Rotigotine transdermal system and evaluation of pain in patients with Parkinson’s disease: a post hoc analysis of the RECOVER study
Rotigotine transdermal system and evaluation of pain in patients with Parkinson's disease: a post hoc analysis of the RECOVER study
Jan Kassubek 0
Kallol Ray Chaudhuri 1 2
Theresa Zesiewicz 6
Erwin Surmann 5
Babak Boroojerdi 4
Kimberly Moran 3
Liesbet Ghys 8
Claudia Trenkwalder 7
0 Department of Neurology, University of Ulm , Oberer Eselsberg 45, 89081 Ulm , Germany
1 MRC Centre for Neurodegeneration Research, King's College , London , UK
2 National Parkinson Foundation Centre of Excellence, King's College Hospital , London , UK
3 UCB Pharma , Smyrna, GA , USA
4 UCB Pharma , Raleigh, NC , USA
5 UCB Pharma , Monheim am Rhein , Germany
6 University of South Florida , Tampa, FL , USA
7 University of Gottingen, Department of Neurosurgery and Paracelsus-Elena Klinik, Center of Parkinsonism and Movement Disorders , Kassel , Germany
8 UCB Pharma , Brussels , Belgium
Background: Pain is a troublesome non-motor symptom of Parkinson's disease (PD). The RECOVER (Randomized Evaluation of the 24-hour Coverage: Efficacy of Rotigotine; Clintrials.gov: NCT00474058) study demonstrated significant improvements in early-morning motor function (UPDRS III) and sleep disturbances (PDSS-2) with rotigotine transdermal system. Improvements were also reported on a Likert pain scale (measuring any type of pain). This post hoc analysis of RECOVER further evaluates the effect of rotigotine on pain, and whether improvements in pain may be attributable to benefits in motor function or sleep disturbance. Methods: PD patients with unsatisfactory early-morning motor impairment were randomized to optimal-dose (up to 16 mg/24 h) rotigotine or placebo, maintained for 4 weeks. Pain was assessed in the early-morning using an 11-point Likert pain scale (rated average severity of pain (of any type) over the preceding 12 hours from 0 [no pain] to 10 [worst pain ever experienced]). Post hoc analyses for patients reporting 'any' pain (pain score 1) at baseline, and subgroups reporting 'mild' (score 1-3), and 'moderate-to-severe' pain (score 4) were performed. Likert pain scale change from baseline in rotigotine-treated patients was further analyzed based on a UPDRS III/PDSS-2 responder analysis (a responder defined as showing a 30% reduction in early morning UPDRS III total score or PDSS-2 total score). As post hoc analyses, all p values presented are exploratory. Results: Of 267 patients with Likert pain data (178 rotigotine, 89 placebo), 187 (70%) reported 'any' pain; of these 87 (33%) reported 'mild', and 100 (37%) 'moderate-to-severe' pain. Change from baseline pain scores decreased with rotigotine compared with placebo in patients with 'any' pain (-0.88 [95% CI: -1.56, -0.19], p = 0.013), and in the subgroup with 'moderate-to-severe' pain (-1.38 [-2.44, -0.31], p = 0.012). UPDRS III or PDSS-2 responders showed greater improvement in pain than non-responders. Conclusions: The results from this post hoc analysis of the RECOVER study suggest that pain was improved in patients with PD treated with rotigotine; this may be partly attributable to benefits in motor function and sleep disturbances. Prospective studies are warranted to investigate this potential benefit and the clinical relevance of these findings.
Parkinson's disease; Pain; Rotigotine; Dopamine receptor agonist
Pain is a common and challenging non-motor symptom
of Parkinsons disease (PD), occurring in 40% to 85% of
patients with PD , with a higher prevalence and
intensity than in age-matched non-PD controls [1-5]. Pain is
rated by patients as one of the most troublesome
symptoms in both early and advanced stages of PD , and is
associated with reduced health-related quality of life
[6-10]. The complexity of PD-associated pain is
exemplified by the many different types and distributions of
pain, and the poor understanding of the mechanisms of
the pain syndrome. The origin of pain in PD may be
directly attributable to the patients motor symptoms such
as rigidity, dystonia, akinesia, or postural abnormalities.
