A Randomized Controlled Exploratory Pilot Study to ... · Web viewPain is a troublesome nonmotor...
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PD0004 DOLORES
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PD0004 DOLORES
A Randomized Controlled Exploratory Pilot Study to Evaluate the Effect
of Rotigotine Transdermal Patch on Parkinson’s Disease–Associated
Chronic Pain
Olivier Rascol, MD, PhD1, Theresa Zesiewicz, MD, FAAN2, K. Ray Chaudhuri, MD,
FRCP, DSc3, Mahnaz Asgharnejad, PharmD4, Erwin Surmann, MSc5, Elisabeth Dohin,
MD6, Sigrid Nilius, PhD5, and Lars Bauer, MD5
1Clinical Investigation Center CIC1436 and Department of Clinical Pharmacolgy and Neurosciences,
INSERM, Toulouse University Hospital and University of Toulouse, Toulouse, France
2University of South Florida Ataxia Research Center, The Frances J. Zesiewicz Foundation for
Parkinson's Disease at USF, Parkinson's Disease and Movement Disorders Clinic at the
PADREC, James A. Haley Veterans' Administration, Tampa, FL, USA
3National Parkinson Foundation International Centre of Excellence, King's College Hospital, Kings
College and Kings Health Partners, London, UK
4UCB Pharma, Raleigh, NC, USA
5UCB Pharma, Monheim am Rhein, Germany
6UCB Pharma, Brussels, Belgium
Corresponding Author:
Lars Bauer, MD, UCB Pharma, Alfred-Nobel Strasse 10, Monheim am Rhein 40789,
Germany
Tel: + 49 2173482201
Email: [email protected]
Declaration of Competing Interests
Theresa Zesiewicz declares no conflict of interest. Olivier Rascol has acted as a scientific
advisor to UCB Pharma. K. Ray Chaudhuri has acted as an advisor to UCB Pharma and
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received educational grants. Mahnaz Asgharnejad, Erwin Surmann, Elisabeth Dohin, Sigrid
Nilius, and Lars Bauer are salaried employees of UCB Pharma.
Acknowledgments
The authors thank the patients and their caregivers in addition to the investigators and their
teams who contributed to this study. The authors also acknowledge Karolina Rzeniewicz,
PhD (Evidence Scientific Solutions, London, UK) for writing and editorial assistance, which
was funded by UCB Pharma, and Cédric Laloyaux, PhD (Strategic Publication Lead
Neurology, UCB Pharma, Brussels, Belgium) for publication coordination.
Funding
This study was supported by UCB Pharma, Monheim am Rhein, Germany.
Word count (body text): 4481; number of figures/tables: 6; number of references: 47
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Abstract
Pain is a troublesome nonmotor symptom of Parkinson’s disease (PD). This double-blind
exploratory pilot study (NCT01744496) was the first to specifically investigate the effect of a
dopamine agonist on PD-associated pain as primary outcome. Patients with advanced-PD
(ie, receiving levodopa) and at least moderate PD-associated chronic pain (≥3 months, ≥4
points on 11-point Likert pain scale) were randomized to rotigotine (optimal/maximum dose
≤16 mg/24h) or placebo, and maintained for 12 weeks. Primary efficacy variable: change in
pain severity (Likert pain scale) from baseline to end of maintenance. Secondary variables
included percentage of responders (≥2-point Likert pain scale reduction), King’s PD Pain
Scale (KPPS) domains, and PD Questionnaire (PDQ-8). Statistical analyses were
exploratory. Of 68 randomized patients, 60 (rotigotine, 30; placebo, 30) were evaluable for
efficacy. A numerical improvement in pain was observed in favor of rotigotine (Likert pain
scale: least-squares mean [95%CI] treatment difference, −0.76 [−1.87 to 0.34]; P=.172), and
proportion of responders was 18/30 (60%) rotigotine versus 14/30 (47%) placebo. An ~2-fold
numerical improvement in KPPS domain “fluctuation-related pain” was observed with
rotigotine versus placebo. Rotigotine improved PDQ-8 versus placebo (−8.01 [−15.56 to
−0.46]; P=.038). These results suggest rotigotine may improve PD-associated pain; a large-
scale confirmatory study is needed.
