Rotigotine transdermal system as add-on to oral dopamine agonist in advanced Parkinson’s disease: an open-label study
Kim et al. BMC Neurology
Rotigotine transdermal system as add-on to oral dopamine agonist in advanced Parkinson's disease: an open-label study
Jong-Min Kim 2
Sun Ju Chung 1
Jae Woo Kim 0
Beom Seok Jeon 5
Pritibha Singh 4
Stephan Thierfelder 4
Junji Ikeda 3
Lars Bauer 4
on behalf of the Asia Pacific Rotigotine Add-on Study Group
0 Department of Neurology, Dong-A University Medical Center , Busan , Republic of Korea
1 Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine , Seoul , Republic of Korea
2 Department of Neurology, Seoul National University Bundang Hospital, Seoul National University College of Medicine , Seongnam-si , Republic of Korea
3 Otsuka Pharmaceutical Company, Ltd. , Tokyo , Japan
4 UCB Pharma , Alfred-Nobel-Str 10, 40789 Monheim am Rhein , Germany
5 Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine , Seoul , Republic of Korea
Background: Achieving optimal symptom control with minimal side effects is a major goal in clinical practice. Dual-agent dopamine receptor agonist (DA) therapy in Parkinson's disease (PD) may represent a promising approach to treatment, as the combination of different pharmacokinetic/pharmacological profiles may result in a lesser need for high dosages and, accordingly, may be well tolerated. The objective of the current study was to investigate safety and efficacy of rotigotine transdermal system as add-on to oral DA in patients with advanced PD inadequately controlled with levodopa and low-dose oral DA. Methods: PD0015 was an open-label, multinational study in patients with advanced-PD and sleep disturbance or early-morning motor impairment. Patients were titrated to optimal dose rotigotine (8 mg/24 h) over 1-4 weeks and maintained for 4-7 weeks (8-week treatment). Dosage of levodopa and oral DA (pramipexole 1.5 mg/day, ropinirole 6.0 mg/day) was stable. Primary variable was Clinical Global Impressions (CGI) item 4: side effects, assessing safety. Other variables included adverse events (AEs), Patient Global Impressions of Change (PGIC), Unified Parkinson's Disease Rating Scale (UPDRS) II and III, Parkinson's Disease Sleep Scale (PDSS-2), Pittsburgh Sleep Quality Index (PSQI), and off time. Results: Of 90 patients who received rotigotine, 79 (88%) completed the study; 5 (6%) withdrew due to AEs. Most (83/89; 93%) had a CGI-4 score <3 indicating that rotigotine add-on therapy did not interfere with functioning; 6 (7%) experienced drug-related AEs that interfered with functioning (score 3). AEs occurring in 5% were application site pruritus (13%), dizziness (10%), orthostatic hypotension (10%), nausea (8%), dyskinesia (8%), and nasopharyngitis (6%). Numerical improvements in motor function (UPDRS III), activities of daily living (UPDRS II), sleep disturbances (PDSS-2, PSQI), and reduction in off time were observed. The majority (71/88; 81%) improved on PGIC. Conclusions: Addition of rotigotine transdermal system to low-dose oral DA in patients with advanced-PD was feasible and may be associated with clinical benefit. Trial registration: ClinicalTrials.gov identifier NCT01723904. Trial registration date: November 6, 2012.
Advanced Parkinson's disease; Dual therapy; Rotigotine transdermal system; Oral dopamine receptor agonist; Safety
Treatment with chronic levodopa for the symptoms of
advanced Parkinson's disease (PD) is often associated with the
development of motor fluctuations and dyskinesia, which
gradually worsen as the disease progresses [1,2]. These
limitations of levodopa therapy have been managed by the use
of concomitant treatment with non-ergot derived
dopamine receptor agonists (DAs). The DAs have some
advantages over levodopa, including longer half-lives , which
may reduce or delay the onset of motor complications.
Achieving optimal symptom control with minimal side
effects is a major goal in clinical practice. Dual-agent DA
therapy in PD may represent a promising approach to
treatment, as the combination of different pharmacokinetic/
pharmacological profiles may result in a lesser need for
high dosages and, accordingly, may be well tolerated [4-6].
