Rotigotine Transdermal Patch in Parkinson’s Disease: A Systematic Review and Meta-Analysis
et al. (2013) Rotigotine Transdermal Patch in Parkinson's Disease: A Systematic Review and Meta-Analysis. PLoS
ONE 8(7): e69738. doi:10.1371/journal.pone.0069738
Rotigotine Transdermal Patch in Parkinson's Disease: A Systematic Review and Meta-Analysis
Chang-Qing Zhou 0
Shan-Shan Li 0
Zhong-Mei Chen 0
Feng-Qun Li 0
Peng Lei 0
Guo-Guang Peng 0
Hideyuki Sawada, National Hospital of Utano, Japan
0 Department of Neurology, The First Affiliated Hospital of Chongqing Medical University , Chongqing , P. R. China
Background and Methods: The efficacy and safety of rotigotine transdermal patch in Parkinson's disease (PD) were studied in some clinical trials. We performed a systematic review and meta-analysis of randomized controlled trials to evaluate the efficacy, tolerability, and safety of rotigotine transdermal patch versus placebo in PD. Results: Six randomized controlled trials (1789 patients) were included in this meta-analysis. As compared with placebo, the use of rotigotine resulted in greater improvements in Unified Parkinson's Disease Rating Scale activities of daily living score (weighted mean difference [WMD] -1.69, 95% confidence interval [CI] -2.18 to -1.19), motor score (WMD -3.86, 95% CI - 4.86 to -2.86), and the activities of daily living and motor subtotal score (WMD -4.52, 95% CI -5.86 to -3.17). Rotigotine was associated with a significantly higher rate of withdrawals due to adverse events (relative risk [RR] 1.82, 95% CI 1.29-2.59), and higher rates of application site reactions (RR 2.92, 95% CI 2.29-3.72), vomiting (RR 5.18, 95% CI 2.25-11.93), and dyskinesia (RR 2.52, 95% CI 1.47-4.32) compared with placebo. No differences were found in the relative risks of headache, constipation, back pain, diarrhea, or serious adverse events. Conclusions: Our meta-analysis showed that the use of rotigotine can reduce the symptoms of PD. However, rotigotine was also associated with a higher incidence of adverse events, especially application site reactions, compared with placebo.
Parkinsons disease (PD) is a chronic and progressive
neurodegenerative disorder characterized by the symptoms of resting
tremor, rigidity, bradykinesia, and postural instability. These
symptoms are largely caused by the progressive loss of
dopaminergic neurons in the substantia nigra compacta, which ultimately
reduces dopaminergic input to the striatum and other brain
regions . PD is the second most prevalent neurodegenerative
disease, and affects approximately 1.7 million Chinese individuals
Although clinical and pathologic studies have failed to
demonstrate the neuroprotective effects of levodopa , levodopa
is considered the most effective drug for managing PD .
However, the initial therapeutic efficacy is often impacted within a
few years by the development of motor complications (fluctuations,
dyskinesias)  that are intractable to treatment. It is now
thought that pulsatile stimulation of striatal dopamine receptors,
caused by intermittent administration of levodopa and erratic
gastrointestinal absorption, plays a key role in the development of
these motor complications .
Rotigotine is a non-ergot dopamine agonist that is suitable for
transdermal delivery via skin patches . Once-daily
administration of a rotigotine transdermal patch (referred to here as
rotigotine) provides stable plasma concentrations of rotigotine over
24 hours  and is associated with high compliance under
clinical practice conditions . Non-oral routes of rotigotine
delivery are particularly useful in patients scheduled for surgery or
in those with dysphagia . In the past decade, some clinical
trials have been carried out to evaluate the efficacy and safety of
rotigotine versus placebo, but one of these trials obtained
inconclusive results . Furthermore, crystal formation was
noted in some rotigotine patches and these crystal-related changes
may reduce its bioavailability and clinical efficacy . The
marketing authorization of rotigotine was suspended by the United
States Food and Drug Administration in 2008 because of this
issue, although rotigotine was reintroduced in the United States in
2012. To date, no meta-analyses of rotigotine have been
performed to evaluate its efficacy in PD. Therefore, we pooled
all the results of randomized controlled trials that were published
up to July 2012, and performed a comprehensive meta-analysis to
evaluate the efficacy, tolerability, and safety of rotigotine in PD.
