Content uploaded by Nagahide Takahashi
Author content
All content in this area was uploaded by Nagahide Takahashi on Nov 07, 2015
Content may be subject to copyright.
ORIGINAL ARTICLE
A randomized, double-blind, placebo-controlled, parallel-group
study to evaluate the effi cacy and safety of osmotic-controlled
release oral delivery system methylphenidate HCl in adults
with attention-defi cit/hyperactivity disorder in Japan
NAGAHIDE TAKAHASHI
1 , TADAISHI KOH
2 , YUSHIN TOMINAGA
3 , YUKI SAITO
4 ,
YUJI KASHIMOTO
5 & TAKA MATSUMURA
6
1
Clinical Responsible Physician Department, Clinical Science Division, Janssen Pharmaceutical K.K, Tokyo, Japan,
2
Clinical Science Initiative Department, Clinical Science Division, Phar maceutical K.K, Tokyo, Japan,
3
Project Lead
Department, Project Development Division, Pharmaceutical K.K, Tokyo, Japan,
4
Biostatistics Department, Quantitavie
Science Division, Pharmaceutical K.K, Tokyo, Japan,
5
Tr ial Management Department, Japan Clinical Operations
Division, Pharmaceutical K.K, Tokyo, Japan, and
6
Clinical Science Division, Pharmaceutical K.K, Tokyo, Japan
Abstract
Objectives. To evaluate the safety and effi cacy of osmotic-controlled release oral delivery system (OROS) methylphenidate
(MPH) HCl in adults with attention-defi cit/hyperactivity disorder (ADHD). Methods. In this study, 284 adults with ADHD
were randomized to OROS MPH or placebo. During the 4-week titration period, patients were titrated from a starting
dose of 18 mg once daily to an individually-optimized dose of up to 72 mg once daily in weekly 18-mg increments. Patients
continued on their individualized dose during the 4-week effi cacy assessment period. The primary effi cacy endpoint was
change in DSM-IV Total ADHD Symptoms subscale score of Conners ’ Adult ADHD Rating Scale-Observer: Screening
Version (CAARS-O:SV) from baseline to endpoint. Results. The mean change in DSM-IV Total ADHD Symptoms subscale
score of CAARS-O:SV was signifi cantly larger with OROS MPH compared with placebo ( P ⬍ 0.0001, ANCOVA). Similar
results were observed for the majority of secondary endpoints, including CAARS-O:SV total score and other subscale
scores. Although treatment-emergent adverse events were reported more frequently in the OROS MPH group (81.8%)
versus the placebo group (53.9%), OROS-MPH showed a well-tolerated safety profi le overall. Conclusions. OROS MPH
in a dose range of 18 – 72 mg once daily was effective and well-tolerated in adult patients with ADHD.
Key words: attention defi cit disorder with hyperactivity , methylphenidate , randomized controlled trial , adult , Japan
Introduction
Attention-defi cit/hyperactivity disorder (ADHD) is
a psychiatric disorder characterized by hyperactive,
impulsive and inattentive behaviour . Although the
onset of ADHD symptoms typically occurs before
the age of 7 according to the Diagnostic And Statis-
tical Manual of Mental Disorders 4th Edition
(DSM-IV) criteria, it is now considered to be a
chronic condition that continues into adulthood in
up to 80% of patients (Takahashi et al. 2011a).
Adults with ADHD experience impairment of exec-
utive functioning, which interferes with their ability
to manage their daily lives, including meeting dead-
lines, staying focused on their work and organizing
their schedule (Baron et al. 2011). The consequences
may include educational underachievement, loss
of employment and diffi culty maintaining interper-
sonal relationships (Biederman et al. 2007; Baron
et al. 2011).
Stimulants, including methylphenidate (MPH)
HCl, are currently the preferred medication for
the fi rst-line treatment of adults with ADHD in
many countries around the world (Baron et al. 2011;
Wilens et al. 2011). Extended-release stimulants are
recommended over their immediate-release coun-
terparts in adult patients because the convenience
of once-daily dosing encourages treatment compli-
ance and the potential for abuse is decreased with
Correspondence: Nagahide Takahashi, MD, PhD, Clinical Responsible Physician Department, Clinical Science Division, Janssen
Pharmaceutical K.K, 5-2 Nishi-kana 3-chome, Chiyoda-ku, Tokyo 101-0065, Japan. Tel: ⫹ 81 3 4411 5509. Fax: ⫹ 81 3 4411 5086.
E-mail: ntakaha4@its.jnj.com
(Recei ved 10 May 2013; accep ted 18 November 2013)
The World Journal of Biological Psychiatry, 2014; Early Online: 1–11
ISSN 1562 -2975 print /ISSN 1814-1412 online © 2014 Infor ma Healt hcare
DOI : 10.3109/ 15622 975.2 013.8 68925
World J Biol Psychiatry Downloaded from informahealthcare.com by 201.210.105.125 on 05/20/14
For personal use only.
2 N. Takahashi et al.
were also required to have a DSM-IV Total ADHD
Symptoms subscale score of ⱖ 24 at baseline on the
investigator-rated Conners ’ Adult ADHD Rating
Scale-Observer: Screening Version (CAARS-O:SV)
(Conners et al. 1999).
Patients were excluded from the study if they were
a non-responder to MPH and/or had a history of
hypersensitivity or intolerance to MPH or had been
treated with MPH or any other medications for
ADHD within 4 weeks before the screening visit.
Investigators determined non-responders to MPH
using all available information, including medical
chart records and information from parents or guard-
ians of patients seeking enrolment in this trial. Other
exclusion criteria included diagnosis of bipolar I dis-
order, schizophrenia, schizoaffective disorder, severe
obsessive compulsive disorder, pervasive developmen-
tal disorder (e.g., autistic disorder or Asperger ’ s
disorder) or suicidality. Patients with confi rmed cancer
or other serious illnesses (e.g., hepatic or renal insuf-
fi ciency or signifi cant cardiac, gastrointestinal, psychi-
atric, or metabolic disturbances) were also excluded.