Rotigotine is a non-ergot derived DA with activity
across D1 through D5 receptors as well as select
adrenergic and serotonergic sites . Continuous transdermal
delivery of rotigotine maintains stable plasma levels over
24 hours with a single daily application , thus
avoiding plasma level peaks and troughs associated with more
pulsatile oral drug delivery. Symptoms of some PD
patients may not be adequately controlled over the entire
24-h range with existing oral DA treatment. Since
rotigotine transdermal system maintains stable plasma
concentration over 24 h, add-on rotigotine may supplement
the effects of oral DAs. Activation of the D1 receptor is
unique to rotigotine among the nonergot-derived DAs;
pramipexole and ropinirole have been shown to act at
the D2 and D3 receptors, but exhibit little or no affinity
at the D1 receptor [9,10]. A synergistic interaction may
exist between D1 and D2 receptors; a D1 receptor
agonist has been shown to act synergistically with a D2
receptor agonist to prolong the motor stimulation induced
by each agonist alone in the MPTP-lesioned monkey
model of PD . Thus, as a result of their different
pharmacokinetic/pharmacological properties, there may
be benefits of dual treatment with transdermally
delivered rotigotine and oral ropinirole or pramipexole.
Significant treatment effects of rotigotine transdermal
system have been observed in double-blind,
placebocontrolled studies as add-on therapy to levodopa in
advanced-stage PD [12,13] (improvements in motor
fluctuations; i.e., on and off time), and also in patients
with PD and unsatisfactory control of early-morning
motor function (improvements in early-morning motor
function and sleep disturbance [a non-motor symptom
of PD]) . In addition, improvements in motor
function and motor fluctuations have been demonstrated
with 3-times-daily oral immediate-release (IR) ropinirole
or pramipexole, or their once-daily oral extended-release
(ER) formulations in combination with levodopa in
patients with advanced PD [15,16].
The objective of this study was to investigate the safety
and efficacy of rotigotine transdermal system as add-on
to therapy with low-dose pramipexole or ropinirole, in
patients with advanced PD. Enrolled patients were
insufficiently controlled with levodopa and low-dose oral DA,
identified as experiencing motor complications and sleep
disturbance or early-morning motor impairment.
Patients enrolled in the PD0015 study included men and
women, aged 3080 years, with idiopathic PD of longer
than 3 years duration, and Hoehn and Yahr stage II-IV. PD
was defined by the presence of bradykinesia and at least
one of the following: resting tremor, rigidity, or impairment
of postural reflexes. In addition, all patients included had
to be taking levodopa (immediate or controlled release,
and at a stable dose) in combination with benserazide or
carbidopa, and a stable low dose of IR or ER pramipexole
(1.5 mg/day) or ropinirole (6.0 mg/day) for at least
28 days before baseline. Patients had to experience motor
fluctuations (wearing off, on-off phenomena, delayed
on or non-on) or dyskinesia, sleep disturbance or
earlymorning motor impairment, as determined by the
investigator, and nocturia for at least 3 nights within 7 days before
baseline. At the screening visit, patients were instructed to
differentiate between off and on states and symptoms of
troublesome dyskinesia for diary recordings. Patients
completed 7 days of diary recordings before beginning study
treatment; four of the diaries had to be determined valid
by the investigator for the patient to be eligible. Permitted
PD medications included anticholinergics, monoamine
oxidase B (MAO-B) inhibitors, N-methyl-D-aspartate (NMDA)
antagonists (e.g., amantadine), and entacapone; permitted
CNS active drugs included sedatives, antidepressants,
anxiolytics, hypnotics. All permitted drugs were required to be at
stable doses for at least 28 days prior to baseline, and were
to remain stable for the duration of the study.
Patients with clinically significant hepatic or renal
impairment were excluded. Prohibited medications included DAs
other than pramipexole or ropinirole, MAO-A inhibitors,
dopamine-releasing substances, dopamine-modulating
substances, tolcapone, budipine, dopamine receptor antagonists
(antiemetics [other than domperidone, e.g.,
metoclopramide], and neuroleptics). The study was conducted in
accordance with Good Clinical Practice and the Declaration
of Helsinki. The study protocol and amendments were
approved by the Institutional Review Board of all 21 centers
(Additional file 1: Table S1). All patients provided written,
informed consent before study participation.