We conducted systematic literature searches of PubMed,
EMBASE, Cochrane Library, and Web of Knowledge up to July
2012 without language limitations. A search strategy was
performed using the following Medical Subject Headings (MeSH)
and keywords: rotigotine, rotigotine transdermal patch, and
transdermal rotigotine in combination with Parkinsons
disease, Parkinsons, and PD. We also manually searched
the references cited in clinical trial reports or reviews to identify
additional relevant clinical trials. To maximize data requisition, we
also contacted the authors whose articles contained insufficient
information, where necessary.
Randomized controlled trials of rotigotine transdermal patch
were included if they reported efficacy data in the form of Unified
Parkinsons Disease Rating Scale (UPDRS) scores (activities of
daily living [ADL] score, motor score, and/or the ADL and motor
subtotal score) and safety data in the form of adverse events.
Additional endpoints included: (1) overall withdrawals and
withdrawals due to adverse events; and (2) serious adverse events.
In trials for which there was more than one publication involving
the same population, the most recent report was selected for
analysis and the earlier articles were reviewed for missing data,
Two investigators (CQZ and FQL) independently evaluated all
of the included trials. Any disagreement was resolved by discussion
with a third investigator (PL). The validated Jadad scale was used
to assess the methodological quality of the included trials .
This scale assesses inherent controllers of bias with the following
quality assessment criteria: use of and methods for generating
randomization, use of and methods for double-blinding, and
description of patient withdrawals/dropouts. One point was given
for each satisfied criterion. The aggregate score was calculated for
each included trial and ranged from 0 (weakest) to 5 (strongest);
trials scoring ,3 were deemed to have lower methodological
Using a pre-designed data extraction form, two investigators
(CQZ and FQL) collected data independently with differences
resolved by a third investigator (PL). The following information
was collected from each trial: first authors surname, year of
publication, details of study design, methodological quality
(assessed using Jadad criteria), patient characteristics (including
gender, age, ethnicity, inclusion criteria, and disease severity at
baseline), sample size, treatment of early- or late-stage disease,
dose of rotigotine, duration of treatment, changes in UPDRS
scores (ADL score, motor score, and the ADL and motor subtotal
score), overall withdrawals, withdrawals due to adverse events, and
the incidence of adverse events.
We combined the results of each trial by using standard
metaanalytic methods to estimate the overall efficacy, tolerability, and
safety. We classified trials according to the randomized treatment
comparison: rotigotine (plus levodopa) versus placebo (plus
The mean changes in UPDRS scores from baseline were treated
as continuous variables and the weighted mean differences
(WMDs) were calculated. Withdrawals and adverse events were
treated as dichotomous variables and reported as relative risks
(RRs) with 95% confidence intervals (CIs). The overall effect was
tested using z scores calculated by Fishers z transformation, with
significance set at P,0.05. Statistical heterogeneity between trials
was evaluated by the x2 and I2 tests, with significance set at
P,0.10. If heterogeneity existed, the random-effect model was
used to combine the results; otherwise, the fixed-effect model was
used. Heterogeneity was only reported where it was statistically
significant. Subgroup and sensitivity analyses were also performed.
All data analyses were carried out using Stata software version
12.0 (Stata Corp LP, College Station, TX, USA).
Search Results and Study Characteristics
The literature searches identified 132 potential articles, of which
12 were randomized controlled clinical trials. Although the results
of the study by Quinn et al.  were inconclusive, we did not
obtain the full-text after contacting the author. Six large-scale
randomized controlled trials involving 1789 patients were
ultimately included in this meta-analysis. The study flow chart is
presented in Figure 1. Of the studies included, three involved early
PD patients who had not taken levodopa , two involved
advanced PD patients who had already taken levodopa ,
and one involved a mixture of patients with the early or advanced
PD . Quality assessment demonstrated that all the trials had
Jadad scores that ranged from 4 to 5. The main characteristics of
these trials are summarized in Table 1.
