Development of a New Once-a-Day Formulation
`of Methylphenidate for the Treatment
`of Attention-deficit/Hyperactivity Disorder
`
`Proof-of-Concept and Proof-of-Product Studies
`
`James Swanson, PhD; Suneel Gupta, PhD; Andrew Lam, PhD; Ira Shoulson, MD;
`Marc Lerner, MD; Nishit Modi, PhD; Elizabeth Lindemulder, PhD; Sharon Wigal, PhD
`
`Background: The duration of action of the immediate(cid:173)
`release formulation of methylphenidate hydrochloride is
`short (3 to 4 hours), and 3 times daily dosing is thought
`to maximize effectiveness across a 12-hour day. The ini(cid:173)
`tial sustained-release formulations of methylphenidate
`had reduced efficacy compared with immediate-release
`methylphenidate and were not well accepted. Tachyphy(cid:173)
`laxis was hypothesized to account for the reduced ef(cid:173)
`fects, and an ascending drug delivery pattern was pro(cid:173)
`posed to overcome this acute tolerance.
`
`Methods: Children with attention-deficit/hyper(cid:173)
`activity disorder were evaluated in a laboratory school
`to characterize onset and duration of the effect of a
`variety of methylphenidate regimens. In a proof-of(cid:173)
`concept study, an experimental ascending profile was
`established by an initial bolus followed by small
`increasing doses of immediate-release methylpheni(cid:173)
`date in capsules administered every 30 minutes fo r 8
`hours. Two proof-of-product studies of a new oral
`once-a-day formulation to deliver methylphenidate by
`an osmotic pump process based on OROS (ALZA
`Corp, Mountain View, CaliO technology (hereafter
`referred to "O ROS-methylphen idate") were con -
`
`ducted: a phannacokinetic study and a pharmacody(cid:173)
`namic study.
`
`Results: The experimental ascending profile matched the
`e[ect of the standard regimen of methylphenidate, 3 times
`daily. In the pharmacokineticstudy, OROS-methylpheni(cid:173)
`date treatment produced a rapid rise followed by increas(cid:173)
`ing plasma concentrations that peaked 7 to 9 hours after
`administration. In the pharmacodynamic study, OROS(cid:173)
`methylphenidate treatment matched the 3 times daily dos(cid:173)
`ing of methylphenidate for onset and duration of emcacy.
`
`Conclusions: These studies demonstrate the transla(cid:173)
`tion of a basic science finding (acute tolerance to clini(cid:173)
`cal doses of methylphenidate) into clinical application
`(the selectio n of a new drug delivery pattern for
`methylphenidate). This approach produced a new prod(cid:173)
`uct (OROS-methylphenidate or Concerta), which proved
`to have the predicted rapid onset (with 1-2 hours) and
`long duration of efficacy (10-12 hours) after a single ad(cid:173)
`ministration in the morning.
`
`Arch Gen Psychiatry. 2003;60:204-211
`
`T HE STIMULANT medication
`
`methylphenidate1 has been
`used fo r al most half a
`century to treat children
`with attention-deficit/
`hyperactivity disorder (ADHD).2 The ef(cid:173)
`ficacy and safety of this clinical practice has
`been established by decades of clinical use
`and thousands of research studies.3 Meth(cid:173)
`ylphenidate hydrochloride has been, by far,
`the most widely used psychotropic medi(cid:173)
`cation in child psychiatry.4
`The immediate-release (IR) formula(cid:173)
`tion of methylphenidate has remained
`unchanged since its introduction in 1957,
`despite some shortcomings. For example,
`IR methylphenidate is relatively short act(cid:173)
`ing,5·6 and 2 or 3 times a day dosing is rec(cid:173)
`ommended to maintain efficacy for 8 to 12
`hours.7· 17 The administration of multiple
`
`doses of medication each day may be in(cid:173)
`convenient and associated with reduced
`compliance. For children, this usually re(cid:173)
`sults in 1 or more doses administered in
`public at school. In addition to possible em(cid:173)
`barrassment to the child, the administra(cid:173)
`tion of methylphenidate o·eatment at school
`creates special problems associated with the
`storage and handling requirements for a
`controlled (Schedule ll) drug. 12
`17
`•
`ln the Multimodality Treatment Study
`of ADHD (MTA), 18 a 3 times daily (TIO)
`regimen of IR methylphenidate was se(cid:173)
`lected as the "state-of-the-art" pharmaco(cid:173)
`logical treatment for ADHD. Long-term ef(cid:173)
`fectiveness of this treatment regimen was
`documented over the course of 14 months
`of treaonent in this large randomized clini(cid:173)
`19 Secondary analysis20 docu(cid:173)
`cal trial. 10
`•
`mented that the MTA regimen of methyl-
`
`From tire University of
`California, Irvine, Department
`of Pediatrics, Child
`Development Center
`(Drs Swanson, Lerner, and
`Wigal); ALZA Co1p,
`Mountain View, Calif
`(Drs Gupta, Lam, Modi,
`and Lindemulder); and the
`Department of Neurology,
`University of Rochester,
`Roe/rester, NY (Dr Slroulson).