Study design
This was a randomized, double-blind, placebo-
controlled, parallel-group phase 3 clinical trial con-
ducted at 39 sites in Japan between 22 February
2011 and 19 April 2012 and consisting of three parts:
a screening period, a double-blind treatment period
and a post-study period. A schematic diagram of the
study design is shown in Figure 1. Initially, patients
underwent a screening period, which consisted of a
single visit 1 – 2 weeks before study agent administra-
tion. During this visit, patients gave their informed
consent and were screened for eligibility. The
screening period also allowed for washout of prohib-
ited medications in order to appropriately assess the
safety and effi cacy of OROS MPH. Up to 4 weeks
before study drug administration were allowed for
washout of medi cations used for the treatment of
ADHD (e.g., MPH and atomoxetine HCl).
The second part of the study was an 8-week dou-
ble-blind phase, which consisted of a 4-week titration
period followed by a 4-week effi cacy assessment
period. Eligible patients were randomized 1:1 to
receive once-daily OROS MPH or placebo in the
morning using a computer-generated randomization
schedule. During the titration period, patients
received a starting dose of OROS MPH 18 mg/day
or placebo for the fi rst week. Each of the following
weeks, the dose was incremented by 18 mg up to a
maximum dose of 72 mg/day until an individually
optimized dose was achieved. Titration continued
until one of the following occurred: either the patient ’ s
DSM-IV Total ADHD Symptoms score of the
extended-release formulations (Biederman et al.
2007; Buitelaar et al. 2009; Baron et al. 2011).
Although the non-stimulant atomoxetine was rec-
ently approved for the treatment of adults with
ADHD in Japan, there is currently no stimulant
approved for the treatment of this patient popula-
tion (Takahashi et al. 2011a; Pharmaceuticals and
Medical Devices Agency 2012). Because of the
growing consensus supporting the use of stimulants
to treat adults with ADHD, the lack of an approved
stimulant for adult ADHD in Japan represents an
unmet medical need.
Osmotic-controlled release oral delivery system
(OROS) MPH HCl extended-release tablets (Con-
certa 2007) are a long-acting preparation of MPH
designed to take effect within 1.5 h and maintain
effectiveness for 12 h after administration (Johnson
& Johnson Pharmaceutical Research & Development
2011). OROS MPH has been shown to be a safe and
effective treatment for ADHD in children and adults
in studies conducted in many countries and areas
around the world (Pelham et al. 2001; Medori et al.
2008). In October 2007, OROS MPH became the
fi rst drug to receive approval in Japan for the
treatment of ADHD; however, its use is currently
restricted to adolescents and children under 18 years
of age and continuous treatment in adults who began
taking OROS MPH before the age of 18 (Takeda
2009). This is a concern because many patients with
ADHD are not diagnosed until adulthood, often
presenting for treatment due to the presence of
comorbid psychiatric conditions, such as anxiety or
depression (Baron et al. 2011). Therefore, there is an
urgent need to evaluate stimulant medications, such
as OROS MPH, in adult patients with ADHD in
Japan so that more treatment options may become
available for this patient population.
This study evaluated the safety and effi cacy of
OROS MPH titrated to a daily dose of 18 to 72 mg
in adults with ADHD.
Methods
Patients
Eligible patients were men and women between 18
and 64 years of age, who met the DSM-IV Text Revi-
sion (DSM-IV-TR) criteria for ADHD (American
Psychiatric Association 2000) both at present and in
childhood (onset of symptoms before the age of
7 years according to DSM-IV-TR criteria) based on
Conners ’ Adult ADHD Diagnostic Interview for
DSM-IV (CAADID) Japanese version at screening.
The CAADID assesses patients based on the 18
symptoms criteria for ADHD contained in the
DSM-IV. To be enrolled in this study, patients
World J Biol Psychiatry Downloaded from informahealthcare.com by 201.210.105.125 on 05/20/14
For personal use only.
OROS MPH in adults with ADHD in Japan 3
Effi cacy evaluation
The primary and secondary analysis populations
included the full analysis set, defi ned as patients who
received at least one dose of study drug and had base-
line and at least one post-dose effi cacy assessment.
The Japanese version of the CAARS-O:SV and
the Conners ’ Adult ADHD Rating Scale-Self:
Screening Version (CAARS-S:SV) were used in this
study (Takahashi et al. 2011b). The CAARS-O:
SV consists of 30 investigator-rated items to measure
symptoms of ADHD in adult patients. Items are
rated on a scale of 0 (not at all) to 3 (very much/very
frequently). The CAARS-O:SV has four subscales:
the DSM-IV Total ADHD Symptoms subscale (18
items), the DSM-IV Inattentive Symptoms subscale
(nine items), the DSM-IV Hyperactive-Impulsive
Symptoms subscale (nine items) and the ADHD
Index (12 items). The CAARS-O:SV also provides a
total score. The CAARS-S:SV has the same struc-
ture as the observer version, but it is based on patient
self-report. For both the CAARS-O:SV and the
CAARS-S:SV, a lower score indicates improvement.
For standardization of the results, all investigators
who administered the CAARS and CAADID were
trained and certifi ed in these assessments before the
study. In addition, the same investigator adminis-
tered the assessments to a specifi c patient at all visits
whenever possible.
Effi cacy was also assessed using the Clinical Global
Impression – Severity (CGI-S) and CGI-C rating
scales. The CGI-S was used to rate the severity of
CAARS-O:SV decreased by 30% from baseline and
the patient received a Clinical Global Impression – -
Change (CGI-C) rating of 1 (very much improved)
or 2 (much improved), or the maximum dose of 72
mg/day was reached. Once an individually optimized
dose had been achieved, patients remained on that
dose until the end of the titration period. If necessary
for safety reasons, the dose could be decreased by
18 mg once during the titration period. Once the
patient ’ s dose was decreased, it could not be subse-
quently increased. During the effi cacy assessment
period, patients continued on their individualized
dose of OROS MPH or matching placebo for the
remainder of the double-blind treatment period.
