Trial Outcomes & Findings for A Phase III, Randomised, Double-blind, Placebo-controlled, Parallel Group Study of Six Months Treatment With Ropinirole PR as Adjunctive Therapy in Patients With Parkinson's Disease Who Are Not Optimally Controlled on L-Dopa (NCT NCT01154166)

Last Updated: 2018-08-06

Results Overview

The "off" state is defined as the state in which Parkinson's Disease (PD) symptoms (lack of mobility, tremor, or rigidity) are not adequately controlled by the drug. Participants were asked to record the duration of their "off " periods in 24-hour diary cards prior to each visit on two days of each relevant week. The total number of awake hours spent "off" per 24-hour period was the sum of the hours recorded on the two 24-hour diary cards. Change from Baseline is calculated as the value at Week 24 minus the Baseline value.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

347 participants

Primary outcome timeframe

Baseline and Week 24 (Visit 13)

Results posted on

2018-08-06

Participant Flow

A total of 347 participants were randomized; however, 2 participants were not dosed after randomization and were excluded from the Safety Population. An additional participant had no post-baseline assessment available and was thus excluded from the Intent-to-Treat Population. Thus, only 344 of the 347 randomized participants "started" the study.

After the 14-day Run-in Phase with placebo, eligible participants (par.) entered the 24-week Treatment Phase (TP) and were randomized 1:1 to ropinirole PR or placebo. After the TP, all par. were down-titrated for 7 days. Those who did not enter the extension study returned for a follow-up visit 4-14 days after the last dose of medication.

Participant milestones

Participant milestones
Measure	Placebo Participants received placebo tablets identical to ropinirole prolonged release (Ro-PR) tablets once daily (OD) in the 24-week Treatment Phase (TP). The L-dopa dose was reduced after a dose of 8 milligrams (mg) or 12 mg of study medication had been achieved. If a loss of symptom control occurred and persisted after study medication had been up-titrated once, participants were to be "rescued" with open-label L-dopa, which was not to exceed the dose being taken at baseline. After the 24-week TP, all participants were down-titrated over a 7-day period. Those participants who did not enter the extension study returned for a follow-up visit 4 to 14 days after the last dose of medication.	Ropinirole PR Participants initially received Ro-PR 2 mg tablets OD in the 24-week TP. The Ro-PR dose was up-titrated weekly by 2 mg for the first 3 weeks of treatment. Later, the daily dose was increased by 4 mg every 2 weeks, up to a maximum dose of 24 mg per day. The L-dopa dose was reduced after a dose of 8 mg or 12 mg of study medication had been achieved. Participants who did not experience symptom improvement after up-titration of Ro-PR by 2 dose levels were allowed to take L-dopa (maximum up to their baseline dose). After the 24-week TP, all participants were down-titrated over a 7-day period. Those participants who did not enter the extension study returned for a follow-up visit 4 to 14 days after the last dose of Ro-PR.
Overall Study STARTED	169	175
Overall Study COMPLETED	135	163
Overall Study NOT COMPLETED	34	12

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Participants received placebo tablets identical to ropinirole prolonged release (Ro-PR) tablets once daily (OD) in the 24-week Treatment Phase (TP). The L-dopa dose was reduced after a dose of 8 milligrams (mg) or 12 mg of study medication had been achieved. If a loss of symptom control occurred and persisted after study medication had been up-titrated once, participants were to be "rescued" with open-label L-dopa, which was not to exceed the dose being taken at baseline. After the 24-week TP, all participants were down-titrated over a 7-day period. Those participants who did not enter the extension study returned for a follow-up visit 4 to 14 days after the last dose of medication.	Ropinirole PR Participants initially received Ro-PR 2 mg tablets OD in the 24-week TP. The Ro-PR dose was up-titrated weekly by 2 mg for the first 3 weeks of treatment. Later, the daily dose was increased by 4 mg every 2 weeks, up to a maximum dose of 24 mg per day. The L-dopa dose was reduced after a dose of 8 mg or 12 mg of study medication had been achieved. Participants who did not experience symptom improvement after up-titration of Ro-PR by 2 dose levels were allowed to take L-dopa (maximum up to their baseline dose). After the 24-week TP, all participants were down-titrated over a 7-day period. Those participants who did not enter the extension study returned for a follow-up visit 4 to 14 days after the last dose of Ro-PR.
Overall Study Adverse Event	14	9
Overall Study Lost to Follow-up	1	1
Overall Study Protocol Violation	4	1
Overall Study Withdrawal by Subject	10	1
Overall Study Lack of Efficacy	3	0
Overall Study Disease Progression	1	0
Overall Study Poor Compliance	1	0

Baseline Characteristics

A Phase III, Randomised, Double-blind, Placebo-controlled, Parallel Group Study of Six Months Treatment With Ropinirole PR as Adjunctive Therapy in Patients With Parkinson's Disease Who Are Not Optimally Controlled on L-Dopa

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=169 Participants Participants received placebo tablets identical to ropinirole prolonged release (Ro-PR) tablets once daily (OD) in the 24-week Treatment Phase (TP). The L-dopa dose was reduced after a dose of 8 milligrams (mg) or 12 mg of study medication had been achieved. If a loss of symptom control occurred and persisted after study medication had been up-titrated once, participants were to be "rescued" with open-label L-dopa, which was not to exceed the dose being taken at baseline. After the 24-week TP, all participants were down-titrated over a 7-day period. Those participants who did not enter the extension study returned for a follow-up visit 4 to 14 days after the last dose of medication.	Ropinirole PR n=175 Participants Participants initially received Ro-PR 2 mg tablets OD in the 24-week TP. The Ro-PR dose was up-titrated weekly by 2 mg for the first 3 weeks of treatment. Later, the daily dose was increased by 4 mg every 2 weeks, up to a maximum dose of 24 mg per day. The L-dopa dose was reduced after a dose of 8 mg or 12 mg of study medication had been achieved. Participants who did not experience symptom improvement after up-titration of Ro-PR by 2 dose levels were allowed to take L-dopa (maximum up to their baseline dose). After the 24-week TP, all participants were down-titrated over a 7-day period. Those participants who did not enter the extension study returned for a follow-up visit 4 to 14 days after the last dose of Ro-PR.	Total n=344 Participants Total of all reporting groups
Age, Continuous	63.6 Years STANDARD_DEVIATION 10.50 • n=5 Participants	64.1 Years STANDARD_DEVIATION 8.99 • n=7 Participants	63.9 Years STANDARD_DEVIATION 9.75 • n=5 Participants
Sex: Female, Male Female	65 Participants n=5 Participants	59 Participants n=7 Participants	124 Participants n=5 Participants
Sex: Female, Male Male	104 Participants n=5 Participants	116 Participants n=7 Participants	220 Participants n=5 Participants
Race/Ethnicity, Customized Oriental	169 participants n=5 Participants	175 participants n=7 Participants	344 participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline and Week 24 (Visit 13)

Population: Intent-to-treat (ITT) Population: all randomized participants who received at least one dose of study medication and for whom at least one post-baseline efficacy assessment was available. In the LOCF dataset, the last available on-therapy observation for a participant is used to estimate missing data points.