Keywords
Parkinson’s disease, pain, dopamine receptor agonist, randomized controlled trial, pilot
study
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Introduction
Pain is a common, but underreported and undertreated nonmotor symptom of Parkinson’s
disease (PD).1-3 Pain has a prevalence of 40% to 85% in PD,3 with pain directly attributed to
PD in 50% to 60% of patients.3-5 Pain negatively affects quality of life,6-9 and has been
reported as the most troublesome symptom in up to 10% of patients with PD.10
The type and distribution of pain experienced in the PD patient population is
heterogeneous, and its pathophysiology is yet to be fully understood. Pain in PD can be
secondary to motor symptoms (eg, associated with rigidity, akinesia, dystonia, or
disturbances of posture), and may also be a consequence of altered pain processing
resulting in a reduced pain threshold.6,8,11 Although there is no current consensus on the
classification of pain in PD,12 a number of classification systems have been proposed based
on cause, origin, location, and chronicity.6,13-17 Pain intensity can be assessed through rating
scales such as an 11-point Likert pain scale (also known as an 11-step numeric rating
scale), the validity of which has been shown across various populations.18-20 In addition, a
PD-specific pain scale, the King’s PD Pain Scale (KPPS), piloted in this study, is now
validated.21
In the absence of controlled studies, current recommendations for pain management
in PD are largely based on empirical evidence.6 Treatment options include pharmacologic
(ie, antiparkinson medication, analgesics, and coanalgesics) and nonpharmacologic options
(ie, botulinum toxin injection [for painful focal dystonia] and deep brain stimulation).6,8
Rotigotine is a nonergoline dopamine receptor agonist with activity across D1
through D5 receptors as well as select adrenergic and serotonergic sites.22 Continuous
transdermal delivery of rotigotine maintains stable plasma levels over 24 hours with a single
daily application.23 In addition, the pharmacokinetic profile of rotigotine is similar in healthy
individuals, and patients with early- or advanced-stage PD.24 Significant treatment benefits
have been observed with rotigotine as monotherapy in early-stage PD and as an add-on
therapy to levodopa in advanced-stage PD. These include improvements in activities of daily
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living and motor symptoms (Unified Parkinson's Disease Rating Scale [UPDRS] II + III) and
clinically relevant reductions in ‘‘off’’ time.25-30 In addition, exploratory data from RECOVER, a
double-blind, placebo-controlled study, suggested that rotigotine may improve pain in
patients with PD. Pain in RECOVER was assessed as an exploratory outcome via an 11-
point Likert pain scale measuring pain of any type.31
The current exploratory pilot study was the first to prospectively investigate the effect
of a dopamine receptor agonist on PD-associated chronic pain as a primary outcome. The
study aims were to collect preliminary information on the potential efficacy of rotigotine on
PD-associated chronic pain and on the different pain types in PD, and to assess the
feasibility of conducting a large-scale confirmatory study.
Methods
Study Design
The study protocol and amendments were reviewed and approved by the national or
regional independent ethics committees or institutional review boards of all 14 participating
centers (in 4 countries) (Supplementary File S1), and all patients provided written, informed
consent for participation. The study was conducted in accordance with Good Clinical
Practice and the Declaration of Helsinki.
The DOLORES (PD0004; ClinicalTrials.gov identifier: NCT01744496) study was
originally planned as a large-scale study. However, after study commencement, a
reassessment of the environment was performed in light of: (1) the results of a double-blind,
placebo-controlled study of nonmotor symptoms in PD, which did not demonstrate a
statistically significant difference between rotigotine and placebo for the primary outcome,
the change in the Non-Motor Symptoms Scale (NMSS) total score, or for the individual item
of the NMSS that assesses pain (exploratory outcome);32 (2) recognition of the complex
heterogeneity of pain in PD; (3) uncertainty in terms of whether PD-associated pain in
general or specific pain types are susceptible to dopaminergic therapy. Thus, following a
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protocol amendment, the DOLORES study was converted into an exploratory pilot study to
collect preliminary information on the potential efficacy of rotigotine on PD-associated
chronic pain. The study design was not amended due to lack of efficacy/meeting the primary
endpoint, and was converted into a pilot study prior to analyses of any data; no interim
analyses took place.
DOLORES was a multicenter, multinational (Germany, Poland, Slovakia, and United
States), double-blind, placebo-controlled, pilot study of rotigotine transdermal patch in
patients with advanced-stage PD (as defined by use of levodopa) experiencing at least
moderate PD-associated chronic pain. Originally initiated as a large-scale study in July 2012,
the number of randomized patients was reduced in July 2013 from ~478 to ~64. Enrollment
was to continue until approximately 64 patients were randomized or until the end of July
2013 (whichever occurred first).
Patients
Adult patients (≥18 years of age) with a diagnosis of idiopathic PD (defined by the cardinal
sign bradykinesia, and the presence of at least 1 of the following: resting tremor, rigidity, or
impairment of postural reflexes) were eligible to participate if they were receiving levodopa
(immediate or sustained release, in combination with benserazide or carbidopa) at a stable
dose of ≥200 mg/d for at least 21 days prior to the first day of pain assessment (levodopa
dose was expected to be maintained for the duration of the study). Eligible patients had to
experience chronic pain associated with PD (dystonia, musculoskeletal, central neuropathic,
or other pains worsened by PD [except dyskinesia]) that had been ongoing for ≥3 months,
and was assessed as at least moderate in intensity (≥4 points on an 11-point Likert pain
scale) at the screening visit. Via assessment of the investigator, chronic pain was to be
considered directly related to PD and not explained by any other health problem, or the
intensity of the chronic pain was to be considered aggravated by PD. Other eligibility criteria
included Hoehn and Yahr stage 2 to 4 in the “on” state and a Mini-Mental State Examination
score ≥25 at screening. Patients were excluded if they were receiving analgesics for pain, Page 6 of 26 Resubmission 1st Draft
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unless the dose had been stable for at least 21 days prior to the first day of pain assessment
(and was expected to remain stable for study duration). Additional exclusion criteria included
chronic migraine (>15 days per month), severe depression, a history of deep brain
stimulation, electroconvulsive therapy within 12 weeks prior to screening, and a previous
diagnosis of severe restless legs syndrome.
