DOLORES: Study to Evaluate the Efficacy of Rotigotine on Parkinson's Disease-Associated Pain

• Sponsor: UCB BIOSCIENCES GmbH (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01744496
• Collaborator: (none)
• Enrollment: 68
• Locations: 16
• Arms: 2
• Duration (Months): 14
• Patients Per Site: 4.3
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This trial is being conducted to compare the impact of Rotigotine and Placebo on Chronic Pain associated with Parkinson's Disease among patients with advanced stages of the disease.

Condition or Disease	Intervention/Treatment	Phase
Advanced Idiopathic Parkinson's Disease	Drug: Rotigotine; Drug: Placebo	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 68 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Multinational, Double-Blind, Placebo-Controlled, 2-Arm Study to Evaluate the Efficacy of Rotigotine on Parkinson's Disease-Associated Pain
• Study Start Date: Nov 1, 2012
• Actual Primary Completion Date: Dec 1, 2013
• Actual Study Completion Date: Jan 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Rotigotine Rotigotine Transdermal Patches	Drug: Rotigotine; Patches will contain 4 mg / 24 h (20 cm^2), 6 mg/ 24 h (30 cm^2), or 8 mg /24 h (40 cm^2) of Rotigotine. Application of study medication starts at the Baseline Visit. Rotigotine will be administered once daily starting at 4 mg / 24 h. Doses will then be up-titrated in weekly increments of 2 mg / 24 h until optimal or maximum dose (16 mg / 24 h) is reached and the Maintenance Period can be started. The duration of the Titration Period will vary from 1 to 7 weeks ± 3 days. The Maintenance Period will last 12 weeks ± 5 days. Thereafter, during the De-escalation Period, the dose of study medication will be decreased by 2 mg / 24 h every other day. The De-escalation Period may last up to 12 days.; Other Names: (6S)-6-propyl-[2 (2 thienyl)ethyl]amino-5,6,7,8-tetrahydro-1-naphthalenol
Placebo Comparator: Placebo Placebo Transdermal Patches	Drug: Placebo; Placebo patches match the size of active patches 20 cm^2, 30 cm^2, or 40 cm^2 and will contain Placebo. Application of Placebo patches starts at the Baseline Visit. Placebo patches will be administered once daily starting with the equivalent of 4 mg / 24 h. Doses will then be up-titrated in weekly equivalents to 2 mg / 24 h until either optimal dose or maximum dose is reached. The maximum dose is the equivalent to 16 mg / 24 h. The duration of the Titration Period will vary from 1 to 7 weeks. The Maintenance Period will last 12 weeks ± 5 days. During the De-escalation Period, the dose of Placebo will be decreased by the equivalent to 2 mg / 24 h every other day. The De-escalation Period may last up to 12 days.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to the End of the Maintenance Period in Pain Severity Assessed Using an 11-point Likert Pain Scale [Baseline (Visit 2) until End of the Maintenance Period (Maintenance Period lasts 12 weeks ± 5 days after an up to 7 weeks Titration Period)]

   An 11-Point Likert Scale was used to assess patients' average daily pain. The subject rated his/her average pain from 0 (no pain) to 10 (worst pain ever experienced). The average pain experienced in the last 7 days was calculated by the mean of the daily Likert Pain Scores within the 7 days prior to the respective visit (ie, Likert Pain Scores with a date of assessment before the date of visit and on or after the date of visit - 7 days). A negative value indicates an improvement.

Secondary Outcome Measures

1. Percentage of Responders at the End of the Maintenance Period [Baseline (Visit 2) until End of the Maintenance Period (Maintenance Period lasts 12 weeks ± 5 days after up to 7 weeks Titration Period)]

   Responders are defined as patients experiencing a 2-Point or more Reduction on an 11-Point Likert Pain Scale from Baseline to the End of the Maintenance Period. An 11-Point Likert Scale was used to assess patients' average daily pain. The patient rated his/her average pain from 0 (no pain) to 10 (worst pain ever experienced).

2. Change From Baseline to the End of the Maintenance Period in the Sum Score of the 8-Item Parkinson's Disease Questionnaire (PDQ-8) [Baseline (Visit 2) until End of the Maintenance Period (Maintenance Period lasts 12 weeks ± 5 days after up to 7 weeks Titration Period)]

   The 8-Item Parkinson's Disease Questionnaire (PDQ-8) (Peto et al, 1998) is a self-administered questionnaire that provides a reliable measure of overall health status. The PDQ-8 contains 8 items of daily living, with 1 item selected from each of the following 8 scales: mobility, Activities of Daily Living (ADL), emotional well being, stigma, social support, cognitions, communication, and bodily discomfort. The total PDQ-8 score is the sum of all the individual items converted to a summary index score between 0 and 100, with lower scores indicating better health. A negative value indicates an improvement.

3. Change From Baseline to the End of the Maintenance Period in the 7-Item Depression Subscore of the Hospital Anxiety and Depression Scale (HADS) [Baseline (Visit 2) until End of the Maintenance Period (Maintenance Period lasts 12 weeks ± 5 days after up to 7 weeks Titration Period)]

   The Hospital Anxiety and Depression Scale (HADS) (Zigmond and Snaith, 1983) is a 14-item self-assessment scale for detecting states of depression and anxiety in the setting of a hospital medical outpatient clinic. It comprises a 7-item anxiety subscale and a 7-item depressive subscale that are also measures of severity of the emotional disorder. The 14 items are scored between 0 and 3. The 7-item depression subscore and 7-item anxiety subscore were calculated as the sum of the 7 corresponding individual scores. A negative value indicates an improvement.