`
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`ALKERMES EXHIBIT 2033
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
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`

`An Example Schedule for the University of California, Irvine, Laboratory School Protocol
`
`Groups 1/2,
`Time of Day
`
`7fi:30AM
`7:30/8 AM
`8/8:30 AM
`8:30/9 AM
`9/9:30 AM
`9:30/10 AM
`10/10:30 AM
`10:30/11 AM
`11/11:30 AM
`11:30 AM/12 PM
`12/12:30 PM
`12:30/1 PM
`1/1:30PM
`1:30/2 PM
`2/2:30 PM
`2:30/3 PM
`3/3:30 PM
`3:30/4 PM
`4/4:30 PM
`4:30/5 PM
`5/5:30 PM
`5:30/6 PM
`6/6:30 PM
`
`TID-Methylphenidate
`Hydrochloride
`
`Experimental
`
`Dose 1
`
`(Peak)
`
`(Trough)
`Dose 2
`
`(Peak)
`
`(Trough)
`Dose 3
`
`(Peak)
`
`Dose 1
`
`Dose 2
`Dose 3
`Dose 4
`Dose 5
`Dose 6
`Dose 7
`Dose 8
`Dose 9
`Dose 10
`Dose 11
`Dose 12
`Dose 13
`Dose 14
`Dose 15
`
`Activity
`Arrival
`
`Cycle 1
`Blood sample
`Cycle 2
`Recess/snack
`Cycle 3
`
`Cycle 4
`Recess/lunch
`Cycle 5
`
`Cycle 6
`Recess
`Cycle 7
`
`Cycle 8
`Recess/snack
`Cycle 9
`
`Cycle 10
`
`Pick-up/depart
`
`Classroom/
`Mathematics Test
`
`Test 1
`Class 1
`Test 2
`Recess 1
`Test3
`Class 2
`Test 4
`Recess 2
`Test 5
`Class 3
`Test 6
`Recess 3
`Test 7
`Class 4
`Test 8
`Recess 4
`Test 9
`Class 5
`Test 10
`Recess 5
`
`Abbreviation: TIO, 3 times daily.
`
`phenidate differed from the regimen prescribed by
`community practitioners, for frequency of dosing (2.9
`doses/d vs 2.1 doses/d) and total daily dose (32.8 mg/d
`VS 18.7 mg/cl).
`Despite the impressive efficacy of IR methylpheni(cid:173)
`19
`20 prob(cid:173)
`date treatment documented by the MTA, 1°·
`·
`lems remain that are inherent to the multiple doses per
`day. An early attempt was made to overcome these short(cid:173)
`comings with a sustained-release (SR) formulation of
`methylphenidate based on a wax-matrix delivery sys(cid:173)
`tem. This SR methylphenidate formulation12 was ap(cid:173)
`proved for the treatment of ADHD over a decade ago, but
`it had delayed onset of action and reduced efficacy com(cid:173)
`pared with the IR methylphenidate formulation and was
`not well accepted in clinical practice. 16
`17
`•
`In 1993, a research program, supported by ALZA
`Corp, Mountain View, Calif, was initiated at the Univer(cid:173)
`sity of California, Irvine (UCI) to address these prob(cid:173)
`lems. The initial step was to conduct "concept discov(cid:173)
`ery" study to understand some basic properties of the time
`course of responses to IR methylphenidate n·eatment. The
`results of this study' 1 showed that a constant ( zero(cid:173)
`order) drug delivery pattern did not maintain efficacy
`across the day; tachyphylaxis (acute tolerance) was pro(cid:173)
`posed to account for this observation. This concept
`implied that the reduced efficacy of existing SR methyl(cid:173)
`phenidate formulations might be the result of nonascend(cid:173)
`ing (ie, 11at or descending) drug delivery profiles, and that
`an ascending (first-order) drug delivery profile would
`overcome the hypothesized acute tolerance. The re(cid:173)
`search program required methodological innova(cid:173)
`tions21-23 (eg, development of the UCI Laboratory School
`Protocol and the applica tion of pharmacokinetic(cid:173)
`pharmacodynamic [PK/PD) modeling), which will be re-
`
`viewed to provide background for the proof-of-concept
`and proof-of-product studies that will be reported herein.
