![Mean scores of ILC items at baseline and after transitioning onto OROS MPH at final visit as assessed by the parents and children/adolescents. Low values indicate high quality of life. Dx ¼ diagnostic procedures; Tx ¼ therapeutic procedures. All changes from baseline to endpoint significant (p50.01 [Wilcoxon tests] except for the following items: parents: physical health, p ¼ 0.9959; children/adolescents: ILC 5 physical health, p ¼ 0.0757).](https://www.researchgate.net/profile/Klaus-Rettig/publication/51519265/figure/fig1/AS:1184755093643264@1659479034306/Mean-scores-of-ILC-items-at-baseline-and-after-transitioning-onto-OROS-MPH-at-final-visit_Q320.jpg)
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Current Medical Research & Opinion 2011, 1–10
0300-7995 Article FT-0155.R1/601733
doi:10.1185/03007995.2011.601733 All rights reserved: reproduction in whole or part not permitted
Original article
Effect of transitioning from extended-release
methylphenidate onto osmotic, controlled-
release methylphenidate in children/
adolescents with ADHD: results of a
3-month non-interventional study
Christian Wolff
Private Practice, Child and Adolescent Medicine,
Hagen, Germany
Adam Alfred
Private Practice, Child and Adolescent Psychiatry,
Munich, Germany
Anton Lindermu
¨ller
Private Practice, Child and Adolescent Psychiatry,
Munich, Germany
Klaus Rettig
G.E.M. Meerbusch, Germany
Fritz Mattejat
Department of Child and Adolescent Psychiatry,
Marburg, Germany
Martin Gerwe
z
Lara Slawik
Janssen, Neuss, Germany
Barbara Scha¨ uble
Janssen EMEA, Neuss, Germany
Address for correspondence:
Barbara Scha
¨uble MD PhD, Janssen EMEA Medical
Affairs, Raiffeisenstrasse 8, D-41470 Neuss, Germany.
Tel.: þ4921379555481; Fax: þ492137955922258;
bschaeu2@its.jnj.com
Key words:
ADHD – Children – Extended-release
methylphenidate – Non-interventional study
Accepted: 27 June 2011; published online: 25 July 2011
Citation: Curr Med Res Opin 2011; 1–10
Abstract
Background:
To explore the clinical outcomes of children/adolescents with ADHD who transitioned from extended-release
methylphenidate (ER MPH, Medikinet Retard*) to osmotic release oral system (OROS) MPH (Concertay).
Methods:
This prospective, non-interventional study included patients aged 6 to 18 years with a confirmed diagnosis
of ADHD who experienced insufficient clinical response and/or poor tolerability on ER MPH. Patients
transitioned onto OROS MPH and were followed for 12 weeks. Symptoms, functional outcome, health-
related quality of life, safety and tolerability were assessed.
Results:
180 patients were included in the intention-to-treat analysis. The mean ER MPH dose before switching was
28.2 mg/day; mean OROS MPH starting dose was 38.1mg/day, increasing to 41.2 mg/day at the final visit.
Mean treatment duration was 79.49 24.22 days (median 85; range 7–136). Several symptomatic and
functional outcomes under OROS MPH treatment changed from baseline and included the Conners’ Parent
Rating Scale (CPRS; 11.7 11.3; p50.0001), C-GAS (12.3 15.2; p50.0001) and ILC-LQ0-28
(parents’ rating 2.9 4.3 and patients’ rating 2.8 3.8; both p50.0001). Improvements in social
interactions, playing with other children, doing household chores, or school homework, going to bed,
and behavior towards visitors/at visits were noted (p50.0001). Approximately 40% of patients reported
better sleep quality and appetite (p50.0001), and 72.8% expressed satisfaction with OROS MPH therapy
compared to previous ER MPH. OROS MPH was well tolerated; the most common AEs after switching, with
an incidence 42% and possibly related to therapy, were involuntary muscle contractions (tics; 8.9%),
insomnia (7.2%) and anorexia (5.0%). No relevant changes in body weight or vital signs were observed.
Three patients reported four serious AEs, but none were considered related to OROS MPH. Limitations
included those associated with the uncontrolled, open-label design, possible inclusion bias and non-
validation of the CPRS in a German population.
Conclusions:
Transitioning onto OROS MPH improved functionality, symptom control and decreased burden of disease in
patients with ADHD who had insufficient response to, and/or poor tolerability of ER MPH. Similarly, care
givers benefited from patients’ treatment and reported significant reduction in their burden of disease and
improvement of their quality of life upon the child’s transition onto OROS MPH.
*Medikinet Retard is a registered trade name of Medice, Bad Iserlohn, Germany.
yConcerta is a registered trade name of Janssen–Cilag GmbH, Neuss, Germany.
zCurrently at Ipsen Pharma, Ettlingen, Germany.
