.71 0.69 0.61 0.01
CON ⫺0.14 0.30 0.37 0.42 0.61 0.56 0.18
SKAMP attention
MCD ⫺0.62 0.60 0.64 0.76 0.59 0.73 0.13
CON ⫺0.65 0.32 0.44 0.53 0.59 0.70 0.36
PERMP (no. correct)
MCD ⫺0.23 0.54 0.49 0.65 0.56 0.61 0.21
CON ⫺0.31 0.34 0.42 0.42 0.55 0.57 0.34
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scores for the secondary outcome measures, the main
effect of treatment was also significant for SKAMP
attention (F[2, 162] ⫽ 35.57, P ⬍ .0001) and PERMP
(F[2, 162] ⫽ 22.76, P ⬍ .0001). In these secondary
analyses, the main effect of site was also significant
(SKAMP attention: F[9, 81] ⫽ 9.43, P ⬍ .0001;
PERMP: F[9, 81] ⫽ 3.41, P ⫽ .0013), but the site ⫻
treatment interactions were not. Pairwise compari-
sons revealed that treatment with MCD resulted in
statistically significantly lower SKAMP attention rat-
ings (mean difference ⫽ 0.86, t[156] ⫽ 3.70, P ⫽
.0003), whereas PERMP scores were not statistically
different at P ⬍ .016 (mean difference ⫽ 5.22, t[156]
⫽ 2.22, P ⫽ .0275).
Safety and Tolerability Outcomes
There was no difference for any comparison of
treatment groups on parent ratings of side effects on
the Barkley Scale. In the ANOVA of the measures of
blood pressure and pulse rate, only 2 statistically
significant differences related to treatment emerged:
1) systolic blood pressure at hour 7.5 had a mean
increase from baseline of 5.2 mm Hg for CON and 0.9
mm Hg for PLA and a decrease of 0.6 mm Hg for
MCD (P ⫽ .0075), and 2) the mean increase from
baseline at hour 1.5 for the pulse rate was 9.6 beats
per minute for MCD, 9.5 beats per minute for CON,
and 3.2 beats per minute for PLA (P ⫽ .0244). There
was no significant difference due to the between-
Fig 2. SKAMP deportment, SKAMP attention, and PERMP scores over time after treatment with MCD (‚), CON (E), or PLA (䡺) for the
3 dose levels. Both MCD and CON were statistically significantly better than PLA at hours 1.5–7.5 for all 3 assessments independent of
dose level (P ⬍ .016), with the exception of CON at the 4.5- and 7.5-hour assessment times for SKAMP deportment and the 3.0- and
4.5-hour assessment times for PERMP at dose level 1 and the 1.5- and 4.5-hour assessment times for SKAMP attention at dose levels 2 and
1, respectively. Asterisks indicate the times at which MCD was statistically significantly better than CON; daggers, the times at which
CON was statistically significantly better than PLA; double daggers, the times at which PLA was statistically significantly better than both
MCD and CON, with the exception of dose-level-1 SKAMP deportment ratings and dose-level-3 PERMP ratings at which PLA was
statistically better than CON only and dose-level-1 and -2 PERMP ratings at which PLA was statistically better than MCD only. The
corresponding ESs for MCD and CON for each session within each dose level are shown in the tables.
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subject effect of dose. These findings are consistent
with other observations of a slight increase in pulse
rate and blood pressure fluctuations with clinical
doses of MPH.
25
No severe AEs occurred. Less than one fourth of
the patients in any treatment group experienced AEs,
and of these AEs, most were mild. Three patients
discontinued study treatment due to AEs that were
judged to be unrelated to the medications. The rea-
sons for discontinuation of treatment were gastroen-
teritis (CON), fever on classroom day (PLA), and
sunburn (PLA). Table 5 displays the most frequent
AEs categorized by body system that occurred in
ⱖ2% of the study sample. Upper abdominal pain
was the most common AE for patients treated with
MCD (3.4%) and CON (4.4%). A higher incidence of
anorexia was seen with the active treatments (2.9%
for MCD, 2.8% for CON) compared with PLA (1.1%),
whereas a higher incidence of vomiting, insomnia,
and irritability was seen with PLA (2.2%, 3.3%, and
2.7%, respectively), compared with MCD (0.6%,
1.7%, and 1.7%, respectively) and CON (0.6%, 1.7%,
and 1.1%, respectively). Overall, the incidence of spe-
cific AEs was low and similar to those reported pre-
viously for MPH
19
DISCUSSION
The current study examined whether the differ-
ences in expected PK profiles for MCD and CON
produce differences in the time course of behavioral
effects as predicted by the PK/PD model used in the
development of both of these formulations.