Musculoskeletal pain is the most commonly reported
type of pain (by up to 70% of patients [1,2,11]) and may
be related to the presence of rigidity and akinesia, as well
as comorbid rheumatologic and orthopedic diseases, which
can result from pathologic postures such as camptocormia
. Pain associated with dystonic symptoms, including
spasms, has been reported by up to 40% of PD patients
[1,2,11] and is often associated with levodopa wearing off
as the disease progresses, particularly in the early morning
. In addition to pain being secondary to motor
symptoms, data also suggest that altered central pain processing
in PD may lead to a decreased pain threshold and
abnormal pain-evoked response, resulting in a predisposition to
develop pain [11,13,14].
Rotigotine is a dopamine receptor agonist 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 . The
RECOVER (Randomized Evaluation of the 24-hour
Coverage: Efficacy of Rotigotine; Clintrials.gov: NCT00474058)
study demonstrated that 4 weeks maintenance with
rotigotine transdermal system significantly improved the
coprimary outcome measures, i.e., early morning motor
function and nocturnal sleep disturbances, in PD patients
with unsatisfactory control of early morning motor
symptoms . In addition, improvements were reported for
other non-motor outcome measures, including a standard
Likert pain scale (measuring any type of pain), the
NonMotor Symptoms Scale (NMSS) total and domain scores,
the short form 8-item Parkinsons Disease Questionnaire
(PDQ-8) total score, and the Nocturnal Akinesia, Dystonia
and Cramps (NADCS) total score .
The current post hoc analysis of the RECOVER study
further investigates the effect of rotigotine transdermal
system on pain among patients with PD who reported
pain at baseline as rated by a Likert pain scale. Post hoc
analyses were also performed to investigate the
possibility that the observed improvements in pain with
rotigotine may at least in part, be directly attributable
to the improvement in motor impairment and sleep
Enrolled patients were men and women aged 18 years or
older, with PD (Hoehn and Yahr Stages IIV), and
unsatisfactory control of early morning motor symptoms as
determined by the investigator. Immediate-release
levodopa was permitted provided the dose was stable for at
least 28 days prior to baseline. The full RECOVER
(Clintrials.gov: NCT00474058) study design including complete
inclusion/exclusion criteria has been published . The
study was conducted in accordance with Good Clinical
Practice and the Declaration of Helsinki. The study
protocol and amendments were approved by the national,
regional, or Independent Ethics Committees or Institutional
Review Boards of all 49 participating centres (in 12
countries) (Additional file 1). All patients provided written,
informed consent before study participation.
Patients were randomized 2:1 to receive transdermal
patches containing rotigotine or placebo; treatment was
titrated to optimal dose (defined as the dose at which
both the investigator and patient felt that early morning
motor impairment was adequately controlled) over 1 to
8 weeks, starting at 2 mg/24 h and increasing to a
maximum of 16 mg/24 h. This dose was maintained for 4
weeks (maintenance phase), during which dose
adjustments (and alteration of levodopa dose) were not
permitted. Visits were scheduled at screening and baseline;
every 2 weeks during dose titration; start and end of
maintenance; and 30 days after treatment ended.
Patients were hospitalized for two nights at baseline and at
the end of maintenance. Patients who withdrew
prematurely were asked to return for a withdrawal visit. All
efficacy outcomes were assessed in the early morning; they
were assessed at baseline before new patch application
(after the first or second night of hospitalization), and at
the end of maintenance, or in the event that a patient
was prematurely withdrawn from the trial.
Assessment of pain
Patient rating of pain was recorded in the early morning,
after the second night of hospitalization, using a
standard 11-point Likert pain scale . The scale rated the
patients average severity of pain (of any type) over the
preceding 12 hours from 0 (no pain) to 10 (worst pain
ever experienced). In this post hoc analysis, Likert pain
scale score change from baseline to end of treatment
was assessed in patients with any pain at baseline, which
was defined as those who recorded a baseline Likert pain
scale score 1. Two further subgroups were defined from
this group: patients reporting mild pain (Likert pain scale
score 13), and those reporting moderate-to-severe pain
(Likert pain scale score 4) at baseline.
Six items were identified within the other assessment
scales used in RECOVER, that also provide an evaluation
of pain: nocturnal cramps (NADCS) ; painful
muscle cramps or spasms due to PD (PDQ-8) ;
nocturnal pain in arms or legs, muscle cramps in arms or
legs, and painful posturing in the morning (Parkinsons
Disease Sleep Scale [PDSS-2]) ; and suffer from pain
not explained by other known conditions (NMSS) .