Study design and procedures
PD0015 (ClinicalTrials.gov:NCT01723904) was a Phase
IIIb, open-label, single-arm study in patients with advanced
PD (between October 2012 and April 2013). Twenty one
centers enrolled patients, who applied at least one
rotigotine patch, in South Korea, Malaysia, Taiwan, Australia, and
Baseline data were recorded following a screening
period of up to 4 weeks. Rotigotine was administered as
once-daily patches of three different sizes; patches
provided nominal doses of rotigotine 2 mg/24 h (10 cm2),
4 mg/24 h (20 cm2), or 6 mg/24 h (30 cm2). The study
consisted of a 1-4-week titration and 4-7-week
maintenance period (total of 8-week treatment); patients were
titrated in weekly increments of 2 mg/24 h rotigotine
to their optimal (or maximal allowed) dose (up to 8 mg/
24 h) (Additional file 2: Figure S1). The optimal dose
was defined as the dose at which both the investigator
and patient felt that sleep disturbance or early-morning
motor impairment was controlled. As this was the first
study of rotigotine used concomitantly with a DA, the
permitted upper doses were considered based on safety
and the potential for overdose from concurrent use of
DAs, in reference to the equivalent dosing regimens
(Additional file 3: Table S2) [4,12,17]. The upper limit
was determined as 1.5 mg/day for pramipexole (approved
dose 4.5 mg/day), 6 mg/day for ropinirole (approved dose
24 mg/day), and 8 mg/24 h for rotigotine (EU-approved
dose 16 mg/24 h). Using these upper dose limits, the
combined total DA dose would not exceed the maximum
approved dose of any of the DAs (see the equivalent dosing
regimens in Additional file 3: Table S2). During titration, if
AEs occurred that might be the result of excessive
dopaminergic stimulation, rotigotine could be back-titrated
once to the previous dose (and the patient was requested
to visit the study site within 1 week for a safety
assessment), the patient began the maintenance phase
immediately at the back-titrated dose. Dose adjustments were not
permitted during maintenance. Clinic visits occurred at
screening, baseline, and weeks 1, 2, 3, 4, 5, and 8 of
titration/maintenance. Patients who withdrew prematurely
were asked to return for a withdrawal visit.
The primary variable was safety, as assessed using the
Clinical Global Impressions (CGI) item 4 score (side
effects) at the end of maintenance: 1 = None, 2 =
Not significantly interfering with patients functioning,
3 = Significantly interfering with the patients
functioning, and 4 = Side effects outweigh therapeutic efficacy.
Other safety evaluations included extent of rotigotine
exposure, and treatment-emergent adverse events (AEs,
regardless of a causal relationship). In addition, AEs of
special interest (those typical of dopaminergic
stimulation, use of a transdermal patch, or complications
related to PD) were pre-identified and assessed. The AEs
of special interest were pre-identified as application site
reactions, nausea and vomiting, somnolence, psychosis,
sleep attacks/sudden onset of sleep, obsessive-compulsive
disorder/impulse-control disorder, postural deformities,
freezing gait, and perception disturbances that required
atypical antipsychotic treatment. In addition, the modified
Minnesota Impulsive Disorder Interview was used to
prompt the investigators and patients to monitor the
emergence of impulse control disorders. Finally, physical
and neurological examinations, changes in laboratory
tests, vital signs, 12-lead electrocardiography (ECG), and
the Columbia-Suicide Severity Rating Scale (C-SSRS) were
Efficacy variables included outcomes assessing motor
symptoms, motor fluctuations, non-motor symptoms
(sleep disturbance), and quality of life. Change from
baseline to end of maintenance was assessed for Unified
Parkinsons Disease Rating Scale (UPDRS) Parts II
(activities of daily living [ADL]; mean for the on and off
state), and III (motor examination; in the on state);
absolute time spent "off " and absolute time spent "on"
without troublesome dyskinesia (assessed from patient
diaries); Parkinson's Disease Sleep Scale version 2 (PDSS-2);
global score of the Pittsburgh Sleep Quality Index (PSQI);
Patient Global Impression of Change (PGIC; change from
baseline in activity limitations, symptoms, emotions, and
overall quality of life; PGIC score 1 = Very much
improved, 2 = Much improved, 3 = Minimally improved,
4 = No change, 5 = Minimally worse, 6 = Much worse,
7 = Very much worse), and the 8-item short-form
Parkinsons Disease Questionnaire (PDQ-8; assessing PD-related
quality of life). Other variables included number of
awakenings during the night and number of nocturias, assessed
from patient diaries.
The primary variable (CGI item 4 score) was analyzed by
the safety set (all enrolled patients who had at least one
rotigotine patch applied during the treatment period),
using last observation carried forward (LOCF). With the
exception of time spent off, efficacy variables were
analyzed using the full analysis set (FAS; all patients who
applied at least one rotigotine patch, and had a baseline and
at least one post-baseline UPDRS III assessment), with
LOCF. Time spent off was analyzed using a subgroup of
the FAS comprising patients who recorded time spent
off at baseline in the patient diary. Efficacy variables were
summarized with univariate statistics (mean SD), and
95% confidence intervals (CI) were calculated for changes
from baseline (i.e., before and after rotigotine add-on).
Patient disposition and baseline characteristics
Of 112 patients who provided informed consent and
were screened, 22 failed screening, and 90 (80%) applied
at least one rotigotine patch and were included in the
safety set. Of these 90 patients, 79 (88%) completed the
study; the remaining 11 patients (12%) withdrew
prematurely due to AEs (n = 5) or for other reasons (n = 6).
