Rotigotine Versus Placebo to Evaluate the Efficacy on Depressive Symptoms in Idiopathic Parkinson's Disease Patients

• Sponsor: UCB Korea Co., Ltd. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01523301
• Collaborator: (none)
• Enrollment: 380
• Locations: 29
• Arms: 2
• Duration (Months): 30
• Patients Per Site: 13.1
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purpose of this study was to show superiority of Rotigotine over placebo on improvement of depressive symptoms in subjects with idiopathic Parkinson's disease.

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

Detailed Description

The study included a maximum 2-week Screening Period, a maximum 4-week Titration Period for early-stage Parkinson's disease or maximum 7-week Titration Period for advanced-stage Parkinson's disease, 8-week Maintenance Period, a maximum 6-day De-escalation Period for early-stage Parkinson's disease or maximum 12-day De-escalation Period for advanced-stage Parkinson's disease and 30-day Safety Follow-Up Period.

The maximum study durations for an individual subject with early-stage Parkinson's disease and with advanced-stage Parkinson's disease were 19 weeks and 23 weeks, respectively.

Study Design

• Study Type: Interventional
• Actual Enrollment: 380 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Double Blind, Placebo-controlled, Parallel, Multicenter, Randomized Interventional Phase IV Study to Evaluate the Efficacy of Rotigotine on Depressive Symptoms in Idiopathic Parkinson's Disease Patients
• Study Start Date: Apr 1, 2012
• Actual Primary Completion Date: Oct 1, 2014
• Actual Study Completion Date: Oct 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Rotigotine Rotigotine, daily doses, treatment group	Drug: Rotigotine; Transdermal Patch Content: 2 mg /24 h (10 cm^2), 4 mg /24 h (20 cm^2), 6 mg /24 h (30 cm^2), 8 mg /24 h (40 cm^2) For early-stage Parkinson's disease, Subjects received Rotigotine patches in escalating weekly dose (starting with daily doses 2 mg/24 h to 8 mg/24 h) for a maximum 4-week Titration Period, then 8 week Maintenance period For advanced-stage Parkinson's disease, Subjects received Rotigotine patches in escalating weekly dose (starting with daily doses 4 mg/24 h to 16 mg/24 h) for a maximum 7-week Titration Period, then 8 week Maintenance period
Placebo Comparator: Placebo Placebo, daily doses, placebo group	Drug: Placebo; Transdermal Patch Size: 10 cm^2, 20 cm^2, 30 cm^2, 40 cm^2 Subjects randomized to placebo received matching placebo patches

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to the End of Maintenance Period in the Score of the Hamilton Depression Scale (HAM-D) [From Baseline (Week 0) to end of Maintenance Period (up to Week 15)]

   The HAM-D consists of 17 items. Nine of the items are scored on a 5-point scale, ranging from 0 to 4. The remaining 8 items are scored on a 3-point scale, from 0 to 2. Therefore, the total score ranges between 0 to 52, with a cutoff score of 15/16 diagnosing major depressive disorder.

Secondary Outcome Measures

1. Change From Baseline to the End of Maintenance Period in the Score of Beck Depression Inventory (BDI-II) [From Baseline (Week 0) to end of Maintenance Period (up to Week 15)]

   The Beck Depression Inventory II (BDI-II) is a self-report instrument to measure Depression symptoms and severity. There are 21 items in the BDI-II. Scores of 0-13 are considered minimal depression; 14-19 indicates mild depression; 20-28 indicates moderate depression; and 29-63 indicates severe depression.

2. Change From Baseline to the End of Maintenance Period in the Score of Unified Parkinson's Disease Rating Scale (UPDRS) Part II (Activities of Daily Living-ADL Subscale) [From Baseline (Week 0) to end of Maintenance Period (up to Week 15)]

   The UPDRS Part II is a tool to measure Activities in Daily Living - it includes speech, salivation, swallowing, handwriting, cutting food and handling utensils, dressing, hygiene, turning in bed and adjusting clothes, falling (unrelated to freezing), freezing when walking, walking, tremor, and sensory complaints related to Parkinsonism. Each of the 13 questions is measured on a scale from 0 (normal) to 4 (severe). The total score of UPDRS part II ranges from 0 (normal) to 52 (severe).