Outcome measures

Outcome measures
Measure	Placebo n=169 Participants Participants received placebo tablets identical to ropinirole prolonged release (Ro-PR) tablets once daily (OD) in the 24-week Treatment Phase (TP). The L-dopa dose was reduced after a dose of 8 milligrams (mg) or 12 mg of study medication had been achieved. If a loss of symptom control occurred and persisted after study medication had been up-titrated once, participants were to be "rescued" with open-label L-dopa, which was not to exceed the dose being taken at baseline. After the 24-week TP, all participants were down-titrated over a 7-day period. Those participants who did not enter the extension study returned for a follow-up visit 4 to 14 days after the last dose of medication.	Ropinirole PR n=175 Participants Participants initially received Ro-PR 2 mg tablets OD in the 24-week TP. The Ro-PR dose was up-titrated weekly by 2 mg for the first 3 weeks of treatment. Later, the daily dose was increased by 4 mg every 2 weeks, up to a maximum dose of 24 mg per day. The L-dopa dose was reduced after a dose of 8 mg or 12 mg of study medication had been achieved. Participants who did not experience symptom improvement after up-titration of Ro-PR by 2 dose levels were allowed to take L-dopa (maximum up to their baseline dose). After the 24-week TP, all participants were down-titrated over a 7-day period. Those participants who did not enter the extension study returned for a follow-up visit 4 to 14 days after the last dose of Ro-PR.
Mean Change From Baseline in Total Awake Time Spent "Off" at Week 24 Using Last Observation Carried Forward (LOCF)	-0.4 hours Standard Deviation 2.47	-2.1 hours Standard Deviation 2.58

SECONDARY outcome

Timeframe: Baseline and Week 24 (Visit 13)

Population: ITT Population. Only those participants contributing data at the indicated time points were analyzed. Data were collected using the LOCF method.

The UPDRS, a clinician-based rating scale, assesses 6 features of PD impairment: (1) mentation, behavior, and mood; (2) activities of daily living; (3) motor examination; (4) complications of therapy; (5) modified Hoehn and Yahr stage; (6) Schwab and England activities of daily living scale. Assessments were conducted when participants had benefit in regard to mobility, tremor, and rigidity. The total motor score (sum of motor examination) ranges from 0 to 108: 0=normal/no symptoms; 108=worst possible case. Change from BL was calculated as the value at Week 24 minus the value at BL.

Outcome measures

Outcome measures
Measure	Placebo n=167 Participants Participants received placebo tablets identical to ropinirole prolonged release (Ro-PR) tablets once daily (OD) in the 24-week Treatment Phase (TP). The L-dopa dose was reduced after a dose of 8 milligrams (mg) or 12 mg of study medication had been achieved. If a loss of symptom control occurred and persisted after study medication had been up-titrated once, participants were to be "rescued" with open-label L-dopa, which was not to exceed the dose being taken at baseline. After the 24-week TP, all participants were down-titrated over a 7-day period. Those participants who did not enter the extension study returned for a follow-up visit 4 to 14 days after the last dose of medication.	Ropinirole PR n=174 Participants Participants initially received Ro-PR 2 mg tablets OD in the 24-week TP. The Ro-PR dose was up-titrated weekly by 2 mg for the first 3 weeks of treatment. Later, the daily dose was increased by 4 mg every 2 weeks, up to a maximum dose of 24 mg per day. The L-dopa dose was reduced after a dose of 8 mg or 12 mg of study medication had been achieved. Participants who did not experience symptom improvement after up-titration of Ro-PR by 2 dose levels were allowed to take L-dopa (maximum up to their baseline dose). After the 24-week TP, all participants were down-titrated over a 7-day period. Those participants who did not enter the extension study returned for a follow-up visit 4 to 14 days after the last dose of Ro-PR.
Mean Change From Baseline (BL) in the Unified Parkinson Disease Rating Scale (UPDRS) Total Motor Score at Week 24 Using LOCF	-0.7 scores on a scale Standard Deviation 9.03	-6.3 scores on a scale Standard Deviation 10.08

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: ITT Population. Data were collected using the LOCF method.

The "off" state is defined as the state in which PD symptoms (lack of mobility, tremor, or rigidity) are not adequately controlled by the drug. Participants were asked to record the duration of their "off" periods in 24-hour diary cards prior to each visit on the same 2 days of each relevant week. The total number of awake hours spent "off" per 24-hour period was the sum of the hours recorded on the two 24-hour diary cards. The percentage of ATSO=ATSO divided by (ATSO + awake time spent "on") \* 100. Change from Baseline was calculated as the value at Week 24 minus the value at Baseline.

Outcome measures

Outcome measures
Measure	Placebo n=169 Participants Participants received placebo tablets identical to ropinirole prolonged release (Ro-PR) tablets once daily (OD) in the 24-week Treatment Phase (TP). The L-dopa dose was reduced after a dose of 8 milligrams (mg) or 12 mg of study medication had been achieved. If a loss of symptom control occurred and persisted after study medication had been up-titrated once, participants were to be "rescued" with open-label L-dopa, which was not to exceed the dose being taken at baseline. After the 24-week TP, all participants were down-titrated over a 7-day period. Those participants who did not enter the extension study returned for a follow-up visit 4 to 14 days after the last dose of medication.	Ropinirole PR n=175 Participants Participants initially received Ro-PR 2 mg tablets OD in the 24-week TP. The Ro-PR dose was up-titrated weekly by 2 mg for the first 3 weeks of treatment. Later, the daily dose was increased by 4 mg every 2 weeks, up to a maximum dose of 24 mg per day. The L-dopa dose was reduced after a dose of 8 mg or 12 mg of study medication had been achieved. Participants who did not experience symptom improvement after up-titration of Ro-PR by 2 dose levels were allowed to take L-dopa (maximum up to their baseline dose). After the 24-week TP, all participants were down-titrated over a 7-day period. Those participants who did not enter the extension study returned for a follow-up visit 4 to 14 days after the last dose of Ro-PR.
Mean Change From Baseline in the Percentage of Awake Time Spent "Off" (ATSO) at Week 24 Using LOCF	-1.8 Percentage of time Standard Deviation 15.88	-13.5 Percentage of time Standard Deviation 15.62

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: ITT Population. Data were collected using the LOCF method.