`
`THE UCI LABO RA TORY SCHOOL PROTOCOL
`
`The UCI Laboratory School Protocol provides tight con(cid:173)
`trol of timing and context of observations so that subjec(cid:173)
`tive and objective measures of methylphenidate efficacy
`can be made precisely and repeatedly across the day.21 In
`this protoc:-ol, children already diagnosed as having ADHD
`and who have a clinical history of beneficial response to
`stimulant medication are evaluated. The clinical diagno(cid:173)
`sis is confirmed by a structured psychiatric interview (eg,
`the Diagnosis Interview Schedule for Children). The es(cid:173)
`tablished treatment is used as an active con trol condition
`in a crossover design that also includes an inactive (pla(cid:173)
`cebo) control and experimental conditions. Typically, each
`condition is established for 1 week, starting on Sunday.
`Once a week (usually on Saturday) groups of children with
`ADHD attend the laboratory school, where they are evalu(cid:173)
`ated for up to 12 hours (eg, 7 AM to 7 PM). Each test day
`consists of cycles of precisely timed activities designed to
`be repeated (Table) . In studies reported herein, a 1-hour
`cycle of activities was used, consisting of capsule admin(cid:173)
`istration (1 minute), computer mathematics tests or li(cid:173)
`brary quiet time (9 minutes), individual classroom seat(cid:173)
`work (20 minutes), capsule administration (1 minute),
`library quiet time or computer mathematics test (9 min(cid:173)
`utes), and group classroom activity (20 minutes) .
`The Swanson, Kotkin, Agler, Mylnn , and Pelham
`(SKAMP)22 teacher-rating scale was developed to evalu(cid:173)
`ate behavior over a short period (eg, a classroom period).21
`The SKAMP items describe specific behaviors that are ex(cid:173)
`pected in the classroom related to attention (eg, getting
`
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`staned, sticking with activities, completing work, and
`stopping for transition) and deportment (ie, remaining
`quiet, remaining seated, interacting with other stu(cid:173)
`dents, and interacting with the teacher) rather than the
`general behaviors described by most other rating scales
`used to assess children with ADHD. Each item is rated
`on a 7-point impairment scale,20 and an average rating
`per item is calculated for the subscales of Attention and
`Deporonent. Test-retest reliability and sensitivity to treat(cid:173)
`ment wi.th stimulant medications have been demon(cid:173)
`strated for the SKA MP subscales. u,23 To supplement these
`subjeclive classroom ratings, short 10-minute objective
`tests (eg, a memory scanning test11 or a mathematics test21
`)
`were designed to be administered by computer after or
`on paper during each classroom probe, and speed and
`accuracy of response on these tasks were used as mea(cid:173)
`sures of academic productivity. By repeating the subjec(cid:173)
`tive and objective measurements at regular times across
`each test day, the time course of effects of methylpheni(cid:173)
`date treatment (relative to placebo) can be estimated.
`The first concept discovery study used the UCl Labo(cid:173)
`ratory School to conduct a "sipping" study, 11 in which
`methylphenidate or placebo was administered in cap(cid:173)
`sules at 30-rninute intervals for 8 hours (Table). We used
`PK/PD modeling to define the dosing regimens that would
`generate fiat and ascending PK profiles, which we con(cid:173)
`trasted with a standard clinical regimen of administra(cid:173)
`tion of IR methylphenidate twice daily (BID). We ad(cid:173)
`dressed 2 basic questions related to key patterns of delivery
`of methylphenidate treaonent: "Is a bolus delivery of meth(cid:173)
`ylphenidate necessary to elicit the full clinical efficacy?"