Concomitant therapy with monoamine oxidase-B inhibitors, anticholinergic agents,
entacapone, amantadine, and antidepressants (eg, selective serotonin reuptake inhibitor,
serotonin-norepinephrine reuptake inhibitor, bupropion, or tricyclic antidepressants) was
permitted, provided that doses remained stable for at least 21 days prior to the first day of
pain assessment and were maintained for the duration of the study. Prohibited medications
included dopamine receptor agonists, dopamine-releasing (eg, methylphenidate,
amphetamine) or -modulating substances (eg, reserpine), α-methyldopa, metoclopramide,
budipine, tolcapone, levodopa-carbidopa intestinal gel (Duodopa®), neuroleptics (including
atypical neuroleptics), monoamine oxidase-A inhibitors, opiates, or opioids (except tramadol
allowed as rescue medication) within 21 days prior to the first day of pain assessment.
Protocol
Eligibility criteria were assessed and patients were enrolled at the screening visit, which took
place during a ≤4-week screening period. Patients were randomized in a 1:1 ratio to receive
either rotigotine or placebo (stratified by site) at baseline, via an interactive voice/web
response system. To randomize a patient, the study investigator or designee contacted the
interactive voice/web response system and was provided with the patient’s randomization
number. Study treatment was administered once daily via a transdermal patch. Active and
placebo patches were matched in size and appearance, with rotigotine patch sizes of 20, 30,
and 40 cm2 corresponding to doses of 4, 6, and 8 mg/24 h, respectively.
Doses were uptitrated weekly over 1 to 7 weeks from 4 mg/24 h rotigotine (or
matching placebo) until the optimal or maximum dose (16 mg/24 h) was reached. The dose
of study medication was regarded as optimal if both the investigator and the patient felt that Page 7 of 26 Resubmission 1st Draft
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PD-associated chronic pain was optimally treated and motor symptoms were adequately
controlled. If an adverse event (AE) occurred that was thought to be the result of excessive
dopaminergic stimulation, the patient was back titrated to his/her previous dose and began
the maintenance period immediately. A single back titration was permitted.
The maintenance period was 12 weeks, during which the dose of study medication
could be adjusted once by ±2 mg/24 h (to ≥4 mg/24 h and ≤16 mg/24 h) in the first 4 weeks.
Following maintenance, patients entered a ≤12-day de-escalation period, prior to a 28-day
safety follow-up visit. Clinic visits occurred at screening and baseline, every 2 weeks during
the titration period, at the start of maintenance (day 1), after 4 weeks of maintenance (day
29), and at the end of the 12-week maintenance period (day 85). Patients who withdrew
prematurely were asked to return for a final withdrawal visit.
Pain Rescue Medication
The use of pain rescue medication (ie, paracetamol [maximum dose, 4000 mg/d] or tramadol
[maximum dose, 200 mg/d], combination not allowed) was permitted if, in the opinion of the
patient and the investigator, the efficacy of the study medication on the PD-associated pain
was not satisfactory. Intake of rescue medication was to be documented daily by the patient.
Outcome Measures
Primary Efficacy Variable
The primary efficacy variable was the change from baseline to end of maintenance (EoM) in
pain severity “average pain experienced in the last 7 days” as assessed by an 11-point Likert
pain scale. Pain was documented using patient diaries that were issued by the investigator.
Diary documentation started 7 days prior to the baseline visit, to allow for the baseline
assessment of the average pain experienced in the last 7 days, and continued daily until the
EoM. Patients recorded the intensity of their PD-associated pain (from 0 [no pain] to 10
[worst pain ever experienced]) over the past 24 hours. Pain intensity could be recorded at
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any time of the day. If the patient suffered from more than 1 PD-associated pain, the worst
pain was to be documented.
Secondary and Other Efficacy Variables
Secondary efficacy variables were the percentage of Likert pain scale responders (patients
with ≥2-point reduction on the Likert pain scale), and mean changes from baseline in the 7
domains of the validated KPPS,21 the 8-item Parkinson’s Disease Questionnaire (PDQ-8)
total score,33 the Hospital Anxiety and Depression Scale (HADS) depression and anxiety
subscores,34 and the UPDRS II + III total score.35 Additional post hoc analyses were
performed on the subgroup of patients who reported “fluctuation-related pain” (domain 3 on
the KPPS) at baseline (ie, patients with a baseline score of >0 for at least 1 of the 3 items in
this domain). In these patients, change from baseline to EoM in the primary efficacy variable
(Likert pain scale) was assessed. Other efficacy variables included the number of patients
with at least 1 intake of a permitted rescue medication for PD-associated chronic pain and
the frequency of use of rescue medications in each treatment group.
Safety and Tolerability
Safety and tolerability assessments included rotigotine dosing, incidence of treatment-
emergent AEs and serious AEs, and discontinuations due to AEs.