These were assessed in the early morning. Baseline
scores of these individual items were assessed in patients
stratified by the severity of overall pain at baseline for
the subgroups with no pain, mild pain, and
moderateto-severe pain, as rated by the Likert pain scale.
The co-primary efficacy measures in RECOVER were
change from baseline in early morning motor function
assessed using the Unified Parkinsons Disease Rating
Scale (UPDRS) Part III (Motor Examination) measured
in the early morning, and nocturnal sleep disturbances
assessed using the modified PDSS-2 total scores. To
investigate the possibility that the observed improvements
in pain with rotigotine may be directly attributable to
the improvement in motor function and sleep disturbance,
the Likert pain scale change from baseline in
rotigotinetreated patients was further analyzed based on a UPDRS
III/PDSS-2 responder analysis. In RECOVER, a patient was
defined as a responder if showing a 30% reduction [23,24]
in early morning UPDRS III total score or PDSS-2 total
score from baseline to end of maintenance. Associations
of change in early morning motor function and nocturnal
sleep disturbances with change in pain were also assessed
using Pearson correlation coefficients for change from
baseline to end of maintenance in rotigotine-treated patients
with pain at baseline (as rated by the Likert pain scale).
Likert pain scale was assessed as change from baseline
to end of treatment, where end of treatment was the
combined results of observations from end of
maintenance and early withdrawal, using data as observed. Likert
pain scale analyses were performed on the full analysis
set (FAS). The FAS included all randomized patients
who received at least one dose of study drug and had a
baseline and at least one post-baseline measurement for
both co-primary efficacy variables. UPDRS Part III and
PDSS-2 were performed on the FAS and were assessed
as change from baseline to end of maintenance, with last
observation carried forward. Differences in
demographics/baseline characteristics between patients with pain
and patients with no pain at baseline (as assessed using
the Likert pain scale) were estimated using t-test for
continuous data, and the Chi-square test for categorical
data. Treatment differences for Likert pain score change
from baseline to end of treatment were estimated using
analysis of covariance (ANCOVA), with treatment and
region as factors and baseline Likert pain value as the
covariate. UPDRS and PDSS-2 30% responder status
differences for Likert pain score change from baseline to
end of treatment were estimated using ANCOVA, with
responder status and region as factors and baseline Likert
pain value as the covariate. As post hoc analyses, all p
values presented are exploratory and do not infer statistical
significance. No adjustments were made for multiplicity
due to closed test procedure for primary efficacy variables.
Patient disposition and baseline characteristics
Of 287 patients randomized (97 placebo, 190 rotigotine),
246 completed the study; 267 patients (89 placebo, 178
rotigotine) were included in the FAS, all of whom had
baseline and follow-up Likert pain scale scores. At
baseline, 187 (70%) patients with a Likert pain scale score 1
were considered to have any pain at baseline; 100 (37%)
patients with a Likert pain scale score 4 were considered
to have moderate-to-severe pain (Table 1). Of these
patients, 21 reported severe pain (defined as Likert pain
scale score 7); this subgroup with severe pain was not
investigated further due to the small sample size, but was
included in the overall analyses. Patients with
moderateto-severe pain at baseline had higher baseline scores on
UPDRS III (p = 0.013) and PDSS-2 (p < 0.0001) than
patients without pain (Table 1).
The mean SD rotigotine dose during the RECOVER
study maintenance period for the different Likert pain
scale subgroups were: 10.3 4.8 mg/24 h (n = 46) for
patients reporting no pain at baseline (pain score = 0),
11.5 4.3 mg/24 h (n = 132) for patients reporting any
pain, 12.0 3.9 mg/24 h (n = 62) for patients reporting
mild pain, and 11.1 4.6 mg/24 h (n = 70) for patients
reporting moderate-to-severe pain.
At baseline, individual item scores from other scales
used in RECOVER assessing pain, i.e., NADCS, PDQ-8,
PDSS-2, and NMSS, were higher (i.e., specific pain more
frequent/more severe) in patients with greater severity of
pain as assessed by the Likert pain scale (Table 2). Change
from baseline data for all items of the PDQ-8 and PDSS-2
showed an improvement with rotigotine versus placebo in
those items assessing pain and are reported elsewhere .