!2011 Informa UK Ltd www.cmrojournal.com Effectiveness of osmotic, controlled-release MPH in ADHD Wolff et al. 1
Introduction
Attention-deficit/hyperactivity disorder (ADHD) is a
highly prevalent neuropsychiatric disorder, with US data
showing that approximately 9.5% of children/adolescents
aged 4–17 years have at some point been diagnosed with
ADHD, as of 2007
1
. The disease is characterized by devel-
opmentally inappropriate levels of inattention, impulsivity
and hyperactivity relative to that of same-aged peers with-
out the disorder
2,3
. It seriously compromises functionality
and health related quality of life (HRQoL) in patients,
parents and peer groups and is associated with a consider-
able emotional and financial burden; the impact is at least
equivalent to that of other chronic mental health condi-
tions and severe physical disorders
2,4,5
.
Management of children and adolescents with ADHD
has focused on symptom control during the school day in
order to improve academic performance but, as noted by
Buitelaar and Medori (2010), therapeutic targets need to
be broadened in scope to include social competencies and
improvements in functionality and other HRQoL aspects
of individuals and their families
2
.
Methylphenidate (MPH) is recognized as part of a mul-
timodal treatment strategy and is the first-line choice of
pharmacotherapy for children and adolescents with
ADHD, decreasing symptom frequency and/or severity.
Several once-daily extended release (ER) MPH formula-
tions are available, providing coverage for about 8 hours
5
.
However, commonly, the effectiveness of ER MPH formu-
lations does not extend beyond the school day into late
afternoon and evening, providing insufficient coverage
throughout the full active day
2
. Osmotic, controlled-
release (OROS) MPH (Concerta*) is a long-acting
MPH formulation which uses osmotic release oral system
(OROS) technology to produce an ascending MPH plasma
profile
6
. In clinical trials, OROS MPH has been shown to
produce an extended duration of ADHD symptom control,
consistent with a 12 hour duration of action
5,7
. To date,
there are no published data reporting in ADHD symptoms,
functionality and HRQoL in patients who switch from an
up to 8 hour duration ER MPH (MedikinetyRetard) to
OROS MPH.
Although controlled clinical trials serve a vital purpose
in terms of determining whether or not a particular inter-
vention works (i.e. efficacy under ideal conditions to
ensure scientific validity) in a specific patient population,
the generalizability of the results may be limited, for exam-
ple by the greater level of care and follow-up than usually
occurs in everyday clinical practice. For interventions with
confirmed clinical efficacy, it is also important to demon-
strate whether they work in naturalistic or ‘real-world’
settings which are influenced by patient/caregiver behav-
iors, adherence to therapy and multiple environmental
factors.
The current naturalistic, non-interventional study was
designed to explore the effectiveness, tolerability and
changes in HRQoL of OROS MPH following a switch
from previous therapy with ER MPH. Data were collected
and analyzed for a large cohort of children and adolescents
with ADHD (ICD-10 criteria [hyperkinetic disorders]) in
whom the switch to OROS MPH was medically indicated
as assessed by the treating physician in routine clinical
practice.
Patients and methods
Participants and study design
This was a multicenter, prospective, open, non-interven-
tional study (42603ATT4037) aimed to explore efficacy,
tolerability and HRQOL outcomes in patients and their
parents/caregivers after transitioning from ER MPH or ato-
moxetine onto OROS MPH. The switch was medically
indicated based on the treating physician’s assessment
before entry into the study. Follow-up after switching to
OROS MPH extended over a 3-month period. The trial
was conducted at 68 private practices (pediatric neurol-
ogy, child and adolescent psychiatry, as well as general
child and adolescent medicine practices) across
Germany. Eligible patients included children/adolescents
aged 6 to 18 years with a diagnosis of ADHD consistent
with ICD-10 criteria (F90.x; hyperkinetic disorders), who
were previously receiving ER MPH or atomoxetine. There
were no exclusion criteria. Results from the atomoxetine
subgroup have been presented separately
8
.
The study protocol recommended that OROS MPH
was prescribed according to its Summary of Product
Characteristics. The starting dose, titration rate and final
dose, as well as all diagnostic procedures, were decided by
the treating physician based on clinical impression.
The study comprised five visits: baseline (week 0;
administration of the first dose of OROS MPH), and
brief follow-up visits after 1, 3 and 6 weeks of OROS
MPH treatment, as well as a final visit after 3 months
(study end), or upon premature termination. Some features
of prior treatment with ER MPH were recorded at baseline.
An independent ethics committee (Freiburg,
Germany) was notified about the study and approved the
protocol. Informed consent or assent was obtained from
each patient and/or caregiver for data collection and
source data verification.
Healthy controls
In the absence of a healthy control group in this study, data
from Professor Mattejat’s Inventory for Assessment of
*Concerta is a registered trade name of Janssen–Cilag GmbH, Neuss, Germany.
yMedikinet Retard is a registered trade name of Medice, Bad Iserlohn, Germany.