8–10,26
Our approach assumed that individual differences in
sensitivity to MPH exist, which may account for
differences across patients in the clinically titrated
doses (ie, the low, medium, and high doses), but that
for any of these titrated doses, the onset of efficacy
would be related directly to plasma concentration
attributed to the IR component and that the maxi-
mum PD response would coincide with the time of
the maximum PK MPH level (ie, T
max
). Based on this
PK/PD model, we predicted that, at any time after
dosing, the magnitude of response would be related
directly to the predicted plasma concentration of
MPH at that time such that differences in response
for the 2 active formulations (ie, MCD and CON)
would be proportional to differences in predicted
plasma concentrations. Most of the predictions of the
PK/PD model were confirmed: At near-equal daily
doses, the larger initial IR MPH bolus of MCD in the
morning and the greater proportion of MPH released
from the ER component of that formulation during
this time were predicted to produce higher expected
plasma concentrations compared with CON, and this
was reflected in superior outcome during this early
postdosing period (1.5–4.5 hours postdose). In the
afternoon (6.0 –7.5 hours postdose), when the combi-
nation of IR and ER components of MCD and CON
were predicted to produce approximately the same
plasma concentrations of MPH, the 2 treatments did
not differ greatly in outcome. Finally, in the early
evening (12 hours postdose) when the ER component
of CON was predicted to deliver more MPH than
that of MCD, CON showed statistical superiority
over MCD.
The prediction that stratification by clinical dose
would equate the effects of different doses was par-
tially supported by this study. The dose effect was
significant for the attention ratings but not for de-
portment ratings or PERMP, and the dose ⫻ treat-
ment interactions were not significant at the adjusted
significance level of P ⬍ .016. However, the high
correlation of bolus dose with ES in the early morn-
ing (1.5 and 3.0 hours) suggests that the patients in
the low-dose subgroup might have benefited from
higher doses. In addition, the high correlations of
effects with the IR MPH dose in the morning sessions
are consistent with the expectation of a similar dose-
response relationship for the IR components of MPH
of either formulation (ie, when adjusted for dose and
expected serum concentration, the response to MPH
from these 2 formulations does not differ). We be-
lieve that this provides a PK/PD explanation for the
statistically and clinically significant superiority of
MCD versus CON seen at the 1.5- and 3.0-hour time
points evaluated in this study.
The a priori hypothesis that provided the rationale
for this study was confirmed: When near-equal daily
doses are compared for MCD and CON, the average
effects of MCD were greater than for CON for the
SKAMP deportment measure across the sessions cor-
responding to a typical school day (1.5–7.5 hours
postdose). Based on the expected relationship of
plasma concentration with classroom behavior, this
Fig 3. ESs for SKAMP deportment, SKAMP attention, and
PERMP scores at hours 1.5 and 3.0 as a function of IR MPH in each
formulation after treatment with MCD (‚) and CON (E).
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effect can be attributed mainly to both the larger
initial IR MPH dose delivered by MCD and, to a
lesser extent, to the different release characteristics of
the ER MPH portion of each formulation.
In addition, the posthoc analysis of the data by
time point indicated a statistically greater effect of
CON than either MCD or PLA 12 hours postdose.
These differences in school-day efficacy versus early-
evening efficacy are noteworthy, and they may help
guide clinical practice in the tailoring of treatments
for individuals.