The "on" state is defined as the state in which the PD symptoms (lack of mobility, tremor, or rigidity) are adequately controlled by the drug. Participants were asked to record the duration of their "on" periods in 24-hour diary cards prior to each visit on the same two days of each relevant week. The total number of awake hours spent "on" per 24-hour period was the sum of the hours recorded on the two 24-hour diary cards. Change from Baseline is calculated as the value at Week 24 minus the Baseline value.

Outcome measures

Outcome measures
Measure	Placebo n=169 Participants Participants received placebo tablets identical to ropinirole prolonged release (Ro-PR) tablets once daily (OD) in the 24-week Treatment Phase (TP). The L-dopa dose was reduced after a dose of 8 milligrams (mg) or 12 mg of study medication had been achieved. If a loss of symptom control occurred and persisted after study medication had been up-titrated once, participants were to be "rescued" with open-label L-dopa, which was not to exceed the dose being taken at baseline. After the 24-week TP, all participants were down-titrated over a 7-day period. Those participants who did not enter the extension study returned for a follow-up visit 4 to 14 days after the last dose of medication.	Ropinirole PR n=175 Participants Participants initially received Ro-PR 2 mg tablets OD in the 24-week TP. The Ro-PR dose was up-titrated weekly by 2 mg for the first 3 weeks of treatment. Later, the daily dose was increased by 4 mg every 2 weeks, up to a maximum dose of 24 mg per day. The L-dopa dose was reduced after a dose of 8 mg or 12 mg of study medication had been achieved. Participants who did not experience symptom improvement after up-titration of Ro-PR by 2 dose levels were allowed to take L-dopa (maximum up to their baseline dose). After the 24-week TP, all participants were down-titrated over a 7-day period. Those participants who did not enter the extension study returned for a follow-up visit 4 to 14 days after the last dose of Ro-PR.
Mean Change From Baseline in Total Awake Time Spent "on" at Week 24 Using LOCF	0.1 hours Standard Deviation 2.48	1.9 hours Standard Deviation 2.44

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: ITT Population. Data were collected using the LOCF method.

Dyskinesias are involuntary twisting, turning movements caused by medication during "on" time in PD. TD is defined as those movements that interfere with function and cause meaningful discomfort. Participants were asked to record the number of awake hours spent "on" without TD in 24-hour diary cards prior to each visit on the same two days of each relevant week. The total number of awake hours spent"on"without TD per 24-hour period was the sum of the hours recorded on the two 24-hour diary cards. Change from Baseline is calculated as the value at Week 24 minus the Baseline value.

Outcome measures

Outcome measures
Measure	Placebo n=169 Participants Participants received placebo tablets identical to ropinirole prolonged release (Ro-PR) tablets once daily (OD) in the 24-week Treatment Phase (TP). The L-dopa dose was reduced after a dose of 8 milligrams (mg) or 12 mg of study medication had been achieved. If a loss of symptom control occurred and persisted after study medication had been up-titrated once, participants were to be "rescued" with open-label L-dopa, which was not to exceed the dose being taken at baseline. After the 24-week TP, all participants were down-titrated over a 7-day period. Those participants who did not enter the extension study returned for a follow-up visit 4 to 14 days after the last dose of medication.	Ropinirole PR n=175 Participants Participants initially received Ro-PR 2 mg tablets OD in the 24-week TP. The Ro-PR dose was up-titrated weekly by 2 mg for the first 3 weeks of treatment. Later, the daily dose was increased by 4 mg every 2 weeks, up to a maximum dose of 24 mg per day. The L-dopa dose was reduced after a dose of 8 mg or 12 mg of study medication had been achieved. Participants who did not experience symptom improvement after up-titration of Ro-PR by 2 dose levels were allowed to take L-dopa (maximum up to their baseline dose). After the 24-week TP, all participants were down-titrated over a 7-day period. Those participants who did not enter the extension study returned for a follow-up visit 4 to 14 days after the last dose of Ro-PR.
Mean Change From Baseline in Total Awake Time "on" Without Troublesome Dyskinesias (TD) at Week 24 Using LOCF	0.3 hours Standard Deviation 2.56	1.7 hours Standard Deviation 2.81

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: ITT Population. Only those participants contributing data at the indicated time points were analyzed. Data were collected using the LOCF method.

The UPDRS assesses six features of PD impairment, including Activities of Daily Living (ADL). The total ADL score ranges from 0 to 52, where 0= normal/no symptoms and 52= worst possible case. Change from Baseline is calculated as the value at Week 24 minus the Baseline value.

Outcome measures

Outcome measures
Measure	Placebo n=167 Participants Participants received placebo tablets identical to ropinirole prolonged release (Ro-PR) tablets once daily (OD) in the 24-week Treatment Phase (TP). The L-dopa dose was reduced after a dose of 8 milligrams (mg) or 12 mg of study medication had been achieved. If a loss of symptom control occurred and persisted after study medication had been up-titrated once, participants were to be "rescued" with open-label L-dopa, which was not to exceed the dose being taken at baseline. After the 24-week TP, all participants were down-titrated over a 7-day period. Those participants who did not enter the extension study returned for a follow-up visit 4 to 14 days after the last dose of medication.	Ropinirole PR n=174 Participants Participants initially received Ro-PR 2 mg tablets OD in the 24-week TP. The Ro-PR dose was up-titrated weekly by 2 mg for the first 3 weeks of treatment. Later, the daily dose was increased by 4 mg every 2 weeks, up to a maximum dose of 24 mg per day. The L-dopa dose was reduced after a dose of 8 mg or 12 mg of study medication had been achieved. Participants who did not experience symptom improvement after up-titration of Ro-PR by 2 dose levels were allowed to take L-dopa (maximum up to their baseline dose). After the 24-week TP, all participants were down-titrated over a 7-day period. Those participants who did not enter the extension study returned for a follow-up visit 4 to 14 days after the last dose of Ro-PR.
Mean Change From Baseline in the UPDRS Activities of Daily Living (ADL) Score at Week 24 Using LOCF	-0.2 scores on a scale Standard Deviation 3.64	-2.2 scores on a scale Standard Deviation 3.93

SECONDARY outcome

Timeframe: Week 24

Population: ITT Population. Only those participants contributing data at the indicated time points were analyzed. Data were collected using the LOCF method.