`and "Will a constant rate of delivery of methylpheni(cid:173)
`date treatment maintain full efficacy over time?"
`Multiple PD measures of efficacy (ie, teacher ratings
`for each classroom session and academic productivity tests
`after each classroom session) at multiple times across the
`day documented11 large effect size estimates(> 1) at the
`pellk ;md trollgh time points for the RTD condition, and
`this provided a "ruler" to gauge the magnitude of effects
`from the other 2 experimental conditions (ie, ascending
`and fiat). The low initial serum concentration of the as(cid:173)
`cending condition produced smaller effect sizes in the
`morning (as expected), but the gradually increasing se(cid:173)
`rum concentrations of the ascending condition produced
`effect sizes in the afternoon that matched the effect size
`estimates for the BID condition, indicating that a bolus dose
`was unnecessary for full efficacy. The constant serum con(cid:173)
`centration of the flat condition resulted in the loss in the
`afternoon of about 40% of the average effect size ob(cid:173)
`served in the BID condition, indicating that a zero-order
`d rug delivery pattern did not maintain full efficacy and sug(cid:173)
`gesting acute tolerance to methylphenidate treatment.24
`
`PK/PD MODELING
`
`blockade of the dopamine transponer and increase in do(cid:173)
`pamine at the synapse). This is considered the basis for
`the observed effects at the behavioral level (eg, decrease
`in ADHD symptoms). We also assumed that acute toler(cid:173)
`ance would start to develop when methylphenidate reached
`the brain, and we designated a second theoretical concen(cid:173)
`tration at an antagonist site (Can t) to account for the ob(cid:173)
`served loss of efficacy over the day.
`This PK/PD model was used to predict profiles for 3
`plausible drug delivery patterns under consideration for
`delivery of methylphenidate by the OROS osmotic tech(cid:173)
`nology (hereafter referred to as "OROS-methylpheni(cid:173)
`date") (Figure 1 ) : a bolus pattern based on a TID regi(cid:173)
`men (10 mgat7:30and 11:30AM and3:30 PM) that would
`extend the duration of efficacy compared with the BID regi(cid:173)
`men; a flat pattern based on the prototype drug delivery
`profile for SR methylphenidate hydrochloride formula(cid:173)
`tions (8 mg at 7:30 AM, followed by small constant 1.25
`mg doses at 30-rninute intervals); and an ascending pat(cid:173)
`tern based on the concept of acute tolerance (8 mg at 7:30
`AM, followed by small and increasing doses of 1.3 to 2.6
`mg at 30-minute intervals). For the flat condition, the emer(cid:173)
`gence of acute tolerance was predicted to gradually re(cid:173)
`duce the constant agonist effect, producing the declining
`profile of the net effect ( Cer- Can tr). For the ascending con(cid:173)
`dition, the rate of increase in drug delivery was set to pro(cid:173)
`duce an ascending agonise effect to overcome the emerg(cid:173)
`ing antagonist effect, so the net effect ( Ce. - Cant,.) was
`predicted to remain constant over the day.
`Before embarking on an expensive technology de(cid:173)
`velopment program to modify the existing OROS tech(cid:173)
`nology to achieve the ascending drug delivery pattern, a
`proof-of-concept study was conducted to provide an em(cid:173)
`pirical Le.st of theoretical prediction that this PK profile
`would produce constant behavioral effects across the day.
`For the proof-of-product studies, the round OROS that pro(cid:173)
`vides a zero-order (fiat) delivery profile was modified to
`be a capsule with an overcoat of IR methylphenidate and
`a drug reservoir consisting of a bilayer of methylpheni(cid:173)
`date and a separate osmotic polymer, surrounded by a semi(cid:173)
`permeable membrane. When taken orally as the single
`administration in the morning, the overcoat of OROS(cid:173)
`methylphenidate was designed to deliver an initial bolus
`of IR methylphenidate to produce a rapid rise in serum
`concentrations of methylphenidate. When in contact with
`water in the gastrointestinal tract, the shape, the proper(cid:173)
`ties of the membrane, the osmotic polymer, and the drug
`reservoir were designed to create an osmotic pump to de(cid:173)
`liver methylphenidate at a first-order rate (ie, an ascend(cid:173)
`ing profile) for about 10 hours after administration. For
`the proof-of-product studies, 18-mg tablets of OROS(cid:173)
`methylphenidate were manufactured, using a 4-mg over(cid:173)
`coat and 14 mg in the drug reservoir. Multiple tablets were
`admin istered to achieve the higher (36-and 54-mg) doses.