3. Change From Baseline to the End of Maintenance Period in the Score of Unified Parkinson's Disease Rating Scale (UPDRS) Part III (Motor Subscale) [From Baseline (Week 0) to end of Maintenance Period (up to Week 15)]

   Improvement of motor symptoms is measured by the change from Baseline in UPDRS Part III motor score. The UPDRS Part III is an accepted and validated scale for the assessment of motor function in Parkinson's disease. Each of the elements in the UPDRS Part III is measured on a scale of 0 to 4, where 0 is normal and 4 represents severe abnormalities. The total score of UPDRS part III ranges from 0 (normal) to 108 (severe abnormalities).

4. Change From Baseline to the End of Maintenance Period in the Combined Score of Unified Parkinson's Disease Rating Scale (UPDRS) Part II (ADL) Plus Part III (Motor Subscale) [From Baseline (Week 0) to end of Maintenance Period (up to Week 15)]

   The combined score of UPDRS part II and UPDRS part III is the sum of the individual scores and threfore ranges from 0 (normal) to 160 (severe).

5. Change From Baseline to the End of Maintenance Period in the Score of Apathy Scale (AS) [From Baseline (Week 0) to end of Maintenance Period (up to Week 15)]

   The AS is an abbreviated version of the Apathy Scale (AS). The AS consists of 14 items phrased as questions that are to be answered on a four-point Likert scale. It was developed specifically for patients with Parkinson Disease (PD). For questions 1-8, the scoring system is the following: not at all = 3 points; slightly = 2 points; some =1 point, a lot = 0 point. For questions 9-14: the scoring system is the following: not at all = 0 points; slightly = 1 point; some = 2 points; a lot = 3 points. Adding all scores provides the final score with a range from 0 to 42.

6. Change From Baseline to the End of Maintenance Period in the Score of Snaith-Hamilton Pleasure Scale (SHAPS) [From Baseline (Week 0) to end of Maintenance Period (up to Week 15)]

   The SHAPS is a self-report instrument developed for the assessment of hedonic capacity. The sum of the 14 items scores ranges from 0 to 14. A higher score represents more anhedonic symptoms.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or female subjects ≥ 20 years old

• Subjects diagnosed with idiopathic Parkinson's disease (according to the United Kingdom Parkinson's Disease Society Brain Bank Diagnostic Criteria for Parkinson's disease) at modified Hoehn and Yahr Scale stages I-III; do not have motor fluctuations, dyskinesia, and have stable motor symptom at least 4 weeks prior to the Screening Visit as judged by the local investigator

• Subject has a Beck Depression Inventory II (BDI-II) score ≥ 16 as evidenced by depression rating scale study in Parkinson's disease (Schrag A et al, 2007)

• Subject has a Mini-Mental State Examination (MMSE) score ≥ 24

• If subject is taking Levodopa (L-DOPA) and derivatives, Monoamine Oxidase (MAO) B-inhibitors, anticholinergics agents, Catechol-O-Methyl Transferase (COMT) inhibitor or N-Methyl-D-Aspartate (NMDA) antagonist, he/she must have been on stable dose for at least 28 days prior to the Screening Visit

• If subject is taking an antidepressant drug such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), bupropion, tricyclic antidepressants (TCAs), he/she must have been on a stable dose for at least 28 days prior to the Screening Visit and be maintained on that dose for the duration of the trial

Exclusion Criteria:

• Subject has any medical or psychiatric condition (ie, bipolar disorder, dementia, hallucinations or psychosis) that, in the opinion of the investigator, could jeopardize or would compromise the subject's ability to participate in this study

• Subject has a lifetime history of suicide attempt (including an active attempt, interrupted attempt, or aborted attempt), or has suicidal ideation in the past 6 months as indicated by a positive response ('Yes') to either Question 4 or Question 5 of the C-SSRS at Screening (Visit 1)

• Current psychotherapy or behavior therapy while participating in this study

• Subject has received electroconvulsive therapy within 12 weeks of the Screening Visit

• Subject who has received dopamine agonists within 28 days of the Screening Visit