The CGI global improvement scale allows the investigator to rate the participant's total improvement since the beginning of treatment (Baseline). Scores on the scale range from 1 to 7 (1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, and 7=very much worse). Participants with a CGI global improvement score of \<=2 (representing much improved or very much improved) were considered to be responders.

Outcome measures

Outcome measures
Measure	Placebo n=168 Participants Participants received placebo tablets identical to ropinirole prolonged release (Ro-PR) tablets once daily (OD) in the 24-week Treatment Phase (TP). The L-dopa dose was reduced after a dose of 8 milligrams (mg) or 12 mg of study medication had been achieved. If a loss of symptom control occurred and persisted after study medication had been up-titrated once, participants were to be "rescued" with open-label L-dopa, which was not to exceed the dose being taken at baseline. After the 24-week TP, all participants were down-titrated over a 7-day period. Those participants who did not enter the extension study returned for a follow-up visit 4 to 14 days after the last dose of medication.	Ropinirole PR n=174 Participants Participants initially received Ro-PR 2 mg tablets OD in the 24-week TP. The Ro-PR dose was up-titrated weekly by 2 mg for the first 3 weeks of treatment. Later, the daily dose was increased by 4 mg every 2 weeks, up to a maximum dose of 24 mg per day. The L-dopa dose was reduced after a dose of 8 mg or 12 mg of study medication had been achieved. Participants who did not experience symptom improvement after up-titration of Ro-PR by 2 dose levels were allowed to take L-dopa (maximum up to their baseline dose). After the 24-week TP, all participants were down-titrated over a 7-day period. Those participants who did not enter the extension study returned for a follow-up visit 4 to 14 days after the last dose of Ro-PR.
Number of Responders Based on the Clinical Global Impression (CGI) Global Improvement Scale Using LOCF	16 participants	77 participants

SECONDARY outcome

Timeframe: Week 24

Population: ITT Population. Only those participants who had their dose of L-dopa reduced were included in this analysis. Data were collected using the LOCF method.

In the event of unacceptable side effects relative to Baseline (e.g., dyskinesias, dystonias \[neurological movement disorder\]) the dosage of L-dopa was reduced. If there was reduction in the side effects and there was loss of symptom control, the dose of study medication was again increased (reinstated) at subsequent visits. If symptoms could still not be controlled, then L-dopa was reinstated; however, the dose could not exceed the baseline dose.

Outcome measures

Outcome measures
Measure	Placebo n=64 Participants Participants received placebo tablets identical to ropinirole prolonged release (Ro-PR) tablets once daily (OD) in the 24-week Treatment Phase (TP). The L-dopa dose was reduced after a dose of 8 milligrams (mg) or 12 mg of study medication had been achieved. If a loss of symptom control occurred and persisted after study medication had been up-titrated once, participants were to be "rescued" with open-label L-dopa, which was not to exceed the dose being taken at baseline. After the 24-week TP, all participants were down-titrated over a 7-day period. Those participants who did not enter the extension study returned for a follow-up visit 4 to 14 days after the last dose of medication.	Ropinirole PR n=111 Participants Participants initially received Ro-PR 2 mg tablets OD in the 24-week TP. The Ro-PR dose was up-titrated weekly by 2 mg for the first 3 weeks of treatment. Later, the daily dose was increased by 4 mg every 2 weeks, up to a maximum dose of 24 mg per day. The L-dopa dose was reduced after a dose of 8 mg or 12 mg of study medication had been achieved. Participants who did not experience symptom improvement after up-titration of Ro-PR by 2 dose levels were allowed to take L-dopa (maximum up to their baseline dose). After the 24-week TP, all participants were down-titrated over a 7-day period. Those participants who did not enter the extension study returned for a follow-up visit 4 to 14 days after the last dose of Ro-PR.
Number of Participants Requiring Reinstatement of L-dopa Following a Dose Reduction Using LOCF	23 participants	13 participants

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: ITT Population. Only those participants contributing data at the indicated time points were analyzed. Data were collected using the LOCF method.

The "off" state is defined as the state in which PD symptoms (lack of mobility, tremor, or rigidity) are not adequately controlled by the drug. Responders are defined as participants who had at least a 20% reduction from Baseline in awake time spent "off" and at least a 20% reduction from Baseline in the L-dopa dose.

Outcome measures

Outcome measures
Measure	Placebo n=162 Participants Participants received placebo tablets identical to ropinirole prolonged release (Ro-PR) tablets once daily (OD) in the 24-week Treatment Phase (TP). The L-dopa dose was reduced after a dose of 8 milligrams (mg) or 12 mg of study medication had been achieved. If a loss of symptom control occurred and persisted after study medication had been up-titrated once, participants were to be "rescued" with open-label L-dopa, which was not to exceed the dose being taken at baseline. After the 24-week TP, all participants were down-titrated over a 7-day period. Those participants who did not enter the extension study returned for a follow-up visit 4 to 14 days after the last dose of medication.	Ropinirole PR n=171 Participants Participants initially received Ro-PR 2 mg tablets OD in the 24-week TP. The Ro-PR dose was up-titrated weekly by 2 mg for the first 3 weeks of treatment. Later, the daily dose was increased by 4 mg every 2 weeks, up to a maximum dose of 24 mg per day. The L-dopa dose was reduced after a dose of 8 mg or 12 mg of study medication had been achieved. Participants who did not experience symptom improvement after up-titration of Ro-PR by 2 dose levels were allowed to take L-dopa (maximum up to their baseline dose). After the 24-week TP, all participants were down-titrated over a 7-day period. Those participants who did not enter the extension study returned for a follow-up visit 4 to 14 days after the last dose of Ro-PR.
Number of Responders to Study Treatment Using LOCF	4 participants	39 participants

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: ITT Population. Only those participants contributing data at the indicated time points were analyzed. Data were collected using the LOCF method.

The HAMD-17 is a 17-item scale that is completed by the investigator. Each item was evaluated and scored using either a 5-point scale (e.g., absent, mild, moderate, severe, very severe) or a 3-point scale (e.g., absent, mild, marked). The total HAMD-17 score (sum of the scores of all 17 items) may range from 0 (least severe) to 52 (most severe). Change from Baseline is calculated as the value at Week 24 minus the Baseline value.