Current Medical Research & Opinion 2011
2Effectiveness of osmotic, controlled-release MPH in ADHD Wolff et al. www.cmrojournal.com !2011 Informa UK Ltd
Quality of Life in Children and Adolescents (ILC) valida-
tion samples were used for comparison
9
: (1) a sample of
9418 ILC questionnaires filled in by healthy children/ado-
lescents and (2) a sample of 1140 ILCs filled in by parents
of healthy youngsters who are different from the first
sample. From these two samples, two samples matching
the gender and age of our study group were drawn.
Sample data is based on a one-time evaluation.
Symptomatic outcome measures
Symptomatic outcomes were assessed using the Conners’
Parent Rating Scale (CPRS). This scale assesses symptoms
of ADHD and other psychopathology and problem behav-
ior in children/adolescents aged 3–17 years, and is one of
the most frequently used scales to assess ADHD
10–12
. The
scale uses a four-point Likert format (0 ¼never, rarely,
1¼sometimes, 2 ¼frequently, 3 ¼very frequently and
regularly).
Scores range from 0 through to the number of items on
the scale multiplied by 3. In the current study, an 18-item
(short-form) version of the CPRS was employed and rat-
ings of 0 (best) to 54 (worst) were possible. Parents were
asked to consider the patient’s behavior during the previ-
ous month at baseline (week 0) and weeks 6 and 12 (study
end, or premature termination).
Health-related quality of life measures
HRQoL outcomes were assessed using the disease non-
specific, validated Inventory for Assessment of Quality of
Life in Children and Adolescents (ILC). The ILC, a short
and practical screening tool (assessment takes 5–15 min-
utes) for children/adolescents includes single-item scores
addressing: (1) school performance, (2) family function-
ing, (3) social integration, (4) interests and hobbies, (5)
physical health, (6) mental health, and (7) global HRQoL
rating
13–15
. The ILC measures these HRQoL aspects over
the past week and is sensitive to therapeutic interventions
and changes in well-being over time. Additional items for
patients and their parents/caregivers only are: (8) problems
(burden of present disorder/disease) and (9) therapy.
Additional items for parents/caregivers only are: (10)
problems (burden of present disorder/disease for parents/
caregivers) and (11) therapy.
Each item is rated on a five-point Likert scale (1 ¼very
good, 2 ¼rather good, 3 ¼mixed, 4 ¼rather bad, 5 ¼very
bad). For children aged 6–11 years, the ILC is administered
in a structured interview; adolescents and parents/care-
givers complete their own questionnaire.
Three scores can be calculated from the seven core
items. For the purpose of this analysis, the overall score
termed ‘LQ0-28’ was calculated if at least four of the seven
items were answered. The LQ0-28 score ranges from
0 (worst) to 28 (best) and is calculated as
LQ0-28: ¼ROUND[ABS(S*7/N)-35] where Nand Sare
the number and sum of answered items, respectively, and
ABS and ROUND the absolute and rounding function.
Functional outcome measures
The Children’s Global Assessment Scale (C-GAS) pro-
vides a global measure of the level of functioning in chil-
dren and adolescents
16
. The scale provides a single global
rating on a scale of 0 (worst) to 100 (best). The C-GAS
was applied by the treating physician at baseline (week 0)
and weeks 6 and 12.
Other assessments
Problems concerning social interactions and tasks were
assessed via several non-validated questions. At each
visit, problems that occurred in late afternoon (4 pm to 8
pm) relating to playing with other children, household
chores, school homework, going to bed, and behavior
towards visitor/at visits were rated using a four-point
scale with the categories being none, mild, moderate and
strong. At each visit, quality of sleep and appetite were also
rated using a five-point scale with the categories being very
good, good, satisfactory, sufficient, and insufficient.
Safety and tolerability
Tolerability parameters included documentation of treat-
ment-emergent adverse events (TEAEs) throughout the
study (weeks 1, 3, 6 and 12), recording of vital signs
(blood pressure and heart rate) at all visits, and body
weight at study start and at the final visit.
Data management and statistical analysis
All documented data were entered into the database using
a double data entry system and then checked for consis-
tency and completeness. AEs were coded according to
WHO Adverse Reaction Terminology (WHOART).
In previous open label studies with OROS MPH, effect
sizes (quotient of observed effect and standard deviation)
ranging from 0.5 to 0.9 on various scales (CPRS, ILC, C-
GAS) have been observed after 12 weeks of treatment. To
verify an effect size of 0.5, 44 patients are required (one
sample t-test, two-tailed with a type I error of a¼0.05 and
a type II error of ¼0.1). A sample size of 200 patients was
thus considered sufficient to evaluate effectiveness with
regard to various parameters in several subgroups of
patients.
Descriptive statistical estimators were used such as fre-
quency counts, arithmetic means SD (standard devia-
tion), median and range depending on the scale level.