Statistical Analyses
As the study was amended to a pilot study, no formal sample size calculation was
performed. However, on the basis of previous post hoc analyses of pain,36 it was anticipated
that a sample size of 60 (rotigotine, 30; placebo, 30) would permit detection of a treatment
difference with approximately 25% power, assuming a conservative SD of 3.0 and an
anticipated difference between placebo and rotigotine of 1.0. It was assumed the obtained
treatment difference would identify any tendencies in treatment response, and indicate
whether a large-scale confirmatory study should be considered. Enrollment of approximately Page 9 of 26 Resubmission 1st Draft
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80 patients was planned, in order to randomize 64 patients (assumed screening failure rate
of 20%) and obtain data from 60 patients (assumed dropout rate of 5%).
Efficacy analyses were conducted for the full analysis set (FAS; all randomized
patients who received at least 1 dose of study medication and who had a valid baseline
measurement and at least 1 valid post-baseline maintenance/withdrawal measurement for
the primary efficacy variable), using the last observation carried forward approach. For the
primary analysis, days under PD-associated pain rescue medication were not considered for
the calculation of average pain. The average pain experienced in the last 7 days was
calculated for the Likert pain scale if ≥5 days or 4 consecutive days with an assessment
(without rescue pain medication) were available. An estimate of treatment effect was
obtained using an analysis of covariance (ANCOVA), with treatment and region (United
States, Europe) as factors and baseline value as a covariate. All analyses were performed in
an exploratory manner; P values < .05 do not infer statistical significance. Analyses of safety
were performed for the safety set (all randomized patients who had at least 1 patch applied
during the treatment period). All statistical analyses were performed using SAS® (SAS
Institute, Cary, North Carolina, United States).
Results
Patients
This study was conducted between November 2012 and January 2014. Of 84 enrolled
patients, 68 were randomized (rotigotine, 35; placebo, 33) (Figure 1). All randomized
patients were included in the safety set.
Overall, baseline characteristics were similar between the 2 treatment groups (Table
1). All patients had advanced-stage PD (as defined by use of levodopa) with bradykinesia
(per the inclusion criteria), and the majority were experiencing motor fluctuations (48/68
[71%]). At screening (assessment of the previous 7 days), 33/68 (49%) patients had PD-
associated pain of moderate intensity (defined by 4–6 points on the 11-point Likert pain
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scale) and 35/68 (51%) patients had severe pain (defined by >6 points). The most common
types of PD-associated pain at baseline were musculoskeletal (38/68 [56%]) and
neuropathic (15/68 [22%]).
In total, 56 patients (rotigotine, 29; placebo, 27) completed the study and 60 patients
(30 in each treatment group) were included in the FAS. Of the 8 patients excluded from the
FAS, most (rotigotine, 3/5; placebo, 2/3) were excluded because of intake of PD-associated
pain rescue medication during the pain assessment period (per the study protocol). In both
treatment groups, AEs were the most common reason for discontinuation and no patients
withdrew because of lack of efficacy (Figure 1).
Efficacy
Primary Efficacy Variable
At the end of the 12-week maintenance period, a numerical improvement in the average pain
severity experienced in the last 7 days (Likert pain scale) was observed in favor of rotigotine
(least-squares [LS] mean [95% CI] treatment difference, –0.76 [–1.87 to 0.34]; P = .172)
(Figure 2).
Secondary Efficacy Variables
The number of Likert pain scale responders (ie, patients with ≥2-point reduction) was higher
with rotigotine (18/30 [60%]) vs placebo (14/30 [47%]), with a percentage difference (95%
CI) between treatments of 13.3% (−11.3 to 35.9).
Numerical differences between treatment groups were observed for 2 out of 7
domains of the KPPS (Figure 3). A numerical change in favor of rotigotine was observed in
“fluctuation-related pain” (mean [SD] change from baseline: rotigotine, −4.2 [6.8]; placebo,
−2.2 [4.6]), whereas a numerical change in favor of placebo was observed in “chronic pain”
(rotigotine, −0.7 [2.9]; placebo, −3.1 [5.6]). Of note, baseline “chronic pain” scores were
lower in the rotigotine group (3.2 [3.7]) than in the placebo group (6.2 [7.2]).
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In total, 40 patients (rotigotine, 19; placebo, 21) reported “fluctuation-related pain”
(domain 3 on the KPPS) at baseline and were included in the post hoc analysis of the Likert
pain scale; in these patients, the mean (SD) change from baseline to EoM in the average
pain experienced in the last 7 days (Likert pain scale) was numerically greater with rotigotine
(mean [SD] change, −3.1 [1.89]; mean [SD] baseline, 6.1 [1.39]) than with placebo (−2.1
[2.72]; 6.3 [1.50]) (LS mean treatment difference [95% CI], −1.07 [−2.52 to 0.38]; P = .1446).
Rotigotine-treated patients had a greater numerical reduction (indicating
improvement) in PDQ-8 total score than those receiving placebo (LS mean [95% CI]
treatment difference, −8.01 [−15.56 to −0.46]; P = .038) (Table 2). In addition, small
numerical changes in favor of rotigotine were observed for the HADS depression subscore
(LS mean [95% CI] treatment difference, −1.02 [−2.76 to 0.73]; P = .247) and HADS anxiety
subscore (−0.58 [−1.85 to 0.70]; P = .371), and for the UPDRS II + III total score (−2.82
[−8.76 to 3.13]; P = .346) (Table 2).