4. Change From Baseline to the End of the Maintenance Period in the 7-Item Anxiety Subscore of the Hospital Anxiety and Depression Scale (HADS) [Baseline (Visit 2) until End of the Maintenance Period (Maintenance Period lasts 12 weeks ± 5 days after up to 7 weeks Titration Period)]

   The Hospital Anxiety and Depression Scale (HADS) (Zigmond and Snaith, 1983) is a 14-item self-assessment scale for detecting states of depression and anxiety in the setting of a hospital medical outpatient clinic. It comprises a 7-item anxiety subscale and a 7-item depressive subscale that are also measures of severity of the emotional disorder. The 14 items are scored between 0 and 3. The 7-item depression subscore and 7-item anxiety subscore were calculated as the sum of the 7 corresponding individual scores. A negative value indicates an improvement.

5. Change From Baseline to the End of the Maintenance Period in the Combined Score of the Unified Parkinson's Disease Rating Scale (UPDRS) Parts II (Activities of Daily Living [ADL] Subscale) and III (Motor Subscale) [Baseline (Visit 2) until End of the Maintenance Period (Maintenance Period lasts 12 weeks ± 5 days after up to 7 weeks Titration Period)]

   Part II of the Unified Parkinson's Disease Rating Scale (UPDRS) assesses the subject's activities of daily living. Part III assesses motor function. The UPDRS is completed by questioning the subject about his/her general state in conjunction with any observations made by the investigator (or designee) since the previous visit. Part II is subject-rated and Part III is physician-rated. The UPDRS Part II (Activities of Daily Living) consists of 13 items scored between 0 and 4. The sum score was calculated as the sum of these 13 individual scores. The UPDRS Part III (motor subscale) consists of 27 items and sub items scored between 0 and 4. The sum score was calculated as sum of these 27 individual scores. The sum score of UPDRS Parts II and III is the sum of the corresponding single sum scores. A negative value indicates an improvement.

6. Change From Baseline to the End of the Maintenance Period in the 7 Domain Scores of Classification of Pain in Parkinson's Disease [Baseline (Visit 2) until End of the Maintenance Period (Maintenance Period lasts 12 weeks ± 5 days after up to 7 weeks Titration Period)]

   The classification of pain in Parkinson's disease scale classifies pain in the following domains: musculoskeletal pain (item 1), chronic pain (items 2 and 3), fluctuation related pain (items 4, 5 and 6), nocturnal pain (items 7 and 8), oro-facial pain (items 9, 10 and 11), discoloration; edema/swelling (items 12 and 13), and radicular pain (item 14). Severity of the pain is measured on a scale from none (0) to severe (3) and frequency is measured on a scale from never (0) to very frequent (4). A score of a single item was calculated by multiplying severity with frequency. A domain score was calculated as the sum of every individual score related to the respective domain. A negative value indicates an improvement.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patient has advanced idiopathic Parkinson's Disease associated chronic pain assessed by a Likert Pain Scale

• Patient is taking Levodopa with a stable daily dose of at least 200 mg for at least 21 days prior to start

• Hoehn and Yahr stage score of II to IV

• Mini-Mental State Examination (MMSE) score ≥ 25

• If an antidepressant drug is taken, the dose must be stable for at least 21 days

Exclusion Criteria:

• Therapy with a Dopamine Agonist within 21 days prior to start

• Discontinuation from previous Dopamine Agonist Therapy due to lack of efficacy

• Therapy with Dopamine-modulating substances 21 days prior to start

• Therapy with analgesics for the treatment for pain, unless the dose has been stable

• Chronic alcohol or drug abuse

• Medical or psychiatric condition that, in the opinion of the investigator, could jeopardize or would compromise the patient's ability to participate in this study

• Hypersensitivity to any components of the Investigational Medicinal Product (IMP) or comparative drugs

• Atypical Parkinson's Disease Syndrome due to drugs

• History of deep brain stimulation

• Significant skin disease that would make transdermal drug use inappropriate

• Electroconvulsive therapy within 12 weeks prior to start

• Evidence of an Impulse Control Disorder

• Previous diagnosis of severe Restless Legs Syndrome

• Chronic Migraine

• Severe Depression

• Symptomatic Orthostatic Hypotension

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	2113	Gilbert	Arizona	United States
2	2120	Sunnyvale	California	United States
3	2109	Tampa	Florida	United States
4	2107	Chicago	Illinois	United States
5	2102	Lexington	Kentucky	United States
6	2118	Advance	North Carolina	United States
7	2117	Cincinnati	Ohio	United States
8	2103	Tulsa	Oklahoma	United States
9	2101	Roanoke	Virginia	United States
10	2104	Milwaukee	Wisconsin	United States
11	1204	Gera		Germany
12	1607	Gdansk		Poland
13	1603	Krakow		Poland
14	1609	Olsztyn		Poland
15	1804	Bratislava		Slovakia
16	1805	Dubnica Nad Vahom		Slovakia

Sponsors and Collaborators

• UCB BIOSCIENCES GmbH

Investigators

• Study Director: UCB Clinical Trial Call Center, [phone] (UCB)

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• FDA Safety Alerts and Recalls

Publications

None provided.