All six trials evaluated the efficacy of rotigotine versus placebo
using UPDRS scores (Table 2). In the four trials [20,2224]
(n = 1105) that assessed UPDRS ADL score and motor score,
patients had a greater response to rotigotine than placebo, as
evidenced by significantly greater reductions from baseline in ADL
score (WMD 1.69, 95% CI 2.18 to 1.19; P,0.0001; Figure 2A)
and motor score (WMD 3.86, 95% CI 4.86 to 2.86; P,0.0001;
Figure 2B). In the three trials  (n = 845) that assessed the
UPDRS ADL and motor subtotal score in early PD, patients had a
greater response to rotigotine than placebo, as evidenced by a
significantly greater reduction from baseline in subtotal score
(WMD 4.52, 95% CI 5.86 to 3.17; P,0.0001; Figure 2C).
In all six trials  that reported the overall number of
patient withdrawals, we found no difference between rotigotine
MC DB Phase III RCT (5)
MC DB Phase III RCT (4)
MC DB Phase III RCT (5)
MC DB Phase III RCT (5)
MC DB Phase III RCT (5)
MC DB Phase III RCT (5)
Rotigotine vs Placebo (195/47),
Rotigotine dose (mg/day): 2, 4,
6, 8, Duration (w): 11
Rotigotine vs Placebo (181/96),
Rotigotine dose (mg/day):
up to 6, Duration (w): 27
Rotigotine vs Placebo (215/118),
Rotigotine dose (mg/day):
up to 8, Duration (w): 37
Mean age (y): 62/65, Men (%): UPDRS ADL, Motor and
68/60, Duration of PD (y): subtotal, dropouts, adverse
Mean age (y): 61/60, Men (%): 55/UPDRS ADL+Motor subtotal,
58, Duration of PD (y): 1.4/1.2 dropouts, adverse events
Rotigotine+LD vs Placebo+LD Mean age (y): 66/66, Men (%): UPDRS ADL and Motor,
(229/120), Rotigotine dose (mg/day): 65/62, Duration of PD (y): dropouts, adverse events,
8, 12, Duration (w): 12 7.7/7.7 on and off time
Rotigotine+LD vs Placebo+LD Mean age (y): 64/65, Men (%): UPDRS ADL and Motor,
(201/100), Rotigotine dose (mg/day): 66/71, Duration of PD (y): dropouts, adverse events,
up to 16, Duration (w): 29 8.9/8.5 on and off time
Abbreviations: MC = multicenter; DB = double-blinded; vs = versus; RCT = randomized controlled trial; Y = year; W = week; UPDRS = unified Parkinsons disease rating
scale; LD = levodopa; ADL = activities of daily living; PSG = Parkinson study group.
a6LD indicates that trial design allowed levodopa to be added to the randomized treatment; the dose of rotigotine is expressed as the delivered dose.
and placebo (RR 0.88, 95% CI 0.641.21; P = 0.44; Figure 3A),
with some evidence of heterogeneity between trials (P = 0.037,
I2 = 57.7%). This heterogeneity was mostly explained by the
atypical results of one study  in which there were significantly
more withdrawals in the placebo group than in the rotigotine
group (25.74% versus 11.27%). Patients withdrew from trial for
various reasons. In the study by Poewe et al. , more patients
withdrew due to unsatisfactory therapeutic effects and consent
withdrawal in the placebo group than in the rotigotine group
(14.85% versus 5.39%). This may be related to a slightly lower
proportion of patients receiving concomitant antiparkinsonian
drugs, in addition to levodopa, in the placebo group (43%) than in
the rotigotine group (52%), and the double-dummy trial design
(rotigotine, pramipexole, and placebo). Other factors that may
contribute to the heterogeneity included the longer duration of PD
in the trial by Poewe et al.  than in the other trials, and the
mean daily dose of levodopa was higher in the trial by Poewe et al.