The doses of MCD and CON compared in this
study meet the published FDA criteria for single-
dose bioequivalence of a modified release oral dos-
age form; however, the results of this study suggest
that the PD effects of these 2 formulations are not
equivalent. Despite the similarity in overall and max-
imum exposure to MPH, the differences in early and
late exposure to MPH with these 2 once-daily formu-
lations result in detectable and potentially important
differences in clinical efficacy during the day. This
suggests that single-dose bioequivalence compari-
sons that are based only on AUC and C
max
may be
insensitive to clinically important differences in PD
effects for this class of agents in this patient popula-
tion.
The site differences in this study deserve some
comment, because this is a common finding in mul-
tisite studies. The site difference was most prominent
for the subjective outcome measures on the SKAMP
rating scale, which depend on the training of the
observers (which is difficult to equate across sites)
and the context of the classroom (which is controlled
but still may vary across sites due to class size,
physical space, and other factors that may not be
standardized). Thus, although the effects of site did
not invalidate the overall analyses, the objective sec-
ondary measure from the 10-minute math test
(PERMP) may provide the most robust surrogate
measures of outcome in this multisite study.
The significance of treatment in the analyses of
effects at time 0 (immediately after dosing) was due
to the superiority of the PLA condition over both
active conditions (MCD or CON). This finding was
not predicted by the PK/PD model, and it deserves
some comment. A superiority of PLA at time 0 has
been noted in almost all the laboratory school stud-
ies, but in each case the sample size was too small to
result in this interesting but small ES reaching statis-
tical significance. However, with the large sample
size used here for the nonequivalence design, the
difference in favor of PLA was statistically signifi-
cant for some measures. We offer 2 speculations
about possible mechanisms that could account for
this unpredicted difference. First, during the time
shortly after dosing, the plasma and brain concentra-
tions of MPH may be very low, and these levels may
have a preferential effect on presynaptic compared
with postsynaptic dopamine receptors. This may
have resulted in the inhibition of dopamine release
and a decrease in synaptic dopamine instead of an
increase, as was expected when the plasma concen-
tration of MPH reached maximum levels between 1.5
and 3.0 hours after dosing. Second, adaptation effects
that produced acute tolerance (tachyphylaxis)
27
may
linger and still have effects the next day before the
next dose of MPH is administered. This may result in
aPD“rebound” such that behavior and performance
are worse in the morning before the single daily dose
is administered.
Limitations
The data for these analyses were from surrogate
measures obtained in the laboratory school setting.
The laboratory school setting controls for context and
timing of the assessments but lacks many features of
the natural environment of the home and the school.
Thus, it is not certain that the same patterns reported
here would be observed in school settings in which
an ADHD student would be in a classroom with a
majority of the students not affected by this disorder.
This is a limitation of the study.
The study was designed to contrast total absorbed
daily doses that were approximately equal, although
this resulted in differences in the initial bolus doses
of the 2 active treatments (MCD and CON). In this
TABLE 5. AEs Occurring in ⱖ2% of Patients: ITT Population
Treatment Group
MCD
(N ⫽ 174)
CON
(N ⫽ 181)
PLA
(N ⫽ 183)
Gastrointestinal disorders 8 (4.6%) 11 (6.1%) 13 (7.1%)
Abdominal pain upper 6 (3.4%) 8 (4.4%) 6 (3.3%)
Vomiting NOS 1 (0.6%) 1 (0.6%) 4 (2.2%)
Infections and infestations 1 (0.6%) 5 (2.8%) 2 (1.1%)
Injury, poisoning, and procedural complications 6 (3.4%) 3 (1.7%) 5 (2.7%)
Metabolism and nutrition disorders 8 (4.6%) 11 (6.1%) 4 (2.2%)
Anorexia 5 (2.9%) 5 (2.8%) 2 (1.1%)
Appetite decreased NOS 3 (1.7%) 6 (3.3%) 1 (0.5%)
Nervous system disorders 6 (3.4%) 10 (5.5%) 10 (5.5%)
Headache NOS 3 (1.7%) 7 (3.9%) 6 (3.3%)
Psychiatric disorders 12 (6.9%) 13 (7.2%) 17 (9.3%)
Insomnia 3 (1.7%) 3 (1.7%) 6 (3.3%)
Irritability 3 (1.7%) 2 (1.1%) 5 (2.7%)
NOS indicates not otherwise specified. Percents are based on the total number (N) of patients treated
in each category. aes are assigned based on the treatment being received at the start of the ae. Patients
are counted only once at body-system level per treatment. Patients with multiple occurrences of the
same event are counted once per treatment.