• Subject who has received neuroleptics, methylphenidate, reserpine, alpha-methyldopa, metoclopramide, levosulpiride or amphetamine derivatives within 28 days of the Screening Visit

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	03	Ansan		Korea, Republic of
2	19	Anyang		Korea, Republic of
3	08	Busan		Korea, Republic of
4	26	Busan		Korea, Republic of
5	23	Chungbuk		Korea, Republic of
6	04	Daegu		Korea, Republic of
7	05	Daegu		Korea, Republic of
8	16	Daejon		Korea, Republic of
9	28	Goyang		Korea, Republic of
10	24	Gwangju		Korea, Republic of
11	29	Gwangju		Korea, Republic of
12	11	Gyeonggi-Do		Korea, Republic of
13	15	Jinju		Korea, Republic of
14	01	Seoul		Korea, Republic of
15	02	Seoul		Korea, Republic of
16	06	Seoul		Korea, Republic of
17	07	Seoul		Korea, Republic of
18	09	Seoul		Korea, Republic of
19	10	Seoul		Korea, Republic of
20	12	Seoul		Korea, Republic of
21	13	Seoul		Korea, Republic of
22	14	Seoul		Korea, Republic of
23	17	Seoul		Korea, Republic of
24	18	Seoul		Korea, Republic of
25	20	Seoul		Korea, Republic of
26	21	Seoul		Korea, Republic of
27	22	Seoul		Korea, Republic of
28	27	Seoul		Korea, Republic of
29	25	Yangsan		Korea, Republic of

Sponsors and Collaborators

• UCB Korea Co., Ltd.

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: UCB Korea Co., Ltd.
• ClinicalTrials.gov Identifier: NCT01523301
• Other Study ID Numbers: SP1041
• First Posted: Feb 1, 2012
• Last Update Posted: Dec 18, 2015
• Last Verified: Nov 1, 2015

• Keywords provided by UCB Korea Co., Ltd.: Rotigotine; Neupro; Depressive Symptom; Idiopathic Parkinson's disease
• Additional relevant MeSH terms: Parkinson Disease; Depression; Rotigotine

Study Results

Participant Flow

Recruitment Details	This double-blind, randomized, multicenter, placebo-controlled, in-Patient study started recruiting in April 2012.
Pre-assignment Detail	Participant flow refers to the Randomized Set (RS), consisting of all randomized subjects.

Arm/Group Title	Rotigotine	Placebo
Arm/Group Description	Rotigotine, daily doses, treatment Group. Early-stage Parkinon´s disease for 1 week: Rotigotine dose at 2 mg/24 h. Advanced-stage Parkinson´s disease for 1 week: Rotigotine dose at 4 mg/24 h. Afterwards the dose has been increased in the Titration Period by 2 mg/24 h each week until either the optimal or maximal dose was reached. All subjects remained 8-weeks in the Maintenance Period. In the De-escalation Period Subjects with early-stage Parkinson´s disease de-escalated their dose by 2 mg/24 h every other day to 2 mg/24h, and then to 0 mg after 2 days. Subjects with advanced-stage Parkinson´s disease de-escalated their dose by 2 mg/24h every other day to 4 mg/24h, and then to 0 mg after 2 days. A Safety Follow-Up Visit was scheduled for all subjects 30 days after their last dose administration.	Placebo, daily doses, placebo Group. Subjects randomized to placebo received matching placebo patches. Early-stage Parkinson´s disease for 1 week: Placebo patches´ dose at 2 mg/24 h. Advanced-stage Parkinson´s disease for 1 week: Placebo patches´dose at 4 mg/24 h. Afterwards the dose has been increased in the Titration Period by 2 mg/24 h each week until either the optimal or maximal dose was reached. All subjects remained 8-weeks in the Maintenance Period. In the De-escalation Period Subjects with early-stage Parkinson´s disease de-escalated their dose by 2 mg/24 h every other day to 2 mg/24h, and then to 0 mg after 2 days. Subjects with advanced-stage Parkinson´s disease de-escalated their dose by 2 mg/24h every other day to 4 mg/24h, and then to 0 mg after 2 days. A Safety Follow-Up Visit was scheduled for all subjects 30 days after their last dose administration.
Period Title: Overall Study
STARTED	184	196
COMPLETED	149	164
NOT COMPLETED	35	32

