BRIGHT: Trial to Evaluate The Efficacy Of Rotigotine on Parkinson's Disease-Associated Motor Symptoms And Apathy

• Sponsor: UCB BIOSCIENCES GmbH (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01782222
• Collaborator: (none)
• Enrollment: 122
• Locations: 42
• Arms: 3
• Duration (Months): 12.9
• Patients Per Site: 2.9
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This trial is being conducted to assess the effects of Rotigotine over Placebo on improvement of Apathy and motor symptoms in subjects with early-stage and advanced stage idiopathic Parkinson´s Disease.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 122 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Multinational, Double-Blind, Placebo-Controlled, 3-Arm, Phase 4 Study To Evaluate The Efficacy Of Rotigotine On Parkinson's Disease-Associated Apathy, Motor Symptoms, And Mood
• Study Start Date: Feb 1, 2013
• Actual Primary Completion Date: Jan 1, 2014
• Actual Study Completion Date: Mar 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Rotigotine, high dose Rotigotine, transdermal patches, maximal 16 mg / 24 hours for patients with advanced Parkinson's Disease and 8 mg / 24 hours for those with early Parkinson's Disease	Drug: Rotigotine; Rotigotine, transdermal patches: 10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours); 40 cm^2 (8 mg / 24 hours) The maximum Rotigotine dose allowed is 8 mg / 24 hours or 16 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours or 8 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation); Other Names: (6S)-6-propyl-[2 (2 thienyl)ethyl]amino-5,6,7,8-tetrahydro-1-naphthalenol
Experimental: Rotigotine, low dose Rotigotine, transdermal patches, optimal dose, maximal 8 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours for those with early Parkinson's Disease	Drug: Rotigotine; Rotigotine, transdermal patches: 10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours); 40 cm^2 (8 mg / 24 hours) The maximum Rotigotine dose allowed is 8 mg / 24 hours or 16 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours or 8 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation); Other Names: (6S)-6-propyl-[2 (2 thienyl)ethyl]amino-5,6,7,8-tetrahydro-1-naphthalenol
Placebo Comparator: Placebo Placebo transdermal patches	Other: Placebo; Placebo, matching transdermal patches Duration: up to 21 weeks (including de-escalation)

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to the End of the Maintenance Period in the Score of the Apathy Evaluation Scale (AS) Rated by the Patient [Baseline (Visit 2) until End of the Maintenance Period / Early Withdrawal (up to 19 weeks after Baseline)]

   The Apathy Scale (AS) is an abbreviated version of the Apathy Evaluation Scale. The AS (Starkstein et al, 1992) consists of 14 items phrased as questions by the examiner that are to be answered on a 4-point Likert scale. It was developed specifically for subjects with Parkinson's disease because the Apathy Evaluation Scale was considered too demanding. The questions comprising the AS were answered by the subject. The total scores for Apathy Evaluation Scale ranges from 0 (best possible outcome) to 42 (worst possible outcome).

2. Change From Baseline to the End of the Maintenance Period in the Total Score of the Unified Parkinson's Disease Rating Scale (UPDRS) Parts II (Activities of Daily Living) + III (Motor Symptoms) [Baseline (Visit 2) until End of the Maintenance Period / Early Withdrawal (up to 19 weeks after Baseline)]

   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.

Secondary Outcome Measures

1. Change From Baseline to the End of the Maintenance Period in the Score of the Apathy Evaluation Scale (AS) Rated by the Caregiver (Where Available) [Baseline (Visit 2) until End of the Maintenance Period / Early Withdrawal (up to 19 weeks after Baseline)]

   The Apathy Scale (AS) is an abbreviated version of the Apathy Evaluation Scale. The AS (Starkstein et al, 1992) consists of 14 items phrased as questions by the examiner that are to be answered on a 4-point Likert scale. It was developed specifically for subjects with Parkinson's disease because the Apathy Evaluation Scale was considered too demanding. The questions comprising the AS were answered by the caregiver. The questions were asked in a structured interview format. The caregiver was interviewed by appropriate medical staff and asked questions about the subject in the third person.The total scores for Apathy Evaluation Scale ranges from 0 (best possible outcome) to 42 (worst possible outcome).

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 / Early Withdrawal (up to 19 weeks after Baseline)]

   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 collects 8 items with 5 categories each (0=never, 1=occasionally, 2=sometimes, 3=often, 4=always or cannot do at all). The total score was calculated by summing the scores of all applicable questions and convert the resulting sum to a summary index score between 0 and 100 by multiplying with 100/32. A negative value indicates an improvement.

3. Change From Baseline to the End of the Maintenance Period in the Sum Score of the Mood / Cognition Domain of the Nonmotor Symptom Assessment Scale (NMSS) [Baseline (Visit 2) until End of the Maintenance Period / Early Withdrawal (up to 19 weeks after Baseline)]

   Nonmotor performance was assessed via the Nonmotor Symptom Assessment Scale (NMSS), an accepted scale that has been validated in an international study (Naidu et al, 2006; Chaudhuri et al, 2007), at the Baseline Visit as well as at the end of the Maintenance Period. The severity and frequency of the subject's nonmotor symptoms were assessed by the investigator (or designee) in the following 9 domain categories: cardiovascular, including falls; sleep/fatigue; mood/cognition; perceptual problems/hallucinations; attention/memory; gastrointestinal tract; urinary; sexual function; and miscellaneous. Items are scored for severity (from 0 (none) to 3 (severe)) and frequency (from 1 (rarely) to 4 (very frequent )). The score was calculated as severity x frequency. The theoretical minimum is 0 (best possible outcome) and maximum total score is 360 points (worst possible outcome).