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study, doses were not evaluated that were equated
for the initial bolus doses of IR MPH, which would
provide another test of the PK/PD model. This is
another limitation of this study.
The study standardized the treatments and evalu-
ated them in a crossover design. However, in clinical
practice, individual differences in efficacy and toler-
ability direct the clinician to tailor treatment by ad-
justing dose or supplementing the ER formulations
with additional IR doses in the morning or afternoon.
These options were not allowed during this study
but may be necessary to optimize the effects of MPH
on groups of children with ADHD. Thus, the effects
of both MCD and CON in the low-dose subgroup
were smaller than in the high-dose subgroup, but we
do not know whether a higher dose in the low-dose
subgroup would have increased the ES. The lack of
tailoring to achieve rigorous experimental control
may be another limitation of this study.
In this study, plans were made to collect plasma
samples from a subset of subjects at 3 sites to allow
assay of MPH. Due to practical difficulties at the
designated sites, complete samples were not ob-
tained from a sufficient number of subjects to reliably
estimate the PK profiles for these patients. Wigal et
al
9
showed that despite lower absolute plasma con
-
centrations of MPH (as expected due to differences in
size), the MPH plasma concentration versus time
profiles after administration of MCD to children with
ADHD were similar to those obtained in healthy
adult subjects. In addition, studies with other MPH
products indicate that the PK profiles of MPH in
adults and school-aged children are qualitatively
similar and that there are no apparent age-related
differences in absorption, distribution, metabolism,
or excretion of MPH.
28–30
Thus, although the differ
-
ences found in the PK profiles of MCD and CON by
Gonzalez et al
15
are expected to apply to children in
this study, the inability to fully confirm this predic-
tion with empirical data are a limitation of this study.
The double-dummy blinding in this study re-
quired overencapsulation of CON in a gelatin cap-
sule. As a result, the CON treatment was adminis-
tered in a form that is not identical to the
commercially available product. Thus, the method of
blinding we chose for CON, in theory, could have
affected the release of the MPH active ingredient.
When designing the study, we were aware that over-
encapsulation of CON in a gelatin capsule had been
used successfully to blind a pivotal dose titration
study of CON.
31
Although this indicates that this
method of blinding is generally acceptable for this
OROS formulation, we took the additional precau-
tion of completing in vitro dissolution testing of our
test materials before dosing, and we were able to
confirm the absence of a significant effect of gelatin
overencapsulation on the release of MPH from CON
tablets in vitro.
CONCLUSIONS
The findings from this study suggest that differ-
ences in the PK profiles of different MPH products
translate into measurable changes in PD profiles, as
predicted by the PK/PD model. This finding is im-
portant because it suggests that, under the right con-
ditions (a carefully controlled laboratory school set-
ting), relatively small differences in the pattern of
release of the total dose and the corresponding dif-
ferences in plasma concentrations of MPH produce
differences in the behavioral effects of MPH that can
be detected and quantified. We believe that these
laboratory school findings increase our understand-
ing of the basic properties of these 2 ER MPH for-
mulations, including their similarities and differ-
ences, and that this can help to guide the selection of
the most appropriate once-daily stimulant treatment
for the child with ADHD.
ACKNOWLEDGMENTS
This study was funded by Celltech Pharmaceuticals Inc.