Other efficacy variables
During the treatment period, 9/30 (30%) rotigotine-treated and 7/30 (23%) placebo-treated
patients had at least 1 intake of rescue medication for PD-associated pain. Patients
receiving rotigotine (n = 9) received rescue medication for a mean (SD) total of 8.0 (9.2)
days, whereas those receiving placebo (n = 7) received medication for 12.9 (21.2) days.
Safety and Tolerability
Rotigotine Exposure
The mean (SD) rotigotine maintenance dose was 14.7 (5.1) mg/24 h. During the course of
the study, 24/35 (69%) rotigotine-treated patients reached the maximum permitted dose of
16 mg/24 h. A maximum dose of 4 mg/24 h was taken by 2/35 (6%) patients, 1/35 (3%)
received 6 mg/24 h, 5/35 (14%) received 10 mg/24 h, and 3/35 (9%) received 14 mg/24 h.
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Seventy-three AEs were reported by 22/35 (63%) patients receiving rotigotine and 66 AEs
were reported by 20/33 (61%) patients receiving placebo. The most common AEs (Medical
Dictionary for Regulatory Activities [MedDRA] preferred term) were nausea and headache
(Table 3). In addition, application site reactions (MedDRA high-level term) occurred in 4/35
(11%) patients receiving rotigotine and 1/33 (3%) patient receiving placebo. Serious AEs
were reported by 2/35 (6%) patients receiving rotigotine (lower leg edema [1 patient],
cerebrovascular accident [1 patient]) and 1/33 (3%) patient receiving placebo (hip fracture).
None of the serious AEs were considered related to study medication by the investigator.
Most patients reported AEs that were mild (rotigotine, 7/35 [20%]; placebo, 6/33 [18%]) or
moderate (rotigotine, 11/35 [31%]; placebo, 12/33 [36%]) in intensity. Severe AEs were
reported by 4/35 (11%) patients receiving rotigotine and 2/33 (6%) patients receiving
placebo. Overall, 35 AEs in 15/35 (43%) patients receiving rotigotine and 22 AEs in 10/33
(30%) patients receiving placebo were considered related to study medication by the
investigator. Overall, 4/35 (11%) patients receiving rotigotine and 3/33 (9%) patients
receiving placebo discontinued owing to AEs. No deaths occurred during the study.
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Discussion
This was the first double-blind placebo-controlled study to investigate the effect of a
dopamine receptor agonist on PD-associated pain. The decision to enroll a smaller number
of patients than initially planned substantially reduced the power of the study; therefore the
results can be considered descriptive only. Numerical improvements were observed in favor
of rotigotine transdermal patch for the primary outcome, the severity of PD-associated pain
experienced in the last 7 days, as assessed by an 11-point Likert pain scale, and for several
secondary outcomes.
A general improvement in PD-associated pain intensity was observed with rotigotine
versus placebo, as indicated by the descriptive treatment difference of 0.76 Likert points. In
addition, the percentage of patients who were responders as assessed by the Likert pain
scale (ie, reported ≥2-point improvement) was numerically higher in the rotigotine group
(60% rotigotine vs 47% placebo). A 2-point reduction on an 11-point Likert pain scale is
generally considered to represent a clinically important difference in pain intensity,37,38
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suggesting that treatment with rotigotine may provide a clinically relevant improvement in
pain in more patients than treatment with placebo.
In line with the published literature,2,5-7 musculoskeletal pain was the most commonly
reported PD-associated pain (56% of patients) at study baseline. As the treatment effect on
PD-associated pain was assessed by the Likert pain scale as a composite of dystonia,
musculoskeletal, central neuropathic, and other pains worsened by PD (except dyskinesia),
it was not possible to determine which, if any in particular, pain type was driving the
improvement in the Likert pain scale. Of note, 71% of patients had motor fluctuations at
baseline, and an approximate 2-fold numerical improvement was observed with rotigotine
versus placebo for the “fluctuation-related pain” domain of the KPPS domain. Furthermore,
the post hoc analysis of patients reporting “fluctuation-related pain” at baseline indicated a
numerical improvement of 1.07 Likert pain scale points with rotigotine versus placebo.
Although not directly comparable, this treatment difference was larger than that observed for
the whole population (0.76 Likert points). These results suggest that rotigotine treatment
may potentially be beneficial for the treatment of fluctuation-related pain. Previous studies
have demonstrated improvements in wearing-off type motor fluctuations with rotigotine in
patients with advanced-stage PD inadequately controlled on levodopa,25-27 and clinical
experience suggests that dopaminergic therapy may provide benefits for those nonmotor
symptoms that are motor fluctuation–related (ie, wearing-off symptoms such as off-period
pain).15,39 It is worth noting that an approximate 4-fold numerical difference in favor of
placebo was observed in KPPS domain of “chronic pain”; however, baseline “chronic pain”
scores were 2-fold higher in the placebo group than in the rotigotine group, thus these
results are difficult to interpret.