Outcome measures

Outcome measures
Measure	Placebo n=161 Participants Participants received placebo tablets identical to ropinirole prolonged release (Ro-PR) tablets once daily (OD) in the 24-week Treatment Phase (TP). The L-dopa dose was reduced after a dose of 8 milligrams (mg) or 12 mg of study medication had been achieved. If a loss of symptom control occurred and persisted after study medication had been up-titrated once, participants were to be "rescued" with open-label L-dopa, which was not to exceed the dose being taken at baseline. After the 24-week TP, all participants were down-titrated over a 7-day period. Those participants who did not enter the extension study returned for a follow-up visit 4 to 14 days after the last dose of medication.	Ropinirole PR n=170 Participants Participants initially received Ro-PR 2 mg tablets OD in the 24-week TP. The Ro-PR dose was up-titrated weekly by 2 mg for the first 3 weeks of treatment. Later, the daily dose was increased by 4 mg every 2 weeks, up to a maximum dose of 24 mg per day. The L-dopa dose was reduced after a dose of 8 mg or 12 mg of study medication had been achieved. Participants who did not experience symptom improvement after up-titration of Ro-PR by 2 dose levels were allowed to take L-dopa (maximum up to their baseline dose). After the 24-week TP, all participants were down-titrated over a 7-day period. Those participants who did not enter the extension study returned for a follow-up visit 4 to 14 days after the last dose of Ro-PR.
Mean Change From Baseline in the Depression Scores on the Hamilton Depression Rating Scale (HAMD-17) Using LOCF	-0.6 scores on a scale Standard Deviation 4.33	-1.6 scores on a scale Standard Deviation 4.38

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: ITT Population. Only those participants contributing data at the indicated time points were analyzed. Data were collected using the LOCF method.

The PDSS uses a series of 15 questions to assess sleep disturbance associated with PD. Participants completed the assessments based on their experiences in the past week by marking a cross on each 10 centimeter (cm) scale (labelled from worst to best state). Responses were quantified by measuring the distance along each line where the cross was placed. The scores for each item ranged from 0 (symptom severe and always experienced) to 10 (symptom free). The maximum cumulative score for the PDSS was thus 150 (free of all symptoms). Change from BL=value at Week 24 minus the BL value.

Outcome measures

Outcome measures
Measure	Placebo n=159 Participants Participants received placebo tablets identical to ropinirole prolonged release (Ro-PR) tablets once daily (OD) in the 24-week Treatment Phase (TP). The L-dopa dose was reduced after a dose of 8 milligrams (mg) or 12 mg of study medication had been achieved. If a loss of symptom control occurred and persisted after study medication had been up-titrated once, participants were to be "rescued" with open-label L-dopa, which was not to exceed the dose being taken at baseline. After the 24-week TP, all participants were down-titrated over a 7-day period. Those participants who did not enter the extension study returned for a follow-up visit 4 to 14 days after the last dose of medication.	Ropinirole PR n=170 Participants Participants initially received Ro-PR 2 mg tablets OD in the 24-week TP. The Ro-PR dose was up-titrated weekly by 2 mg for the first 3 weeks of treatment. Later, the daily dose was increased by 4 mg every 2 weeks, up to a maximum dose of 24 mg per day. The L-dopa dose was reduced after a dose of 8 mg or 12 mg of study medication had been achieved. Participants who did not experience symptom improvement after up-titration of Ro-PR by 2 dose levels were allowed to take L-dopa (maximum up to their baseline dose). After the 24-week TP, all participants were down-titrated over a 7-day period. Those participants who did not enter the extension study returned for a follow-up visit 4 to 14 days after the last dose of Ro-PR.
Mean Change From Baseline (BL) in the Parkinson's Disease Sleep Scale (PDSS) Total Score Using LOCF	-1.7 scores on a scale Standard Deviation 20.57	0.5 scores on a scale Standard Deviation 21.22

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: ITT Population. Only those participants contributing data at the indicated time points for the indicated domain were analyzed. Data were collected using the LOCF method.

The PDQ39 is a 39 item self-administered questionnaire. The questionnaire covers eight domains of health that are reported as adversely affected by patients with PD. Participants were asked to rate responses on a scale from 0 to 4 ("never" to "always"). The overall index score is the mean of the eight individual domain scores measured on a continuous scale ranging from 0 (no problem at all) to 100 (maximum level of the problem). Change from Baseline is calculated as the value at Week 24 minus the Baseline value.

Outcome measures

Outcome measures
Measure	Placebo n=160 Participants Participants received placebo tablets identical to ropinirole prolonged release (Ro-PR) tablets once daily (OD) in the 24-week Treatment Phase (TP). The L-dopa dose was reduced after a dose of 8 milligrams (mg) or 12 mg of study medication had been achieved. If a loss of symptom control occurred and persisted after study medication had been up-titrated once, participants were to be "rescued" with open-label L-dopa, which was not to exceed the dose being taken at baseline. After the 24-week TP, all participants were down-titrated over a 7-day period. Those participants who did not enter the extension study returned for a follow-up visit 4 to 14 days after the last dose of medication.	Ropinirole PR n=170 Participants Participants initially received Ro-PR 2 mg tablets OD in the 24-week TP. The Ro-PR dose was up-titrated weekly by 2 mg for the first 3 weeks of treatment. Later, the daily dose was increased by 4 mg every 2 weeks, up to a maximum dose of 24 mg per day. The L-dopa dose was reduced after a dose of 8 mg or 12 mg of study medication had been achieved. Participants who did not experience symptom improvement after up-titration of Ro-PR by 2 dose levels were allowed to take L-dopa (maximum up to their baseline dose). After the 24-week TP, all participants were down-titrated over a 7-day period. Those participants who did not enter the extension study returned for a follow-up visit 4 to 14 days after the last dose of Ro-PR.
Mean Change From Baseline in the Parkinson's Disease Quality of Life Scores (PDQ39) Using LOCF Mobility Domain; n=160, 170	2.5 scores on a scale Standard Deviation 17.30	-5.7 scores on a scale Standard Deviation 18.10
Mean Change From Baseline in the Parkinson's Disease Quality of Life Scores (PDQ39) Using LOCF Activities of Daily Living Domain; n=160, 170	-0.3 scores on a scale Standard Deviation 18.65	-5.9 scores on a scale Standard Deviation 18.20
Mean Change From Baseline in the Parkinson's Disease Quality of Life Scores (PDQ39) Using LOCF Emotional Wellbeing Domain; n=160, 170	-0.8 scores on a scale Standard Deviation 15.30	-4.8 scores on a scale Standard Deviation 17.37
Mean Change From Baseline in the Parkinson's Disease Quality of Life Scores (PDQ39) Using LOCF Stigma Domain; n=160, 170	-1.1 scores on a scale Standard Deviation 18.17	-5.1 scores on a scale Standard Deviation 18.01
Mean Change From Baseline in the Parkinson's Disease Quality of Life Scores (PDQ39) Using LOCF Social Support Domain; n=157, 167	-0.7 scores on a scale Standard Deviation 15.21	-0.4 scores on a scale Standard Deviation 14.63
Mean Change From Baseline in the Parkinson's Disease Quality of Life Scores (PDQ39) Using LOCF Cognitive Impairment Domain; n=160, 170	-0.8 scores on a scale Standard Deviation 13.28	-1.1 scores on a scale Standard Deviation 14.36
Mean Change From Baseline in the Parkinson's Disease Quality of Life Scores (PDQ39) Using LOCF Communication Domain; n=160, 170	2.6 scores on a scale Standard Deviation 17.21	-1.1 scores on a scale Standard Deviation 12.28
Mean Change From Baseline in the Parkinson's Disease Quality of Life Scores (PDQ39) Using LOCF Bodily Discomfort Domain; n=160, 170	0.7 scores on a scale Standard Deviation 19.15	-3.5 scores on a scale Standard Deviation 19.16