• Responsible Party: UCB BIOSCIENCES GmbH
• ClinicalTrials.gov Identifier: NCT01744496
• Other Study ID Numbers: PD0004; 2012-002608-42
• First Posted: Dec 6, 2012
• Last Update Posted: May 1, 2015
• Last Verified: Apr 1, 2015

• Keywords provided by UCB BIOSCIENCES GmbH: Parkinson's Disease; Rotigotine; Chronic Pain; Nonmotor symptoms
• Additional relevant MeSH terms: Parkinson Disease; Rotigotine

Study Results

Participant Flow

Recruitment Details	The study was conducted in Europe and USA. Recruitment was planned to continue until approximately 64 patients were randomized in the study. Subjects were randomized in a 1:1 ratio to either Rotigotine or Placebo. To achieve this, approximately 28 investigational sites were planned to participate in this hypothesis-generating pilot study.
Pre-assignment Detail	The Participant Flow population refers to the Randomized Set (RS). The RS includes all subjects who were randomized.

Arm/Group Title	Placebo	Rotigotine
Arm/Group Description	Placebo Transdermal Patches Placebo: Placebo patches matched the size of active patches 20 cm^2, 30 cm^2, or 40 cm^2 and contained Placebo. Application of Placebo patches started at the Baseline Visit. Placebo patches were administered once daily starting with the equivalent of 4 mg / 24 h. Doses were then up-titrated in weekly equivalents to 2 mg / 24 h until either optimal dose or maximum dose was reached. The maximum dose was the equivalent to 16 mg / 24 h. The duration of the Titration Period varied from 1 to 7 weeks. The Maintenance Period lasted 12 weeks ± 5 days. During the De-Escalation Period, the dose of Placebo will be decreased by the equivalent to 2 mg / 24 h every other day. The De-Escalation Period might have lasted up to 12 days.	Rotigotine Transdermal Patches Rotigotine: Patches contained 4 mg / 24 h (20 cm^2), 6 mg/ 24 h (30 cm^2), or 8 mg /24 h (40 cm^2) of Rotigotine. Application of study medication started at the Baseline Visit. Rotigotine was administered once daily starting at 4 mg / 24 h. Doses were then up-titrated in weekly increments of 2 mg / 24 h until optimal or maximum dose (16 mg / 24 h) was reached and the Maintenance Period could be started. The duration of the Titration Period varied from 1 to 7 weeks ± 3 days. The Maintenance Period lasted 12 weeks ± 5 days. Thereafter, during the De-Escalation Period, the dose of study medication was decreased by 2 mg / 24 h every other day. The De-Escalation Period might have lasted up to 12 days.
Period Title: Titration Period
STARTED	33	35
COMPLETED	31	33
NOT COMPLETED	2	2
Period Title: Titration Period
STARTED	31	33
COMPLETED	27	29
NOT COMPLETED	4	4

Baseline Characteristics

Arm/Group Title	Placebo	Rotigotine	Total
Arm/Group Description	Placebo Transdermal Patches Placebo: Placebo patches matched the size of active patches 20 cm^2, 30 cm^2, or 40 cm^2 and contained Placebo. Application of Placebo patches started at the Baseline Visit. Placebo patches were administered once daily starting with the equivalent of 4 mg / 24 h. Doses were then up-titrated in weekly equivalents to 2 mg / 24 h until either optimal dose or maximum dose was reached. The maximum dose was the equivalent to 16 mg / 24 h. The duration of the Titration Period varied from 1 to 7 weeks. The Maintenance Period lasted 12 weeks ± 5 days. During the De-Escalation Period, the dose of Placebo was decreased by the equivalent to 2 mg / 24 h every other day. The De-Escalation Period might have lasted up to 12 days.	Rotigotine Transdermal Patches Rotigotine: Patches contained 4 mg / 24 h (20 cm^2), 6 mg/ 24 h (30 cm^2), or 8 mg /24 h (40 cm^2) of Rotigotine. Application of study medication started at the Baseline Visit. Rotigotine was administered once daily starting at 4 mg / 24 h. Doses were then up-titrated in weekly increments of 2 mg / 24 h until optimal or maximum dose (16 mg / 24 h) was reached and the Maintenance Period could be started. The duration of the Titration Period varied from 1 to 7 weeks ± 3 days. The Maintenance Period lasted 12 weeks ± 5 days. Thereafter, during the De-Escalation Period, the dose of study medication was decreased by 2 mg / 24 h every other day. The De-Escalation Period might have lasted up to 12 days.	Total of all reporting groups
Overall Participants	33	35	68
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	15 45.5%	12 34.3%	27 39.7%
>=65 years	18 54.5%	23 65.7%	41 60.3%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65.3 (13.8)	66.5 (11.9)	65.9 (12.8)
Sex: Female, Male (Count of Participants)
Female	16 48.5%	16 45.7%	32 47.1%
Male	17 51.5%	19 54.3%	36 52.9%
Race/Ethnicity, Customized (participants) [Number]
American Indian / Alaskan native	0 0%	0 0%	0 0%
Asian	1 3%	0 0%	1 1.5%
Black	0 0%	0 0%	0 0%
Native Hawaiian or other Pacific Islander	0 0%	0 0%	0 0%
White	32 97%	35 100%	67 98.5%
Other / mixed	0 0%	0 0%	0 0%
Weight (kilograms) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms]	80.15 (20.00)	77.80 (13.71)	78.94 (16.97)
Height (centimeters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeters]	167.17 (9.92)	168.63 (9.87)	167.92 (9.85)
Body Mass Index (BMI) (kilogram per squaremeter) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram per squaremeter]	28.54 (6.21)	27.42 (4.74)	27.96 (5.49)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to the End of the Maintenance Period in Pain Severity Assessed Using an 11-point Likert Pain Scale
Description	An 11-Point Likert Scale was used to assess patients' average daily pain. The subject rated his/her average pain from 0 (no pain) to 10 (worst pain ever experienced). The average pain experienced in the last 7 days was calculated by the mean of the daily Likert Pain Scores within the 7 days prior to the respective visit (ie, Likert Pain Scores with a date of assessment before the date of visit and on or after the date of visit - 7 days). A negative value indicates an improvement.
Time Frame	Baseline (Visit 2) until End of the Maintenance Period (Maintenance Period lasts 12 weeks ± 5 days after an up to 7 weeks Titration Period)