Current Medical Research & Opinion 2011
!2011 Informa UK Ltd www.cmrojournal.com Effectiveness of osmotic, controlled-release MPH in ADHD Wolff et al. 3
Pre–post comparisons were performed using Wilcoxon’s
test for dependent samples. All tests were performed
two-sidedly in an exploratory sense without adjustment
for multiple testing.
The evaluations were performed according to the
intention-to-treat (ITT) principle. All enrolled patients
who had received at least one dose of OROS MPH and
who had at least one follow-up effectiveness assessment
were available for the ITT analysis of effectiveness and
safety data. Effectiveness data were presented as changes
from baseline, missing values were imputed by the last
observation carried forward (LOCF) method where
appropriate.
Relationships between ILC-LQ0-28 scores for parents
and children, and scores from the Conners’ Parent Rating
Scale and C-GAS were investigated using Spearman’s
rank correlation coefficients.
Results
A total of 224 patients participated in the study. However,
44 of these were previously treated with atomoxetine and
were excluded from the current analyses due to consider-
able pharmacokinetic and pharmacodynamic differences.
This subset has been reported separately
8
. Thus, current
analyses include 180 patients previously treated with ER
MPH and these patients constitute both the ITT popula-
tion and the safety analysis set.
Baseline demographics and disease
characteristics
Relevant demographic data for the 180 patients in the ITT
analysis set are summarized in Table 1. The vast majority
of patients were boys (86.7%) and nearly two-thirds were
children (aged 6 to512 years).
The major reason for switching to OROS MPH was
insufficient effectiveness with previous therapy (95.6%
of patients including 20.6% who also reported an adverse
event). The median duration of previous therapy with ER
MPH was 35.6 (range: 1.0–151.1) weeks and the mean
final dose prior to treatment with OROS MPH was
28.2 14.2 mg/day. The mean time between discontinu-
ing ER MPH and starting on OROS MPH was 1.5 13.6
days (Table 2); however, more than 90% of patients tran-
sitioned onto OROS MPH within 1 day of stopping pre-
vious treatment with ER MPH: 115 out of 180 children
received the final dose of ER MPH at the time of the first
study visit. In 43 patients, the last intake of ER MPH was
the day before study inclusion. In the remainder of patients
(N¼22), intake was more than 1 day before baseline
assessment.
Table 1. Demographic data and disease characteristics (ITT sample;
n¼180).
Baseline characteristics
Gender, n(%)
Female 24 (13.3)
Male 156 (86.7)
Mean SD 11.5 2.3
Minimum, median, maximum 6.8, 11.4, 17.8
Age at study start (years) categories
6–9 (incl. 1 patient aged 5.6 years) 32 (17.8)
10–12 83 (46.1)
13–15 56 (31.1)
16–18 9 (5.0)
Age at first diagnosis of disease (years)
Valid responses 170
Mean SD 8.1 2.3
Minimum, median, maximum 1.0, 8.0, 15.0
Duration of disease at study start (years)
Mean SD 3.4 2.1
Minimum, median, maximum 0.5, 2.8, 11.7
Diagnosis of ADHD (ICD-10)
a
F90.0: disturbance of activity and attention 106 (58.9)
F90.1: hyperkinetic conduct disorder 77 (42.8)
F90.8: other hyperkinetic disorder 2 (1.1)
F90.9: hyperkinetic disorder, unspecified 4 (2.2)
others 5 (2.8)
Previous and/or concomitant diseases (ICD-10)
a
None 85 (47.2)
F91.X: conduct disorder 39 (21.7)
F91: incl. F91.3 oppositional defiant disorder 31 (17.2)
F41: anxiety disorder 8 (4.4)
F42: obsessive–compulsive disorder 2 (1.1)
F1X: substance abuse 1 (0.6)
a
Multiple responses possible.
Table 2. Details of pre-study and study medication (ITT sample; n¼180).
Previous treatment
Reason for transitioning onto OROS MPH, n(%)
Insufficient effectiveness 135 (75.0)
Adverse events 8 (4.4)
Combination of both 37 (20.6)
Duration of previous treatment (weeks)
Mean SD 39.5 27.2
Minimum, median, maximum 1.0, 35.6, 151.1
Time between previous treatment discontinuation and study start (days)
Mean SD 1.5 13.6
Minimum, median, maximum 17.0, 0.0, 158.0
Final dose of ER MPH prior to treatment with OROS MPH (mg/day)
Mean SD 28.2 14.2
Minimum, median, maximum 10.0, 22.5, 120.0
Final dose of ER MPH prior to treatment with OROS MPH
(mg/kg/bodyweight)
Mean SD 0.75 0.37
Minimum, median, maximum 0.22, 0.69, 2.67
Dose of OROS MPH
Mean starting dose (mg/day) 38.1 15.1
Minimum, median, maximum 18, 36, 108
Last visit 41.2 14.2
Minimum, median, maximum 18, 36, 108
Difference (mean SD) 3.1 8.5
Wilcoxon p-value 0.0003
ER ¼extended-release; IR ¼immediate-release; MPH ¼methylphenidate;
OROS ¼osmotic release oral system; SD ¼standard deviation.