Baseline Characteristics

Arm/Group Title	Rotigotine	Placebo	Total Title
Arm/Group Description	Rotigotine, daily doses, treatment Group. Early-stage Parkinon´s disease for 1 week: Rotigotine dose at 2 mg/24 h. Advanced-stage Parkinson´s disease for 1 week: Rotigotine dose at 4 mg/24 h. Afterwards the dose has been increased in the Titration Period by 2 mg/24 h each week until either the optimal or maximal dose was reached. All subjects remained 8-weeks in the Maintenance Period. In the De-escalation Period Subjects with early-stage Parkinson´s disease de-escalated their dose by 2 mg/24 h every other day to 2 mg/24h, and then to 0 mg after 2 days. Subjects with advanced-stage Parkinson´s disease de-escalated their dose by 2 mg/24h every other day to 4 mg/24h, and then to 0 mg after 2 days. A Safety Follow-Up Visit was scheduled for all subjects 30 days after their last dose administration.	Placebo, daily doses, placebo Group. Subjects randomized to placebo received matching placebo patches. Early-stage Parkinson´s disease for 1 week: Placebo patches´ dose at 2 mg/24 h. Advanced-stage Parkinson´s disease for 1 week: Placebo patches´dose at 4 mg/24 h. Afterwards the dose has been increased in the Titration Period by 2 mg/24 h each week until either the optimal or maximal dose was reached. All subjects remained 8-weeks in the Maintenance Period. In the De-escalation Period Subjects with early-stage Parkinson´s disease de-escalated their dose by 2 mg/24 h every other day to 2 mg/24h, and then to 0 mg after 2 days. Subjects with advanced-stage Parkinson´s disease de-escalated their dose by 2 mg/24h every other day to 4 mg/24h, and then to 0 mg after 2 days. A Safety Follow-Up Visit was scheduled for all subjects 30 days after their last dose administration.
Overall Participants	184	196	380
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65.6 (8.9)	64.9 (8.2)	65.2 (8.5)
Age, Customized (participants) [Number]
<=18 years	0 0%	0 0%	0 0%
>18-<65 years	76 41.3%	88 44.9%	164 43.2%
>=65 years	108 58.7%	108 55.1%	216 56.8%
Sex: Female, Male (Count of Participants)
Female	96 52.2%	122 62.2%	218 57.4%
Male	88 47.8%	74 37.8%	162 42.6%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	61.54 (9.68)	62.24 (9.84)	61.90 (9.76)
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	160.04 (8.41)	159.17 (8.14)	159.59 (8.27)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to the End of Maintenance Period in the Score of the Hamilton Depression Scale (HAM-D)
Description	The HAM-D consists of 17 items. Nine of the items are scored on a 5-point scale, ranging from 0 to 4. The remaining 8 items are scored on a 3-point scale, from 0 to 2. Therefore, the total score ranges between 0 to 52, with a cutoff score of 15/16 diagnosing major depressive disorder.
Time Frame	From Baseline (Week 0) to end of Maintenance Period (up to Week 15)

Outcome Measure Data

Analysis Population Description

Efficacy Evaluable Set (EES) consisted of all subjects from the Full Analysis Set (FAS) with a baseline total HAM-D score of 12 or larger.

Arm/Group Title	Efficacy Evaluable Set (Rotigotine Treated Subjects)	Efficacy Evaluable Set (Placebo Treated Subjects)
Arm/Group Description	Rotigotine, daily doses, treatment Group. The Efficacy Evaluable Set (EES) consisted of all subjects who received at least one dose of study medication, had a valid Baseline and at least 1 valid post-Baseline HAM-D 17 measurement and who had a Baseline HAM-D 17 score of 12 or higher.	Placebo, daily doses, placebo Group. The Efficacy Evaluable Set (EES) consisted of all subjects who received at least one dose of study medication, had a valid Baseline and at least 1 valid post-Baseline HAM-D 17 measurement and who had a Baseline HAM-D 17 score of 12 or higher.
Measure Participants	120	131
Least Squares Mean (95% Confidence Interval) [units on a scale]	-4.79	-3.68