`
`ln a 3-compartment PK/PD model, we made provisions
`for a lag due to gastrointestinal absorption time and the
`time for blood flow to distribute methylphenidate in plasma
`to the site of action in the brain. 25.26 We estimated the theo(cid:173)
`retical methylphenidate concentration at the effect site (Ce),
`which was assumed to produce a cascade of processes that
`result in the indirect agonist effect at the neural level (eg,
`
`METHODS
`
`Children aged 7 Lo 13 years, who met DSM-IV criteria for a di(cid:173)
`agnosis of ADHD and who were being treated with 5 Lo 15 mg
`of IR methylphenidate hydrochloride administered BID or TIO,
`were recruited and evaluated in protocols approved by the UCl
`investigational review board. Double-blind procedures were
`implemented by administration of methylphenidate or placebo
`
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`

`in capsules. Subjective ratings of Attention and Deporuuem from
`the SKAMP rating scale and Lheobjective performance scores on
`the mathematics test (Speed and Accuracy) were used as surro(cid:173)
`gate measures of efficacy. These measures were evaluated in an
`analysis of variance (ANOVA) model with within-subject (re(cid:173)
`peated measure) factors in a crossover design.
`Cohorts of children with ADHD were evaluated over mul(cid:173)
`tiple, nonconsecutive test days in the UC! Laboratory School. 21
`On the first day, the children were introduced to the staff and to
`each other, divided into 2 classes of 8 students based on age, and
`familiarized with Lhe facility and the laboratory school. On each
`of the test days, children had breakfast at home and arrived at
`the Child Development Center school around 7 AM. A !-hour cyde
`of activities was repeated across the test day (Table). Classroom
`behavior was evaluated during classroom probes, and after each
`of these sessions, teachers completed the classroom SKAMP rat(cid:173)
`ing scale. The subjective ratings of Attention and Deportment were
`specified as the primary outcome measures for onset and dura(cid:173)
`tion of efficacy. The computerized mathematics test was admin(cid:173)
`istered during key cycles, and objective Speed and Accuracy scores
`were specified as secondary outcome measures to complement
`the subjective ratings of behavior in the classroom.
`
`PART 1: PROOF OF CONCEPT
`
`Two cohorts of 16 children were recruited for this s tudy. Meth(cid:173)
`ylphenidate or placebo was given in capsules at 30-minute in(cid:173)
`tervals throughout the day, with the methylphenidate content
`of t he capsu Jes set to establish 2 drug conditions: standard (TlD)
`and experimental (ascending) regimens. In the TIO regimen, 3
`of the capsules (those administered at 7:30 and 11:30 AM and
`3:30 PM) contained equal doses of lR methylphenidate. The per(cid:173)
`administration dose was selected based on each subject's clini(cid:173)
`cally titrated morning dose rounded off to the nearest 5-mg dose
`(ie, 5, 10, or 15 mg), which resulted in a total daily dose of 15,
`30, or 45 mg. In the ascending regimen the first capsule (admin(cid:173)
`istered at 7:30 AM) contained 80% of each child's morning dose
`(ie, 4, 8, or 12 mg), the second capsule contained placebo, and
`subsequent capsules contained small but increasing doses of meth(cid:173)
`ylphenidate prescribed by PK/PD modeling to counteract acute
`tolerance. This accumulated to total daily doses of 18, 36, or 54
`mg, respectively. The PK/PD model predicted the profiles for the
`J theoretical concentrations (Ce, Cant, and Ce- Cant) that are
`shown in Figure l for the TlD and ascending dosing regimen.
`The time course of efficacy documented by surrogate measures
`in the UCI Laboratory School were expected to follow the time
`course of the net effects (Ce- Cant) in the PK/PD model.
`ln the ANO VA, a 3 X 5-factorial design was used with fixed(cid:173)
`effect factors of treatment (T!D, ascending, and placebo) and
`session (5 structured classroom sessions scheduled to co(cid:173)
`incide with the TID peaks and troughs expected to occur at 9
`and 11 AM and 1, 3, and 5 PM). Random effect factors for se(cid:173)
`quence (orders 1-6) and period (test days 1, 2, and 3) were in(cid:173)
`cluded to account for intersubject and intrasubject variaLions.