The fi nal part of the study, the post-study phase,
consisted of a single follow-up visit 1 week after the
patient ’ s fi nal dose of study agent. During the post-
study visit, additional safety data were collected, and
patients were assessed for possible symptoms of
withdrawal.
Ethical considerations
The study protocol and amendments were reviewed
by an institutional review board, and the study was
conducted in accordance with the ethical principles
of the Declaration of Helsinki, Good Clinical Prac-
tice (GCP), and applicable regulatory requirements.
The study is registered at ClinicalTrials.gov
(NCT01323192). All patients provided their written
consent to participate in the study.
Double-blind phase (8 weeks)
Efficacy assessment
period (4 weeks)
Titration period (4 weeks)
Screening
phase
Post-study
phase
OROS MPH treatment
Placebo treatment
Washout,
eligibility
For all
patients
who
received
the study
treatment
Patients
completed
the study
Baseline entry,
randomization
Informed
consent
49-week open
label long-term
extension study
Visit
Week
Day
1
-2/-1
-14/-7
8
8
56
9
9
+7
7
6
42
6
4
28
5
3
21
2
-
0
4
2
14
3
1
7
18 mg
36 mg
18 mg
54 mg
36 mg
18 mg
72 mg
54 mg
36 mg
18 mg
Individualized
dose
Figure 1. Study design. OROS, osmotic-controlled release oral delivery system; MPH, methylphenidate.
World J Biol Psychiatry Downloaded from informahealthcare.com by 201.210.105.125 on 05/20/14
For personal use only.
4 N. Takahashi et al.
completed suicide; if the same patient experienced
multiple events, all events were used for analysis. The
C-SSRS was administered at baseline, Week 2, Week
4, Week 6, the end of the double-blind phase (Week
8) and the post-study visit.
Sample size determination
The calculation of sample size was based on results
from a completed international Phase 3 study
(Medori et al. 2008). The mean (SD) change from
baseline to endpoint in the DSM-IV Total ADHD
Symptoms subscale (18 items) of the investigator-
rated CAARS-O:SV in the placebo, OROS MPH 18
mg/day, OROS MPH 36 mg/day and OROS MPH
72 mg/day groups was – 7.6 (9.93), – 10.6 (10.34),
– 11.5 (9.97) and – 13.7 (11.11), respectively (Medori
et al. 2008). The mean difference between the pla-
cebo group and each active dose group (18, 36 and
72 mg) was 3.0, 3.9 and 6.1, respectively (Medori
et al. 2008). Based on these results, assuming a mean
difference between the OROS MPH group and the
placebo group of 4.0 and a standard deviation of
each treatment group of 10.0, the required number
of patients for analysis in this study was 133 per
treatment group to achieve a power of 90%. Assum-
ing that approximately 5% of enrolled patients would
be excluded from analyses, a total of 280 patients
(140 patients per treatment group) were planned to
be enrolled to ensure at least 133 evaluable patients
per treatment group.
Randomization and blinding
Patients were randomly assigned to receive OROS
MPH or placebo based on a computer-generated
randomization schedule prepared before the study
by the sponsor or under the supervision of the spon-
sor. The randomization was balanced by using ran-
domly permuted blocks of treatment and was
stratifi ed by study centre. Study drug code numbers
were preprinted on the study drug labels and were
assigned to patients as they qualifi ed for the study
and were randomly assigned to treatment.
To maintain the study blind, the study drug con-
tainer had a multipart label containing the protocol
number, medication kit number, code number and
other information on each part. It was impossible to
identify the study drug by using the label informa-
tion. The study drugs were identical in appearance
and were packaged in identical containers. Data that
may potentially unblind the treatment assignment
(e.g., study agent serum concentrations) were to be
handled with special care to ensure that the integrity
of the blind was maintained and the potential for
the patient ’ s illness on a seven-point scale ranging
from 1 (not ill) to 7 (extremely ill). The CGI-C was
used to rate the patient ’ s total improvement due to
treatment with the study agent on a seven-point scale
ranging from 1 (very much improved) to 7 (very
much worse). A lower score on the CGI-S or CGI-C
rating scales indicates improvement. The Quality
of Life Enjoyment and Satisfaction Questionnaire
Short Form (Q-LES-Q-SF) was used to assess the
degree of enjoyment and satisfaction experienced
by patients in various areas of daily functioning,
including physical health, feelings, work, household
duties, leisure time activities and social relations.
The Q-LES-Q-SF is a self-administered question-
naire that consists of 16 items rated on a scale from
1 (very poor) to 5 (very good). A higher total score
on the Q-LES-Q-SF indicates improvement.
The primary effi cacy endpoint was the change
in DSM-IV Total ADHD Symptoms subscale scores
from baseline to the end of the double-blind treat-
ment period. Secondary effi cacy endpoints included
the change in CAARS-O:SV total score and subscale
scores (other than the DSM-IV Total ADHD Symp-
toms subscale) and the change in CAARS-S:SV total
score and subscale scores. CGI-S score, CGI-C
score and Q-LES-Q-SF total score were also included
as secondary effi cacy endpoints.
Safety evaluation
Treatment-emergent adverse events (TEAEs) were
recorded for the safety analyses, which also included
clinical laboratory test results, vital sign measure-
ments, electrocardiogram (ECG) parameters and
body weight. The safety analysis population was
defi ned as all patients who received at least one dose
of study drug.
To assess the potential for abuse of study drug, a
six-item questionnaire was administered at the post-
study visit (Week 9). Patients were asked to choose
the most appropriate answer to questions asking
about their experiences in obtaining, taking and run-
ning out/not taking study drug, as well as the con-
sistency between prescribed and actual dose of drug
taken.