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Efficacy Evaluable Set (Rotigotine Treated Subjects), Efficacy Evaluable Set (Placebo Treated Subjects)
	Comments	The change from Baseline to the end of the Maintenance period in the score of the HAM-D of rotigotine-treated subjects has been compared with those subjects on placebo in the EES. The null hypothesis (H0) was that there was no difference in the change of the HAM-D score between the active treatment and the placebo group. The alternative hypothesis (H1) was that there was a difference in the change of HAM-D score between the rotigotine and the placebo arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.1286
	Comments	The null hypothesis was assessed with a 2-sided test and not rejected at p≤0.05.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Mean
	Estimated Value	-1.12
	Confidence Interval	(2-Sided) 95%; -2.56 to 0.33
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline to the End of Maintenance Period in the Score of Beck Depression Inventory (BDI-II)
Description	The Beck Depression Inventory II (BDI-II) is a self-report instrument to measure Depression symptoms and severity. There are 21 items in the BDI-II. Scores of 0-13 are considered minimal depression; 14-19 indicates mild depression; 20-28 indicates moderate depression; and 29-63 indicates severe depression.
Time Frame	From Baseline (Week 0) to end of Maintenance Period (up to Week 15)

Outcome Measure Data

Analysis Population Description

Efficacy Evaluable Set (EES) consisted of all subjects from the Full Analysis Set (FAS) with a baseline total HAM-D score of 12 or larger.

Arm/Group Title	Efficacy Evaluable Set (Rotigotine Treated Subjects)	Efficacy Evaluable Set (Placebo Treated Subjects)
Arm/Group Description	Rotigotine, daily doses, treatment Group. The Efficacy Evaluable Set (EES) consisted of all subjects who received at least one dose of study medication, had a valid Baseline and at least 1 valid post-Baseline HAM-D 17 measurement and who had a Baseline HAM-D 17 score of 12 or higher.	Placebo, daily doses, placebo Group. The Efficacy Evaluable Set (EES) consisted of all subjects who received at least one dose of study medication, had a valid Baseline and at least 1 valid post-Baseline HAM-D 17 measurement and who had a Baseline HAM-D 17 score of 12 or higher.
Measure Participants	120	131
Least Squares Mean (95% Confidence Interval) [units on a scale]	-5.87	-4.68

3. Secondary Outcome

Title	Change From Baseline to the End of Maintenance Period in the Score of Unified Parkinson's Disease Rating Scale (UPDRS) Part II (Activities of Daily Living-ADL Subscale)
Description	The UPDRS Part II is a tool to measure Activities in Daily Living - it includes speech, salivation, swallowing, handwriting, cutting food and handling utensils, dressing, hygiene, turning in bed and adjusting clothes, falling (unrelated to freezing), freezing when walking, walking, tremor, and sensory complaints related to Parkinsonism. Each of the 13 questions is measured on a scale from 0 (normal) to 4 (severe). The total score of UPDRS part II ranges from 0 (normal) to 52 (severe).
Time Frame	From Baseline (Week 0) to end of Maintenance Period (up to Week 15)

Outcome Measure Data

Analysis Population Description

Efficacy Evaluable Set (EES) consisted of all subjects from the Full Analysis Set (FAS) with a baseline total HAM-D score of 12 or larger.

Arm/Group Title	Efficacy Evaluable Set (Rotigotine Treated Subjects)	Efficacy Evaluable Set (Placebo Treated Subjects)
Arm/Group Description	Rotigotine, daily doses, treatment Group. The Efficacy Evaluable Set (EES) consisted of all subjects who received at least one dose of study medication, had a valid Baseline and at least 1 valid post-Baseline HAM-D 17 measurement and who had a Baseline HAM-D 17 score of 12 or higher.	Placebo, daily doses, placebo Group. The Efficacy Evaluable Set (EES) consisted of all subjects who received at least one dose of study medication, had a valid Baseline and at least 1 valid post-Baseline HAM-D 17 measurement and who had a Baseline HAM-D 17 score of 12 or higher.
Measure Participants	120	131
Least Squares Mean (95% Confidence Interval) [units on a scale]	-1.13	-0.10