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS). The FAS is a subset of the Safety Set and includes all subjects who were randomized, received at least 1 dose of study medication, and had a valid primary efficacy Baseline measurement and at least 1 valid post-Baseline Maintenance or valid Withdrawal primary efficacy measurement.

Arm/Group Title	Placebo	Rotigotine
Arm/Group Description	Placebo Transdermal Patches Placebo: Placebo patches matched the size of active patches 20 cm^2, 30 cm^2, or 40 cm^2 and contained Placebo. Application of Placebo patches started at the Baseline Visit. Placebo patches were administered once daily starting with the equivalent of 4 mg / 24 h. Doses were then up-titrated in weekly equivalents to 2 mg / 24 h until either optimal dose or maximum dose was reached. The maximum dose was the equivalent to 16 mg / 24 h. The duration of the Titration Period varied from 1 to 7 weeks. The Maintenance Period lasted 12 weeks ± 5 days. During the De-Escalation Period, the dose of Placebo was decreased by the equivalent to 2 mg / 24 h every other day. The De-Escalation Period might have lasted up to 12 days.	Rotigotine Transdermal Patches Rotigotine: Patches contained 4 mg / 24 h (20 cm^2), 6 mg/ 24 h (30 cm^2), or 8 mg /24 h (40 cm^2) of Rotigotine. Application of study medication started at the Baseline Visit. Rotigotine was administered once daily starting at 4 mg / 24 h. Doses were then up-titrated in weekly increments of 2 mg / 24 h until optimal or maximum dose (16 mg / 24 h) was reached and the Maintenance Period could be started. The duration of the Titration Period varied from 1 to 7 weeks ± 3 days. The Maintenance Period lasted 12 weeks ± 5 days. Thereafter, during the De-Escalation Period, the dose of study medication was decreased by 2 mg / 24 h every other day. The De-Escalation Period might have lasted up to 12 days.
Measure Participants	30	30
Mean (Standard Deviation) [scores on a scale]	-2.2 (2.78)	-2.8 (1.84)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rotigotine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.172
	Comments
	Method	ANCOVA
	Comments	ANCOVA model for the change from Baseline to the End of Treatment containing treatment and region as factors and Baseline value as a covariate.
Method of Estimation	Estimation Parameter	Least Square Mean
	Estimated Value	-0.76
	Confidence Interval	(2-Sided) 95%; -1.87 to 0.34
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.55
	Estimation Comments

2. Secondary Outcome

Title	Percentage of Responders at the End of the Maintenance Period
Description	Responders are defined as patients experiencing a 2-Point or more Reduction on an 11-Point Likert Pain Scale from Baseline to the End of the Maintenance Period. An 11-Point Likert Scale was used to assess patients' average daily pain. The patient rated his/her average pain from 0 (no pain) to 10 (worst pain ever experienced).
Time Frame	Baseline (Visit 2) until End of the Maintenance Period (Maintenance Period lasts 12 weeks ± 5 days after up to 7 weeks Titration Period)

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS). The FAS is a subset of the Safety Set and includes all subjects who were randomized, received at least 1 dose of study medication, and had a valid primary efficacy Baseline measurement and at least 1 valid post-Baseline Maintenance or valid Withdrawal primary efficacy measurement.