Baseline demographic data are presented in Table 1.
Safety and tolerability
The mean (SD) duration of rotigotine exposure was
58.7 14.9 days. A total of 84 patients (93%) entered
maintenance. The maintenance dose was 2 mg/24 h in
14 patients, 4 mg/24 h in 19 patients, 6 mg/24 h in 16
patients, and 8 mg/24 h in 35 patients (mean SD dose:
5.71 2.28 mg/24 h). Of the 11 patients who
discontinued the study, six patients discontinued during the first
2 weeks of titration (at 2 mg/24 h), and the remaining
five patients discontinued after between 43 and 56 days
(i.e., approx. 68 weeks) of rotigotine treatment.
The dose of concomitant oral DA at baseline (as
rotigotine converted dose) was 2 mg/24 h in 30 patients,
Table 1 Patient demographics and baseline
characteristics, safety set
Age, mean SD, years
Duration of PD, mean SD, years
Hoehn and Yahr Stage during on, n (%)
n = 90
0.9 0.5 (n = 51; 57%)
3.4 2.0 (n = 39; 43%)
4 mg/24 h in 29 patients, and 6 mg/24 h in 31 patients
(mean SD dose: 4.02 1.66 mg/24 h). There was no
obvious relationship between the dose of oral DA and
dose of rotigotine (Additional file 4: Figure S2).
Primary outcome: safety assessed by CGI item 4
Most patients (83/89; 93%) had a score of <3 on CGI
item 4 (score of 1: 61/89; 69%, score of 2: 22/89; 25%) at
end of treatment, indicating that rotigotine add-on
therapy did not interfere with the patients functioning. At
end of maintenance, a total of six patients (7%)
experienced AEs, considered related to study drug by the
investigator, that interfered with the patients functioning
(score 3). Three of these six patients were receiving
2 mg/24 h rotigotine at the time of the AE (Table 2).
Fifty eight patients (64%) experienced a total of 147 AEs.
AEs occurring with an overall incidence of 5% or higher
were application site pruritus reported by 12 patients
(13%), dizziness (9; 10%), orthostatic hypotension (9;
10%), nausea (7; 8%), dyskinesia (7; 8%), and
nasopharyngitis (5; 6%). The incidence of AEs by 1) rotigotine
dose, and 2) oral DA dose is presented in Additional file
5: Table S3, and 3) by total DA dose is presented in
Additional file 6: Table S4.
Forty four patients (49%) experienced at least one AE
during titration, and 25 patients (30%) experienced at
least one AE during maintenance. The majority of AEs
were mild or moderate in intensity; six patients (7%)
experienced at least one severe AE. Six serious AEs were
reported in five patients (6%): hallucination, subdural
hemorrhage, nasopharyngeal cancer, delirium,
confusional state, and urinary retention. Except for the
hallucination, all the events were considered unrelated to
rotigotine. No deaths were reported.
Five patients were prematurely withdrawn from the
study due to AEs (primary reason for withdrawal):
dyskinesia (one patient), orthostatic hypotension (one
patient), worsening of Parkinsons disease (one patient),
subdural hemorrhage (one patient), dizziness,
hyperhidrosis, insomnia, and nausea (one patient). One patient,
whose primary reason for withdrawal was due to
noncompliance, also discontinued the study due to an AE
(nausea). Down-titration of rotigotine was performed in
15 patients due to AEs.
Of the AEs of special interest, 22 (24%) patients
experienced application site reactions, eight (9%) nausea and
vomiting (seven nausea [preferred term; PT], one
vomiting [PT]), four (4%) somnolence (three insomnia [PT],
one somnolence [PT]), four (4%) psychosis (two
hallucination [PT], one confusional state [PT], one delirium
[PT]), and one (1%) patient experienced
obsessivecompulsive disorder/impulse-control disorder.
Hoehn and Yahr Stage during off, n (%)
Levodopa dosage, mean SD, mg/day
Oral dopamine receptor agonists dosage,
mean SD, mg/day
Oral dopamine receptor agonist formulation, n (%)
Treatment-related AE Intensity
(CGI item 4 score) of AE
Rotigotine dose Action taken Oral DA (actual
(study phase) at with rotigotine dose [converted
AE onset rotigotine dose])
Levodopa Severity of disease:
dose mg/day Hoehn & Yahr Stage
during on; duration
11 mg/24 h 600
3.5 mg/24 h 675
Patient 4: Nausea,
hyperhidrosis (score 4)
Patient 5: Rash, dizziness
postural (score 3)
Moderate, 8 mg/24 h
Patient 6: Worsening
of PD (score 4)
CGI item 4 score: 1 = none, 2 = not significantly interfering with patients functioning, 3 = significantly interfering with the patients functioning, 4 = side effects
outweigh therapeutic efficacy.