4. Change From Baseline to the End of the Maintenance Period in the Sum Score of the Snaith Hamilton Pleasure Scale (SHAPS) [Baseline (Visit 2) until End of the Maintenance Period / Early Withdrawal (up to 19 weeks after Baseline)]

   The Snaith Hamilton Pleasure Scale (SHAPS) (Snaith et al, 1995) is a self-report instrument developed for the assessment of hedonic capacity. The sum of the 14 items scores range from 0 to 14. A higher score represents more anhedonic symptoms.

5. Change From Baseline to the End of the Maintenance Period in the Sum Score of the Beck Depression Inventory Second Edition (BDI-II) [Baseline (Visit 2) until End of the Maintenance Period / Early Withdrawal (up to 19 weeks after Baseline)]

   The Beck Depression Inventory (BDI) is a self-report instrument to measure depression symptoms and severity (Beck et al, 1961). The BDI-II is a revised version of the scale in order to be more consistent with the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for depression (Beck et al, 1996). There are 21 items in the BDI-II, classified as cognitive-affective (Items 1-13) and somatic-performance (Items 14-21) subscales. The degree of severity is indicated on a 4-point scale; items are rated from 0 (not at all) to 3 (extreme form of each symptom). Scores of 0-13 indicate minimal depression, 14-19 indicate mild depression, 20-28 indicate moderate depression, and 29-63 indicate severe depression.

6. Change From Baseline to the End of the Maintenance Period in the Sum Score of the Unified Parkinson's Disease Rating Scale (UPDRS) Part III (Motor Subscale) in "on" State [Baseline (Visit 2) until End of the Maintenance Period / Early Withdrawal (up to 19 weeks after Baseline)]

   Part III of the Unified Parkinson's Disease Rating Scale (UPDRS) 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. The UPDRS Part III (motor subscale) had to be measured in the "on" state and consisted of 27 items and sub items scored between 0 and 4. The sum score ranged between 0 and 108 and was calculated as sum of the 27 individual scores. If 1 or more items were missing and could not be substituted with a previous post-Baseline value, the sum score was also missing. A negative value indicates an improvement.

7. Change From Baseline to the End of the Maintenance Period in the Score of the Clinical Global Impression Scale (CGI) Item I (Severity of Illness) [Baseline (Visit 2) until End of the Maintenance Period/Early Withdrawal (up to 19 weeks after Baseline)]

   The Clinical Global Impression (CGI) scales (Guy and Bonato, 1970) were initially developed for a risk-benefit estimation within the treatment of mentally ill patients. The 4 global scales (severity of illness, change in severity from Baseline, therapeutic efficacy, and tolerability of treatment) are used as different measures of treatment outcome in different kinds of pharmacological studies. The CGI Item 1 (severity of illness) collected 1 answer out of 8 categories (0-'Not assessed', 1-'Normal, not at all ill', 2-'Borderline ill', 3-'Mildly ill', 4-'Moderately ill', 5-'Markedly ill', 6-'Severely ill', and 7-'Among the most extremely ill patients') at each assessment. The category 0-'Not assessed' was considered as missing and therefore used neither for calculation nor for display purposes.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Patients with early or advanced idiopathic Parkinson's Disease

• Patients with advanced idiopathic Parkinson's Disease: intake of Levodopa on a stable dose of at least 200 mg/day

• Unsatisfactory control of Parkinson's Disease motor symptoms under current treatment

• Patients experiencing Apathy associated with Parkinson's Disease

• Hoehn and Yahr stage score of I to IV

• Mini-Mental State Examination score ≥ 25

• If an antidepressant drug is taken, the dose must be stable

Exclusion Criteria:

• Therapy with a Dopamine agonist

• Discontinuation from pervious therapy with a dopamine agonist after an adequate length of treatment, at adequate dose, due to lack of efficacy

• Any medical or psychiatric condition that jeopardizes / compromises patient's ability for participation

• Patient has received Neuroleptics, Dopamine releasing substances, Dopamine modulating substances, Alpha-Methyldopa, Metoclopramide, MAO-A inhibitors, Budipine, or Tolcapone

• Electroconvulsive therapy

• Patient has a

• current/anticipated psychotherapy or behavior therapy

• history of deep brain stimulation

• history of suicide attempt or has suicidal ideation

• impulse control disorder

• severe Depression

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	4320	Birmingham	Alabama	United States
2	4309	Oxnard	California	United States
3	4306	Ormond Beach	Florida	United States
4	4311	Palm Beach Gardens	Florida	United States
5	4313	Tampa	Florida	United States
6	4314	Decatur	Georgia	United States
7	4318	Chicago	Illinois	United States
8	4316	Winfield	Illinois	United States
9	4322	Des Moines	Iowa	United States
10	4304	Kansas City	Kansas	United States
11	4326	Springfield	Massachusetts	United States
12	4330	Ocean Springs	Mississippi	United States
13	4302	Las Vegas	Nevada	United States
14	4303	Commack	New York	United States
15	4317	New York	New York	United States
16	4323	New York	New York	United States
17	4319	Asheville	North Carolina	United States
18	4325	Charlotte	North Carolina	United States
19	4329	Akron	Ohio	United States
20	4312	Cincinnati	Ohio	United States
21	4324	Beaufort	South Carolina	United States
22	4332	Charleston	South Carolina	United States
23	4305	San Antonio	Texas	United States
24	4307	Salt Lake City	Utah	United States
25	4333	Virginia Beach	Virginia	United States
26	3001	Innsbruck		Austria
27	3003	Linz		Austria
28	3301	Budapest		Hungary
29	3302	Debrecen		Hungary
30	3509	Gdansk		Poland
31	3506	Gdynia		Poland
32	3504	Poznan		Poland
33	3801	Banska Bystrica		Slovakia
34	3805	Bratislava		Slovakia
35	3806	Krompachy		Slovakia
36	3807	Zilina		Slovakia
37	3901	Ljubljana		Slovenia
38	4001	Barcelona		Spain
39	4006	Barcelona		Spain
40	4009	Oviedo		Spain
41	4005	Sevilla		Spain
42	4010	Sevilla		Spain