As suicide risk has not yet been evaluated in adults
with ADHD receiving OROS MPH, patients in this
study were also administered the Columbia-Suicide
Severity Rating Scale (C-SSRS) to evaluate suicidal
tendency. The C-SSRS contains two categories –
suicidal ideation and suicidal behaviour. Suicidal
ideation responses are scaled from 1 to 5, with a
higher number indicating a high degree of severity,
while suicidal behaviour was classifi ed as actual
attempt, interrupted attempt, aborted attempt, pre-
paratory acts or behaviour, suicidal behaviour, or
World J Biol Psychiatry Downloaded from informahealthcare.com by 201.210.105.125 on 05/20/14
For personal use only.
OROS MPH in adults with ADHD in Japan 5
CGI-C scores. For missing data in the effi cacy anal-
yses, the last observation carried forward (LOCF)
method was used. All statistical tests were performed
at the 5% level of signifi cance (two-sided). For cal-
culation of confi dence intervals (CIs), two-tailed
95% CIs were used. No adjustments were made for
multiple comparisons.
Results
Of the 306 patients who provided informed consent,
284 patients were randomized to treatment and
were included in the safety analysis population, and
283 patients were included in the full analysis set
(Figure 2). One patient in the placebo group was
excluded from the full analysis set because no post-
dose effi cacy data were available for this patient. The
demographic and baseline characteristics were well-
balanced between treatment groups (OROS MPH
group, n ⫽ 143; placebo group, n ⫽ 141; Table I). Of
the randomized patients, 134 (93.7%) patients in
the OROS MPH group and 135 (95.7%) patients
in the placebo group completed the double-blind
treatment period. Within 3 months prior to screen-
ing, 14.7% of patients in the OROS MPH group
and 12.1% of patients in the placebo group received
one or more psychotropic agents for ADHD.
The mean duration of exposure to study drug was
54.0 days in the OROS MPH group and 55.1 days
bias was minimized. This could include making
special provisions, such as segregating the data in
question from view by the investigators, clinical
team, or others as appropriate until the time of data-
base lock and unblinding.
Statistical analyses
An analysis of covariance (ANCOVA) model using
treatment and sex as factors and baseline score as a
covariate was used to assess the change from base-
line in CAARS-O:SV, CAARS-S:SV and Q-LES-
Q-SF scores. For the change from baseline in
DSM-IV Total ADHD Symptoms subscale score,
subgroup analyses were performed by the same
ANCOVA model used for the primary analysis, and
using the following factors: age at ADHD diagnosis,
type of ADHD at entry, current psychiatric comor-
bidity, history of or current psychiatric comorbidity,
age at informed consent, sex, body mass index
(BMI) at baseline, exposure to MPH during the
3-month period before screening, fi nal dose of study
drug and baseline DSM-IV Total ADHD Symptoms
subscale score of the CAARS-O:SV. CGI-S score
was analysed using an ANCOVA model on the ranks
of change from baseline with treatment as a factor
and baseline score as a covariate. An analysis of vari-
ance (ANOVA) model on the ranks of actual values
with treatment as a factor was used to evaluate
Screened patients
N = 306
Randomized patients
N = 284
Placebo
n = 141
Completed
n = 134
Completed
n = 135
Discontinued n = 9
AE, n = 6
Withdrawal
of consent, n = 3
Discontinued n = 6
AE, n = 1
Noncompliance with
study drug, n = 3
Nonmedical
reasons, n = 1
Withdrawal
of consent, n = 1
OROS MPH
n = 143
Figure 2. Disposition of study patients. OROS, osmotic-controlled release oral delivery system; MPH, methylphenidate; AE, adverse
event.
World J Biol Psychiatry Downloaded from informahealthcare.com by 201.210.105.125 on 05/20/14
For personal use only.
6 N. Takahashi et al.
effi cacy endpoint, none of the examined factors
appeared to affect the treatment effect of OROS
MPH relative to placebo (data not shown).
The mean changes from baseline to the end of the
double-blind period were signifi cantly larger in
the OROS MPH group than in the placebo group
for the CAARS-O:SV total score ( P ⫽ 0.0002) and
subscale scores (Inattentive Symptoms, P ⬍ 0.0001;
Hyperactive-impulsive Symptoms, P ⫽ 0.0053; ADHD
Index, P ⫽ 0.0030; Table II). The mean changes
from baseline were also signifi cantly larger in the
OROS MPH group than in the placebo group for
the CAARS-S:SV total score ( P ⫽ 0.0003) and sub-
scale scores (Total ADHD Symptoms, P ⫽ 0.0003;
Inattentive Symptoms, P ⬍ 0.0001; Hyperactive-
impulsive Symptoms, P ⫽ 0.0471; ADHD Index,
P ⫽ 0.0006; Table II).
The improvement in CGI-S score and CGI-C
score was signifi cantly greater in the OROS MPH
group than in the placebo group ( P ⬍ 0.0001; Table
II). The frequency distribution of CGI-S and
CGI-C scores over time are shown in Figure 4. For
both CGI-S and CGI-C scores, a greater percent-
age of patients in the OROS MPH group experi-
enced improvement compared with the placebo
group. The percentage of patients assessed as “ mod-
erately ill ” or worse on the CGI-S scale decreased
from 97.2% at baseline to 43.4% at endpoint in
the OROS MPH group and from 92.9 to 62.1%
in the placebo group. At endpoint, the percentage
in the placebo group. The majority of patients
( ⱖ 93%) in both groups received the study drug for
at least 50 days. The mean dose and mean fi nal dose
of study drug was 44.2 and 51.5 mg, respectively, in
the OROS MPH group and 50.7 and 61.1 mg,
respectively, in the placebo group. At Week 8 (the
end of the double-blind period), 42.5% of patients
in the OROS MPH group and 72.1% of patients in
the placebo group received the maximum dose of
72 mg/day. The remaining patients in the OROS
MPH group received 18 mg/day (11.9%), 36 mg/day
(26.9%), or 54 mg/day (18.7%) at Week 8.