We thank the following clinical investigators, who participated
in this study: Joseph Biederman (Massachusetts General Hospital,
Cambridge, MA), Ann Childress (Nevada Behavioral Health, Inc,
Las Vegas, NV), Flemming Graae (New York Presbyterian Hospi-
tal, New York, NY), Laurence Greenhill (New York State Psychi-
atric Institute, New York, NY), Scott Kollins (Duke Family and
Child Clinic, Durham, NC), Frank Lopez (Children’s Develop-
mental Center, Maitland, FL), Tim Wigal (University of California
at Irvine Child Development Center, Irvine, CA), Eliot Moon (Elite
Clinical Trials, Inc, Temecula, CA), John Turnbow (Behavioral
Neurology, Lubbock, TX), and Matthew Brams (Bayou City Re-
search, Ltd, Houston, TX). We also thank Cynthia Ingerick-Holt
(Celltech Pharmaceuticals Inc, Rochester, NY) and Carrie Cain
(Celltech Pharmaceuticals Inc) for their role in overseeing the
compliance activities for this study and Stuart Arbuckle (Celltech
Pharmaceuticals Inc) for help in the design of the study.
REFERENCES
1. Goldman LS, Genel M, Bezman RJ, Slanetz PJ. Diagnosis and treatment
of attention-deficit/hyperactivity disorder in children and adolescents.
Council on Scientific Affairs, American Medical Association. JAMA.
1998;279:1100–1107
2. Mannuzza S, Klein RG. Long-term prognosis in attention deficit/
hyperactivity disorder. Child Adolesc Psychiatr Clin N Am. 2000;9:711–726
3. American Academy of Pediatrics, Subcommittee on Attention-Deficit/
Hyperactivity Disorder, Committee on Quality Improvement. Clinical
practice guideline: treatment of the school-aged child with attention-
deficit/hyperactivity disorder. Pediatrics. 2001;108:1033–1044
4. Swanson JM, Kinsbourne M, Roberts W, Zucker K. A time-response
analysis of the effect of stimulant medication on the learning ability of
children referred for hyperactivity. Pediatrics. 1978;61:21–29
5. Greenhill LL. Pharmacologic treatment of attention deficit hyperactivity
disorder. Psychiatr Clin North Am. 1992;15:1–27
6. Greenhill LL, Perel JM, Rudolf G, et al. Correlations between motor
persistence and plasma levels of methylphenidate-treated boys with
ADHD. Int J Neuropsychopharmacol. 2001;4:207–215
7. Pelham WE Jr, Sturges J, Hoza J, et al. Sustained release and standard
methylphenidate effects on cognitive and social behavior in children
with ADHD. Pediatrics. 1987;80:491–501
8. Swanson J, Gupta S, Lam A, et al. Development of a new once-daily
formulation of methylphenidate for the treatment of ADHD: proof of
product studies. Arch Gen Psychiatry. 2003;60:204–211
9. Wigal SB, Sanchez DY, DeCory HH, D’Imperio JM, Swanson JM. Selec-
tion of the optimal dose ratio for a controlled-delivery formulation of
methylphenidate. J Appl Res. 2003;3:1–18
10. Swanson JM, Lerner M, Wigal T, et al. The use of a laboratory school
protocol to evaluate concepts about efficacy and side effects of new
formulations of stimulant medications. J Atten Disord. 2002;6(suppl
1):S73–S87
11. Wolraich ML, Greenhill LL, Pelham W, et al. Randomized, controlled
trial of OROS methylphenidate once a day in children with attention-
deficit/hyperactivity disorder. Pediatrics 2001;108:883– 892
12. Greenhill LL, Findling RL, Swanson JM; ADHD Study Group. A dou-
ble-blind, placebo-controlled study of modified-release methylpheni-
date in children with attention-deficit/hyperactivity disorder. Pediatrics.