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: NCT01782222
• Other Study ID Numbers: PD0005; 2012-002840-26
• First Posted: Feb 1, 2013
• Last Update Posted: Aug 31, 2018
• Last Verified: Jul 1, 2018

• Keywords provided by UCB BIOSCIENCES GmbH: Parkinson's Disease; Rotigotine; Apathy; Nonmotor; Motor; Neupro
• Additional relevant MeSH terms: Parkinson Disease; Rotigotine

Study Results

Participant Flow

Recruitment Details	This study was planned to be conducted globally with 480 subjects (160 subjects per treatment group for the Full Analysis Set). Approx. 600 subjects were planned for enrollment in order to obtain 504 subjects for randomization. Subjects were randomized in a 1:1:1 ratio to either Rotigotine low dose, Rotigotine high dose or Placebo.
Pre-assignment Detail	The Participant Flow refers to the Randomized Set (RS). The RS included all subjects who were randomized. The outcome of the Interim Analysis was to stop the study, i.e. no more subjects were enrolled into the study and all included subjects completed the study as planned.

Arm/Group Title	Placebo	Rotigotine, Low Dose	Rotigotine, High Dose
Arm/Group Description	Placebo transdermal patches Placebo: Placebo, matching transdermal patches Duration: up to 21 weeks (including de-escalation)	Rotigotine, transdermal patches, optimal dose, maximal 8 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours for those with early Parkinson's Disease Rotigotine: Rotigotine, transdermal patches: 10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours); 40 cm^2 (8 mg / 24 hours) The maximum Rotigotine dose allowed was 8 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation)	Rotigotine, transdermal patches, maximal 16 mg / 24 hours for patients with advanced Parkinson's Disease and 8 mg / 24 hours for those with early Parkinson's Disease Rotigotine: Rotigotine, transdermal patches: 10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours); 40 cm^2 (8 mg / 24 hours) The maximum Rotigotine dose allowed was 16 mg / 24 hours for patients with advanced Parkinson's Disease and 8 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation)
Period Title: Overall Study
STARTED	40	41	41
COMPLETED	32	30	37
NOT COMPLETED	8	11	4

Baseline Characteristics

Arm/Group Title	Placebo	Rotigotine, Low Dose	Rotigotine, High Dose	Total
Arm/Group Description	Placebo transdermal patches Placebo: Placebo, matching transdermal patches Duration: up to 21 weeks (including de-escalation)	Rotigotine, transdermal patches, optimal dose, maximal 8 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours for those with early Parkinson's Disease Rotigotine: Rotigotine, transdermal patches: 10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours); 40 cm^2 (8 mg / 24 hours) The maximum Rotigotine dose allowed was 8 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation)	Rotigotine, transdermal patches, maximal 16 mg / 24 hours for patients with advanced Parkinson's Disease and 8 mg / 24 hours for those with early Parkinson's Disease Rotigotine: Rotigotine, transdermal patches: 10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours); 40 cm^2 (8 mg / 24 hours) The maximum Rotigotine dose allowed was 16 mg / 24 hours for patients with advanced Parkinson's Disease and 8 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation)	Total of all reporting groups
Overall Participants	40	41	41	122
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	69.0 (11.7)	68.1 (10.5)	70.2 (8.0)	69.1 (10.1)
Age, Customized (participants) [Number]
>18 - < 65 years	14 35%	17 41.5%	12 29.3%	43 35.2%
≥ 65 years	26 65%	24 58.5%	29 70.7%	79 64.8%
Sex: Female, Male (Count of Participants)
Female	18 45%	14 34.1%	14 34.1%	46 37.7%
Male	22 55%	27 65.9%	27 65.9%	76 62.3%
Race/Ethnicity, Customized (participants) [Number]
Black	1 2.5%	2 4.9%	1 2.4%	4 3.3%
White	38 95%	39 95.1%	40 97.6%	117 95.9%
Other/mixed	1 2.5%	0 0%	0 0%	1 0.8%
Weight (kilograms) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms]	79.59 (14.73)	77.34 (17.93)	78.96 (15.96)	78.62 (16.17)
Height (centimeters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeters]	167.16 (10.34)	169.25 (10.76)	170.88 (10.94)	169.10 (10.70)
Body Mass Index (BMI) (kilogram per square meter) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram per square meter]	28.53 (4.79)	26.86 (4.89)	26.90 (3.86)	27.42 (4.57)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to the End of the Maintenance Period in the Score of the Apathy Evaluation Scale (AS) Rated by the Patient
Description	The Apathy Scale (AS) is an abbreviated version of the Apathy Evaluation Scale. The AS (Starkstein et al, 1992) consists of 14 items phrased as questions by the examiner that are to be answered on a 4-point Likert scale. It was developed specifically for subjects with Parkinson's disease because the Apathy Evaluation Scale was considered too demanding. The questions comprising the AS were answered by the subject. The total scores for Apathy Evaluation Scale ranges from 0 (best possible outcome) to 42 (worst possible outcome).
Time Frame	Baseline (Visit 2) until End of the Maintenance Period / Early Withdrawal (up to 19 weeks after Baseline)

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS). The FAS included 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 for both primary efficacy variables.