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: ITT Population. Only those participants who had their dose of L-dopa reduced were included in this analysis. Data were collected using the LOCF method.

The mean number of days after which the dose of L-dopa was readministered after the reduction in dose was recorded.

Outcome measures

Outcome measures
Measure	Placebo n=64 Participants Participants received placebo tablets identical to ropinirole prolonged release (Ro-PR) tablets once daily (OD) in the 24-week Treatment Phase (TP). The L-dopa dose was reduced after a dose of 8 milligrams (mg) or 12 mg of study medication had been achieved. If a loss of symptom control occurred and persisted after study medication had been up-titrated once, participants were to be "rescued" with open-label L-dopa, which was not to exceed the dose being taken at baseline. After the 24-week TP, all participants were down-titrated over a 7-day period. Those participants who did not enter the extension study returned for a follow-up visit 4 to 14 days after the last dose of medication.	Ropinirole PR n=111 Participants Participants initially received Ro-PR 2 mg tablets OD in the 24-week TP. The Ro-PR dose was up-titrated weekly by 2 mg for the first 3 weeks of treatment. Later, the daily dose was increased by 4 mg every 2 weeks, up to a maximum dose of 24 mg per day. The L-dopa dose was reduced after a dose of 8 mg or 12 mg of study medication had been achieved. Participants who did not experience symptom improvement after up-titration of Ro-PR by 2 dose levels were allowed to take L-dopa (maximum up to their baseline dose). After the 24-week TP, all participants were down-titrated over a 7-day period. Those participants who did not enter the extension study returned for a follow-up visit 4 to 14 days after the last dose of Ro-PR.
Time to Reinstatement of L-dopa Following a Reduction in Dose Using LOCF	114.3 days Standard Deviation 4.69	162.9 days Standard Deviation 3.55

Adverse Events

Placebo

Serious events: 8 serious events

Other events: 105 other events

Deaths: 0 deaths

Ropinirole PR

Serious events: 9 serious events

Other events: 129 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

GSK Response Center

GlaxoSmithKline

Phone: 866-435-7343

Results disclosure agreements

Principal investigator is a sponsor employee GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
Publication restrictions are in place