4. Secondary Outcome

Title	Change From Baseline to the End of Maintenance Period in the Score of Unified Parkinson's Disease Rating Scale (UPDRS) Part III (Motor Subscale)
Description	Improvement of motor symptoms is measured by the change from Baseline in UPDRS Part III motor score. The UPDRS Part III is an accepted and validated scale for the assessment of motor function in Parkinson's disease. Each of the elements in the UPDRS Part III is measured on a scale of 0 to 4, where 0 is normal and 4 represents severe abnormalities. The total score of UPDRS part III ranges from 0 (normal) to 108 (severe abnormalities).
Time Frame	From Baseline (Week 0) to end of Maintenance Period (up to Week 15)

Outcome Measure Data

Analysis Population Description

Efficacy Evaluable Set (EES) consisted of all subjects from the Full Analysis Set (FAS) with a baseline total HAM-D score of 12 or larger.

Arm/Group Title	Efficacy Evaluable Set (Rotigotine Treated Subjects)	Efficacy Evaluable Set (Placebo Treated Subjects)
Arm/Group Description	Rotigotine, daily doses, treatment Group. The Efficacy Evaluable Set (EES) consisted of all subjects who received at least one dose of study medication, had a valid Baseline and at least 1 valid post-Baseline HAM-D 17 measurement and who had a Baseline HAM-D 17 score of 12 or higher.	Placebo, daily doses, placebo Group. The Efficacy Evaluable Set (EES) consisted of all subjects who received at least one dose of study medication, had a valid Baseline and at least 1 valid post-Baseline HAM-D 17 measurement and who had a Baseline HAM-D 17 score of 12 or higher.
Measure Participants	120	131
Least Squares Mean (95% Confidence Interval) [units on a scale]	-3.07	-1.65

5. Secondary Outcome

Title	Change From Baseline to the End of Maintenance Period in the Combined Score of Unified Parkinson's Disease Rating Scale (UPDRS) Part II (ADL) Plus Part III (Motor Subscale)
Description	The combined score of UPDRS part II and UPDRS part III is the sum of the individual scores and threfore ranges from 0 (normal) to 160 (severe).
Time Frame	From Baseline (Week 0) to end of Maintenance Period (up to Week 15)

Outcome Measure Data

Analysis Population Description

Efficacy Evaluable Set (EES) consisted of all subjects from the Full Analysis Set (FAS) with a baseline total HAM-D score of 12 or larger.

Arm/Group Title	Efficacy Evaluable Set (Rotigotine Treated Subjects)	Efficacy Evaluable Set (Placebo Treated Subjects)
Arm/Group Description	Rotigotine, daily doses, treatment Group. The Efficacy Evaluable Set (EES) consisted of all subjects who received at least one dose of study medication, had a valid Baseline and at least 1 valid post-Baseline HAM-D 17 measurement and who had a Baseline HAM-D 17 score of 12 or higher.	Placebo, daily doses, placebo Group. The Efficacy Evaluable Set (EES) consisted of all subjects who received at least one dose of study medication, had a valid Baseline and at least 1 valid post-Baseline HAM-D 17 measurement and who had a Baseline HAM-D 17 score of 12 or higher.
Measure Participants	120	131
Least Squares Mean (95% Confidence Interval) [units on a scale]	-4.20	-1.81

6. Secondary Outcome

Title	Change From Baseline to the End of Maintenance Period in the Score of Apathy Scale (AS)
Description	The AS is an abbreviated version of the Apathy Scale (AS). The AS consists of 14 items phrased as questions that are to be answered on a four-point Likert scale. It was developed specifically for patients with Parkinson Disease (PD). For questions 1-8, the scoring system is the following: not at all = 3 points; slightly = 2 points; some =1 point, a lot = 0 point. For questions 9-14: the scoring system is the following: not at all = 0 points; slightly = 1 point; some = 2 points; a lot = 3 points. Adding all scores provides the final score with a range from 0 to 42.
Time Frame	From Baseline (Week 0) to end of Maintenance Period (up to Week 15)

Outcome Measure Data

Analysis Population Description

Efficacy Evaluable Set (EES) consisted of all subjects from the Full Analysis Set (FAS) with a baseline total HAM-D score of 12 or larger.