Arm/Group Title	Placebo	Rotigotine, Low Dose	Rotigotine, High Dose
Arm/Group Description	Placebo transdermal patches Placebo: Placebo, matching transdermal patches Duration: up to 21 weeks (including de-escalation)	Rotigotine, transdermal patches, optimal dose, maximal 8 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours for those with early Parkinson's Disease Rotigotine: Rotigotine, transdermal patches: 10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours); 40 cm^2 (8 mg / 24 hours) The maximum Rotigotine dose allowed was 8 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation)	Rotigotine, transdermal patches, maximal 16 mg / 24 hours for patients with advanced Parkinson's Disease and 8 mg / 24 hours for those with early Parkinson's Disease Rotigotine: Rotigotine, transdermal patches: 10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours); 40 cm^2 (8 mg / 24 hours) The maximum Rotigotine dose allowed was 16 mg / 24 hours for patients with advanced Parkinson's Disease and 8 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation)
Measure Participants	40	36	40
Mean (Standard Deviation) [scores on a scale]	-4.4 (4.9)	-4.6 (6.7)	-4.9 (5.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rotigotine, Low Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.977
	Comments
	Method	ANCOVA
	Comments	ANCOVA model for the change from Baseline to End of Maintenance containing treatment and disease stage as factors, and Baseline value as covariate.
Method of Estimation	Estimation Parameter	Least Square Mean
	Estimated Value	0.04
	Confidence Interval	(2-Sided) 95%; -2.42 to 2.50
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.24
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rotigotine, High Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.859
	Comments
	Method	ANCOVA
	Comments	ANCOVA model for the change from Baseline to End of Maintenance containing treatment and disease stage as factors, and Baseline value as covariate.
Method of Estimation	Estimation Parameter	Least Square Mean
	Estimated Value	-0.22
	Confidence Interval	(2-Sided) 95%; -2.61 to 2.18
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.21
	Estimation Comments

2. Primary Outcome

Title	Change From Baseline to the End of the Maintenance Period in the Total Score of the Unified Parkinson's Disease Rating Scale (UPDRS) Parts II (Activities of Daily Living) + III (Motor Symptoms)
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 / Early Withdrawal (up to 19 weeks after Baseline)

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS). The FAS included 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 for both primary efficacy variables.

Arm/Group Title	Placebo	Rotigotine, Low Dose	Rotigotine, High Dose
Arm/Group Description	Placebo transdermal patches Placebo: Placebo, matching transdermal patches Duration: up to 21 weeks (including de-escalation)	Rotigotine, transdermal patches, optimal dose, maximal 8 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours for those with early Parkinson's Disease Rotigotine: Rotigotine, transdermal patches: 10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours); 40 cm^2 (8 mg / 24 hours) The maximum Rotigotine dose allowed was 8 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation)	Rotigotine, transdermal patches, maximal 16 mg / 24 hours for patients with advanced Parkinson's Disease and 8 mg / 24 hours for those with early Parkinson's Disease Rotigotine: Rotigotine, transdermal patches: 10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours); 40 cm^2 (8 mg / 24 hours) The maximum Rotigotine dose allowed was 16 mg / 24 hours for patients with advanced Parkinson's Disease and 8 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation)
Measure Participants	40	36	40
Mean (Standard Deviation) [scores on a scale]	-4.8 (10.4)	-12.4 (14.0)	-10.7 (8.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rotigotine, Low Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.005
	Comments
	Method	ANCOVA
	Comments	ANCOVA model for the change from Baseline to End of Maintenance containing treatment and disease stage as factors, and Baseline value as covariate.
Method of Estimation	Estimation Parameter	Least Square Mean
	Estimated Value	-7.29
	Confidence Interval	(2-Sided) 95%; -12.30 to -2.28
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.53
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rotigotine, High Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.015
	Comments
	Method	ANCOVA
	Comments	ANCOVA model for the change from Baseline to End of Maintenance containing treatment and disease stage as factors, and Baseline value as covariate.
Method of Estimation	Estimation Parameter	Least Square Mean
	Estimated Value	-6.06
	Confidence Interval	(2-Sided) 95%; -10.90 to -1.21
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.45
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline to the End of the Maintenance Period in the Score of the Apathy Evaluation Scale (AS) Rated by the Caregiver (Where Available)
Description	The Apathy Scale (AS) is an abbreviated version of the Apathy Evaluation Scale. The AS (Starkstein et al, 1992) consists of 14 items phrased as questions by the examiner that are to be answered on a 4-point Likert scale. It was developed specifically for subjects with Parkinson's disease because the Apathy Evaluation Scale was considered too demanding. The questions comprising the AS were answered by the caregiver. The questions were asked in a structured interview format. The caregiver was interviewed by appropriate medical staff and asked questions about the subject in the third person.The total scores for Apathy Evaluation Scale ranges from 0 (best possible outcome) to 42 (worst possible outcome).
Time Frame	Baseline (Visit 2) until End of the Maintenance Period / Early Withdrawal (up to 19 weeks after Baseline)

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS). The FAS included 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 for both primary efficacy variables.