Restriction type: OTHER

Measure	Placebo n=170 participants at risk Participants received placebo tablets identical to ropinirole prolonged release (Ro-PR) tablets once daily (OD) in the 24-week Treatment Phase (TP). The L-dopa dose was reduced after a dose of 8 milligrams (mg) or 12 mg of study medication had been achieved. If a loss of symptom control occurred and persisted after study medication had been up-titrated once, participants were to be "rescued" with open-label L-dopa, which was not to exceed the dose being taken at baseline. After the 24-week TP, all participants were down-titrated over a 7-day period. Those participants who did not enter the extension study returned for a follow-up visit 4 to 14 days after the last dose of medication.	Ropinirole PR n=175 participants at risk Participants initially received Ro-PR 2 mg tablets OD in the 24-week TP. The Ro-PR dose was up-titrated weekly by 2 mg for the first 3 weeks of treatment. Later, the daily dose was increased by 4 mg every 2 weeks, up to a maximum dose of 24 mg per day. The L-dopa dose was reduced after a dose of 8 mg or 12 mg of study medication had been achieved. Participants who did not experience symptom improvement after up-titration of Ro-PR by 2 dose levels were allowed to take L-dopa (maximum up to their baseline dose). After the 24-week TP, all participants were down-titrated over a 7-day period. Those participants who did not enter the extension study returned for a follow-up visit 4 to 14 days after the last dose of Ro-PR.
Cardiac disorders Coronary artery disease	0.59% 1/170 • Adverse event (AE) and serious adverse event (SAE) data are presented for the On-treatment Phase (Week 1 to Week 24) plus the 7-day Down-titration Period. SAEs and non-serious AEs were collected in the Safety Population, consisting of all participants who received at least one dose of randomized study medication (placebo or active drug). This does not include placebo given during the Placebo Run-in Period.	0.57% 1/175 • Adverse event (AE) and serious adverse event (SAE) data are presented for the On-treatment Phase (Week 1 to Week 24) plus the 7-day Down-titration Period. SAEs and non-serious AEs were collected in the Safety Population, consisting of all participants who received at least one dose of randomized study medication (placebo or active drug). This does not include placebo given during the Placebo Run-in Period.
Cardiac disorders Atrial fibrillation	0.00% 0/170 • Adverse event (AE) and serious adverse event (SAE) data are presented for the On-treatment Phase (Week 1 to Week 24) plus the 7-day Down-titration Period. SAEs and non-serious AEs were collected in the Safety Population, consisting of all participants who received at least one dose of randomized study medication (placebo or active drug). This does not include placebo given during the Placebo Run-in Period.	0.57% 1/175 • Adverse event (AE) and serious adverse event (SAE) data are presented for the On-treatment Phase (Week 1 to Week 24) plus the 7-day Down-titration Period. SAEs and non-serious AEs were collected in the Safety Population, consisting of all participants who received at least one dose of randomized study medication (placebo or active drug). This does not include placebo given during the Placebo Run-in Period.
Infections and infestations Lung infection	0.59% 1/170 • Adverse event (AE) and serious adverse event (SAE) data are presented for the On-treatment Phase (Week 1 to Week 24) plus the 7-day Down-titration Period. SAEs and non-serious AEs were collected in the Safety Population, consisting of all participants who received at least one dose of randomized study medication (placebo or active drug). This does not include placebo given during the Placebo Run-in Period.	0.00% 0/175 • Adverse event (AE) and serious adverse event (SAE) data are presented for the On-treatment Phase (Week 1 to Week 24) plus the 7-day Down-titration Period. SAEs and non-serious AEs were collected in the Safety Population, consisting of all participants who received at least one dose of randomized study medication (placebo or active drug). This does not include placebo given during the Placebo Run-in Period.
Infections and infestations Pneumonia	0.00% 0/170 • Adverse event (AE) and serious adverse event (SAE) data are presented for the On-treatment Phase (Week 1 to Week 24) plus the 7-day Down-titration Period. SAEs and non-serious AEs were collected in the Safety Population, consisting of all participants who received at least one dose of randomized study medication (placebo or active drug). This does not include placebo given during the Placebo Run-in Period.	0.57% 1/175 • Adverse event (AE) and serious adverse event (SAE) data are presented for the On-treatment Phase (Week 1 to Week 24) plus the 7-day Down-titration Period. SAEs and non-serious AEs were collected in the Safety Population, consisting of all participants who received at least one dose of randomized study medication (placebo or active drug). This does not include placebo given during the Placebo Run-in Period.
Infections and infestations Upper respiratory tract infection	0.00% 0/170 • Adverse event (AE) and serious adverse event (SAE) data are presented for the On-treatment Phase (Week 1 to Week 24) plus the 7-day Down-titration Period. SAEs and non-serious AEs were collected in the Safety Population, consisting of all participants who received at least one dose of randomized study medication (placebo or active drug). This does not include placebo given during the Placebo Run-in Period.	0.57% 1/175 • Adverse event (AE) and serious adverse event (SAE) data are presented for the On-treatment Phase (Week 1 to Week 24) plus the 7-day Down-titration Period. SAEs and non-serious AEs were collected in the Safety Population, consisting of all participants who received at least one dose of randomized study medication (placebo or active drug). This does not include placebo given during the Placebo Run-in Period.
Injury, poisoning and procedural complications Femoral neck fracture	0.00% 0/170 • Adverse event (AE) and serious adverse event (SAE) data are presented for the On-treatment Phase (Week 1 to Week 24) plus the 7-day Down-titration Period. SAEs and non-serious AEs were collected in the Safety Population, consisting of all participants who received at least one dose of randomized study medication (placebo or active drug). This does not include placebo given during the Placebo Run-in Period.	0.57% 1/175 • Adverse event (AE) and serious adverse event (SAE) data are presented for the On-treatment Phase (Week 1 to Week 24) plus the 7-day Down-titration Period. SAEs and non-serious AEs were collected in the Safety Population, consisting of all participants who received at least one dose of randomized study medication (placebo or active drug). This does not include placebo given during the Placebo Run-in Period.
Injury, poisoning and procedural complications Fracture	0.00% 0/170 • Adverse event (AE) and serious adverse event (SAE) data are presented for the On-treatment Phase (Week 1 to Week 24) plus the 7-day Down-titration Period. SAEs and non-serious AEs were collected in the Safety Population, consisting of all participants who received at least one dose of randomized study medication (placebo or active drug). This does not include placebo given during the Placebo Run-in Period.	0.57% 1/175 • Adverse event (AE) and serious adverse event (SAE) data are presented for the On-treatment Phase (Week 1 to Week 24) plus the 7-day Down-titration Period. SAEs and non-serious AEs were collected in the Safety Population, consisting of all participants who received at least one dose of randomized study medication (placebo or active drug). This does not include placebo given during the Placebo Run-in Period.
Injury, poisoning and procedural complications Muscle strain	0.59% 1/170 • Adverse event (AE) and serious adverse event (SAE) data are presented for the On-treatment Phase (Week 1 to Week 24) plus the 7-day Down-titration Period. SAEs and non-serious AEs were collected in the Safety Population, consisting of all participants who received at least one dose of randomized study medication (placebo or active drug). This does not include placebo given during the Placebo Run-in Period.	0.00% 0/175 • Adverse event (AE) and serious adverse event (SAE) data are presented for the On-treatment Phase (Week 1 to Week 24) plus the 7-day Down-titration Period. SAEs and non-serious AEs were collected in the Safety Population, consisting of all participants who received at least one dose of randomized study medication (placebo or active drug). This does not include placebo given during the Placebo Run-in Period.
Gastrointestinal disorders Gastric ulcer	0.59% 1/170 • Adverse event (AE) and serious adverse event (SAE) data are presented for the On-treatment Phase (Week 1 to Week 24) plus the 7-day Down-titration Period. SAEs and non-serious AEs were collected in the Safety Population, consisting of all participants who received at least one dose of randomized study medication (placebo or active drug). This does not include placebo given during the Placebo Run-in Period.	0.00% 0/175 • Adverse event (AE) and serious adverse event (SAE) data are presented for the On-treatment Phase (Week 1 to Week 24) plus the 7-day Down-titration Period. SAEs and non-serious AEs were collected in the Safety Population, consisting of all participants who received at least one dose of randomized study medication (placebo or active drug). This does not include placebo given during the Placebo Run-in Period.