The baseline mean (SD) DSM-IV Total ADHD
Symptoms subscale score of the CAARS-O:SV was
similar between groups: 31.8 (5.96) for the OROS
MPH group versus 31.5 (6.44) for the placebo
group. The least-squares mean change in the DSM-IV
Total ADHD Symptoms subscale score of the
CAARS-O:SV from baseline to the end of the
double-blind period was – 12.5 (95% CI, – 14.0 to
– 11.0) in the OROS MPH group and –
7.9 (95% CI,
– 9.5 to ⫺ 6.4) in the placebo group (Table II). The
decrease (improvement) was signifi cantly larger in
the OROS MPH group ( P ⬍ 0.0001). A statistically
signifi cant difference between the OROS MPH and
placebo groups with regard to the mean change from
baseline in the Total ADHD Symptoms score of the
CAARS-O:SV was initially observed at Week 2;
this difference was maintained in subsequent weeks
(Figure 3). In the subgroup analyses of the primary
Table I. Demographic and baseline characteristics (safety analysis population).
Characteristic
OROS MPH
( n ⫽ 143)
Placebo
( n ⫽ 141)
Age, years
Mean (SD) 33.4 (8.85) 34.1 (9.05)
Range 18 – 58 19 – 59
Gender, n (%)
Male 71 (49.7) 68 (48.2)
Female 72 (50.3) 73 (51.8)
Age at initial ADHD diagnosis, years
Mean (SD) 31.4 (9.81) 32.4 (9.98)
Range 5 – 58 1 – 58
Type of ADHD at study entry, n (%)
Predominantly inattentive 80 (55.9) 79 (56.0)
Predominantly hyperactive-impulsive 1 (0.7) 1 (0.7)
Combined type 62 (43.4) 61 (43.3)
Type of ADHD in childhood, n (%)
Predominantly inattentive 77 (53.8) 78 (55.3)
Predominantly hyperactive-impulsive 1 (0.7) 0 (0)
Combined type 65 (45.5) 63 (44.7)
Baseline DSM-IV Total ADHD
Symptoms score of CAARS-O:SV
Mean (SD) 31.8 (5.96) 31.5 (6.42)
OROS, osmotic-controlled release oral delivery system; MPH, methylphenidate; SD, standard deviation;
ADHD, attention-defi cit/hyperactivity disorder; DSM-IV, Diagnostic And Statistical Manual of Mental
Disorders 4th Edition; CAARS-O:SV, Conners ’ Adult ADHD Rating Scale-Observer: Screening
Version.
World J Biol Psychiatry Downloaded from informahealthcare.com by 201.210.105.125 on 05/20/14
For personal use only.
OROS MPH in adults with ADHD in Japan 7
a ⱖ 5% higher incidence in the OROS MPH group
than in the placebo group.
There were two serious TEAEs (psychotic disor-
der and pneumothorax spontaneous tension, n ⫽ 1
for each) reported in the OROS MPH group. The
relationship between the study drug and psychotic
disorder was considered probable, while pneumotho-
rax spontaneous tension was considered by the inves-
tigator to be unrelated to the study drug. There were
no serious TEAEs in the placebo group. No deaths
were reported in this study. Discontinuation of study
drug due to one or more TEAEs was reported in 6
(4.2%) patients in the OROS MPH group and one
(0.7%) patient in the placebo group.
During the post-study period, 13 (9.1%) patients
in the OROS MPH group and fi ve (3.5%) patients
in the placebo group experienced at least one AE.
The only AE that was reported by more than one
patient in the OROS MPH group during the post-
study period was nasopharyngitis ( n ⫽ 3).
of patients assessed as “ much improved ” or “ very
much improved ” on the CGI-C scale was 48.3% in
the OROS MPH group and 27.9% in the placebo
group. Based on Q-LES-Q-SF total scores, there
was no signifi cant difference in daily functioning
between the OROS MPH group and the placebo
group (Table II).
The overall incidence of TEAEs was higher in the
OROS MPH group (117/143; 81.8%) than in the
placebo group (76/141; 53.9%). TEAEs occurring
in ⱖ 5% of patients in either treatment group during
the double-blind period are shown in Figure 5. The
most commonly reported TEAEs in the OROS MPH
group ( ⱖ 5% of patients) were decreased appetite
(39.9%), palpitations (18.2%), nasopharyngitis
(16.8%), nausea (14.7%), thirst (14.0%), insomnia
(10.5%), headache (8.4%), weight decrease (7.0%)
and tachycardia (5.6%). Among the commonly
reported TEAEs, decreased appetite, palpitations,
nausea, thirst, weight decrease and tachycardia had
Table II. Change from baseline to end of double-blind period (LOCF) for effi cacy analyses.