AE considered related to study treatment by the investigator.
*Rotigotine dose at AE onset plus converted rotigotine dose of oral DA.
AE: adverse events; IR: immediate release; ER: extended release; PD: Parkinsons disease; LOCF: last observation carried forward; FAS: full analysis set.
There were no clinically relevant changes in laboratory
parameters, vital signs, ECGs, physical and neurological
examinations, or the C-SSRS.
Motor function (UPDRS III) and ability to carry out ADL
(UPDRS II) was improved following the addition of
rotigotine to the existing treatment with low oral DA (Figure 1).
Mean (SD) UPDRS III score (on state) at baseline was
22.0 11.3, and change from baseline to end of titration/
maintenance was 5.3 8.3 (95% CI: 7.1, 3.6). Mean
(SD) UPDRS II score (average of on and off states)
at baseline was 9.2 4.5, and change from baseline
was 1.5 3.8 (95% CI: 2.3, 0.7). The upper limits of
95% CI were below 0, suggesting an improvement in both
motor function and patients ability to carry out ADL.
Improvements were also observed in absolute time spent
off and absolute time on without troublesome
dyskinesia (Figure 1); mean (SD) absolute off time change
from baseline was 2.1 2.9 h (95% CI: 2.7, 1.5); mean
(SD) absolute time spent on without troublesome
dyskinesia change from baseline was 1.9 3.1 h (95% CI: 1.2,
2.5). When considering the oral DA formulation,
there was no obvious difference in the improvement in
time spent off between the IR and ER formulations:
mean (SD) absolute off time change from baseline
was 2.3 3.0 (95% CI: 3.1,1.4) for patients receiving IR
oral DA (baseline 6.4 2.5; n = 46), and 1.9 2.7 (95%
CI: 2.8,0.9) for patients receiving ER oral DA (baseline
6.0 3.2; n = 34).
Improvements in items relating to disturbed sleep
(a non-motor symptom of PD) were observed, including
PDSS-2 total score, PSQI global score, number of
awakenings during the night, and number of nocturias
(Figure 2); mean (SD) PDSS-2 total score change from
baseline was 3.2 7.5 (95% CI: 4.8, 1.6), and mean
PSQI global score change from baseline was 0.7 3.0
(95% CI: 1.4, 0.1). The mean (SD) change from baseline
in the number of awakenings during the night was 0.2
0.6 (95% CI: 0.31, 0.04) and for nocturias was 0.2 0.5
(95% CI: 0.3, 0.1). Improvements (i.e., upper limits of
95% CI below 0) were also observed following addition of
rotigotine treatment in two of the three domains of the
PDSS-2 (disturbed sleep and motor symptoms at
night), and six of 15 individual items. Worsening of the
individual PDSS-2 item of distressing hallucination was
observed (Figure 3).
The majority of patients reported an improvement on
the PGIC (71/88; 81%), with 29/88 (33%) reporting
much improved or very much improved, and only
3% (3/88) reporting a deterioration of much worse or
very much worse. Mean (SD) PDQ-8 total score at
baseline was 29.4 17.0, and change from baseline to
the end of titration/maintenance was 6.6 14.2 (95%
UPDRS III (motor symptoms) % responders
UPDRS II (activities of daily living) (20% improvement in UPDRS score)
UPDRS III UPDRS II
(motor symptoms)(activities of
Figure 1 UPDRS Parts II and III, UPDRS responder analysis, time spent off, and time spent on with troublesome dyskinesia, FAS,
LOCF. Before rotigotine add-on: baseline; after rotigotine add-on: end of maintenance. 95% CI does not contain zero (for change from
baseline [i.e., before to after rotigotine add-on]). UPDRS: Unified Parkinsons Disease Rating Scale; FAS: full analysis set; LOCF: last observation
CI: 9.7, 3.6). The upper limit of 95% CI was below 0,
suggesting an improvement in items assessing PD-related
quality of life.
This open-label study was the first study of rotigotine
transdermal system used as an adjunct to treatment with
an oral DA. The majority of patients in this study were
Hoehn and Yahr stage II-III, and all were inadequately
controlled with a treatment regimen of levodopa and
low-dose oral pramipexole or ropinirole, presenting with
early-morning motor impairment or nocturnal sleep
disturbance. The study identified no major safety concerns
when rotigotine was added to this treatment regimen.
The addition of rotigotine was also associated with
numerical improvements in efficacy outcomes, including
motor function and sleep disturbances.