In patients with any pain at baseline as rated by the
Likert pain scale, change in Likert pain score from
baseline to end of treatment decreased with rotigotine
treatment compared with placebo, with a least squares (LS)
mean [95% CI] treatment difference of -0.88 [-1.56, -0.19],
p = 0.013. This was also the case in the subgroup of patients
Time since diagnosis, years
Taking levodopa (advanced PD)
UPDRS III total score
PDSS-2 total score
No pain (n = 80)
(pain score 0)
66.4 9.3 (3786)
4.7 4.4 (0.022.9)
Any pain (n = 187)
(pain score 1)
Mild pain (n = 87) Moderate-to-severe pain (n = 100)
(pain score 13) (pain score 4)
63.8 9.8 (3785); (p = 0.048)
63.1 10.4 (3785); (p = 0.032) 64.5 9.3 (4083); (p = 0.175)
69 (37); (p = 0.199)
23 (26); (p = 0.738) 46 (46); (p = 0.018)
4.9 4.4 (0.025.6); (p = 0.820)
4.5 3.8 (0.017.2); (p = 0.765) 5.1 4.9 (0.025.6); (p = 0.555)
156 (83); (p = 0.252)
70 (80); (p = 0.639)
29.2 11.9; (p = 0.621)
18.6 9.2; (p = 0.048)
86 (86); (p = 0.138)
Data are mean SD (range) or number of patients (%). Data are presented for the FAS.
P values (t-test for continuous data, Chi-square test for categorical data; exploratory analyses) are reported for patients with Any pain, Mild pain, and
Moderate-to-severe pain vs patients with No pain at baseline (assessed by the Likert pain scale).
FAS: full analysis set; PD: Parkinsons disease; PDSS-2: Parkinsons Disease Sleep Scale; SD: standard deviation; UPDRS III: Unified Parkinsons Disease Rating Scale.
with moderate-to-severe pain (-1.38 [CI: -2.44, -0.31], p =
0.012), but was not observed in patients with mild pain
Rotigotine-treated patients defined as UPDRS Part III
30% responders, showed a greater improvement on the
Likert pain scale than the non-responders. This was the
case for the patient group reporting any pain at baseline
(LS mean [95% CI] responder status difference -1.31
[-2.05, -0.57], p = 0.0007) and for the subgroup reporting
moderate-to-severe pain at baseline (-1.99 [-3.23, -0.74],
p = 0.002) (Figure 2A). Similarly, rotigotine-treated
patients classified as PDSS-2 30% responders showed a
greater improvement on the pain scale than the
nonresponders (Figure 2B). Pearson correlation coefficients
(r) between change from baseline to end of maintenance
in UPDRS III and PDSS-2 with Likert pain scale score
change from baseline (rotigotine-treated patients) are
presented in Additional file 2: Table S1; there was a
small association between change in pain and changes in
motor function (r = 0.40 [patients with mild pain], and
r = 0.31 [patients with moderate-to-severe pain]) and
nocturnal sleep disturbances (r = 0.30 [patients with
mild pain], and r = 0.16 [patients with
moderate-to-severe pain]). Results were comparable for Spearman
rank-order correlation coefficients (data not shown).
Our results show that more than two-thirds (70%) of
patients who participated in the RECOVER study reported
experiencing pain at baseline, in the 12 hours preceding
the early-morning assessments as rated by the Likert
pain scale (score 1). Over a third (37%) reported
moderate-to-severe pain (score 4), supporting prior
observations documenting pain as a common non-motor
symptom of PD [1-5]. The efficacy results from this post
hoc analysis suggest that 4 weeks of treatment with
optimal-dose rotigotine, up to 16 mg/24 h, improved
pain in patients reporting any pain at baseline, and in
the subgroup reporting moderate-to-severe pain.
The Likert pain scale indicates both presence and
severity of pain without distinguishing different types of
pain or causality. However, of note, patients who
reported pain at baseline appeared to have more advanced
motor symptoms of PD based on higher UPDRS Part III
score (p = 0.013 in patients with moderate-to-severe
pain vs patients with no pain), and greater nocturnal
sleep disturbance, as assessed by PDSS-2 (p <0.05 in
patients with any pain, mild pain and
moderate-to-severe pain vs patients with no pain). In addition, the
proportion of patients receiving levodopa was
numerically larger and mean disease duration was longer than
in patients who did not report any pain at baseline
(p >0.05). This would suggest that the symptoms of pain
observed at baseline in these patients may, at least in
part, be related to the severity of symptoms of PD. There
did not appear to be any difference in mean rotigotine
maintenance dose between the different pain subgroups.
