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of 2 Resubmission 1st Draft

October 2015

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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.

Adverse EventsPage 12 of 26 Resubmission 1st Draft

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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.

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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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