2002;109(3). Available at: www.pediatrics.org/cgi/content/full/109/
3/e39
13. US Food and Drug Administration. Center for Drug Evaluation and
http://www.pediatrics.org/cgi/content/full/113/3/e206 e215
by guest on June 4, 2013pediatrics.aappublications.orgDownloaded from
Reporting: Approval package for NDA 21-121 (Concerta), medical re-
view document: clinical review. Rockville, MD: US Food and Drug
Administration; 2000:4
14. Metadate CD (R549C) [package insert]. Rochester, NY: Celltech Phar-
maceuticals, Inc; 2002
15. Gonzalez MA, Pentikis HS, Andrl N, et al. Methylphenidate bioavail-
ability from two extended-release formulations. Int J Clin Pharmacol
Ther. 2002;40:175–184
16. Swanson JM, Agler D, Fineberg E, et al. University of California, Irvine,
laboratory school protocol for pharmacokinetic and pharmacodynamic
studies. In: Greenhill LL, Osman BB, eds. Ritalin: Theory and Practice. 2nd
ed. New York, NY: Mary Ann Liebert, Inc; 2000:405– 430
17. Wigal SB, Gupta S, Guinta D, et al. Reliability and validity of the
SKAMP rating scale in a laboratory setting. Psychopharmacol Bull. 1998;
34:47–53
18. Swanson J, Wigal S, Greenhill L, et al. Objective and subjective mea-
sures of pharmacodynamic effects of Adderall in the treatment of
children with ADHD in a controlled analog classroom setting. Psycho-
pharmacol Bull. 1998;34:55– 60
19. Barkley RA, McMurray MB, Edelbrock CS, Robbins K. Side effects of
methylphenidate in children with attention deficit hyperactivity
disorder: a systemic, placebo-controlled evaluation. Pediatrics. 1990;86:
184–192
20. Senn S. Statistical Issues in Drug Development. Chichester, United
Kingdom: Wiley; 1998
21. Spearman C. Correlation calculated from faulty data. Br J Psychol.
1910;3:271–295
22. Brown W. Some experimental results in the correlation of mental abil-
ities. Br J Psychol. 1910;3:296 –322
23. Conners CK, Epstein JN, March JS, et al. Multimodal treatment of
ADHD in the MTA: an alternative outcome analysis. J Am Acad Child
Adolesc Psychiatry. 2001;40:159 –167
24. Swanson JS, Kraemer HC, Hinshaw SP, et al. Success rates based on
severity of ADHD and ODD symptoms at the end of treatment. JAm
Acad Child Adolesc Psychiatry. 2001;40:168 –179
25. Rapport MD, Moffitt C. Attention deficit/hyperactivity disorder and
methylphenidate. A review of height/weight, cardiovascular, and so-
matic complaint side effects. Clin Psychol Rev. 2002;22:1107–1131
26. Swanson JM, Volkow ND. Pharmacokinetic and pharmacodynamic
properties of stimulants: implications for the design of new treatments
for ADHD. Behav Brain Res. 2002;130:73–78
27. Swanson JM, Gupta S, Gointa D, et al. Clin Pharmacol Ther. 1999;66:
295–305
28. Patrick KS, Mueller RA, Gualtieri CT, Breese GR. Pharmacokinetics and
actions of methylphenidate. In: Meltzer HY, ed. Psychopharmacology: The
Third Generation of Progress. New York, NY: Raven Press; 1987:1387–1395
29. Gualtieri CT, Wargin W, Kanoy R, et al. Clinical studies of methylpheni-
date serum levels in children and adults. J Am Acad Child Adolesc
Psychiatry. 1982;21:19 –26
30. Wargin W, Patrick K, Kilts C, et al. Pharmacokinetics of methylpheni-
date in man, rat, and monkey. J Pharmacol Exp Ther. 1983;226:382–386
31. Pelham WE, Gnagy EM, Burrows-Maclean L, et al. Once-a-day Concerta
methylphenidate versus three-times-daily methylphenidate in labora-
tory and natural settings. Pediatrics 2001;107(6). Available at:
www.pediatrics.org/cgi/content/full/107/6/e105
e216 COMPARISON OF ER MPH FORMULATIONS IN CHILDREN WITH ADHD
by guest on June 4, 2013pediatrics.aappublications.orgDownloaded from
2004;113;e206Pediatrics
DeCory, Sharon J. Hirshe Dirksen and Simon J. Hatch
L. Greenhill, Joseph Biederman, Scott Kollins, Annamarie Stehli Nguyen, Heleen H.
James M. Swanson, Sharon B. Wigal, Tim Wigal, Edmund Sonuga-Barke, Laurence
School (The Comacs Study)
in Children With Attention-Deficit/Hyperactivity Disorder in the Laboratory
A Comparison of Once-Daily Extended-Release Methylphenidate Formulations
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