Arm/Group Title	Placebo	Rotigotine, Low Dose	Rotigotine, High Dose
Arm/Group Description	Placebo transdermal patches Placebo: Placebo, matching transdermal patches Duration: up to 21 weeks (including de-escalation)	Rotigotine, transdermal patches, optimal dose, maximal 8 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours for those with early Parkinson's Disease Rotigotine: Rotigotine, transdermal patches: 10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours); 40 cm^2 (8 mg / 24 hours) The maximum Rotigotine dose allowed was 8 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation)	Rotigotine, transdermal patches, maximal 16 mg / 24 hours for patients with advanced Parkinson's Disease and 8 mg / 24 hours for those with early Parkinson's Disease Rotigotine: Rotigotine, transdermal patches: 10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours); 40 cm^2 (8 mg / 24 hours) The maximum Rotigotine dose allowed was 16 mg / 24 hours for patients with advanced Parkinson's Disease and 8 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation)
Measure Participants	16	16	13
Mean (Standard Deviation) [scores on a scale]	-1.5 (7.0)	-4.8 (8.0)	-5.5 (6.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rotigotine, Low Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.200
	Comments
	Method	ANCOVA
	Comments	ANCOVA model for the change from Baseline to End of Maintenance containing treatment and disease stage as factors, and Baseline value as covariate.
Method of Estimation	Estimation Parameter	Least Square Mean
	Estimated Value	-3.20
	Confidence Interval	(2-Sided) 95%; -8.17 to 1.76
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.46
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rotigotine, High Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.239
	Comments
	Method	ANCOVA
	Comments	ANCOVA model for the change from Baseline to End of Maintenance containing treatment and disease stage as factors, and Baseline value as covariate.
Method of Estimation	Estimation Parameter	Least Square Mean
	Estimated Value	-3.04
	Confidence Interval	(2-Sided) 95%; -8.19 to 2.10
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.55
	Estimation Comments

4. 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 collects 8 items with 5 categories each (0=never, 1=occasionally, 2=sometimes, 3=often, 4=always or cannot do at all). The total score was calculated by summing the scores of all applicable questions and convert the resulting sum to a summary index score between 0 and 100 by multiplying with 100/32. A negative value indicates an improvement.
Time Frame	Baseline (Visit 2) until End of the Maintenance Period / Early Withdrawal (up to 19 weeks after Baseline)

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS). The FAS included 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 for both primary efficacy variables.

Arm/Group Title	Placebo	Rotigotine, Low Dose	Rotigotine, High Dose
Arm/Group Description	Placebo transdermal patches Placebo: Placebo, matching transdermal patches Duration: up to 21 weeks (including de-escalation)	Rotigotine, transdermal patches, optimal dose, maximal 8 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours for those with early Parkinson's Disease Rotigotine: Rotigotine, transdermal patches: 10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours); 40 cm^2 (8 mg / 24 hours) The maximum Rotigotine dose allowed was 8 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation)	Rotigotine, transdermal patches, maximal 16 mg / 24 hours for patients with advanced Parkinson's Disease and 8 mg / 24 hours for those with early Parkinson's Disease Rotigotine: Rotigotine, transdermal patches: 10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours); 40 cm^2 (8 mg / 24 hours) The maximum Rotigotine dose allowed was 16 mg / 24 hours for patients with advanced Parkinson's Disease and 8 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation)
Measure Participants	40	36	40
Mean (Standard Deviation) [scores on a scale]	-3.8 (14.0)	-5.1 (20.4)	-10.0 (15.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rotigotine, Low Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.519
	Comments
	Method	ANCOVA
	Comments	ANCOVA model for the change from Baseline to End of Maintenance containing treatment and disease stage as factors, and Baseline value as covariate.
Method of Estimation	Estimation Parameter	Least Square Mean
	Estimated Value	-2.09
	Confidence Interval	(2-Sided) 95%; -8.48 to 4.31
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.23
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rotigotine, High Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.111
	Comments
	Method	ANCOVA
	Comments	ANCOVA model for the change from Baseline to End of Maintenance containing treatment and disease stage as factors, and Baseline value as covariate.
Method of Estimation	Estimation Parameter	Least Square Mean
	Estimated Value	-5.06
	Confidence Interval	(2-Sided) 95%; -11.29 to 1.17
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.15
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline to the End of the Maintenance Period in the Sum Score of the Mood / Cognition Domain of the Nonmotor Symptom Assessment Scale (NMSS)
Description	Nonmotor performance was assessed via the Nonmotor Symptom Assessment Scale (NMSS), an accepted scale that has been validated in an international study (Naidu et al, 2006; Chaudhuri et al, 2007), at the Baseline Visit as well as at the end of the Maintenance Period. The severity and frequency of the subject's nonmotor symptoms were assessed by the investigator (or designee) in the following 9 domain categories: cardiovascular, including falls; sleep/fatigue; mood/cognition; perceptual problems/hallucinations; attention/memory; gastrointestinal tract; urinary; sexual function; and miscellaneous. Items are scored for severity (from 0 (none) to 3 (severe)) and frequency (from 1 (rarely) to 4 (very frequent )). The score was calculated as severity x frequency. The theoretical minimum is 0 (best possible outcome) and maximum total score is 360 points (worst possible outcome).
Time Frame	Baseline (Visit 2) until End of the Maintenance Period / Early Withdrawal (up to 19 weeks after Baseline)

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS). The FAS included 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 for both primary efficacy variables.