Arm/Group Title	Placebo	Rotigotine
Arm/Group Description	Placebo Transdermal Patches Placebo: Placebo patches matched the size of active patches 20 cm^2, 30 cm^2, or 40 cm^2 and contained Placebo. Application of Placebo patches started at the Baseline Visit. Placebo patches were administered once daily starting with the equivalent of 4 mg / 24 h. Doses were then up-titrated in weekly equivalents to 2 mg / 24 h until either optimal dose or maximum dose was reached. The maximum dose was the equivalent to 16 mg / 24 h. The duration of the Titration Period varied from 1 to 7 weeks. The Maintenance Period lasted 12 weeks ± 5 days. During the De-Escalation Period, the dose of Placebo was decreased by the equivalent to 2 mg / 24 h every other day. The De-Escalation Period might have lasted up to 12 days.	Rotigotine Transdermal Patches Rotigotine: Patches contained 4 mg / 24 h (20 cm^2), 6 mg/ 24 h (30 cm^2), or 8 mg /24 h (40 cm^2) of Rotigotine. Application of study medication started at the Baseline Visit. Rotigotine was administered once daily starting at 4 mg / 24 h. Doses were then up-titrated in weekly increments of 2 mg / 24 h until optimal or maximum dose (16 mg / 24 h) was reached and the Maintenance Period could be started. The duration of the Titration Period varied from 1 to 7 weeks ± 3 days. The Maintenance Period lasted 12 weeks ± 5 days. Thereafter, during the De-Escalation Period, the dose of study medication was decreased by 2 mg / 24 h every other day. The De-Escalation Period might have lasted up to 12 days.
Measure Participants	30	30
Number [percentage of responders]	46.7	60

3. Secondary Outcome

Title	Change From Baseline to the End of the Maintenance Period in the Sum Score of the 8-Item Parkinson's Disease Questionnaire (PDQ-8)
Description	The 8-Item Parkinson's Disease Questionnaire (PDQ-8) (Peto et al, 1998) is a self-administered questionnaire that provides a reliable measure of overall health status. The PDQ-8 contains 8 items of daily living, with 1 item selected from each of the following 8 scales: mobility, Activities of Daily Living (ADL), emotional well being, stigma, social support, cognitions, communication, and bodily discomfort. The total PDQ-8 score is the sum of all the individual items converted to a summary index score between 0 and 100, with lower scores indicating better health. A negative value indicates an improvement.
Time Frame	Baseline (Visit 2) until End of the Maintenance Period (Maintenance Period lasts 12 weeks ± 5 days after up to 7 weeks Titration Period)

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS). The FAS is a subset of the Safety Set and includes all subjects who were randomized, received at least 1 dose of study medication, and had a valid primary efficacy Baseline measurement and at least 1 valid post-Baseline Maintenance or valid Withdrawal primary efficacy measurement.

Arm/Group Title	Placebo	Rotigotine
Arm/Group Description	Placebo Transdermal Patches Placebo: Placebo patches matched the size of active patches 20 cm^2, 30 cm^2, or 40 cm^2 and contained Placebo. Application of Placebo patches started at the Baseline Visit. Placebo patches were administered once daily starting with the equivalent of 4 mg / 24 h. Doses were then up-titrated in weekly equivalents to 2 mg / 24 h until either optimal dose or maximum dose was reached. The maximum dose was the equivalent to 16 mg / 24 h. The duration of the Titration Period varied from 1 to 7 weeks. The Maintenance Period lasted 12 weeks ± 5 days. During the De-Escalation Period, the dose of Placebo was decreased by the equivalent to 2 mg / 24 h every other day. The De-Escalation Period might have lasted up to 12 days.	Rotigotine Transdermal Patches Rotigotine: Patches contained 4 mg / 24 h (20 cm^2), 6 mg/ 24 h (30 cm^2), or 8 mg /24 h (40 cm^2) of Rotigotine. Application of study medication started at the Baseline Visit. Rotigotine was administered once daily starting at 4 mg / 24 h. Doses were then up-titrated in weekly increments of 2 mg / 24 h until optimal or maximum dose (16 mg / 24 h) was reached and the Maintenance Period could be started. The duration of the Titration Period varied from 1 to 7 weeks ± 3 days. The Maintenance Period lasted 12 weeks ± 5 days. Thereafter, during the De-Escalation Period, the dose of study medication was decreased by 2 mg / 24 h every other day. The De-Escalation Period might have lasted up to 12 days.
Measure Participants	29	30
Mean (Standard Deviation) [scores on a scale]	-3.77 (13.93)	-12.40 (19.25)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rotigotine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.038
	Comments
	Method	ANCOVA
	Comments	ANCOVA model for the change from Baseline to the End of Treatment containing treatment and region as factors and Baseline value as a covariate.
Method of Estimation	Estimation Parameter	Least Square Mean
	Estimated Value	-8.01
	Confidence Interval	(2-Sided) 95%; -15.56 to -0.46
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.77
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline to the End of the Maintenance Period in the 7-Item Depression Subscore of the Hospital Anxiety and Depression Scale (HADS)
Description	The Hospital Anxiety and Depression Scale (HADS) (Zigmond and Snaith, 1983) is a 14-item self-assessment scale for detecting states of depression and anxiety in the setting of a hospital medical outpatient clinic. It comprises a 7-item anxiety subscale and a 7-item depressive subscale that are also measures of severity of the emotional disorder. The 14 items are scored between 0 and 3. The 7-item depression subscore and 7-item anxiety subscore were calculated as the sum of the 7 corresponding individual scores. A negative value indicates an improvement.
Time Frame	Baseline (Visit 2) until End of the Maintenance Period (Maintenance Period lasts 12 weeks ± 5 days after up to 7 weeks Titration Period)

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS). The FAS is a subset of the Safety Set and includes all subjects who were randomized, received at least 1 dose of study medication, and had a valid primary efficacy Baseline measurement and at least 1 valid post-Baseline Maintenance or valid Withdrawal primary efficacy measurement.