than in another trial of advanced PD patients . When we
excluded the trial by Poewe et al. , there was no heterogeneity
(P = 0.61, I2 = 0%) and no difference was also found between
rotigotine and placebo (RR 1.03, 95% CI 0.831.27; P = 0.80). In
all six trials that reported the number of patient withdrawals due to
adverse events, the outcome occurred in 139/1215 (11.4%)
patients treated with rotigotine, and in 37/577 (6.4%) patients
treated with placebo. Rotigotine was associated with a significantly
higher rate of withdrawals due to adverse events compared with
placebo (RR 1.82, 95% CI 1.292.59; P = 0.0008; Figure 3B).
All six trials reported adverse events with an incidence of $5%
in the rotigotine group. The results of the meta-analysis of adverse
events that were reported in at least three trials are summarized in
Table 3 and the pooled incidence rates of adverse events in PD
patients treated with rotigotine are presented in Figure 4. The
most commonly reported adverse events and serious adverse
events are discussed below.
All six trials reported the incidence of application site reactions
and its incidence was significantly higher with rotigotine than with
placebo (RR 2.92, 95% CI 2.293.72; P,0.0001; Figure 5A). The
incidence of dizziness was reported in all six trials, and its
incidence was significantly higher with rotigotine than with
placebo (RR 1.47, 95% CI 1.121.95; P = 0.006; Figure 5B). In
all six trails that reported the incidence of headache, no difference
was found between rotigotine and placebo (RR 1.27, 95% CI
0.921.76; P = 0.15; Figure 5C). In the four trials [19,21,23,24]
that reported the incidence of serious adverse events, no difference
was also found between rotigotine and placebo (RR 1.14, 95% CI
0.731.80; P = 0.56; Figure 5D).
Subgroup and Sensitivity Analyses
In subgroup analyses, UPDRS scores and overall withdrawals
were analyzed separately in early PD patients who had not taken
levodopa and in advanced PD patients who had already taken
levodopa (Table 2). The results of these subgroup analyses were
consistent with the results for all PD patients combined. The
number of patients who withdrew due to adverse events was
significantly greater in the rotigotine group than in the placebo
group among early PD patients (RR 2.72, 95% CI 1.574.70;
P = 0.0004), but no difference was found in advanced PD patients
(RR 1.40, 95% CI 0.822.37; P = 0.22). When the incidence of
adverse events was reanalyzed in early PD patients who had not
taken levodopa and in advanced PD patients who had already
taken levodopa, the results were consistent with those reported for
each of the meta-analyses in all patients, except for dizziness,
nausea, somnolence, and insomnia (Table 3). Although rotigotine
was associated with significantly higher incidences of dizziness,
nausea, and insomnia in all patients and in early PD patients
compared with placebo, no difference was found in advanced PD
patients. Although rotigotine was associated with a significantly
higher incidence of somnolence in all PD patients, no differences
between rotigotine and placebo were found in early PD patients or
in advanced PD patients.
Figure 2. Impact of rotigotine versus placebo on UPDRS scores. Panel A: UPDRS ADL score. Panel B: UPDRS motor score. Panel C: UPDRS ADL
and motor subtotal score. Abbreviations: UPDRS = unified Parkinsons disease rating scale; ADL = activities of daily living.
Abbreviations: UPDRS = unified Parkinsons disease rating scale; PD = Parkinsons disease; WMD = weighted mean difference; RR = relative risk; CI = confidence interval;
LD = levodopa; ADL = activities of daily living; N/A = not available.
a+LD indicates that patients also took levodopa during the trials.
ADL+motor subtotal score
Withdrawals due to adverse events
Early and advanced PD
Figure 3. Effect of rotigotine versus placebo on withdrawals. Panel A: Overall withdrawals. Panel B: Withdrawals due to adverse events.