Arm/Group Title	Placebo	Rotigotine, Low Dose	Rotigotine, High Dose
Arm/Group Description	Placebo transdermal patches Placebo: Placebo, matching transdermal patches Duration: up to 21 weeks (including de-escalation)	Rotigotine, transdermal patches, optimal dose, maximal 8 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours for those with early Parkinson's Disease Rotigotine: Rotigotine, transdermal patches: 10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours); 40 cm^2 (8 mg / 24 hours) The maximum Rotigotine dose allowed was 8 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation)	Rotigotine, transdermal patches, maximal 16 mg / 24 hours for patients with advanced Parkinson's Disease and 8 mg / 24 hours for those with early Parkinson's Disease Rotigotine: Rotigotine, transdermal patches: 10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours); 40 cm^2 (8 mg / 24 hours) The maximum Rotigotine dose allowed was 16 mg / 24 hours for patients with advanced Parkinson's Disease and 8 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation)
Measure Participants	39	32	39
Mean (Standard Deviation) [scores on a scale]	-4.6 (7.9)	-9.8 (12.1)	-9.8 (10.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rotigotine, Low Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.060
	Comments
	Method	ANCOVA
	Comments	ANCOVA model for the change from Baseline to End of Treatment containing treatment and disease stage as factors, and Baseline value as covariate.
Method of Estimation	Estimation Parameter	Least Square Mean
	Estimated Value	-3.62
	Confidence Interval	(2-Sided) 95%; -7.39 to 0.15
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.90
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rotigotine, High Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.034
	Comments
	Method	ANCOVA
	Comments	ANCOVA model for the change from Baseline to End of Treatment containing treatment and disease stage as factors, and Baseline value as covariate.
Method of Estimation	Estimation Parameter	Least Square Mean
	Estimated Value	-3.88
	Confidence Interval	(2-Sided) 95%; -7.46 to -0.30
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.80
	Estimation Comments

6. Secondary Outcome

Title	Change From Baseline to the End of the Maintenance Period in the Sum Score of the Snaith Hamilton Pleasure Scale (SHAPS)
Description	The Snaith Hamilton Pleasure Scale (SHAPS) (Snaith et al, 1995) is a self-report instrument developed for the assessment of hedonic capacity. The sum of the 14 items scores range from 0 to 14. A higher score represents more anhedonic symptoms.
Time Frame	Baseline (Visit 2) until End of the Maintenance Period / Early Withdrawal (up to 19 weeks after Baseline)

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS). The FAS included 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 for both primary efficacy variables.

Arm/Group Title	Placebo	Rotigotine, Low Dose	Rotigotine, High Dose
Arm/Group Description	Placebo transdermal patches Placebo: Placebo, matching transdermal patches Duration: up to 21 weeks (including de-escalation)	Rotigotine, transdermal patches, optimal dose, maximal 8 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours for those with early Parkinson's Disease Rotigotine: Rotigotine, transdermal patches: 10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours); 40 cm^2 (8 mg / 24 hours) The maximum Rotigotine dose allowed was 8 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation)	Rotigotine, transdermal patches, maximal 16 mg / 24 hours for patients with advanced Parkinson's Disease and 8 mg / 24 hours for those with early Parkinson's Disease Rotigotine: Rotigotine, transdermal patches: 10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours); 40 cm^2 (8 mg / 24 hours) The maximum Rotigotine dose allowed was 16 mg / 24 hours for patients with advanced Parkinson's Disease and 8 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation)
Measure Participants	40	36	40
Mean (Standard Deviation) [scores on a scale]	-0.5 (2.5)	-1.3 (2.2)	-0.9 (2.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rotigotine, Low Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.334
	Comments
	Method	ANCOVA
	Comments	ANCOVA model for the change from Baseline to End of Maintenance containing treatment and disease stage as factors, and Baseline value as covariate.
Method of Estimation	Estimation Parameter	Least Square Mean
	Estimated Value	-0.38
	Confidence Interval	(2-Sided) 95%; -1.16 to 0.40
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.39
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rotigotine, High Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.968
	Comments
	Method	ANCOVA
	Comments	ANCOVA model for the change from Baseline to End of Maintenance containing treatment and disease stage as factors, and Baseline value as covariate.
Method of Estimation	Estimation Parameter	Least Square Mean
	Estimated Value	0.02
	Confidence Interval	(2-Sided) 95%; -0.74 to 0.77
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.38
	Estimation Comments

7. Secondary Outcome

Title	Change From Baseline to the End of the Maintenance Period in the Sum Score of the Beck Depression Inventory Second Edition (BDI-II)
Description	The Beck Depression Inventory (BDI) is a self-report instrument to measure depression symptoms and severity (Beck et al, 1961). The BDI-II is a revised version of the scale in order to be more consistent with the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for depression (Beck et al, 1996). There are 21 items in the BDI-II, classified as cognitive-affective (Items 1-13) and somatic-performance (Items 14-21) subscales. The degree of severity is indicated on a 4-point scale; items are rated from 0 (not at all) to 3 (extreme form of each symptom). Scores of 0-13 indicate minimal depression, 14-19 indicate mild depression, 20-28 indicate moderate depression, and 29-63 indicate severe depression.
Time Frame	Baseline (Visit 2) until End of the Maintenance Period / Early Withdrawal (up to 19 weeks after Baseline)

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS). The FAS included 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 for both primary efficacy variables.