Current Medical Research & Opinion 2011
4Effectiveness of osmotic, controlled-release MPH in ADHD Wolff et al. www.cmrojournal.com !2011 Informa UK Ltd
Treatment with OROS MPH
The mean starting dose of OROS MPH was 38.1
15.1 mg/day, increasing slightly to 41.2 14.2 mg/day at
the final visit. The average treatment duration was
79.49 24.22 days. No dose change between first and
last visit was reported in 76.7% of patients, with a dose
increase in 20.0% of patients and 3.3% of patients report-
ing a dose decrease. A total of 83% of the subjects com-
pleted the 12-week study; main reasons for premature
withdrawal were adverse events (7%) and/or lack of
effectiveness (5%).
Effectiveness
Problems concerning social interactions and tasks
For all items (playing with other children, household
chores, school homework, going to bed, and behavior
towards visitor/at visits) improvements were observed for
the entire sample. Mean values at baseline and at the end
of the study are displayed in Figure 1 and the switch to
OROS MPH resulted in beneficial changes for all five
items (p50.0001).
Conners’ Parent Rating Scale
The mean CPRS score showed a clinically relevant
decrease from 28.7 11.1 at baseline to 17.6 11.4 at
study end (p50.0001) after transitioning onto OROS
MPH (Figure 2).
C-GAS
At baseline, the majority of patients (63.3%) had C-GAS
scores ranging from 41 to 70. At least a ‘major’ impairment
of functioning or worse (C-GAS score541) was recorded
for 16.7% of patients, whereas 20.0% of patients had no
Playing with
other
children
Household
chores
3
2.5
2
1.5
Mean scores for problem items
1
0.5
0
BAS
W01
W03
W06
W12
BAS
W01
W03
W06
W12
BAS
W01
W03
W06
W12
BAS
W01
W03
W06
W12
BAS
W01
W03
W06
W12
Homework Going to bed Visitors/
visits
Figure 1. Mean scores for problems concerning social interactions and tasks occurring in late afternoon (4 pm to 8 pm) at ER MPH baseline (BAS) and after
transitioning onto OROS MPH at weeks 1, 3, 6 and 12. Lower scores denote improvements. Scoring of each item (degree of problem): 0 ¼none, 1 ¼mild,
2¼moderate, 3 ¼severe. All changes from baseline to endpoint significant with p50.0001 (Wilcoxon tests). A lower score denotes improvement.
35 Total score
Inattention score
*
Hyperactivity score
30
25
20
15
10
5
Baseline (ER MPH) Week 6 (OROS MPH) Week 12 (OROS MPH)
0
Figure 2. Mean Conners’ Parent Rating Scale (CPRS) scores in children with
ADHD transitioning from ER MPH to OROS MPH at baseline, week 6 and
week 12. Total CPRS scores and those for the composite dimensions
(inattention and hyperactivity) are shown. Lower mean scores denote
improvement. *Change from baseline to endpoint significant ( p50.0001;
Wilcoxon test).
Current Medical Research & Opinion 2011
!2011 Informa UK Ltd www.cmrojournal.com Effectiveness of osmotic, controlled-release MPH in ADHD Wolff et al. 5
more than a ‘slight’ impairment in functioning or better
(score 470) (Figure 3). C-GAS scores were positively
correlated with ILC-LQ0-28 scores and were negatively
correlated with scores from the CPRS (Table 3).
Health Related Quality of Life (ILC)
The mean ILC-LQ0-28 score increased from 16.6 4.0 at
baseline to 19.3 3.9 at the end of the study (p50.0001)
according to parents’ ratings, and from 18.3 4.0 at base-
line to 21.1 3.4 at the end of the study (p50.0001)
according to patients’ ratings denoting a higher health
related quality of life (Figure 4). A positive, though
modest correlation was noted between parents’ and
patients’ pre–post change scores (Table 3), i.e. high
scores from parents were associated with high scores from
patients. As shown in Figure 4, the mean parent and
patient ratings at week 12 closely matched ratings reported
for scores recorded for matched healthy individuals.
Mean parent and patient scores for the individual ILC
items at baseline and at the end of the study are displayed
in Figure 5. Clinically relevant changes were observed for
all seven core items except physical health (p50.001).
Mean rating scores for the additional question concern-
ing the patient’s burden associated with ADHD were
decreased by 0.47 1.14 (p50.0001) when assessed by
patients and 0.80 1.18 (p50.0001) when assessed by
parents (Figure 5). This was the item with the largest
mean improvement for both groups (patients and parents).