The observed potential beneficial effects of rotigotine on pain are supported by the
results of a recent noninterventional study (NEUPAD; NCT01606670). In NEUPAD, the
perception of the “affective dimension” of PD-associated pain numerically improved in
patients receiving rotigotine treatment for the first time.40 Although this study used a
questionnaire not specific to PD (the German Pain Questionnaire), the results suggest that Page 15 of 26 Resubmission 1st Draft
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rotigotine may improve PD-associated pain. Furthermore, a post hoc analysis of the
RECOVER study indicated that patients who responded to treatment with rotigotine with at
least a 30% improvement in their early morning motor function (UPDRS III) or nocturnal
sleep disturbances (modified Parkinson's Disease Sleep Scale [PDSS-2]) showed greater
improvement in pain (Likert pain scale assessment) than UPDRS III/PDSS-2
nonresponders,36 suggesting that the observed improvement may have been partly
attributable to benefits in motor function and sleep disturbances.36 Although limited data are
available, other potential treatments for PD-associated pain have also been investigated in
recent years. Levodopa has been shown to raise the off-period objective pain threshold in
patients with PD;41,42 however, these studies were conducted in patients with pain‐free PD,
thus whether levodopa may improve PD-associated pain is currently not known. A recent
study demonstrated that subthalamic nucleus deep brain stimulation improved off-period
pain, with beneficial effects persisting after 8 years of follow-up. However, new pain (mostly
musculoskeletal) developed in 75% of patients during the follow-up period.43 Furthermore, a
recent small observational study in 16 patients with PD demonstrated benefits of the
analgesic oxycodone/naloxone prolonged-release tablet for the treatment of chronic pain
symptom.44 These results have been recently confirmed in a large randomized placebo-
controlled study of oxycodone/naloxone prolonged-release tablets for severe PD-associated
pain.45 Therefore, the treatment of pain in PD is certainly receiving increased attention.
However, the ultimate goal of developing pragmatic therapeutic recommendations for pain
associated with PD will depend on the standardization of the different types of pain, the
understanding of pain mechanisms, and the responsiveness of pain to various types of
therapy.
A relatively large numerical improvement (exploratory P value of < .05) was observed
with rotigotine in PD-related quality of life (PDQ-8). This improvement may be related to the
beneficial effects of rotigotine on PD-associated pain, and other motor and nonmotor
symptoms. Therefore, the overall therapeutic benefit of rotigotine in patients with PD-
associated chronic pain may extend beyond the numerical reduction in pain intensity to Page 16 of 26 Resubmission 1st Draft
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generally improve quality of life. This may be particularly important in this patient population,
as patients with PD-associated chronic pain report a reduced quality of life than those with
pain unrelated to PD and those with no pain.16
The efficacy of rotigotine in improving UPDRS II and III subscores has been
consistently shown in large-scale studies in advanced-stage PD.25-27 Thus, the relatively
small numerical improvement in the UPDRS II + III total score (exploratory P value > .05) in
the current study was likely due to patients being included based on the severity of their PD-
associated pain rather than the severity of motor symptoms (which were reasonably well
controlled in this patient population) and the activities of daily living symptoms. Rotigotine
was generally well tolerated in a dose range of 4 to 16 mg/24 h, with few patients
discontinuing the study as a result of AEs, and AEs were consistent with the known safety
profile of rotigotine.
An important limitation of this exploratory pilot study is the fact that the study was not
powered to detect statistically significant treatment differences owing to the small sample
size. Thus, these data are interpreted with caution. However, as the observed treatment
difference for the primary efficacy variable (0.76 Likert points) approached the anticipated
treatment difference (1.0), further investigation in a large-scale confirmatory study may be
considered to fully evaluate the efficacy of rotigotine on pain associated with PD. It is also
worth noting that the percentage of Likert pain scale responders in the placebo group was
relatively high in our study (47% vs 60% in the rotigotine group). This large response rate
may be due to the fact that subjective measures, such as pain, are prone to expectancy
effects,46 and, particularly, that placebo analgesia is commonly documented.47
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Conclusions
In summary, the results of this exploratory pilot study suggest that rotigotine transdermal
patch may improve PD-associated chronic pain in patients with advanced-stage PD. Further
investigation via an adequately powered, large-scale confirmatory study is needed to fully
evaluate efficacy of rotigotine on PD-associated pain.
References1. Sophie M, Ford B. Management of pain in Parkinson's disease. CNS Drugs.
2012;26(11):937-948.
2. Rana AQ, Kabir A, Jesudasan M, Siddiqui I, Khondker S. Pain in Parkinson's
disease: Analysis and literature review. Clinical Neurology and Neurosurgery.
2013;115(11):2313-2317.
3. Broen MP, Braaksma MM, Patijn J, Weber WE. Prevalence of pain in Parkinson's
disease: a systematic review using the modified QUADAS tool. Movement Disorders.
2012;27(4):480-484.
Page 18 of 26 Resubmission 1st Draft
October 2015
PD0004 DOLORES
4. Li W, Chen Y, Yin B, Zhang L. Pain in Parkinson's Disease Associated with COMT
Gene Polymorphisms. Behavioural Neurology. 2014;2014:304203.