The addition of rotigotine was generally well tolerated,
with the majority of patients (93%) not experiencing
drug-related AEs that interfered with functioning, as
assessed by the primary outcome (CGI item 4). In the
patients experiencing drug-related AEs that interfered
with functioning (CGI item 4 3), there was no obvious
relationship with the total DA dose (i.e., sum of
rotigotine and oral DA dose) or levodopa dose. Of note, the
majority of patients experienced an improvement on the
PGIC (81%), demonstrating that most patients
considered rotigotine add-on therapy as beneficial.
Figure 2 PDSS-2 total score, PSQI global score, number of awakenings during night time, and number of nocturias, FAS, LOCF. Before
rotigotine add-on: baseline; after rotigotine add-on: end of maintenance. 95% CI does not contain zero (for change from baseline [i.e., before
to after rotigotine add-on]). PDSS-2: Parkinsons Disease Sleep Scale; PSQI: Pittsburgh Sleep Quality Index; FAS: full analysis set; LOCF: last
observation carried forward.
PDSS-2 total score
PSQI global score
The AE profile was similar to previous studies of
rotigotine in patients with advanced PD, with typical
dopaminergic side-effects and application site reactions
observed, and AEs were comparable with those seen
with ropinirole or pramipexole [12-14,18]. They were
generally mild or moderate in intensity and led to
discontinuation in 6% patients. There was no apparent
relationship between the incidence of the most common
AEs and the dose of rotigotine, dose of oral DA, or total
DA dose. However, as the number of patients receiving
the different doses was relatively low, it is not possible
to reach conclusions on any potential AE dose-response
relationship. Hallucination was reported as an AE in two
patients, and the incidence of other dopaminergic AEs
including somnolence and impulsive behavior were low
(one patient each), and there were no reports of sleep
attacks. Therefore, taken together with the CGI item
4 results, the combination of low-dose rotigotine with a
low-dose oral DA is likely feasible from a safety perspective.
Numerical improvements in patients motor function
(UPDRS III) and ability to carry out ADL (UPDRS II)
were observed following rotigotine add-on therapy. A
reduction in off time was observed, with a corresponding
prolongation of time spent on without troublesome
dyskinesia (patient diary). This suggests that the
improvement in on time was not at the expense of
increased dyskinesia. The current study was not
designed to investigate the effect of the oral DA
formulation (i.e., IR vs ER) on the efficacy outcomes; however,
the formulation of the oral DA did not appear to have
an obvious effect on the improvement in off time.
Improvements in the non-motor symptom of sleep
disturbance (PDSS-2, PSQI, and patient diaries), and
PD-related quality of life (PDQ-8) were also observed.
In some patients with PD, symptoms may not be
adequately controlled with existing oral DA treatment, and
the dose cannot be sufficiently increased due to adverse
drug reactions. In addition, in some cases, night-time
symptoms may be observed although the current dose
of DA improves day-time symptoms. In the present
study, the patients were taking seemingly low doses
of pramipexole/ropinirole, yet they were receiving
stable doses which were maximal for the individual (i.e.,
best pharmacological therapy). The patients were
inadequately controlled on these doses, and the addition of
rotigotine aimed to further control their symptoms. We
observed that concurrent activation of D2 and D3
receptors following dual DA therapy was feasible, at least in
the dose ranges used. However, the mechanism/s by
which rotigotine added to pramipexole or ropinirole
induced potential benefits on efficacy outcomes (e.g.,
motor control, fluctuations, sleep disturbance) can only
be speculated. They may result from the increase in DA
total dose (i.e., leading to more robust activation of
D2/D3 receptors), the different DA receptor profiles
(i.e., stimulation of D1 receptor, which is unique to
rotigotine, combined with D2/D3 activation) and/or the different
There are some potential limitations to consider. First,
as there was no comparator arm or control group, and
no statistical significance testing was performed, this
limits the conclusions that can be drawn. Second, the
ability to generalize the results of this study is restricted
by the entry criteria of the study, and so limited to
patients with advanced PD inadequately controlled on
levodopa and a low-dose oral DA. Third, longer term
safety cannot be concluded from this 8-week study.
Finally, to prevent potential overstimulation of D2/D3
receptor after concomitant use of rotigotine-pramipexole
and rotigotine-ropinirole, less than half of the respective
approved maximum doses were used in this study.
Therefore, we cannot conclude whether higher doses may
provide further benefits or be associated with safety concerns.
In summary, this study demonstrates that addition of
rotigotine transdermal system to a low-dose oral DA
was feasible and may be associated with clinical benefit
in patients with advanced PD inadequately controlled on
levodopa and a low-dose oral DA. Dual therapy with
rotigotine transdermal system and a low-dose oral DA in
PD may represent a promising approach to treatment.