The most marked rotigotine treatment effect, i.e.,
improvement in pain, was seen in patients with the most
pronounced pain, i.e., the moderate-to-severe pain
subgroup, while no relevant improvement compared with
placebo was observed in the subgroup of patients with
Pain score 4
Baseline score: 4.1 1.9 3.7 2.0
n = 55 n = 132
LS mean [95% CI] treatment difference; ANCOVA
-0.88 [-1.56, -0.19] -0.37 [-1.20, 0.46] -1.38 [-2.44, -0.31]
p = 0.013 p = 0.380 p = 0.012
Figure 1 Likert pain scale change from baseline in patients with pain at baseline. ANCOVA model with treatment and region as factors
and baseline pain score as the covariate. ANCOVA: analysis of covariance; CI: confidence interval; LS: least square; SD: standard deviation.
mild pain. However, the number of patients in this
subgroup with mild pain may not have been sufficient to
detect an effect for only mild symptoms. In addition, by
definition, patients in this subgroup had lower baseline
Likert pain scores (i.e., score 13), and there was
therefore less scope to detect a treatment effect.
Patients who responded to treatment with rotigotine
with at least a 30% improvement in their early morning
motor function (UPDRS Part III) or nocturnal sleep
disturbances (PDSS-2) showed a greater improvement in
overall pain compared with the UPDRS III/ PDSS-2
non-responders, supporting the concept that the pain
reported was to some extent related to their symptoms
of PD. In addition, baseline scores of the individual items
of the other scales used in RECOVER that assessed pain
(from the NADCS, PDQ-8, PDSS-2, and NMSS) were
higher in patients with pain as assessed by the Likert pain
scale than in patients with no pain (p <0.001 in patients
with moderate-to-severe pain vs patients with no pain
for all individual items assessing pain). This again suggests
Likert pain scale by UPDRS III responder status
Pain score 4
Likert pain scale by PDSS-2 responder status
Pain score 4
n = 84
n = 48
n = 37
n = 26
n = 47
n = 22
n = 63
n = 69
n = 27
n = 36
n = 36
n = 33
that the pain measured by the Likert pain scale was likely
to capture types of pain assessed with these items, e.g., pain
in limbs, muscle cramps due to PD, and painful posturing.
A previous post hoc analysis of the RECOVER study,
evaluating individual items of the PDSS-2 and PDQ-8, showed
that the prevalence of four items recording the presence of
pain ranged from 27% (painful posturing in the morning)
to 38% (painful muscle cramps or spasms), and suggested
that rotigotine had a beneficial effect on painful muscle
cramps or spasms due to PD, frequency of nocturnal pain
in arms or legs, nocturnal muscle cramps in arms or legs,
and painful posturing in the morning . These
symptoms can be signs of the off state of PD, which may have
predominated at that time, and possibly be associated with
levodopa wearing off. All patients in the RECOVER study
had inadequate control of early morning motor function. It
is therefore possible that patients who were taking
levodopa may have been under dosed, and this may also be a
factor contributing to the pain reported in these patients.
Taken together, these data suggest that the improvement
in pain with rotigotine may, at least in part, be secondary
to improvements in motor symptoms, including dystonic
symptoms at night or in the early morning.
Pain in patients with PD has previously been described
to fluctuate with motor fluctuations, with more frequent
and severe pain in off compared with on states .
However, as the correlation analyses in the current study
showed a small association between change in pain and
changes in motor function (r = 0.310.40) and nocturnal
sleep disturbances (r = 0.160.30), the pain reported by
the patients may also include pain unrelated to motor
function or sleep disturbance. Pain in PD should
therefore be considered as a non-motor symptom in PD per
se, and may also be linked to alterations in pain
sensation [11,13,14,27,28]. Although the extent of
dopaminergic neuron involvement in pain perception is not
established, studies have suggested that dopaminergic
stimulation of striatal dopamine D2/D3 receptors may
improve pain .
In the RECOVER study population, improvements
were also observed in favor of rotigotine in scales/items
assessing the neuropsychiatric symptoms of depression,
apathy and anhedonia (secondary or post hoc exploratory
analyses) [17,30]. It is possible that elevated mood may
have contributed to improvements in subjective pain and,
conversely, improvements in pain may have contributed
to improvements in mood. However, it is not possible to
characterize the interaction between the observed
improvements in pain and neuropsychiatric symptoms from
this post hoc analysis.