Effi cacy measure OROS MPH ( n ⫽ 143) Placebo ( n ⫽ 140) P value
CAARS-O:SV
DSM-IV Total ADHD Symptoms
LS means (95% CI) change ⫺ 12.5 ( ⫺ 14.0 to ⫺ 11.0) ⫺ 7.9 ( ⫺ 9.5 to ⫺ 6.4) ⬍ 0.0001
Total score
Mean (SD) change ⫺ 19.5 (15.42) ⫺ 12.5 (15.87) 0.0002
Inattentive Symptoms
Mean (SD) change ⫺ 8.0 (6.26) ⫺ 5.0 (5.93) ⬍ 0.0001
Hyperactive-impulsive Symptoms
Mean (SD) change ⫺ 4.5 (4.51) ⫺ 2.9 (4.84) 0.0053
ADHD Index
Mean (SD) change ⫺ 7.0 (6.99) ⫺ 4.6 (6.95) 0.0030
CAARS-S:SV
DSM-IV Total ADHD Symptoms
Mean (SD) change ⫺ 10.7 (9.85)
a ⫺ 6.6 (10.06) 0.0003
Total score
Mean (SD) change ⫺ 18.0 (16.45)
a ⫺ 10.9 (16.55) 0.0003
Inattentive Symptoms
Mean (SD) change ⫺ 6.5 (6.35)
a ⫺ 3.4 (5.99) ⬍ 0.0001
Hyperactive-impulsive Symptoms
Mean (SD) change ⫺ 4.2 (4.73)
a ⫺ 3.2 (5.02) 0.0471
ADHD Index
Mean (SD) change ⫺ 7.3 (7.24)
a ⫺ 4.3 (6.69) 0.0006
CGI-S
Median (range) change ⫺ 1.0 ( ⫺ 5 to 1) ⫺ 1.0 ( ⫺ 4 to 2) ⬍ 0.0001
CGI-C
Median (range) change 3 (1 to 6) 3 (1 to 6) ⬍ 0.0001
Q-LES-Q-SF
Mean (SD) change 2.4 (14.00)
b 0.8 (12.69) 0.4041
LOCF, last observation carried forward; OROS, osmotic-controlled release oral delivery system; MPH,
methylphenidate; CAARS-O:SV, Conners ’ Adult ADHD Rating Scale-Observer: Screening Version;
DSM-IV, Diagnostic And Statistical Manual of Mental Disorders 4th Edition; ADHD, attention-defi cit/
hyperactivity disorder; LS, least squares; CI, confi dence interval; SD, standard deviation; CAARS-S:SV,
Conners ’ Adult ADHD Rating Scale-Self: Screening Version; CGI-S, Clinical Global Impression – Severity;
CGI-C, Clinical Global Impression – Change; Q-LES-Q-SF, Quality of Life Enjoyment and Satisfaction
Questionnaire Short Form.
a n ⫽ 141.
b n ⫽ 142.
World J Biol Psychiatry Downloaded from informahealthcare.com by 201.210.105.125 on 05/20/14
For personal use only.
8 N. Takahashi et al.
in Japan. OROS MPH was effective and well-
tolerated in adults, consistent with previous studies
in other adult patient populations (Biederman et al.
2007; Medori et al. 2008). Based on analysis of the
primary endpoint, OROS MPH was statistically
superior to placebo. The superiority of OROS MPH
in reducing ADHD symptoms was initially observed
at Week 2 and continued throughout the remainder
of the double-blind period. Subgroup analyses of
the primary endpoint confi rmed that no specifi c fac-
tor, such as age at ADHD diagnosis, type of ADHD
at entry, or baseline DSM-IV Total ADHD Symp-
toms subscale score of the CAARS-O:SV, affected
responsiveness to OROS MPH in this patient popu-
lation. The results of the majority of the secondary
endpoints consistently demonstrated the superiority
of OROS MPH over placebo except Q-LES-Q-SF.
Because ADHD was originally considered to only
affect children and adolescents, there have been
many more studies of this condition in these patient
populations than in adults (Asherson et al. 2007).
Therefore, the validity of the diagnosis of ADHD
in adults is still questioned by some clinicians and
researchers (Medori et al. 2008). More recently,
awareness of adult ADHD has increased due
to mounting evidence supporting the persistence
of symptoms into adulthood (Kooij et al. 2005;
Buitelaar et al. 2009). In addition, treatment with
No AEs related to drug abuse or misuse were
reported during the double-blind or post-study period.
Additionally, a minority of patients indicated that they
wanted to take more than the prescribed dose ( n ⫽ 9
in the OROS MPH group and n ⫽ 8 in the placebo
group) or to continue taking study drug for any rea-
son other than drug effi cacy ( n ⫽ 5 in the OROS
MPH group and none in the placebo group).
In general, no clinically signifi cant trend in vital
signs, body weight, clinical laboratory test values, or
ECG parameters was observed in either group.
However, 10 patients in the OROS MPH group
experienced weight decrease compared with no
patients in the placebo group.
At any time during double-blind phase, nine
(6.3%) patients in the OROS MPH and nine (6.4%)
patients in the placebo group answered “ yes ” to at
least one of fi ve questions asking about suicidal ide-
ation. One patient in the placebo group answered
“ yes ” to two of six questions asking about suicidal
behaviour, while no patient in the OROS MPH
group answered “ yes ” to these questions.
Discussion
This study was designed to evaluate the effi cacy and
safety of OROS MPH in adult patients with ADHD
–20
–15
–10
–5
0
5
Endpoint864321Baseline
Change from baseline (mean ± SE)
Number of patients
OROS MPH
Placebo
P value
143
140
142
140
0.0796
142
140
0.0131
143
140
0.0014
143
140
0.0007
143
140
0.0001
143
140
<0.0001
143
140
<0.0001
PlaceboOROS MPH
Week
Figure 3. Mean change from baseline in DSM-IV Total ADHD Symptoms score of CAARS-O:SV over time. DSM-IV, Diagnostic And
Statistical Manual of Mental Disorders 4th Edition; ADHD, attention-defi cit/hyperactivity disorder; CAARS-O:SV, Conners ’ Adult
ADHD Rating Scale-Observer: Screening Version; OROS, osmotic-controlled release oral delivery system; MPH, methylphenidate;
SE, standard error.
World J Biol Psychiatry Downloaded from informahealthcare.com by 201.210.105.125 on 05/20/14
For personal use only.