`
`PART 2: PROOF OF PRODUCT
`
`For the PK study, a cohort of 16 subjects was evaluated in
`a 3-way crossover study o f equivale nt doses of OROS(cid:173)
`methylphenidate and TID-methylphenidate administered in the
`fasting state and the OROS-methylphenidate dose administered
`with a high-fat breakfast. In the UC! Laboratory School proto(cid:173)
`col, a 1-hour cycle of acLivilies was repeated 10 limes (Table).
`Each cycle included provisions for a blood sample, a classroom
`session, or a recess period. Each subject's established clinical dose
`was used to detennine whether a subject received a low (5-mg
`TlD= lS mg/d), medium (10-mgTID=30 mg/d), or high (15-mg
`TIO= 4S mg/d) dosage oflR methylphenidate hydrochloride, and
`
`1---- Ce -
`
`Ce-cant
`
`--- - cant I
`
`0
`
`8
`
`-8+ - -~ -~ -~ -~ -~ -~ -~~
`
`[[]
`
`8
`
`-----
`
`ot4:--==-~=====~
`
`·,.
`
`-8+ - -~ -~ -~ -~ -~ -~ -~~
`
`,,,------------------
`
`,,, .... '
`
`.............. ..
`
`,----------
`------.
`,.,,"' 01"'"""'."""---------::-----
`
`-8+ - -~ -~ -~ -~ -~ -~ -~~
`10
`12
`16
`14
`0
`6
`8
`2
`Time, h
`
`Figure 1. Effect site (Ce), antagonist site (Cant), and net (Ce- Cant) profiles
`from pharmacokinetic-pharmacodynamic modeling for the following 3
`conditions: A, those receiving a regimen of immediate-release
`methylphenidate hydrochloride 3 times daily; B, those receiving a bolus that
`created a flat pattern based on the prototype drug delivery profile for
`sustained-release methylphenidate hydrochloride formulations (ie, 8 mg at
`7:30 AM, followed by small constant 1.25-mg doses at 30-minute intervals);
`and C, those receiving a bolus that created an ascending pattern based on
`the concept of acute tolerance (8 mg at 7:30 AM, followed by small and
`increasing doses from 1.3 to 2.6 mg at 30-minute intervals). See the
`"PK/PD Modeling" subsection of the introductory section for an
`explanation of the flat and ascending net effects.
`
`a conversion algorithm was used to set the corresponding OROS(cid:173)
`methylphenidate dosage (18, 36, or 54 mg.Id).
`For the PD study, 2 cohorts of 32 subjects were recruited
`for randomized, 3-way, crossover Lrial in which a double(cid:173)
`blind, double-dummy procedure was used to disguise the 3 treat(cid:173)
`ments (OROS-methylphenidate, TID-methylphenidate, and
`placebo). The treatments were established by contents of 2 cap(cid:173)
`sules administered at 7:30 AM and single capsules at 11:30 AM
`and 3:30 PM. The low, medium, or high methylphenidate dose
`
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`[Kl
`
`4
`
`"' Asttnding C0ndition
`• TIO-Treated Condition
`• Placebo-Treated Condition
`
`efficacy measure as the difference between the least squares mean
`of each active treatment and placebo divided by the estimate
`of intrapatient variation (root-mean-square error of the A NOVA
`mixed-effects model) . 28.29
`
`0
`
`9 AM
`
`11 AM
`
`3 PII
`1PM
`Primary Session nme, h
`
`5PII
`
`[fil 24
`
`~ .; 20
`~
`8.
`~ 16
`a:
`13
`
`I!' 8 12
`
`E
`0
`~ a: 8
`
`4
`
`8AM
`
`10AM
`
`12 PM
`nme. h
`
`2 PM
`
`4 PM
`
`Figure 2_ Results of the proof-of-concept study: the Attention and
`Periormance subscales of the Swanson, Kotkin, Agler, Mylnn, and Pelham
`(SKAMP)22 rating scale and the percentage of errors made on the
`computerized mathematics test.
`
`regimens were set based on each individual's clinical history.
`Each ueatment began on a Sunday and ended 1 week later.