5. Mao C-J, Chen J-P, Zhang X-Y, et al. Parkinson’s disease patients with pain suffer
from more severe non-motor symptoms. Neurological Sciences. 2015;36(2):263-268.
6. Wasner G, Deuschl G. Pains in Parkinson disease--many syndromes under one
umbrella. Nat Rev Neurol. 2012;8(5):284-294.
7. Defazio G, Gigante A, Mancino P, Tinazzi M. The epidemiology of pain in
Parkinson’s disease. Journal of Neural Transmission. 2013;120(4):583-586.
8. Ha AD, Jankovic J. Pain in Parkinson's disease. Movement Disorders.
2012;27(4):485-491.
9. Truini A, Frontoni M, Cruccu G. Parkinson's disease related pain: a review of recent
findings. Journal of Neurology. 2013;260(1):330-334.
10. Politis M, Wu K, Molloy S, P GB, Chaudhuri KR, Piccini P. Parkinson's disease
symptoms: the patient's perspective. Movement Disorders. 2010;25(11):1646-1651.
11. Cury RG, Galhardoni R, Fonoff ET, et al. Sensory abnormalities and pain in
Parkinson disease and its modulation by treatment of motor symptoms. Eur J Pain.
2015.
12. Fil A, Cano-de-la-Cuerda R, Munoz-Hellin E, Vela L, Ramiro-Gonzalez M,
Fernandez-de-Las-Penas C. Pain in Parkinson disease: a review of the literature.
Parkinsonism Relat Disord. 2013;19(3):285-294; discussion 285.
13. Ford B. Pain in Parkinson's disease. Clinical Neuroscience. 1998;5(2):63-72.
14. Ford B. Pain in Parkinson's disease. Movement Disorders. 2010;25 Suppl 1:S98-103.
15. Chaudhuri KR, Schapira AHV. Non-motor symptoms of Parkinson's disease:
dopaminergic pathophysiology and treatment. The Lancet Neurology. 2009;8(5):464-
474.
16. Nègre-Pagès L, Regragui W, Bouhassira D, Grandjean H, Rascol O. Chronic pain in
Parkinson's disease: the cross-sectional French DoPaMiP survey. Movement
Disorders. 2008;23(10):1361-1369.Page 19 of 26 Resubmission 1st Draft
October 2015
PD0004 DOLORES
17. Tinazzi M, Recchia S, Simonetto S, et al. Muscular pain in Parkinson's disease and
nociceptive processing assessed with CO2 laser-evoked potentials. Movement
Disorders. 2010;25(2):213-220.
18. Plan EL, Elshoff JP, Stockis A, Sargentini-Maier ML, Karlsson MO. Likert Pain Score
Modeling: A Markov Integer Model and an Autoregressive Continuous Model. Clinical
Pharmacology and Therapeutics. 2012;91(5):820-828.
19. Ferreira-Valente MA, Pais-Ribeiro JL, Jensen MP. Validity of four pain intensity rating
scales. Pain. 2011;152(10):2399-2404.
20. Hjermstad MJ, Fayers PM, Haugen DF, et al. Studies Comparing Numerical Rating
Scales, Verbal Rating Scales, and Visual Analogue Scales for Assessment of Pain
Intensity in Adults: A Systematic Literature Review. Journal of Pain and Symptom
Management.41(6):1073-1093.
21. Chaudhuri KR, Rizos A, Trenkwalder C, et al. King's Parkinson's disease pain scale,
the first scale for pain in PD: An international validation. Movement Disorders.
2015:Jun 11 [Epub ahead of print].
22. Scheller D, Ullmer C, Berkels R, Gwarek M, Lubbert H. The in vitro receptor profile of
rotigotine: a new agent for the treatment of Parkinson's disease. Naunyn-
Schmiedebergs Archives of Pharmacology. 2009;379(1):73-86.
23. 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. Clinical Therapeutics.
2012;34(4):966-978.
24. Elshoff J-P, Cawello W, Andreas J-O, Mathy F-X, Braun M. An Update on
Pharmacological, Pharmacokinetic Properties and Drug–Drug Interactions of
Rotigotine Transdermal System in Parkinson’s Disease and Restless Legs
Syndrome. Drugs. 2015;75(5):487-501.
Page 20 of 26 Resubmission 1st Draft
October 2015
PD0004 DOLORES
25. Poewe WH, Rascol O, Quinn N, et al. Efficacy of pramipexole and transdermal
rotigotine in advanced Parkinson's disease: a double-blind, double-dummy,
randomised controlled trial. The Lancet Neurology. 2007;6(6):513-520.
26. LeWitt PA, Lyons KE, Pahwa R. Advanced Parkinson disease treated with rotigotine
transdermal system: PREFER Study. Neurology. 2007;68(16):1262-1267.
27. Nicholas AP, Borgohain R, Chana P, et al. A randomized study of rotigotine dose
response on 'off' time in advanced Parkinson's disease. Journal of Parkinson's
disease. 2014;4(3):361-373.
28. Jankovic J, Watts RL, Martin W, Boroojerdi B. Transdermal rotigotine: double-blind,
placebo-controlled trial in Parkinson disease. Archives of Neurology. 2007;64(5):676-
682.