OROS MPH in adults with ADHD in Japan 9
EndpointWeek 8Week 4BaselineEndpointWeek 8Week 4Baseline
Patients (%)
Not ill/borderline ill
PlaceboOROS MPH
0
20
40
60
80
100
Mildly ill Moderately ill
Markedly ill Severely ill/extremely ill
EndpointWeek 8Week 4EndpointWeek 8Week 4
Patients (%)
Very much improved
PlaceboOROS MPH
0
20
40
60
80
100
Much improved Minimally improved
No change Minimally worse/much worse/very much worse
(A)
(B)
Figure 4. Frequency distribution of (A) CGI-S and (B) CGI-C scores over time. CGI-S, Clinical Global Impression – Severity; CGI-C,
Clinical Global Impression – Change; OROS, osmotic-controlled release oral delivery system; MPH, methylphenidate.
medication has been shown to reduce ADHD symp-
toms in adults with similar effi cacy to that seen
in children (Asherson et al. 2007; Medori et al.
2008). In this study, adult patients were screened
for inclusion using the Japanese version of the
CAADID to confi rm the diagnosis of ADHD. The
psychometric properties of the original English
version of this structured interview have been eval-
uated and have been found to be adequate for the
diagnosis of ADHD in adult patients (Epstein and
Kollins 2006). Additionally, the Japanese version
has been validated from the English version (Takahashi
et al. 2011b). A confi rmed diagnosis of ADHD
based on the CAADID is widely used as a criterion
for inclusion in clinical trials in adult patient popu-
lations (Medori et al. 2008; Buitelaar et al. 2011;
Takahashi et al. 2011a).
While treatment with OROS MPH resulted in
statistically signifi cant improvements in ADHD
symptoms relative to placebo, a smaller reduction in
ADHD symptoms was observed in the placebo
group. The placebo effect that was observed in this
study is consistent with previous studies that evalu-
ated OROS MPH in other adult patient populations
(Biederman et al. 2007; Medori et al. 2008; Buitelaar
et al. 2009, 2011). One possible explanation for the
placebo effect observed in this study is that there
may have been an apparent benefi t for patients to
World J Biol Psychiatry Downloaded from informahealthcare.com by 201.210.105.125 on 05/20/14
For personal use only.
10 N. Takahashi et al.
reported in 18.2% of patients in this study. The low
risk of suicide of OROS MPH was also confi rmed.
The potential for abuse continues to be a major
concern for regulatory authorities in Japan regarding
the use of stimulants for the treatment of adult
patients with ADHD (Takahashi et al. 2011a). In
comparison with immediate-release formulations of
MPH, extended-release OROS MPH has been
shown to have a lower risk of misuse (Biederman
et al. 2007; Buitelaar et al. 2009). The results of this
study support the low abuse potential of OROS
MPH. During the double-blind and post-study peri-
ods, there were no AEs related to drug abuse or mis-
use reported. Data from a questionnaire support this
notion. In addition, only one AE (nasopharyngitis)
was reported by more than one patient in the OROS
MPH group during the post-study period. This sug-
gests that after discontinuation of treatment with
OROS MPH, there were no dominant AEs that
would be indicative of a withdrawal phenomenon.
This will be further confi rmed in a 49-week open
label long-term extension study in which patients
who completed this study were eligible to enroll.
A limitation of this study was the short treatment
period (8 weeks); additional studies will be needed
to evaluate the long-term effi cacy and safety of
OROS MPH in adults. A longer study period could
assess whether the short-term effects observed in
this study are maintained over the course of long-
term treatment. Additionally, it is possible that
a signifi cant improvement in Q-LES-Q-SF score
in the OROS MPH group compared with the pla-
cebo group may have emerged if the study had been
enrol in the study, including those who were ran-
domized to the placebo group. Although initiation of
new psychosocial treatment for patients was restricted
during the observation period, all patients in the
study could obtain medical advice and education
about their illness from the investigators.
There are several possible reasons for the low
dropout rate that was observed in this study. First,
MPH had been approved for the treatment of chil-
dren with ADHD in Japan, but there was no medica-
tion approved for adults with ADHD at the time of
the study. Because of this situation, it could be con-
sidered that the motivation for patients to continue
participation in this study was very high. Second,
there was a dose titration period in this trial, which
may have decreased the rate of dropout due to lack
of effi cacy or AEs. Third, only patients who com-
pleted this initial study were eligible for enrolment
in the open label long-term extension study.
The results of this study support the safety of
OROS MPH for use in adult patients. Among the
commonly reported TEAEs, several were observed
more frequently with OROS MPH than placebo,
including decreased appetite, palpitations and weight
decrease. These were expected, mild to moderate
in severity, and did not generally lead to treatment
discontinuation. Additionally, with the exception of
palpitations, these AEs were similar to those observed
in studies that have been conducted in other adult
patient populations (Medori et al. 2008). In a study
conducted in Europe, the incidence of palpitations
was 3.9% among patients treated with OROS MPH
(Medori et al. 2008). In contrast, palpitations were
0 5 10 15 20 25 30 35 40 45 50
Weight decrease
Thirst
Nausea
Tachycardia
Palpitations
Headache
Insomnia
Decreased appetite
Nasopharyngitis 16.8%
39.9%
10.5%
8.4%
18.2%
0%
5.6%
14.7%
14.0%
7.0%
13.5%
7.1%
9.9%
6.4%
1.4%
2.8%
4.3%
0%
PlaceboOROS MPH
Patients (%)
Figure 5. TEAEs occurring in ⱖ 5% of patients in either treatment group during the double-blind period. TEAE, treatment-emergent
adverse event; OROS, osmotic-controlled release oral delivery system; MPH, methylphenidate.
World J Biol Psychiatry Downloaded from informahealthcare.com by 201.210.105.125 on 05/20/14
For personal use only.
OROS MPH in adults with ADHD in Japan 11
Asherson P , Chen W , Craddock B , Taylor E . 2007 . Adult atten-
tion-defi cit hyperactivity disorder: recognition and treatment in
general adult psychiatry . Br J Psychiatry 190 : 4 – 5 .
Baron DA , Pato MT , Cyr RL . 2011 . Treatment of adults with
attention-defi cit/hyperactivity disorder . J Am Osteopath Assoc
111 : 610 – 614 .