`In the natural environment, effectiveness was measured with
`the Conners, Loney, and Milich ( CLAM) rating scale,20.21.27 which
`was completed by a parent and a teacher each Friday to summa(cid:173)
`rize the child's behavior at home and at school during the previ(cid:173)
`ous week. The 16-item ClAM rating scale includes the 5 Inat(cid:173)
`tention/Overactivity (1/0) items and 5 OppositionaVDeflance (0/0)
`items of the IOWA (Inattention and Overactivity With Aggres(cid:173)
`sion) Conners rating scale. Each item was rated on a 4-pointscale
`(1, not at all; 2, just a little; 3, pretty much; and 4, very much)
`and summary scores (sum of the VO items and sum of the 0/D
`items) were calculated for the 2 subscales. The 1/0 rating by the
`community schoolteacher was specified a priori as the primary
`outcome measure of this study. The Swanson, Nolan, and Pel(cid:173)
`ham (SNAP) rating scale19 was completed by the community
`schoolteacher and the parent at the end of each week. In addi(cid:173)
`tion to the effectiveness and efficacy measures, adverse effects were
`actively solicited and assessed and information about sleep, ap(cid:173)
`petite, and tics was collected using a parent questionnaire.
`On each Saturday, the cohort anended the UCI Labora(cid:173)
`tory School and followed the schedule shown in the Table. The
`laboratory schoolteacher completed the SKAMP rating scale af(cid:173)
`ter the multiple classroom sessions of each laboratory school
`day. Vital signs (blood pressure and pulse rate) were obtained
`after each classroom session.
`A mixed-effects ANOV A model was used for the analysis
`of the efficacy measurements. This A OVA model included the
`fixed-effect factors of treaunent, sequence, and period, and ran(cid:173)
`dom-effect interpatient and intrapatient factors. Paired com(cid:173)
`parisons were also performed betv..-een placebo and each of the
`active drug conditions, and between the 2 active drug condi(cid:173)
`tions. Effect sizes were calculated for each treatment for each
`
`RESULTS
`
`PART 1: PROOF OF CON CEPT
`
`Twenty-eight boys and 4 girls (aged , 7-12 years; mean
`age, 9.9 years) were enrolled in this study. At baseline,
`this group was taking an average initial methylpheni(cid:173)
`date h ydrochloride dose of 11.6 mg (0 .4 mg/kg) , an d the
`average absolute daily d ose was 28 .9 mg (0.9 mg/kg per
`day). Based on prestudy initial (morning) dose, each sub(cid:173)
`ject was assigned to a low 5-mg dose (n= 7), an interme(cid:173)
`diate 10-mg dose ( n=17), or a high 15-mg dose (n =8)
`condition. Two children left the study prematurely be(cid:173)
`cause of other personal commitments, so 30 of the 32
`children enrolled in this trial co mpleted all 3 treatments
`and were included in the analysis.
`The results are shown in Figure 2 A, where the av(cid:173)
`erage SKAMP attention ratings for each of the treat(cid:173)
`ments are presented fo r the 5 classroom sessions timed
`to coincide with the expected peaks and troughs of the
`TID condition. In the ANOVA, the main effect of treat(cid:173)
`ment was significant (F2.m= 125; P<.001). Paired com(cid:173)
`parisons revealed that teacher ratings of attention in both
`the TID and ascending conditions differed from placebo
`at each of the 5 time poin ts. An effect size (difference from
`the placebo divided by a pooled estimate of the SD from
`the AN OVA) was calculated for each classroom session.
`The overall (average) effect sizes were large ( > 1.5) for
`the TID and ascending conditions, which did not d iffer
`significantly in the specific comparisons of onset of ef(cid:173)
`ficacy (at the 9 AM session, 1 1/2 h ours after the morning
`TID dose) and duration of efficacy (at the 5 PM session,
`3 1/ 2 hours ;1fter the l;1st Tln dose).
`The average scores for accuracy of performance on
`the objective mathematics test are shown in Figure 2B.