Pre–post difference scores for the parents’ burden associ-
ated with ADHD decreased significantly from baseline,
with an average pre-post difference in scores of
0.76 1.16 (p50.0001).
ILC-LQ0-28 change scores from parents and patients
and CPRS change scores were negatively correlated, i.e.
high scores from the ILC-LQ0-28 (parents or patients)
were associated with low scores on the CPRS (Table 3).
Mean ILC-LQ0-28 total scores from patients and par-
ents, classified by gender and age groups, were compared
with data obtained from healthy controls (874 parents and
4725 children/adolescents; data not shown). Overall,
ratings by parents and patients demonstrated marked
improvements in HRQoL, particularly in adolescent
boys, reaching similar scores for healthy controls.
Females had notably lower baseline scores and experienced
large improvements during follow up. The two individual
ILC-LQ0-28 items with the worst baseline scores were
school performance (item 1) and mental health (item 6)
(data not shown). At baseline, scores for study patients
were consistently worse than scores for healthy controls;
at study end, improvements reached, or in some cases
exceeded, those of healthy controls regardless of age or
gender.
Quality of sleep and appetite
Overall, small but significant improvements in quality
of sleep (p¼0.0005) and appetite (p50.0001)
were observed. Quality of sleep and appetite improved in
38.4% and 40.2% of patients, respectively, and worsened
in 22.3% and 21.9% of patients, respectively.
20.61
18.32
20.86
21.32
*
*
16.55
Baseline (ER MPH) Baseline (ER MPH)
Healthy comparison group
Treatment group
Week 12 (OROS MPH) Week 12 (OROS MPH)
parents
children/adolescents
19.28
Figure 4. Mean ILC-LQ0-28 total scores in children with ADHD transitioning
from ER MPH to OROS MPH. High scores denote high quality of life.
*Changes from baseline to endpoint significant (p50.0001, Wilcoxon test).
75
70
65
Mean C-GAS scores
60
55
50
Baseline (ER MPH) Week6 (OROS MPH) Week12 (OROS MPH)
*
Figure 3. Mean C-GAS scores in children with ADHD transitioning from ER
MPH at baseline to OROS MPH after 6 and 12 weeks of treatment. Higher
mean scores denote improvement. *Change from baseline to endpoint
significant (p50.0001; Wilcoxon test).
Table 3. Spearman rank correlations between ILC-LQ0-28, Conners’
Parent Rating Scale (CPRS) and Children’s Global Assessment Scale
(C-GAS) scores (n¼180; intention-to-treat, last observation carried
forward [LOCF]).
Scale 1 Scale 2 Correlation coefficients
Difference last value
(LOCF) – baseline
ILC-LQ0-28 (parents) ILC-LQ0-28
(children)
0.502
ILC-LQ0-28 (parents) CPRS 0.624
ILC-LQ0-28 (parents) C-GAS 0.524
ILC-LQ0-28 (children) CPRS 0.391
ILC-LQ0-28 (children) C-GAS 0.375
CPRS C-GAS 0.606
Current Medical Research & Opinion 2011
6Effectiveness of osmotic, controlled-release MPH in ADHD Wolff et al. www.cmrojournal.com !2011 Informa UK Ltd
Satisfaction with OROS MPH was rated at least as
‘good’ in 72.2% of patients. Compared with previous ER
MPH therapy, 25.6% and 47.2% of patients were either
‘very satisfied’ or ‘satisfied’ with OROS MPH.
Safety and tolerability
In total, 196 TEAEs (treatment emergent adverse events)
were reported by 96 of the 180 patients (53.3%). A causal
relationship between the TEAE and OROS MPH admin-
istration was assessed as at least possible for 102 of these
196 TEAEs in 61 patients (33.9%). The incidences of the
most common TEAEs are presented in Table 4.
Overall, the most commonly reported TEAEs were
involuntary muscle contractions (tics), insomnia and
anorexia (10.6%, 8.3%, and 5.0% of patients, respec-
tively). These were also the most commonly reported
AEs with at least a possible causal relationship with
OROS MPH (8.9%, 7.2%, and 5.0% of patients, respec-
tively). Tics and/or insomnia led to premature termination
in 1.1% and 1.7% of patients, respectively, whereas other
TEAEs were reported as the reason for premature termina-
tion in one or two patients only. Four serious adverse
events were reported in three patients including convul-
sion, bronchitis, and suicide attempt by self induction of
a hypoglycemic coma. None of the reported events were
considered to be related to OROS MPH treatment.
At each visit, patients or parents were specifically asked
about the presence of tics and 12.9% of patients reported
tics at baseline. During the course of the study, 5.0%
of patients reported worsening only (i.e. new tics and/or
deteriorations of existing tics), 2.8% of patients reported
improvement only (i.e. disappearance and/or improve-
ments of existing tics), and 4.4% of patients reported
both worsening and improvement.