Arm/Group Title	Efficacy Evaluable Set (Rotigotine Treated Subjects)	Efficacy Evaluable Set (Placebo Treated Subjects)
Arm/Group Description	Rotigotine, daily doses, treatment Group. The Efficacy Evaluable Set (EES) consisted of all subjects who received at least one dose of study medication, had a valid Baseline and at least 1 valid post-Baseline HAM-D 17 measurement and who had a Baseline HAM-D 17 score of 12 or higher.	Placebo, daily doses, placebo Group. The Efficacy Evaluable Set (EES) consisted of all subjects who received at least one dose of study medication, had a valid Baseline and at least 1 valid post-Baseline HAM-D 17 measurement and who had a Baseline HAM-D 17 score of 12 or higher.
Measure Participants	120	131
Least Squares Mean (95% Confidence Interval) [units on a scale]	-1.93	-0.67

7. Secondary Outcome

Title	Change From Baseline to the End of Maintenance Period in the Score of Snaith-Hamilton Pleasure Scale (SHAPS)
Description	The SHAPS is a self-report instrument developed for the assessment of hedonic capacity. The sum of the 14 items scores ranges from 0 to 14. A higher score represents more anhedonic symptoms.
Time Frame	From Baseline (Week 0) to end of Maintenance Period (up to Week 15)

Outcome Measure Data

Analysis Population Description

Efficacy Evaluable Set (EES) consisted of all subjects from the Full Analysis Set (FAS) with a baseline total HAM-D score of 12 or larger.

Arm/Group Title	Efficacy Evaluable Set (Rotigotine Treated Subjects)	Efficacy Evaluable Set (Placebo Treated Subjects)
Arm/Group Description	Rotigotine, daily doses, treatment Group. The Efficacy Evaluable Set (EES) consisted of all subjects who received at least one dose of study medication, had a valid Baseline and at least 1 valid post-Baseline HAM-D 17 measurement and who had a Baseline HAM-D 17 score of 12 or higher.	Placebo, daily doses, placebo Group. The Efficacy Evaluable Set (EES) consisted of all subjects who received at least one dose of study medication, had a valid Baseline and at least 1 valid post-Baseline HAM-D 17 measurement and who had a Baseline HAM-D 17 score of 12 or higher.
Measure Participants	120	131
Least Squares Mean (95% Confidence Interval) [units on a scale]	-0.82	-0.60