Arm/Group Title	Placebo	Rotigotine
Arm/Group Description	Placebo Transdermal Patches Placebo: Placebo patches matched the size of active patches 20 cm^2, 30 cm^2, or 40 cm^2 and contained Placebo. Application of Placebo patches started at the Baseline Visit. Placebo patches were administered once daily starting with the equivalent of 4 mg / 24 h. Doses were then up-titrated in weekly equivalents to 2 mg / 24 h until either optimal dose or maximum dose was reached. The maximum dose was the equivalent to 16 mg / 24 h. The duration of the Titration Period varied from 1 to 7 weeks. The Maintenance Period lasted 12 weeks ± 5 days. During the De-Escalation Period, the dose of Placebo was decreased by the equivalent to 2 mg / 24 h every other day. The De-Escalation Period might have lasted up to 12 days.	Rotigotine Transdermal Patches Rotigotine: Patches contained 4 mg / 24 h (20 cm^2), 6 mg/ 24 h (30 cm^2), or 8 mg /24 h (40 cm^2) of Rotigotine. Application of study medication started at the Baseline Visit. Rotigotine was administered once daily starting at 4 mg / 24 h. Doses were then up-titrated in weekly increments of 2 mg / 24 h until optimal or maximum dose (16 mg / 24 h) was reached and the Maintenance Period could be started. The duration of the Titration Period varied from 1 to 7 weeks ± 3 days. The Maintenance Period lasted 12 weeks ± 5 days. Thereafter, during the De-Escalation Period, the dose of study medication was decreased by 2 mg / 24 h every other day. The De-Escalation Period might have lasted up to 12 days.
Measure Participants	28	28
Mean (Standard Deviation) [scores on a scale]	-1.7 (4.3)	-1.9 (4.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rotigotine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.247
	Comments
	Method	ANCOVA
	Comments	ANCOVA model for the change from Baseline to the End of Treatment containing treatment and region as factors and Baseline value as a covariate.
Method of Estimation	Estimation Parameter	Least Square Mean
	Estimated Value	-1.02
	Confidence Interval	(2-Sided) 95%; -2.76 to 0.73
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.87
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline to the End of the Maintenance Period in the 7-Item Anxiety Subscore of the Hospital Anxiety and Depression Scale (HADS)
Description	The Hospital Anxiety and Depression Scale (HADS) (Zigmond and Snaith, 1983) is a 14-item self-assessment scale for detecting states of depression and anxiety in the setting of a hospital medical outpatient clinic. It comprises a 7-item anxiety subscale and a 7-item depressive subscale that are also measures of severity of the emotional disorder. The 14 items are scored between 0 and 3. The 7-item depression subscore and 7-item anxiety subscore were calculated as the sum of the 7 corresponding individual scores. A negative value indicates an improvement.
Time Frame	Baseline (Visit 2) until End of the Maintenance Period (Maintenance Period lasts 12 weeks ± 5 days after up to 7 weeks Titration Period)

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS). The FAS is a subset of the Safety Set and includes all subjects who were randomized, received at least 1 dose of study medication, and had a valid primary efficacy Baseline measurement and at least 1 valid post-Baseline Maintenance or valid Withdrawal primary efficacy measurement.

Arm/Group Title	Placebo	Rotigotine
Arm/Group Description	Placebo Transdermal Patches Placebo: Placebo patches matched the size of active patches 20 cm^2, 30 cm^2, or 40 cm^2 and contained Placebo. Application of Placebo patches started at the Baseline Visit. Placebo patches were administered once daily starting with the equivalent of 4 mg / 24 h. Doses were then up-titrated in weekly equivalents to 2 mg / 24 h until either optimal dose or maximum dose was reached. The maximum dose was the equivalent to 16 mg / 24 h. The duration of the Titration Period varied from 1 to 7 weeks. The Maintenance Period lasted 12 weeks ± 5 days. During the De-Escalation Period, the dose of Placebo was decreased by the equivalent to 2 mg / 24 h every other day. The De-Escalation Period might have lasted up to 12 days.	Rotigotine Transdermal Patches Rotigotine: Patches contained 4 mg / 24 h (20 cm^2), 6 mg/ 24 h (30 cm^2), or 8 mg /24 h (40 cm^2) of Rotigotine. Application of study medication started at the Baseline Visit. Rotigotine was administered once daily starting at 4 mg / 24 h. Doses were then up-titrated in weekly increments of 2 mg / 24 h until optimal or maximum dose (16 mg / 24 h) was reached and the Maintenance Period could be started. The duration of the Titration Period varied from 1 to 7 weeks ± 3 days. The Maintenance Period lasted 12 weeks ± 5 days. Thereafter, during the De-Escalation Period, the dose of study medication was decreased by 2 mg / 24 h every other day. The De-Escalation Period might have lasted up to 12 days.
Measure Participants	28	28
Mean (Standard Deviation) [scores on a scale]	-1.0 (3.2)	-1.8 (3.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rotigotine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.371
	Comments
	Method	ANCOVA
	Comments	ANCOVA model for the change from Baseline to the End of Treatment containing treatment and region as factors and Baseline value as a covariate.
Method of Estimation	Estimation Parameter	Least Square Mean
	Estimated Value	-0.58
	Confidence Interval	(2-Sided) 95%; -1.85 to 0.70
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.64
	Estimation Comments