Gastrointestinal disorders Inguinal hernia	0.00% 0/170 • Adverse event (AE) and serious adverse event (SAE) data are presented for the On-treatment Phase (Week 1 to Week 24) plus the 7-day Down-titration Period. SAEs and non-serious AEs were collected in the Safety Population, consisting of all participants who received at least one dose of randomized study medication (placebo or active drug). This does not include placebo given during the Placebo Run-in Period.	0.57% 1/175 • Adverse event (AE) and serious adverse event (SAE) data are presented for the On-treatment Phase (Week 1 to Week 24) plus the 7-day Down-titration Period. SAEs and non-serious AEs were collected in the Safety Population, consisting of all participants who received at least one dose of randomized study medication (placebo or active drug). This does not include placebo given during the Placebo Run-in Period.
Metabolism and nutrition disorders Electrolyte imbalance	0.00% 0/170 • Adverse event (AE) and serious adverse event (SAE) data are presented for the On-treatment Phase (Week 1 to Week 24) plus the 7-day Down-titration Period. SAEs and non-serious AEs were collected in the Safety Population, consisting of all participants who received at least one dose of randomized study medication (placebo or active drug). This does not include placebo given during the Placebo Run-in Period.	0.57% 1/175 • Adverse event (AE) and serious adverse event (SAE) data are presented for the On-treatment Phase (Week 1 to Week 24) plus the 7-day Down-titration Period. SAEs and non-serious AEs were collected in the Safety Population, consisting of all participants who received at least one dose of randomized study medication (placebo or active drug). This does not include placebo given during the Placebo Run-in Period.
Metabolism and nutrition disorders Hypoglycemia	0.00% 0/170 • Adverse event (AE) and serious adverse event (SAE) data are presented for the On-treatment Phase (Week 1 to Week 24) plus the 7-day Down-titration Period. SAEs and non-serious AEs were collected in the Safety Population, consisting of all participants who received at least one dose of randomized study medication (placebo or active drug). This does not include placebo given during the Placebo Run-in Period.	0.57% 1/175 • Adverse event (AE) and serious adverse event (SAE) data are presented for the On-treatment Phase (Week 1 to Week 24) plus the 7-day Down-titration Period. SAEs and non-serious AEs were collected in the Safety Population, consisting of all participants who received at least one dose of randomized study medication (placebo or active drug). This does not include placebo given during the Placebo Run-in Period.
Renal and urinary disorders Neurogenic bladder	0.00% 0/170 • Adverse event (AE) and serious adverse event (SAE) data are presented for the On-treatment Phase (Week 1 to Week 24) plus the 7-day Down-titration Period. SAEs and non-serious AEs were collected in the Safety Population, consisting of all participants who received at least one dose of randomized study medication (placebo or active drug). This does not include placebo given during the Placebo Run-in Period.	0.57% 1/175 • Adverse event (AE) and serious adverse event (SAE) data are presented for the On-treatment Phase (Week 1 to Week 24) plus the 7-day Down-titration Period. SAEs and non-serious AEs were collected in the Safety Population, consisting of all participants who received at least one dose of randomized study medication (placebo or active drug). This does not include placebo given during the Placebo Run-in Period.
Renal and urinary disorders Urinary retention	0.00% 0/170 • Adverse event (AE) and serious adverse event (SAE) data are presented for the On-treatment Phase (Week 1 to Week 24) plus the 7-day Down-titration Period. SAEs and non-serious AEs were collected in the Safety Population, consisting of all participants who received at least one dose of randomized study medication (placebo or active drug). This does not include placebo given during the Placebo Run-in Period.	0.57% 1/175 • Adverse event (AE) and serious adverse event (SAE) data are presented for the On-treatment Phase (Week 1 to Week 24) plus the 7-day Down-titration Period. SAEs and non-serious AEs were collected in the Safety Population, consisting of all participants who received at least one dose of randomized study medication (placebo or active drug). This does not include placebo given during the Placebo Run-in Period.
Eye disorders Cataract	0.59% 1/170 • Adverse event (AE) and serious adverse event (SAE) data are presented for the On-treatment Phase (Week 1 to Week 24) plus the 7-day Down-titration Period. SAEs and non-serious AEs were collected in the Safety Population, consisting of all participants who received at least one dose of randomized study medication (placebo or active drug). This does not include placebo given during the Placebo Run-in Period.	0.00% 0/175 • Adverse event (AE) and serious adverse event (SAE) data are presented for the On-treatment Phase (Week 1 to Week 24) plus the 7-day Down-titration Period. SAEs and non-serious AEs were collected in the Safety Population, consisting of all participants who received at least one dose of randomized study medication (placebo or active drug). This does not include placebo given during the Placebo Run-in Period.
General disorders Hernia	0.59% 1/170 • Adverse event (AE) and serious adverse event (SAE) data are presented for the On-treatment Phase (Week 1 to Week 24) plus the 7-day Down-titration Period. SAEs and non-serious AEs were collected in the Safety Population, consisting of all participants who received at least one dose of randomized study medication (placebo or active drug). This does not include placebo given during the Placebo Run-in Period.	0.00% 0/175 • Adverse event (AE) and serious adverse event (SAE) data are presented for the On-treatment Phase (Week 1 to Week 24) plus the 7-day Down-titration Period. SAEs and non-serious AEs were collected in the Safety Population, consisting of all participants who received at least one dose of randomized study medication (placebo or active drug). This does not include placebo given during the Placebo Run-in Period.
Hepatobiliary disorders Cholecystitis	0.00% 0/170 • Adverse event (AE) and serious adverse event (SAE) data are presented for the On-treatment Phase (Week 1 to Week 24) plus the 7-day Down-titration Period. SAEs and non-serious AEs were collected in the Safety Population, consisting of all participants who received at least one dose of randomized study medication (placebo or active drug). This does not include placebo given during the Placebo Run-in Period.	0.57% 1/175 • Adverse event (AE) and serious adverse event (SAE) data are presented for the On-treatment Phase (Week 1 to Week 24) plus the 7-day Down-titration Period. SAEs and non-serious AEs were collected in the Safety Population, consisting of all participants who received at least one dose of randomized study medication (placebo or active drug). This does not include placebo given during the Placebo Run-in Period.
Nervous system disorders Akinesia	0.59% 1/170 • Adverse event (AE) and serious adverse event (SAE) data are presented for the On-treatment Phase (Week 1 to Week 24) plus the 7-day Down-titration Period. SAEs and non-serious AEs were collected in the Safety Population, consisting of all participants who received at least one dose of randomized study medication (placebo or active drug). This does not include placebo given during the Placebo Run-in Period.	0.00% 0/175 • Adverse event (AE) and serious adverse event (SAE) data are presented for the On-treatment Phase (Week 1 to Week 24) plus the 7-day Down-titration Period. SAEs and non-serious AEs were collected in the Safety Population, consisting of all participants who received at least one dose of randomized study medication (placebo or active drug). This does not include placebo given during the Placebo Run-in Period.
Psychiatric disorders Hallucination	0.59% 1/170 • Adverse event (AE) and serious adverse event (SAE) data are presented for the On-treatment Phase (Week 1 to Week 24) plus the 7-day Down-titration Period. SAEs and non-serious AEs were collected in the Safety Population, consisting of all participants who received at least one dose of randomized study medication (placebo or active drug). This does not include placebo given during the Placebo Run-in Period.	0.00% 0/175 • Adverse event (AE) and serious adverse event (SAE) data are presented for the On-treatment Phase (Week 1 to Week 24) plus the 7-day Down-titration Period. SAEs and non-serious AEs were collected in the Safety Population, consisting of all participants who received at least one dose of randomized study medication (placebo or active drug). This does not include placebo given during the Placebo Run-in Period.