There are several limitations of this post hoc analysis
to consider. First, these analyses are exploratory in
nature therefore the statistical significance or clinical
relevance of the observed improvements in pain, following
treatment with rotigotine cannot be determined from
these results. Second, because patients were not selected
for the RECOVER study based on symptoms of pain,
post hoc selection using subjective Likert pain scales
scores may have biased the results. Third, the limitation
of the Likert pain scale to assess general pain, i.e., its
inability to record information on the types and causes of
pain, and also the retrospective observation limited to
the preceding 12 hours. It is also important to note that
the clinical relevance of the arbitrary categorization of
patients as reporting mild and moderate-to-severe pain
on the Likert pain scale has not been defined. However,
as there is currently no validated pain scale for patients
with PD, we relied on a standard Likert pain scale,
accepting that this scale is not specific to PD-related or
Despite the limitations of this post hoc analysis, these
data support existing information that pain is a prevalent
non-motor symptom associated with PD. This study has
begun to characterize some of the types (e.g., cramps,
spasms, painful posturing) and distribution of pain (e.g.,
pain in limbs) that may be improved with rotigotine; our
results also suggest that the improvement in pain was to
some extent attributable to the benefits in motor
function and nocturnal sleep disturbances, such as dystonic
symptoms at night or in the early morning. Prospective
studies are warranted to investigate the potential
improvements in pain with rotigotine transdermal system,
and to determine the clinical relevance of these findings.
Additional file 1: Independent Ethics Committees or Institutional
Review Boards of participating centres in the RECOVER study.
Additional file 2: Table S1. Pearson correlation coefficients (r) for
change from baseline in Likert pain scale score with UPDRS III and
PDSS-2 change from baseline in rotigotine-treated patients.
JK has received personal compensation for activities with UCB Pharma,
GlaxoSmithKline, Teva, Medtronic, and Boehringer Ingelheim Pharmaceuticals,
Inc. as a consultant and honoraria for academic lectures from Merz and Bayer.
KRC serves as the European Editor of Basal Ganglia, as an editorial board
member of Parkinsonism and Related Disorders, and the Journal of Parkinsons
Disease, and as the Liaison and PR Committee Chairman of the Movement
Disorder Society; has received honoraria for academic lectures at sponsored
symposiums from UCB Pharma, Britannia, GlaxoSmithKline, Abbott, Teva,
Medtronic, and Boehringer Ingelheim Pharmaceuticals, Inc.; and has received
educational grants for research from UCB Pharma, Abbott, Boehringer
Ingelheim Pharmaceuticals, Inc., and Britannia. TAZ has received compensation
from UCB Pharma, GlaxoSmithKline, Teva, Edison Pharmaceuticals, General
Electric, and the Friedreichs Ataxia Research Alliance (FARA). ES is an employee
of UCB Pharma, Monheim am Rhein, Germany. BB is an employee of UCB
Pharma, Raleigh, NC, USA and receives stock options from this employment.
KM is an employee of UCB Pharma, Smyrna, GA, USA and receives stock
options from this employment. LG was an employee of UCB Pharma, Brussels,
Belgium, during the development of the manuscript. CT is a consultant for
and/or has received honoraria/research support from Vifor Pharma,
UCB Pharma, Mundipharma, Britannia, Novartis, Boehringer Ingelheim
Pharmaceuticals, Inc., GlaxoSmithKline, Teva Neuroscience and Desitin.
JK, KRC, TZ, BB, and CT participated in the analysis and interpretation of data,
and were involved in revising the manuscript critically for important
intellectual content. ES participated in the design of the current post hoc
analyses, performed the statistical analysis, and was involved in revising the
manuscript critically for important intellectual content. KM and LG participated
in the design of the current post hoc analyses, participated in the analysis and
interpretation of data, and were involved in revising the manuscript
critically for important intellectual content. All authors read and approved the
The RECOVER study and the current post hoc analysis were funded by UCB
Pharma, Brussels, Belgium. The sponsor was involved in the design of the
post hoc analysis, the analysis and interpretation of data, and in the decision
to submit the paper for publication. The authors acknowledge Emily
Thompson, PhD, Evidence Scientific Solutions, London, UK, for medical
writing and editorial assistance, which was funded by UCB Pharma,
Brussels, Belgium, Ging-Ging Li CMPP (Global Publications Manager,
Movement & Sleep Disorders, UCB Pharma, Brussels, Belgium) for publication
coordination, and Elisabeth Dohin (UCB Pharma Brussels, Belgium) for critical
review of the manuscript.
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