6. Secondary Outcome

Title	Change From Baseline to the End of the Maintenance Period in the Combined Score of the Unified Parkinson's Disease Rating Scale (UPDRS) Parts II (Activities of Daily Living [ADL] Subscale) and III (Motor Subscale)
Description	Part II of the Unified Parkinson's Disease Rating Scale (UPDRS) assesses the subject's activities of daily living. Part III assesses motor function. The UPDRS is completed by questioning the subject about his/her general state in conjunction with any observations made by the investigator (or designee) since the previous visit. Part II is subject-rated and Part III is physician-rated. The UPDRS Part II (Activities of Daily Living) consists of 13 items scored between 0 and 4. The sum score was calculated as the sum of these 13 individual scores. The UPDRS Part III (motor subscale) consists of 27 items and sub items scored between 0 and 4. The sum score was calculated as sum of these 27 individual scores. The sum score of UPDRS Parts II and III is the sum of the corresponding single sum scores. A negative value indicates an improvement.
Time Frame	Baseline (Visit 2) until End of the Maintenance Period (Maintenance Period lasts 12 weeks ± 5 days after up to 7 weeks Titration Period)

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS). The FAS is a subset of the Safety Set and includes all subjects who were randomized, received at least 1 dose of study medication, and had a valid primary efficacy Baseline measurement and at least 1 valid post-Baseline Maintenance or valid Withdrawal primary efficacy measurement.

Arm/Group Title	Placebo	Rotigotine
Arm/Group Description	Placebo Transdermal Patches Placebo: Placebo patches matched the size of active patches 20 cm^2, 30 cm^2, or 40 cm^2 and contained Placebo. Application of Placebo patches started at the Baseline Visit. Placebo patches were administered once daily starting with the equivalent of 4 mg / 24 h. Doses were then up-titrated in weekly equivalents to 2 mg / 24 h until either optimal dose or maximum dose was reached. The maximum dose was the equivalent to 16 mg / 24 h. The duration of the Titration Period varied from 1 to 7 weeks. The Maintenance Period lasted 12 weeks ± 5 days. During the De-Escalation Period, the dose of Placebo was decreased by the equivalent to 2 mg / 24 h every other day. The De-Escalation Period might have lasted up to 12 days.	Rotigotine Transdermal Patches Rotigotine: Patches contained 4 mg / 24 h (20 cm^2), 6 mg/ 24 h (30 cm^2), or 8 mg /24 h (40 cm^2) of Rotigotine. Application of study medication started at the Baseline Visit. Rotigotine was administered once daily starting at 4 mg / 24 h. Doses were then up-titrated in weekly increments of 2 mg / 24 h until optimal or maximum dose (16 mg / 24 h) was reached and the Maintenance Period could be started. The duration of the Titration Period varied from 1 to 7 weeks ± 3 days. The Maintenance Period lasted 12 weeks ± 5 days. Thereafter, during the De-Escalation Period, the dose of study medication was decreased by 2 mg / 24 h every other day. The De-Escalation Period might have lasted up to 12 days.
Measure Participants	29	30
Mean (Standard Deviation) [scores on a scale]	-5.1 (11.7)	-8.3 (11.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rotigotine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.346
	Comments
	Method	ANCOVA
	Comments	ANCOVA model for the change from Baseline to the End of Treatment containing treatment and region as factors and Baseline value as a covariate.
Method of Estimation	Estimation Parameter	Least Square Mean
	Estimated Value	-2.82
	Confidence Interval	(2-Sided) 95%; -8.76 to 3.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.97
	Estimation Comments

7. Secondary Outcome

Title	Change From Baseline to the End of the Maintenance Period in the 7 Domain Scores of Classification of Pain in Parkinson's Disease
Description	The classification of pain in Parkinson's disease scale classifies pain in the following domains: musculoskeletal pain (item 1), chronic pain (items 2 and 3), fluctuation related pain (items 4, 5 and 6), nocturnal pain (items 7 and 8), oro-facial pain (items 9, 10 and 11), discoloration; edema/swelling (items 12 and 13), and radicular pain (item 14). Severity of the pain is measured on a scale from none (0) to severe (3) and frequency is measured on a scale from never (0) to very frequent (4). A score of a single item was calculated by multiplying severity with frequency. A domain score was calculated as the sum of every individual score related to the respective domain. A negative value indicates an improvement.
Time Frame	Baseline (Visit 2) until End of the Maintenance Period (Maintenance Period lasts 12 weeks ± 5 days after up to 7 weeks Titration Period)

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS). The FAS is a subset of the Safety Set and includes all subjects who were randomized, received at least 1 dose of study medication, and had a valid primary efficacy Baseline measurement and at least 1 valid post-Baseline Maintenance or valid Withdrawal primary efficacy measurement.