Arm/Group Title	Placebo	Rotigotine, Low Dose	Rotigotine, High Dose
Arm/Group Description	Placebo transdermal patches Placebo: Placebo, matching transdermal patches Duration: up to 21 weeks (including de-escalation)	Rotigotine, transdermal patches, optimal dose, maximal 8 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours for those with early Parkinson's Disease Rotigotine: Rotigotine, transdermal patches: 10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours); 40 cm^2 (8 mg / 24 hours) The maximum Rotigotine dose allowed was 8 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation)	Rotigotine, transdermal patches, maximal 16 mg / 24 hours for patients with advanced Parkinson's Disease and 8 mg / 24 hours for those with early Parkinson's Disease Rotigotine: Rotigotine, transdermal patches: 10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours); 40 cm^2 (8 mg / 24 hours) The maximum Rotigotine dose allowed was 16 mg / 24 hours for patients with advanced Parkinson's Disease and 8 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation)
Measure Participants	39	31	39
Mean (Standard Deviation) [scores on a scale]	-3.3 (7.0)	-2.9 (5.9)	-3.7 (5.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rotigotine, Low Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.899
	Comments
	Method	ANCOVA
	Comments	ANCOVA model for the change from Baseline to End of Maintenance containing treatment and disease stage as factors, and Baseline value as covariate.
Method of Estimation	Estimation Parameter	Least Square Mean
	Estimated Value	0.16
	Confidence Interval	(2-Sided) 95%; -2.34 to 2.66
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.26
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rotigotine, High Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.785
	Comments
	Method	ANCOVA
	Comments	ANCOVA model for the change from Baseline to End of Treatment containing treatment and disease stage as factors, and Baseline value as covariate.
Method of Estimation	Estimation Parameter	Least Square Mean
	Estimated Value	-0.33
	Confidence Interval	(2-Sided) 95%; -2.68 to 2.03
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.19
	Estimation Comments

8. Secondary Outcome

Title	Change From Baseline to the End of the Maintenance Period in the Sum Score of the Unified Parkinson's Disease Rating Scale (UPDRS) Part III (Motor Subscale) in "on" State
Description	Part III of the Unified Parkinson's Disease Rating Scale (UPDRS) 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. The UPDRS Part III (motor subscale) had to be measured in the "on" state and consisted of 27 items and sub items scored between 0 and 4. The sum score ranged between 0 and 108 and was calculated as sum of the 27 individual scores. If 1 or more items were missing and could not be substituted with a previous post-Baseline value, the sum score was also missing. A negative value indicates an improvement.
Time Frame	Baseline (Visit 2) until End of the Maintenance Period / Early Withdrawal (up to 19 weeks after Baseline)

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS). The FAS included 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 for both primary efficacy variables.

Arm/Group Title	Placebo	Rotigotine, Low Dose	Rotigotine, High Dose
Arm/Group Description	Placebo transdermal patches Placebo: Placebo, matching transdermal patches Duration: up to 21 weeks (including de-escalation)	Rotigotine, transdermal patches, optimal dose, maximal 8 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours for those with early Parkinson's Disease Rotigotine: Rotigotine, transdermal patches: 10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours); 40 cm^2 (8 mg / 24 hours) The maximum Rotigotine dose allowed was 8 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation)	Rotigotine, transdermal patches, maximal 16 mg / 24 hours for patients with advanced Parkinson's Disease and 8 mg / 24 hours for those with early Parkinson's Disease Rotigotine: Rotigotine, transdermal patches: 10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours); 40 cm^2 (8 mg / 24 hours) The maximum Rotigotine dose allowed was 16 mg / 24 hours for patients with advanced Parkinson's Disease and 8 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation)
Measure Participants	40	36	40
Mean (Standard Deviation) [scores on a scale]	-3.4 (8.2)	-8.9 (10.4)	-8.1 (7.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rotigotine, Low Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.014
	Comments
	Method	ANCOVA
	Comments	ANCOVA model for the change from Baseline to End of Maintenance containing treatment and disease stage as factors, and Baseline value as covariate.
Method of Estimation	Estimation Parameter	Least Square Mean
	Estimated Value	-4.96
	Confidence Interval	(2-Sided) 95%; -8.91 to -1.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.99
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rotigotine, High Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.013
	Comments
	Method	ANCOVA
	Comments	ANCOVA model for the change from Baseline to End of Maintenance containing treatment and disease stage as factors, and Baseline value as covariate.
Method of Estimation	Estimation Parameter	Least Square Mean
	Estimated Value	-4.83
	Confidence Interval	(2-Sided) 95%; -8.63 to -1.03
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.92
	Estimation Comments

9. Secondary Outcome

Title	Change From Baseline to the End of the Maintenance Period in the Score of the Clinical Global Impression Scale (CGI) Item I (Severity of Illness)
Description	The Clinical Global Impression (CGI) scales (Guy and Bonato, 1970) were initially developed for a risk-benefit estimation within the treatment of mentally ill patients. The 4 global scales (severity of illness, change in severity from Baseline, therapeutic efficacy, and tolerability of treatment) are used as different measures of treatment outcome in different kinds of pharmacological studies. The CGI Item 1 (severity of illness) collected 1 answer out of 8 categories (0-'Not assessed', 1-'Normal, not at all ill', 2-'Borderline ill', 3-'Mildly ill', 4-'Moderately ill', 5-'Markedly ill', 6-'Severely ill', and 7-'Among the most extremely ill patients') at each assessment. The category 0-'Not assessed' was considered as missing and therefore used neither for calculation nor for display purposes.
Time Frame	Baseline (Visit 2) until End of the Maintenance Period/Early Withdrawal (up to 19 weeks after Baseline)

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS). The FAS included 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 for both primary efficacy variables.