Biederman J , Mick EO , Surman C , Doyle R , Hammerness P ,
Michel E , et al . 2007 . Comparative acute effi cacy and tolerability
of OROS and immediate release formulations of methylphenidate
in the treatment of adults with attention-defi cit/hyperactivity dis-
order . BMC Psychiatr y 7 : 49 .
Buitelaar JK , Ramos-Quiroga JA , Casas M , Kooij JJ , Niemela A ,
Konofal E , et al . 2009 . Safety and tolerability of fl exible dosages
of prolonged-release OROS methylphenidate in adults with
attention-defi cit/hyperactivity disorder . Neuropsychiatr Dis
Treat 5 : 457 – 466 . Epub@2009 Sep 15:457 – 466.
Buitelaar JK , Trott GE , Hofecker M , Waechter S , Berwaerts J ,
Dejonkheere J , et al . 2011 . Long-term effi cacy and safety
outcomes with OROS-MPH in adults with ADHD . Int J
Neuropsychopharmacol 15 : 1 – 13 .
Concer ta [package insert] . Tokyo: Janssen Pharmaceutical KK ;
2007 .
Conners CK , Erhardt D , Sparrow E . 1999 . Conners ’ Adult ADHD
Rating Scales (CAARS): Technical Manual . NY: Multi-Health
Systems Inc .
Epstein JN , Kollins SH . 2006 . Psychometric properties of an adult
ADHD diagnostic interview . J Atten Disord 9 : 504 – 514 .
Johnson & Johnson Pharmaceutical Research & Development .
2011 . Investigator ’ s Brochure, CONCERTA
®
(methylpheni-
date HCl) . Edition 16.
Kooij JJ , Buitelaar JK , van den Oord EJ , Furer JW , Rijnders CA ,
Hodiamont PP . 2005 . Internal and external validity of
attention-defi cit hyperactivity disorder in a population-based
sample of adults . Psychol Med 35 : 817 – 827 .
Medori R , Ramos-Quiroga JA , Casas M , Kooij JJ , Niemela A ,
Trott GE , et al . 2008 . A randomized, placebo-controlled trial
of three fi xed dosages of prolonged-release OROS methylphe-
nidate in adults with attention-defi cit/hyperactivity disorder .
Biol Psychiatry 63 : 981 – 989 .
Pelham WE , Gnagy
EM , Burrows-Maclean L , Williams A ,
Fabiano GA , Morrisey SM , et al . 2001 . Once-a-day Concerta
methylphenidate versus three-times-daily methylphenidate in
laboratory and natural settings . Pediatrics 107 : E105 .
Pharmaceuticals and Medical Devices Agency . 2012 . [in Japanese].
Available at: http://www.info.pmda.go.jp/shinyaku/P201200114/
53047100_22100AMX00644_A100_1.pdf.
Takahashi M , Takita Y , Goto T , Ichikawa H , Saito K ,
Matsumoto H , et al . 2011a . An open-label, dose-titration
tolerability study of atomoxetine hydrochloride in Japanese
adults with attention-defi cit/hyperactivity disorder . Psychiatry
Clin Neurosci 65 : 55 – 63 .
Takahashi M , Takita Y , Ichikawa
H , Enomoto T , Okada T ,
Saito K , et al . 2011b . Reliability and Validity of the Japanese
Version of CAARS-Screening Version (CAARS-SV), Adult
ADHD Symptom Rating Scale [in Japanese] . Seishin Igaku
53 : 23 – 34 .
Takeda T . 2009 . Psychopharmacology for attention-defi cit/hyper-
activity disorder in Japan . Curr Attention Dis Rep 1 : 21 – 28 .
Wilens TE , Morrison NR , Prince J . 2011 . An update on the
pharmacotherapy of attention-defi cit/hyperactivity disorder in
adults . Expert Rev Neurother 11 : 1443 – 1465 .
conducted over a longer period of time. The contin-
ued safety and effi cacy of OROS MPH in adults will
be assessed in the long-term extension study. Third,
ADHD is more likely to be complicated with other
psychiatric illness, such as anxiety disorders. We
excluded these patients in this study, and the effi cacy
of OROS MPH for these patients should be tested
in the future. It could be considered that excluding
non-responders to MPH from this study may have
had a positive bias on patient selection. However,
no patient was excluded from the study due to
this exclusion criterion, so it is unlikely that this
exclusion had an effect on the overall results. Finally,
this study was funded and executed by Janssen
Pharmaceuticals, which could be perceived as a
potential confl ict of interest. It should be noted
that the study was performed by strictly following
GCP guidelines.
In conclusion, the results of this study demon-
strated that OROS MPH in a dose range of 18 – 72
mg/day was effective in the treatment of ADHD
in adult patients. Compared with placebo, patients
who received OROS MPH experienced signifi cant
improvements in ADHD symptoms based on mul-
tiple measures of assessment. OROS MPH was
also well-tolerated in adult patients in Japan, with an
AE profi le that was mostly similar to other clinical
studies in distinct patient populations.
Acknowledgements
We would like to acknowledge all patients, physicians
and research coordinators who participated in this
clinical trial.
Statement of interest
NT, TK, YT, YS, YK and TM are employees of
Janssen Pharmaceutical KK, Japan.
This study was supported by Janssen Pharmaceu-
tical KK, Japan. Editorial support was provided by
Allison Michaelis, PhD, of Medergy and was funded
by Janssen Global Services, LLC.
References
American Psychiatric Association . 2000 . Attention-defi cit and dis-
ruptive behavior disorders . In: Diagnostic and statistical man-
ual of mental disorders. 4th ed. text revision (DSM-IV-TR) .
Washington, DC: American Psychiatric Association . p 85 – 93 .
Supplementary material available online
Supplementary Table I to be found online at http://
informahealthcare.com/doi/abs/10.3109/15622975.
2013.868925.
World J Biol Psychiatry Downloaded from informahealthcare.com by 201.210.105.125 on 05/20/14
For personal use only.