Adverse Events

Time Frame	Treatment-emergent Adverse Events (TEAE) were collected during the study, which began in April 2012 and concluded in October 2014.
Adverse Event Reporting Description	TEAEs are comprised of the Safety Population, which consists of all randomized subjects who received at least 1 dose of study medication.
Arm/Group Title	Rotigotine		Placebo
Arm/Group Description	Rotigotine, daily doses, treatment Group. Early-stage Parkinon´s disease for 1 week: Rotigotine dose at 2 mg/24 h. Advanced-stage Parkinson´s disease for 1 week: Rotigotine dose at 4 mg/24 h. Afterwards the dose has been increased in the Titration Period by 2 mg/24 h each week until either the optimal or maximal dose was reached. All subjects remained 8-weeks in the Maintenance Period. In the De-escalation Period Subjects with early-stage Parkinson´s disease de-escalated their dose by 2 mg/24 h every other day to 2 mg/24h, and then to 0 mg after 2 days. Subjects with advanced-stage Parkinson´s disease de-escalated their dose by 2 mg/24h every other day to 4 mg/24h, and then to 0 mg after 2 days. A Safety Follow-Up Visit was scheduled for all subjects 30 days after their last dose administration.		Placebo, daily doses, placebo Group. Subjects randomized to placebo received matching placebo patches. Early-stage Parkinson´s disease for 1 week: Placebo patches´ dose at 2 mg/24 h. Advanced-stage Parkinson´s disease for 1 week: Placebo patches´dose at 4 mg/24 h. Afterwards the dose has been increased in the Titration Period by 2 mg/24 h each week until either the optimal or maximal dose was reached. All subjects remained 8-weeks in the Maintenance Period. In the De-escalation Period Subjects with early-stage Parkinson´s disease de-escalated their dose by 2 mg/24 h every other day to 2 mg/24h, and then to 0 mg after 2 days. Subjects with advanced-stage Parkinson´s disease de-escalated their dose by 2 mg/24h every other day to 4 mg/24h, and then to 0 mg after 2 days. A Safety Follow-Up Visit was scheduled for all subjects 30 days after their last dose administration.
All Cause Mortality
	Rotigotine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Rotigotine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/184 (3.3%)		14/196 (7.1%)
Cardiac disorders
Angina pectoris	0/184 (0%)	0	1/196 (0.5%)	1
Congenital, familial and genetic disorders
Spondylolisthesis	1/184 (0.5%)	1	0/196 (0%)	0
Gastrointestinal disorders
Small intestinal obstruction	0/184 (0%)	0	1/196 (0.5%)	1
General disorders
Chest discomfort	0/184 (0%)	0	1/196 (0.5%)	4
Hepatobiliary disorders
Hepatitis	1/184 (0.5%)	1	0/196 (0%)	0
Jaundice	1/184 (0.5%)	1	0/196 (0%)	0
Bile duct stone	0/184 (0%)	0	1/196 (0.5%)	1
Immune system disorders
Kidney transplant rejection	1/184 (0.5%)	1	0/196 (0%)	0
Injury, poisoning and procedural complications
Contusion	0/184 (0%)	0	1/196 (0.5%)	1
Fall	0/184 (0%)	0	1/196 (0.5%)	1
Jaw fracture	0/184 (0%)	0	2/196 (1%)	2
Ligament rupture	0/184 (0%)	0	1/196 (0.5%)	2
Skin laceration	0/184 (0%)	0	1/196 (0.5%)	1
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion	1/184 (0.5%)	1	0/196 (0%)	0
Myalgia	1/184 (0.5%)	1	0/196 (0%)	0
Osteoarthritis	1/184 (0.5%)	1	0/196 (0%)	0
Back Pain	0/184 (0%)	0	1/196 (0.5%)	1
Lumbar spinal stenosis	0/184 (0%)	0	1/196 (0.5%)	1
Rotator cuff syndrome	0/184 (0%)	0	1/196 (0.5%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cervix carcinoma stage IV	0/184 (0%)	0	1/196 (0.5%)	1
Nervous system disorders
Dizziness	1/184 (0.5%)	1	0/196 (0%)	0
Tremor	1/184 (0.5%)	1	0/196 (0%)	0
Headache	0/184 (0%)	0	1/196 (0.5%)	1
Psychiatric disorders
Anxiety	0/184 (0%)	0	1/196 (0.5%)	1
Suicide attempt	0/184 (0%)	0	1/196 (0.5%)	1
Other (Not Including Serious) Adverse Events
	Rotigotine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	112/184 (60.9%)		91/196 (46.4%)
Gastrointestinal disorders
Nausea	42/184 (22.8%)	52	15/196 (7.7%)	16
Vomiting	13/184 (7.1%)	14	2/196 (1%)	2
Constipation	10/184 (5.4%)	12	10/196 (5.1%)	10
General disorders
Application site pruritus	19/184 (10.3%)	20	10/196 (5.1%)	12
Application site erythema	11/184 (6%)	11	5/196 (2.6%)	6
Asthenia	5/184 (2.7%)	5	11/196 (5.6%)	13
Infections and infestations
Nasopharyngitis	7/184 (3.8%)	8	13/196 (6.6%)	15
Nervous system disorders
Dizziness	28/184 (15.2%)	31	25/196 (12.8%)	27
Headache	19/184 (10.3%)	22	20/196 (10.2%)	23
Psychiatric disorders
Suicidal ideation	21/184 (11.4%)	25	22/196 (11.2%)	25
Insomnia	13/184 (7.1%)	13	6/196 (3.1%)	7
Skin and subcutaneous tissue disorders
Pruritus	12/184 (6.5%)	12	2/196 (1%)	3

Limitations/Caveats

[Not Specified]

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

UCB has > 60 but <= 180 days to review results communications prior to public release and may delete information that is confidential and compromises ongoing studies or is considered proprietary. This restriction is not intended to compromise the objective scientific integrity of the manuscript, it being understood that the results shall be published regardless of outcome.