Arm/Group Title	Placebo	Rotigotine, Low Dose	Rotigotine, High Dose
Arm/Group Description	Placebo transdermal patches Placebo: Placebo, matching transdermal patches Duration: up to 21 weeks (including de-escalation)	Rotigotine, transdermal patches, optimal dose, maximal 8 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours for those with early Parkinson's Disease Rotigotine: Rotigotine, transdermal patches: 10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours); 40 cm^2 (8 mg / 24 hours) The maximum Rotigotine dose allowed was 8 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation)	Rotigotine, transdermal patches, maximal 16 mg / 24 hours for patients with advanced Parkinson's Disease and 8 mg / 24 hours for those with early Parkinson's Disease Rotigotine: Rotigotine, transdermal patches: 10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours); 40 cm^2 (8 mg / 24 hours) The maximum Rotigotine dose allowed was 16 mg / 24 hours for patients with advanced Parkinson's Disease and 8 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation)
Measure Participants	40	36	40
Normal, not ill at all	1 2.5%	1 2.4%	2 4.9%
Borderline ill	6 15%	2 4.9%	3 7.3%
Mildly ill	19 47.5%	16 39%	21 51.2%
Moderately ill	9 22.5%	10 24.4%	12 29.3%
Markedly ill	2 5%	1 2.4%	1 2.4%
Severely ill	1 2.5%	1 2.4%	0 0%
Amongst the most extremely ill subjects	0 0%	0 0%	0 0%
Missing	2 5%	5 12.2%	1 2.4%

Adverse Events

Time Frame	Treatment Emergent Adverse Events (TEAEs) were reported from Baseline up to the Safety Follow-up Visit (approximately during 19 weeks).
Adverse Event Reporting Description	The Baseline Analysis Population refers 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, Low Dose		Rotigotine, High Dose
Arm/Group Description	Placebo transdermal patches Placebo: Placebo, matching transdermal patches Duration: up to 21 weeks (including de-escalation)		Rotigotine, transdermal patches, optimal dose, maximal 8 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours for those with early Parkinson's Disease Rotigotine: Rotigotine, transdermal patches: 10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours); 40 cm^2 (8 mg / 24 hours) Optimal dosage: The maximum Rotigotine dose allowed was 8 mg / 24 hours or 16 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours or 8 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation)		Rotigotine, transdermal patches, maximal 16 mg / 24 hours for patients with advanced Parkinson's Disease and 8 mg / 24 hours for those with early Parkinson's Disease Rotigotine: Rotigotine, transdermal patches: 10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours); 40 cm^2 (8 mg / 24 hours) Optimal dosage: The maximum Rotigotine dose allowed was 8 mg / 24 hours or 16 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours or 8 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation)
All Cause Mortality
	Placebo		Rotigotine, Low Dose		Rotigotine, High Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Rotigotine, Low Dose		Rotigotine, High Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/40 (10%)		2/41 (4.9%)		1/41 (2.4%)
Gastrointestinal disorders
Small intestinal obstruction	0/40 (0%)	0	1/41 (2.4%)	1	0/41 (0%)	0
Abdominal pain	1/40 (2.5%)	1	0/41 (0%)	0	0/41 (0%)	0
Ileus	0/40 (0%)	0	1/41 (2.4%)	1	0/41 (0%)	0
Infections and infestations
Abscess	0/40 (0%)	0	1/41 (2.4%)	1	0/41 (0%)	0
Sepsis	1/40 (2.5%)	1	0/41 (0%)	0	0/41 (0%)	0
Nervous system disorders
Cerebral haematoma	0/40 (0%)	0	0/41 (0%)	0	1/41 (2.4%)	1
Cerebrovascular accident	1/40 (2.5%)	1	0/41 (0%)	0	0/41 (0%)	0
Transient ischaemic attack	1/40 (2.5%)	1	0/41 (0%)	0	0/41 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		Rotigotine, Low Dose		Rotigotine, High Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/40 (45%)		17/41 (41.5%)		15/41 (36.6%)
Gastrointestinal disorders
Constipation	1/40 (2.5%)	1	2/41 (4.9%)	2	3/41 (7.3%)	3
Nausea	4/40 (10%)	5	4/41 (9.8%)	5	2/41 (4.9%)	2
Dry mouth	0/40 (0%)	0	0/41 (0%)	0	3/41 (7.3%)	3
General disorders
Application site pruritus	2/40 (5%)	2	4/41 (9.8%)	4	1/41 (2.4%)	2
Oedema peripheral	1/40 (2.5%)	1	2/41 (4.9%)	2	3/41 (7.3%)	3
Injury, poisoning and procedural complications
Fall	2/40 (5%)	3	3/41 (7.3%)	3	2/41 (4.9%)	2
Nervous system disorders
Somnolence	3/40 (7.5%)	3	2/41 (4.9%)	2	4/41 (9.8%)	5
Dyskinesia	2/40 (5%)	3	3/41 (7.3%)	3	1/41 (2.4%)	1
Headache	4/40 (10%)	6	1/41 (2.4%)	1	3/41 (7.3%)	6
Psychiatric disorders
Depression	2/40 (5%)	2	4/41 (9.8%)	4	1/41 (2.4%)	1
Insomnia	6/40 (15%)	6	1/41 (2.4%)	1	2/41 (4.9%)	2
Suicidal ideation	3/40 (7.5%)	3	1/41 (2.4%)	1	1/41 (2.4%)	1

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.