On average, almost no weight changes were observed
during the study. No clinically relevant changes in vital
signs were observed.
Discussion
This multicenter, non-interventional study conducted in
children/adolescents with ADHD explored clinical out-
comes following a switch of treatment from ER MPH to
once-daily OROS MPH. Compared with baseline, there
were clinically relevant symptomatic and functional
improvements after transitioning to OROS MPH as
assessed by CPRS (mean change from baseline:
11.2 11.3; p50.0001), C-GAS (mean change from base-
line: 11.8 15.1; p50.0001) and ILC-LQ0-28 scores
(2.7 4.2 for parents and 2.8 3.8 for patients; both
p50.0001). Furthermore, social interactions and tasks
such as playing with other children, household chores,
4
3.8
3.6
3.4
3.2
3
2.8
Mean scores of single ILC items
2.6
2.4
2.2
2
1.8
1.6
1.4
Parents: baseline
ILC1: school performance
ILC2: family functioning
ILC3: social integration
ILC4: interests and hobbies
ILC5: physical health
ILC6: mental health
ILC7: global QoL
ILC8: burden disease
ILC9: burdenDx/Tx
ILC10: burden disease (parents)
ILC11: Dx/Tx (parents)
Children: baseline
Parents: week 12
Children: week 12
Figure 5. Mean scores of ILC items at baseline and after transitioning onto OROS MPH at final visit as assessed by the parents and children/adolescents.
Low values indicate high quality of life. Dx ¼diagnostic procedures; Tx ¼therapeutic procedures. All changes from baseline to endpoint significant ( p50.01
[Wilcoxon tests] except for the following items: parents: physical health, p¼0.9959; children/adolescents: ILC 5 physical health, p¼0.0757).
Current Medical Research & Opinion 2011
!2011 Informa UK Ltd www.cmrojournal.com Effectiveness of osmotic, controlled-release MPH in ADHD Wolff et al. 7
school homework, going to bed, and behavior towards vis-
itors/at visits ameliorated. Approximately 40% of patients
experienced improvement (p50.0001) in sleep quality
and appetite, and almost three-quarters (72.8%) expressed
satisfaction with OROS MPH therapy compared to previ-
ous treatment with ER MPH.
In the current study, 75% of patients who were receiv-
ing treatment with ER MPH switched to OROS MPH due
to insufficient effectiveness. The symptomatic and func-
tional improvements after transition to OROS MPH may,
in part, be due to an increase in daily MPH dose from
28.1 mg/day on the previous MPH formulation to
41.4 mg/day on OROS MPH at final visit. However, it
should be noted that with the OROS MPH formulation,
the daily MPH dose is released over a longer period after
intake than the ER MPH formulation patients were being
treated with before so that this apparent dose increase
reflects rather a more continued exposure over the day
than a dose increase over the same period of time after
intake. The Medikinet Retard ER MPH formulation con-
tains equal portions of immediate release and extended
release pellets with chemical efficacy documented up to
7ghours after intake in a classroom setting
17
. OROS
MPH delivers 22% of MPH as immediate release followed
by an ascending profile for about 10 hours after adminis-
tration with a documented efficacy up to 12 hours after
intake
18
. Indeed, Sonuga-Barke and colleagues showed
that differences in the pharmacokinetic profiles of
OROS MPH (up to 12 hour duration of action) and a
once-daily ER MPH formulation (Metadatez) resulted in
predictably different efficacy profiles over 12 hours in a
classroom setting
19
. Thus, the current study may translate
differences in duration of action into a clinical setting and
may suggest that longer duration of treatment effect is
associated with improved peer interaction, functionality
and decreased burden of disease in caregivers and affected
children and adolescents.
An important aspect of the current study was to explore
symptoms as well as functional impairment of children
with ADHD. The often difficult behavior of children
and adolescents with ADHD can impact greatly on
family life with an attendant decrease in HRQoL for all
persons involved. In recent years, HRQoL has become an
increasingly important outcome measure in both clinical
research and clinical practice
5
. In our study, parents and
patients alike reported improvements in patients’ HRQoL
as indicated by significantly higher ILC-LQ0-28 scores
from baseline to study end and parents also reported an
improvement in daily functioning in their children
(p50.0001 for both groups). As expected, there was a
negative correlation between functionality (C-GAS) and
symptomatic (CPRS) scores, and between symptomatic
and HRQoL (ILC-LQ-028) scores; positive correlations
were shown between functionality and HRQoL.
Furthermore, parents’ own quality of life became higher
(ILC items 10 and 11).
Overall, ratings by parents and patients demonstrated
marked improvements in HRQoL, particularly in adoles-
cent boys as well as girls, reaching scores which were
very similar to those obtained for healthy controls. It is
notable that girls started with remarkably low baseline
scores and experienced large improvements during
follow up. Improvements in parent-assessed HRQoL
were consistent for male and female patients across all
Table 4. Adverse events occurring in 2% of patients (n¼180, intention-to-treat sample).