In the analysis of overall withdrawals, there was statistically
significant heterogeneity due to the study by Poewe et al. .
When this trial was excluded, no difference was also found
between rotigotine and placebo (RR 1.03, 95% CI 0.831.27;
P = 0.80). In the trial by Poewe et al. , application site
reactions were reported as erythema and pruritus, but the exact
incidence of application site reactions was not reported. Therefore,
we used the total incidence of erythema and pruritus instead of the
incidence of application site reactions and combined it with the
incidences of application site reactions reported in the other five
studies (RR 2.92, 95% CI 2.293.72; P,0.0001). After excluding
the study by Poewe et al. , we reanalyzed the results to
perform the sensitivity analysis. Finally, the results were consistent
with those of the previous analysis (RR 3.07, 95% CI 2.373.99;
P,0.0001). Since all the trials included had Jadad scores of 4 or
higher and there were no open-label trails, we were unable to
conduct these sensitivity analyses.
This is the first meta-analysis of randomized controlled trials to
assess the efficacy, tolerability, and safety of rotigotine in PD
patients. Our results demonstrated that rotigotine was associated
with significant improvements in PD symptoms, as evidenced by
reductions in UPDRS ADL score, motor score, and the ADL and
motor subtotal score compared with placebo. The magnitude of
reduction in UPDRS ADL score (1.69) in the overall cohort of
PD patients was slightly greater than that in early PD patients (
1.64) but smaller than that in advanced PD patients (2.2) when
we compared the results with those of two meta-analyses of
dopamine agonists [25,26]. In early PD patients who had not
taken levodopa, the reduction in UPDRS ADL score (1.31) was
smaller than that reported for early PD patients (1.64) in
dopamine agonists . In advanced PD patients who had already
taken levodopa, the reduction in UPDRS ADL score (2.37) was
higher than that reported for advanced PD patients (2.2) in the
earlier study . However, the reduction in UPDRS motor score
(3.86) was smaller than that reported for early PD patients (5.32)
and advanced PD patients (5.56) [25,26]. In the subgroup
analysis, the effect sizes of rotigotine versus placebo in UPDRS
motor score among early (3.96) and advanced PD patients (4.37)
were small as compared with those of dopamine agonists in
previous studies [25,26]. This may be due to the shorter
observation period of the rotigotine trials [19,22]. In advanced
PD, patients treated with rotigotine also exhibit a significant
reduction in off time and an increase in on time without
troublesome dyskinesia as compared with patients treated with
placebo (data not shown). Although there were only two trials of
advanced PD, the reduction in off time (1.56) was similar to
that reported for dopamine agonists (1.2) . In the present
study, the reductions in UPDRS motor score and off time were
statistically significant and meet the newly suggested criteria for
clinical relevance where reductions in motor score of 3.5 points
and off time of 1 hour are considered to be the minimal
clinically important changes in early and advanced PD .
Although rotigotine was not associated with a significant
increase in the overall withdrawals from trials, it was associated
with a significant increase in withdrawals due to adverse events
(11.4%) compared with placebo (6.4%). The rate of withdrawals
due to adverse events among rotigotine-treated patients was
similar to that in meta-analyses of dopamine agonists (11.9%) and
monoamine oxidase type B inhibitors (10.2%) [25,28]. In our
subgroup analysis, rotigotine was associated with a significant
increase in the rate of withdrawals due to adverse events in early
PD patients but not in advanced PD patients as compared with
placebo. The results in advanced PD patients were not statistically
significant and could be attributed to the finding that one trial
included worsening of PD as an adverse event .
Application site reactions
Early and advanced PD
No. of trials RR(95%CI)
Abbreviations: PD = Parkinsons disease; RR = relative risk; CI = confidence interval; ROT = rotigotine; PLA = placebo; LD = levodopa; vs = versus; N/A = not available.
a+LD indicates that patients also took levodopa during the trials.
Figure 5. Effect of rotigotine versus placebo on the incidence of adverse events. Panel A: Application site reactions. Panel B: Dizziness.