Equivalent dose should be taken into consideration
when the DAs are used concomitantly, and the
maximum dose of DAs should not exceed the upper limit of
the approved dose of any of the DAs. Double-blind
controlled studies are required to determine the significance
and clinical relevance of these findings.
Additional file 1: Table S1. Institutional Review Board review results at
each trial site in the PD0015 study.
Additional file 2: Figure S1. Study design.
Additional file 3: Table S2. General recommendations for equivalent
dosing regimens. Doses in bold show permitted maximum dose of each
dopamine receptor agonist in the PD0015 study. Pramipexole doses are
expressed in terms of pramipexole dihydrochloride monohydrate
(pramipexole salt); 1.0 mg pramipexole salt corresponds to 0.7 mg of
pramipexole monohydrate (pramipexole base).
Additional file 4: Figure S2. Oral DA and rotigotine dose distribution,
safety set. Converted rotigotine dose. Dose of rotigotine presented by
dose at end of titration. DA: dopamine receptor agonist.
Additional file 5: Table S3. Adverse events (AEs) (titration/maintenance
phase) occurring in at least 5% of patients reported by rotigotine and
oral DA dose. AEs occurring in at least 5% of all patients during the
entire study. Converted rotigotine dose. DA: dopamine receptor agonist.
Additional file 6: Table S4. Adverse events (AEs) (titration/maintenance
phase) occurring in 5% of patients reported by total DA dose. AEs
occurring in at least 5% of all patients during the entire study.
Converted rotigotine dose. DA: dopamine receptor agonist.
This study was supported by UCB Pharma, Monheim am Rhein, Germany,
and Otsuka Pharmaceutical Company, Ltd., Tokyo, Japan. JMK, SJC, JWK, and
BSJ received grant payments for enrolling patients into the study. BSJ has
received research grant support from Korean Ministry of Health, Seoul
National University Hospital, Lundbeck, Novartis, Ipsen, Samil, and AbbVie;
has served as a paid consultant for Lundbeck; and has received honoraria
from Ipsen. PS, ST, and LB are employees of UCB Pharma, Monheim am
Rhein, Germany; LB holds stock options from this employment. JI is an
employee of Otsuka Pharmaceutical Company, Ltd., Tokyo, Japan.
JMK was involved in the conception, organization and execution of this
study, and analysis or interpretation of data. SJC was involved in the
execution of this study, and analysis or interpretation of data. JWK was
involved in the execution of the study, and analysis or interpretation of data.
BSJ was involved in the conception, organization and execution of this
study, and analysis or interpretation of data. PS was involved in the study
concept or design, statistical analysis design, and analysis or interpretation of
data. ST was involved in the conception, organization and execution of this
study, and analysis or interpretation of data. JI contributed to the design of
the study protocol, management of the study, and analysis or interpretation
of data. LB participated in the conception and organization of this study, and
analysis or interpretation of data. All authors were involved in drafting or
critically revising the manuscript for important intellectual content and the
final approval of the published manuscript.
This study was supported by UCB Pharma, Monheim am Rhein, Germany,
and Otsuka Pharmaceutical Company, Ltd. Tokyo, Japan. The sponsors were
involved in the design of the study, the analysis and interpretation of data,
and in the decision to submit the paper for publication. The authors
acknowledge the Asia Pacific Rotigotine Add-on Study Group for their
contributions to data acquisition; Korea: Young-Ho Sohn (Severance
Hospital), Myung Sik Lee (Gangnam Severance Hospital), Sun Ju Chung
(Asan Medical Center), Sang Jin Kim (Inje University Busan Paik Hospital), Jin
Whan Cho (Samsung Medical Center), Hee Tae Kim (Hanyang University
Hospital), Kun Woo Park (Korea University Anam Hospital), Ho-Won Lee
(Kyungpook National University Medical Center), Beom Seok Jeon (Seoul
National University Hospital), Jong Min Kim (Seoul National University
Bundang Hospital), Jae Woo Kim (Dong-A University Medical Center);
Malaysia: Looi Irene (Hospital Seberang Jaya), Zariah Bt Abd Aziz (Hospital
Sultanah Nur Zahirah), Siew Hung Sim (Hospital Umum Sarawak); Taiwan:
Chon-Haw Tsai (China Medical University Hospital), Tian-Jun Zheng (ChiMei
Medical Center-Yongkang), Ruey-Meei Wu (National Taiwan University
Hospital); Australia: Raymond Schwartz (Southern Neurology St George
Private Hospital), Roy Beran (Strategic Health Evaluators), Andrew Evans
(Flemington Neurology), Michael Hayes (Concord Hospital); Singapore: Louis Tan
(National Neuroscience Institute), Eng King Tan (Singapore General Hospital).