`The youngest children could not solve th e 2-digit math(cid:173)
`ematics problems as they were presented on the com(cid:173)
`puter, so only 23 of the 31 subjects contributed data on
`this task. The main effect of condition was s ignificant in
`the ANOVA o f speed (F2518 =49.2, P<.001) and accu(cid:173)
`racy (F2_518=42.9 ; P< .001 ) . Paired comparison s re(cid:173)
`vealed that performance was s uperior in the TID and as(cid:173)
`cending conditions compared with performance in the
`placebo condition. Individual comparisons at each time
`point confirmed that the mathematics performance in the
`TID and ascending conditions was superior compared
`with the p lacebo condition after the 10 AM test and did
`not d iffer significantly from each other at any of the test
`times. ln comparison to placebo, the overall effect sizes
`were 0.9 for speed and 0.7 for accuracy in the TID con(cid:173)
`dition and 0 .9 for both speed and accuracy in th e as(cid:173)
`cending condition, which confirms the general pattern
`reflected by the subjective teacher ratings.
`T h e effects of treatment on blood pressure and
`heart rate were evaluated by the A OVA. Both the TID(cid:173)
`methylphenidate and experimental conditions produced
`small but statistically sign ificant (P<.05) increases simi-
`
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`18
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`0
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`D Parent or caregiver
`• Laboratory Scilool Teacher
`• Community Scilool Teacher
`
`• OROS·Methylphenidate Hydrocilloride
`High-rat Oreakfast (n = 15)
`• TID-Methytphenidate Fasting (n = 15)
`• OROS-Methylphenidate Fasting (n=15)
`
`6
`Time. h
`
`8
`
`10
`
`12
`
`Q.L.L-.....C..___;
`TID-Methylphenidate
`Hydrochtoride-Trea1ed
`Condition
`
`OROS·
`Methylphenidate-Treated
`Condition
`
`Placebo-Treated
`Condition
`
`Figure 3. The pharmacokinetic profiles from a 3-way crossover study of
`immediate release OROS-methyfphenidate hydrochloride administered with
`a (high-fat breakfast) and without (fasting) food. and TIO (3 times
`daily)-methylphenidate administered in the fasting state. OROS is a new oral
`once-a-day formulation to deliver methylphenidate by osmotic pump process
`based on OROS technology (ALZA Corp, Mountain View, Calif).
`
`Figure 4. IOWA (Inattention and Overactivity With Aggression) Conners
`rating scale from 3 sources (parent, University of California, Irvine,
`Laboratory School teacher. and community schoolteacher) in the
`proof-of-product study of the OROS-methylphenidate hydrochloride-treated
`condition, TIO (3 times daily)--methylphenidate-treated condition, and
`placebo-treated condition.
`
`lar to those seen with IR methylphenidate.16 Statistically
`significant drug effects on systolic blood pressure (3-4
`mm Hg), diastolic blood pressure (3-5 mm Hg), and
`heart rate (4-7/min) were observed at 9:30 AM and 1:30
`and 4:30 PM.
`On the adverse effects rating scale, teachers indi(cid:173)
`cated that some adverse effects (eg, irritability, motor tics,
`and buccolingual movements) decreased in the medica(cid:173)
`tion conditions relative to the placebo condition. These
`decreased ratings may seem incongruous with the label
`and concept of "adverse effect," but this pattern is con(cid:173)
`sistent with a double-blind titration trial of methylphe(cid:173)
`nidate effects in a large sample of more than 200 chil(cid:173)
`dren in the MTA. 20 The teachers noted appetite loss in
`more subjects in the medication conditions (TID, n=6;
`ascending, n= 7) than in the placebo condition ( n = 1);
`this was also consistent with the findings of the MTA ti(cid:173)
`tr.ition tri,il. The frequencies of parent reports of so(cid:173)
`matic complaints (primarily headaches or stomach(cid:173)
`aches) were similar in the TIO methylphenidate ( n=9),
`ascending (n=5) , and placebo (n=8) conditions.
`Parents described only 60% of children as having their
`usual evening food intake in both medication conditions,
`but this did not differ from placebo (59%). Parent ratings
`indicated good or excellent sleep quality for 90% of chil(cid:173)
`dren in the placebo condition, which did not differ from
`the TID and ascending conditions (both 87%). Sleep on(cid:173)
`set (as determined by an actigraph [MiniMotion Logger;
`Ambulatmy Monito1ing, Ardsley, NY), a motion detector
`worn on the wrist for the week of each condition) was de(cid:173)
`layed slightly in the medication conditions (ascending, 0.65
`h; TID, 0.55 h) compared with the placebo condition (0.11
`h), and these differences were statistically significant. A
`detailed accounting of the sleep assessment will be pre(cid:173)
`sented in a separate paper.
`
`PART 2: PK A D