Panel C: Headache. Panel D: Serious adverse events.
The results of pooled incidences of adverse events showed that
application site reactions, nausea, and somnolence were the most
common adverse events in the overall cohort of patients and in
subgroups of early and advanced PD patients who received
rotigotine. These findings were consistent with those of a study of
rotigotine in early and advanced PD patients aged ,65 or $65
years . Although a study of ropinirole previously evaluated
some of the adverse events associated with rotigotine , the
fundamental objective was to evaluate the safety of ropinirole;
therefore, application site reactions and serious adverse events, in
particular, were not assessed. In the present study, more trials were
included and adverse events reported in at least three trials were
studied. We found that application site reactions were the most
common adverse events and patients treated with rotigotine had
about threefold greater risk of developing application site reactions
in the overall cohort and in subgroups of early and advanced PD
patients. Erythema and pruritus were the most commonly
reported skin reactions. Although application site reactions
occurred in up to 32.7% of patients in the rotigotine group, most
events were reported to be mild to moderate, and the incidence
was similar to that of other transdermal patches, including
rivastigmine (31%) . However, in the subgroup analysis, the
incidence of application site reactions was higher in early PD
patients than in advanced PD patients. This was probably due to
one study  that reported the incidences of erythema and
pruritus, but not other skin reactions.
In the present study, we evaluated four gastrointestinal side
effects including nausea, diarrhea, vomiting, and constipation.
Although rotigotine is delivered through a transdermal patch,
early PD patients had about fivefold greater risk of developing
vomiting and about twofold greater risk of developing nausea
when treated with rotigotine compared with placebo. These results
are consistent with those reported by Kulisevsky et al. .
However, rotigotine was not associated with increased risks of
diarrhea and constipation. Rotigotine also increased the risk of
dyskinesia by about twofold in advanced PD patients. In the
overall cohort of PD patients and early PD patients, rotigotine was
also associated with significantly increased risks of dizziness and
insomnia but not of serious adverse events, headache, or back
pain. In the overall and subgroup analyses, we found some
discrepancies in the incidences of nausea, somnolence, dizziness,
and insomnia. Because of the small number of studies available for
the subgroup analyses, further studies are needed to clarify the
impact of rotigotine on the incidence of these events.
There are some limitations that should be mentioned to
appropriately interpret the results of our study. First, in some
comparisons, especially in subgroup analyses, there were only one
or two clinical trials available, sometimes with a relatively low
incidence of events, which means that the results of these analyses
cannot be generalized. Second, the safety and tolerability variables
were considered as secondary objectives, and most trials did not
report adverse events with incidences of ,5%. Furthermore, a
classic bias in analyses of adverse events in randomized controlled
trials is the inclusion of studies with short observation periods.
Therefore, the conclusions can only be drawn for the most
common adverse events and the overall incidence of adverse
events might have been underestimated. Finally, the assessment of
publication bias was not performed because only six trials were
included in the present study.
In conclusion, our meta-analysis showed that the use of
rotigotine transdermal patch can reduce the symptoms of PD.
However, rotigotine was also associated with a higher incidence of
adverse events, especially application site reactions, compared with
placebo. Although refrigerated storage of rotigotine transdermal
patch at 28uC can reduce the development of crystals, the
definitive resolution of the problem is to reformulate the drug
product. The manufacturer recently reformulated the patch ,
and the reformulated patch can be stored at room temperature
without the development of crystals. Further studies are also
necessary to evaluate the reformulated patch.
PRISMA 2009 Checklist for the meta-analysis.
We are indebted to the authors of the primary studies.
Conceived and designed the experiments: CQZ GGP. Performed the
experiments: CQZ SSL ZMC FQL PL GGP. Analyzed the data: CQZ
SSL GGP. Contributed reagents/materials/analysis tools: CQZ SSL ZMC
FQL PL. Wrote the paper: CQZ GGP. Collected the data: CQZ FQL PL.
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