The authors also acknowledge Emily Thompson, PhD, Evidence Scientific
Solutions, London, UK, for writing and editorial assistance towards the
development of the manuscript, which was funded by UCB Pharma, Brussels,
Belgium, and Azita Tofighy, Publications Manager, UCB Pharma, Brussels,
Belgium, for publication coordination.
1. Ahlskog JE , Muenter MD . Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature . Mov Disord . 2001 ; 16 : 448 - 58 .
2. Jankovic J. Motor fluctuations and dyskinesias in Parkinson's disease: clinical manifestations . Mov Disord . 2005 ; 20 Suppl 11:S11-6.
3. Kvernmo T , Hrtter S , Burger E. A review of the receptor-binding and pharmacokinetic properties of dopamine agonists . Clin Ther . 2006 ; 28 : 1065 - 78 .
4. Reichmann H , Herting B , Mller A , Sommer U. Switching and combining dopamine agonists . J Neural Transm . 2003 ; 110 : 1393 - 400 .
5. Junghanns S , Glckler T , Reichmann H. Switching and combining of dopamine agonists . J Neurol . 2004 ;251 Suppl 6:VI/19- 23 .
6. Stocchi F , Vacca L , Berardelli A , Onofrj M , Manfredi M , Ruggieri S. Dual dopamine agonist treatment in Parkinson's disease . J Neurol . 2003 ; 250 : 822 - 6 .
7. Scheller D , Ullmer C , Berkels R , Gwarek M , Lbbert H. The in vitro receptor profile of rotigotine: a new agent for the treatment of Parkinson's disease . Naunyn Schmiedebergs Arch Pharmacol . 2009 ; 379 : 73 - 86 .
8. Elshoff JP , Braun M , Andreas JO , Middle M , Cawello W. Steady-state plasma concentration profile of transdermal rotigotine: an integrated analysis of three, open-label, randomized, phase I multiple dose studies . Clin Ther . 2012 ; 34 : 966 - 78 .
9. Millan MJ . From the cell to the clinic: a comparative review of the partial D (2)/D(3)receptor agonist and alpha2-adrenoceptor antagonist, piribedil, in the treatment of Parkinson's disease . Pharmacol Ther . 2010 ; 128 : 229 - 73 .
10. Radad K , Gille G , Rausch WD . Short review on dopamine agonists: insight into clinical and research studies relevant to Parkinson's disease . Pharmacol Rep . 2005 ; 57 : 701 - 12 .
11. Vermeulen RJ , Drukarch B , Sahadat MC , Goosen C , Wolters EC , Stoof JC . The dopamine D1 agonist SKF 81297 and the dopamine D2 agonist LY 171555 act synergistically to stimulate motor behavior of 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine-lesioned parkinsonian rhesus monkeys . Mov Disord . 1994 ; 9 : 664 - 72 .
12. Poewe WH , Rascol O , Quinn N , Tolosa E , Oertel WH , Martignoni E , et al. Efficacy of pramipexole and transdermal rotigotine in advanced Parkinson's disease: a double-blind, double-dummy, randomised controlled trial . Lancet Neurol . 2007 ; 6 : 513 - 20 .
13. LeWitt PA , Lyons KE , Pahwa R. Advanced Parkinson disease treated with rotigotine transdermal system : PREFER Study. Neurology. 2007 ; 68 : 1262 - 7 .
14. Trenkwalder C , Kies B , Rudzinska M , Fine J , Nikl J , Honczarenko K , et al. Rotigotine effects on early morning motor function and sleep in Parkinson's disease: a double-blind, randomized, placebo-controlled study (RECOVER) . Mov Disord . 2011 ; 26 : 90 - 9 .
15. Schapira AH , Barone P , Hauser RA , Mizuno Y , Rascol O , Busse M , et al. Extended-release pramipexole in advanced Parkinson disease: a randomized controlled trial . Neurology . 2011 ; 77 : 767 - 74 .
16. Stocchi F , Giorgi L , Hunter B , Schapira AH . PREPARED: comparison of prolonged and immediate release ropinirole in advanced Parkinson's disease . Mov Disord . 2011 ; 26 : 1259 - 65 .
17. Giladi N , Boroojerdi B , Korczyn AD , Burn DJ , Clarke CE , Schapira AH . Rotigotine transdermal patch in early Parkinson's disease: a randomized, double-blind, controlled study versus placebo and ropinirole . Mov Disord . 2007 ; 22 : 2398 - 404 .
18. Etminan M , Gill S , Samii A. Comparison of the risk of adverse events with pramipexole and ropinirole in patients with Parkinson's disease: a meta-analysis . Drug Saf . 2003 ; 26 : 439 - 44 .