Arm/Group Title	Placebo	Rotigotine
Arm/Group Description	Placebo Transdermal Patches Placebo: Placebo patches matched the size of active patches 20 cm^2, 30 cm^2, or 40 cm^2 and contained Placebo. Application of Placebo patches started at the Baseline Visit. Placebo patches were administered once daily starting with the equivalent of 4 mg / 24 h. Doses were then up-titrated in weekly equivalents to 2 mg / 24 h until either optimal dose or maximum dose was reached. The maximum dose was the equivalent to 16 mg / 24 h. The duration of the Titration Period varied from 1 to 7 weeks. The Maintenance Period lasted 12 weeks ± 5 days. During the De-Escalation Period, the dose of Placebo was decreased by the equivalent to 2 mg / 24 h every other day. The De-Escalation Period might have lasted up to 12 days.	Rotigotine Transdermal Patches Rotigotine: Patches contained 4 mg / 24 h (20 cm^2), 6 mg/ 24 h (30 cm^2), or 8 mg /24 h (40 cm^2) of Rotigotine. Application of study medication started at the Baseline Visit. Rotigotine was administered once daily starting at 4 mg / 24 h. Doses were then up-titrated in weekly increments of 2 mg / 24 h until optimal or maximum dose (16 mg / 24 h) was reached and the Maintenance Period could be started. The duration of the Titration Period varied from 1 to 7 weeks ± 3 days. The Maintenance Period lasted 12 weeks ± 5 days. Thereafter, during the De-Escalation Period, the dose of study medication was decreased by 2 mg / 24 h every other day. The De-Escalation Period might have lasted up to 12 days.
Measure Participants	29	30
Musculoskeletal Pain	-1.4 (3.6)	-1.5 (4.2)
Chronic Pain	-3.1 (5.6)	-0.7 (2.9)
Fluctuation-Related Pain	-2.2 (4.6)	-4.2 (6.8)
Nocturnal Pain	-2.9 (6.1)	-2.4 (5.3)
Oro-Facial Pain	-0.4 (2.5)	-0.6 (2.3)
Discoloration; Edema/Swelling	-1.8 (4.9)	-1.7 (3.4)
Radicular Pain	-1.3 (3.8)	-1.1 (3.7)

Adverse Events

Time Frame	Treatment Emergent Adverse Events were reported from Baseline up to the Safety Follow-up Visit (approximately during 25 weeks).
Adverse Event Reporting Description	Adverse Events refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.
Arm/Group Title	Placebo		Rotigotine
Arm/Group Description	Placebo Transdermal Patches Placebo: Placebo patches matched the size of active patches 20 cm^2, 30 cm^2, or 40 cm^2 and contained Placebo. Application of Placebo patches started at the Baseline Visit. Placebo patches were administered once daily starting with the equivalent of 4 mg / 24 h. Doses were then up-titrated in weekly equivalents to 2 mg / 24 h until either optimal dose or maximum dose was reached. The maximum dose was the equivalent to 16 mg / 24 h. The duration of the Titration Period varied from 1 to 7 weeks. The Maintenance Period lasted 12 weeks ± 5 days. During the De-Escalation Period, the dose of Placebo was decreased by the equivalent to 2 mg / 24 h every other day. The De-Escalation Period might have lasted up to 12 days.		Rotigotine Transdermal Patches Rotigotine: Patches contained 4 mg / 24 h (20 cm^2), 6 mg/ 24 h (30 cm^2), or 8 mg /24 h (40 cm^2) of Rotigotine. Application of study medication started at the Baseline Visit. Rotigotine was administered once daily starting at 4 mg / 24 h. Doses were then up-titrated in weekly increments of 2 mg / 24 h until optimal or maximum dose (16 mg / 24 h) was reached and the Maintenance Period could be started. The duration of the Titration Period varied from 1 to 7 weeks ± 3 days. The Maintenance Period lasted 12 weeks ± 5 days. Thereafter, during the De-Escalation Period, the dose of study medication was decreased by 2 mg / 24 h every other day. The De-Escalation Period might have lasted up to 12 days.
All Cause Mortality
	Placebo		Rotigotine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Rotigotine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/33 (3%)		2/35 (5.7%)
General disorders
Oedema peripheral	0/33 (0%)	0	1/35 (2.9%)	1
Injury, poisoning and procedural complications
Hip fracture	1/33 (3%)	1	0/35 (0%)	0
Nervous system disorders
Cerebrovascular accident	0/33 (0%)	0	1/35 (2.9%)	1
Other (Not Including Serious) Adverse Events
	Placebo		Rotigotine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/33 (51.5%)		20/35 (57.1%)
Gastrointestinal disorders
Diarrhoea	2/33 (6.1%)	2	0/35 (0%)	0
Nausea	2/33 (6.1%)	3	8/35 (22.9%)	11
General disorders
Application site erythema	0/33 (0%)	0	3/35 (8.6%)	3
Fatigue	1/33 (3%)	1	2/35 (5.7%)	2
Infections and infestations
Upper respiratory tract infection	2/33 (6.1%)	2	1/35 (2.9%)	1
Urinary tract infection	0/33 (0%)	0	2/35 (5.7%)	2
Injury, poisoning and procedural complications
Fall	0/33 (0%)	0	2/35 (5.7%)	3
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	2/33 (6.1%)	2	1/35 (2.9%)	1
Nervous system disorders
Dyskinesia	2/33 (6.1%)	2	2/35 (5.7%)	2
Hyperkinesia	2/33 (6.1%)	2	0/35 (0%)	0
Headache	4/33 (12.1%)	11	6/35 (17.1%)	7
Dizziness	3/33 (9.1%)	3	3/35 (8.6%)	3
Psychiatric disorders
Insomnia	1/33 (3%)	1	3/35 (8.6%)	3
Skin and subcutaneous tissue disorders
Rash	2/33 (6.1%)	2	2/35 (5.7%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.