29. Watts RL, Jankovic J, Waters C, Rajput A, Boroojerdi B, Rao J. Randomized, blind,
controlled trial of transdermal rotigotine in early Parkinson disease. Neurology.
2007;68(4):272-276.
30. 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. Movement Disorders.
2007;22(16):2398-2404.
31. Trenkwalder C, Kies B, Rudzinska M, et al. Rotigotine effects on early morning motor
function and sleep in Parkinson's disease: a double-blind, randomized, placebo-
controlled study (RECOVER). Movement Disorders. 2011;26(1):90-99.
32. Antonini A, Bauer L, Dohin E, et al. Effects of rotigotine transdermal patch in patients
with Parkinson's disease presenting with non-motor symptoms – results of a double-
blind, randomized, placebo-controlled trial. European Journal of Neurology. 2015:n/a-
n/a.
33. Peto V, Jenkinson C, Fitzpatrick R. PDQ-39: a review of the development, validation
and application of a Parkinson's disease quality of life questionnaire and its
associated measures. Journal of Neurology. 1998;245 Suppl 1:S10-14.Page 21 of 26 Resubmission 1st Draft
October 2015
PD0004 DOLORES
34. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta
Psychiatrica Scandinavica. 1983;67(6):361-370.
35. . The Unified Parkinson's Disease Rating Scale (UPDRS): status and
recommendations. Movement Disorders. 2003;18(7):738-750.
36. Kassubek J, Chaudhuri KR, Zesiewicz T, et al. Rotigotine transdermal system and
evaluation of pain in patients with Parkinson's disease: a post hoc analysis of the
RECOVER study. BMC Neurology. 2014;14:42.
37. Dworkin RH, Turk DC, McDermott MP, et al. Interpreting the clinical importance of
group differences in chronic pain clinical trials: IMMPACT recommendations. Pain.
2009;146(3):238-244.
38. Farrar JT, Young JP, Jr., LaMoreaux L, Werth JL, Poole RM. Clinical importance of
changes in chronic pain intensity measured on an 11-point numerical pain rating
scale. Pain. 2001;94(2):149-158.
39. Chaudhuri KR, Healy DG, Schapira AH. Non-motor symptoms of Parkinson's
disease: diagnosis and management. The Lancet Neurology. 2006;5(3):235-245.
40. Schwarz J, Kassubek J, Oehlwein C, et al. A multicenter, non-interventional study
with rotigotine to evaluate the perception of pain associated with idiopathic
Parkinson’s disease: the NEUPAD study. Presented at: Deutschen Gesellschaft für
Neurologie - 88th Jahreskongress; 23-26 September 2015; Düsseldorf, Germany
41. Brefel-Courbon C, Payoux P, Thalamas C, et al. Effect of levodopa on pain threshold
in Parkinson's disease: a clinical and positron emission tomography study.
Movement Disorders. 2005;20(12):1557-1563.
42. Gerdelat-Mas A, Simonetta-Moreau M, Thalamas C, et al. Levodopa raises objective
pain threshold in Parkinson's disease: a RIII reflex study. Journal of Neurology,
Neurosurgery and Psychiatry. 2007;78(10):1140-1142.
43. Jung YJ, Kim HJ, Jeon BS, Park H, Lee WW, Paek SH. An 8-Year Follow-up on the
Effect of Subthalamic Nucleus Deep Brain Stimulation on Pain in Parkinson Disease.
JAMA Neurol. 2015;72(5):504-510.Page 22 of 26 Resubmission 1st Draft
October 2015
PD0004 DOLORES
44. Madeo G, Schirinzi T, Natoli S, et al. Efficacy and safety profile of prolonged release
oxycodone in combination with naloxone (OXN PR) in Parkinson's disease patients
with chronic pain. Journal of Neurology. 2015.
45. Trenkwalder C, Chaudhuri KR, Martinez-Martin P, et al. Prolonged release
oxycodone/naloxone for the treatment of severe Parkinson's disease-related pain:
PANDA - a double-blind, randomized, placebo-controlled study. Lancet Neurology.
2015 [Accepted for publication].
46. Schwarz KA, Buchel C. Cognition and the Placebo Effect - Dissociating Subjective
Perception and Actual Performance. PLoS One. 2015;10(7):e0130492.
47. Buchel C, Geuter S, Sprenger C, Eippert F. Placebo analgesia: a predictive coding
perspective. Neuron. 2014;81(6):1223-1239.
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Figure Legends
Figure 1. Patient flow diagram.
aPatient left town; bPersonal reasons. FAS, full analysis set; SS, safety set.
Figure 2. Primary Efficacy Variable: Change from baseline to EoM in average pain
experienced in the last 7 days as assessed by Likert pain scale (full analysis set, last
observation carried forward).
Exploratory analysis; P values do not infer statistical significance.
ANCOVA, analysis of covariance; EoM, end of maintenance; LS, least squares.
Figure 3. Secondary Efficacy Variable: Change from baseline to EoM in the 7 domains of
the King’s PD Pain Scale (full analysis set, last observation carried forward).
aOne patient without post-baseline values.
EoM, end of maintenance.
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