Adverse event (AE)*All AEs Related AEs AEs as reason for
treatment discontinuation
n%n% n %
Muscle contractions involuntary 19 10.56 16 8.89 2 1.11
Insomnia 15 8.33 13 7.22 3 1.67
Anorexia 9 5.00 9 5.00 1 0.56
Abdominal pain 7 3.89 4 2.22 – –
Infection viral 7 3.89 – – – –
Accident 6 3.33 – – – –
Vomiting 6 3.33 1 0.56 – –
Aggressive reaction 5 2.78 4 2.22 1 0.56
Fatigue 5 2.78 4 2.22 1 0.56
Headache 5 2.78 2 1.11 – –
Nervousness 5 2.78 4 2.22 2 1.11
Bronchitis 4 2.22 – – – –
Concentration impaired 4 2.22 3 1.67 1 0.56
Diarrhea 4 2.22 1 0.56 – –
Emotional lability 4 2.22 4 2.22 2 1.11
Personality disorder 4 2.22 2 1.11 1 0.56
Weight decrease 4 2.22 4 2.22 – –
Patients with at least one AE 96 53.33 61 33.89 12 6.67
*Multiple AEs per patient possible.
zMetadate is a registered trade name of UCB, Inc., Smyrna, GA, USA.
Current Medical Research & Opinion 2011
8Effectiveness of osmotic, controlled-release MPH in ADHD Wolff et al. www.cmrojournal.com !2011 Informa UK Ltd
age ranges. In general, improvements in the two indi-
vidual ILC items which had the worst baseline scores
(school performance and mental health) reached, or in
some cases exceeded, scores for healthy controls regard-
less of age or gender. This may be a result of good
knowledge about the disease, children’s needs and med-
ical intervention.
In line with data reported in the Summary of Product
Characteristics, OROS MPH was generally safe and well
tolerated in the present study. The most commonly
reported TEAEs were involuntary muscle contractions
(tics) (10.6% of patients), insomnia (8.3%) and anorexia
(5.0%). Tics and/or insomnia led to premature termina-
tion in 1.1% and 1.7% of patients, respectively.
From patients’ or parents’ perspective, improved perfor-
mance and execution of daily tasks are equally important.
Based on parents’ feedback, transitioning onto OROS
MPH improved homework, family and other social inter-
action in a relevant degree. The main limitation of this
study is its uncontrolled, open-label design; however, the
naturalistic design was intentional so as to be able to
explore the clinical effectiveness of OROS MPH in every-
day clinical practice. In the current study, the switch to
OROS MPH was medically indicated and planned by the
patient’s own treating physician because of insufficient
efficacy and/or poor tolerability to previous treatment
with ER MPH. The associated inclusion bias needs to be
taken into consideration when results are interpreted.
Lastly, it should be noted that the CPRS has not been
validated for the German population, although a trans-
lated version is commonly used. Despite these limitations
and cautions, in this naturalistic setting the transition from
ER MPH onto OROS MPH was associated with a clini-
cally relevant improvement of ADHD symptoms and func-
tioning impacted positively on patients’ and parents’
HRQoL. Overall, OROS MPH was generally safe and
well tolerated and patients, as well as their carers, were
largely satisfied with treatment.
Conclusion
As such, the results of our study suggest a clinically mean-
ingful increase in efficacy upon transitioning onto OROS
MPH in the treatment of children/adolescents with
ADHD who had insufficient response to and/or poor tol-
erability with ER MPH.
Transparency
Declaration of funding
The study was funded by Janssen–Cilag GmbH, Neuss,
Germany.
Declaration of financial/other relationships
K.R. is a consultant working for GEM, Meerbusch, Germany,
who was hired by Janssen–Cilag to carry out the statistical anal-
yses. L.S. and B.S are employees of Janssen-Cilag; at the time the
study was conducted, M.G. was also an employee of Janssen-
Cilag. M.G. is currently employed by Ipsen Pharma. A.L. has,
in the past 3 years, been a speaker for Shire and Novartis. He is
not an employee or a shareholder of any of these companies,
and has no other financial or material support, including expert
testimony, patents or royalties. F.M., A.A. and C.W. have dis-
closed that they have no significant relationships with or
financial interests in any commercial companies related to this
study or article.
Acknowledgements
The authors thank Andreas Schmidt MD PhD for the design of
the study and medical oversight and Steve Clissold PhD and
David Figgitt PhD, Content Ed Net, for providing editorial assis-
tance in the preparation of this manuscript. This editorial support
was funded by Janssen–Cilag GmbH, Germany. We also thank
Detlef Wermelskirchen PhD, and Sascha Alexander Dichter MD
for their critical review and comments on previous versions
of this paper and all investigators, caregivers and patients who
participated in this study.
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