Trial Outcomes & Findings for Polysomnography Study of GSK1838262 Extended Release Tablets Versus Placebo in RLS and Associated Sleep Disturbance (NCT NCT00748098)

NCT ID: NCT00748098

Last Updated: 2013-07-22

Results Overview

PSG is a comprehensive recording of the bio-physiological changes that occur during sleep. It is also known as a "sleep study" that monitors participants as they sleep or try to sleep. WTDS, defined as the total amount of time spent awake after falling asleep until the last awakening, was measured by PSG. Change from baseline was calculated as the Week 4 and Week 10 values minus the baseline value. Mean change from baseline was adjusted for treatment, pooled center, and period effects.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 136 participants
• Primary outcome timeframe: Baseline, Week 4/10 (representing the last week of each intervention period, i.e. Weeks 4 and 10)
• Results posted on: 2013-07-22

Participant Flow

Participant milestones

Measure	Placebo Followed by GEn 1200 mg/Day Participants randomized to matching placebo administered once daily with food at 5 pm during the 28-day First Treatment Intervention Period and the 7-day First Taper Period. No treatment was given during the 7-day Washout. Gabapentin enacarbil (GEn) 1200 mg/day administered once daily with food at 5 pm during the 28-day Second Treatment Intervention Period (Days 1-3, 600 mg). GEn 600 mg administered once daily with food at 5 pm during the 7-day Second Taper Period. No treatment was given during Follow-up.	GEn 1200 mg/Day Followed by Placebo Participants randomized to GEn 1200 mg/day administered once daily with food at 5 pm during the 28-day First Treatment Intervention Period (Days 1-3, 600 mg). GEn 600 mg administered once daily with food at 5 pm during the 7-day First Taper Period. No treatment was given during 7-day Washout. Matching placebo administered once daily with food at 5 pm during the 28-day Second Treatment Intervention Period and the 7-day Second Taper Period. No treatment was given during Follow-up.
First Treatment Intervention Period STARTED	69	67
First Treatment Intervention Period COMPLETED	64	66
First Treatment Intervention Period NOT COMPLETED	5	1
First Taper Period STARTED	64	66
First Taper Period COMPLETED	61	65
First Taper Period NOT COMPLETED	3	1
1-Week Washout Period STARTED	61	65
1-Week Washout Period COMPLETED	59	64
1-Week Washout Period NOT COMPLETED	2	1
Second Treatment Intervention Period STARTED	59	64
Second Treatment Intervention Period COMPLETED	53	61
Second Treatment Intervention Period NOT COMPLETED	6	3
Second Taper Period STARTED	53	61
Second Taper Period COMPLETED	53	61
Second Taper Period NOT COMPLETED	0	0

Reasons for withdrawal

Measure	Placebo Followed by GEn 1200 mg/Day Participants randomized to matching placebo administered once daily with food at 5 pm during the 28-day First Treatment Intervention Period and the 7-day First Taper Period. No treatment was given during the 7-day Washout. Gabapentin enacarbil (GEn) 1200 mg/day administered once daily with food at 5 pm during the 28-day Second Treatment Intervention Period (Days 1-3, 600 mg). GEn 600 mg administered once daily with food at 5 pm during the 7-day Second Taper Period. No treatment was given during Follow-up.	GEn 1200 mg/Day Followed by Placebo Participants randomized to GEn 1200 mg/day administered once daily with food at 5 pm during the 28-day First Treatment Intervention Period (Days 1-3, 600 mg). GEn 600 mg administered once daily with food at 5 pm during the 7-day First Taper Period. No treatment was given during 7-day Washout. Matching placebo administered once daily with food at 5 pm during the 28-day Second Treatment Intervention Period and the 7-day Second Taper Period. No treatment was given during Follow-up.
First Treatment Intervention Period Adverse Event	1	1
First Treatment Intervention Period Protocol Violation	1	0
First Treatment Intervention Period Lost to Follow-up	1	0
First Treatment Intervention Period Withdrawal by Subject	2	0
First Taper Period Protocol Violation	1	0
First Taper Period Withdrawal by Subject	2	0
First Taper Period Protocol Stopping Criteria Met	0	1
1-Week Washout Period Adverse Event	0	1
1-Week Washout Period Withdrawal by Subject	2	0
Second Treatment Intervention Period Adverse Event	4	1
Second Treatment Intervention Period Lost to Follow-up	1	1
Second Treatment Intervention Period Withdrawal by Subject	1	1

Baseline Characteristics

Polysomnography Study of GSK1838262 Extended Release Tablets Versus Placebo in RLS and Associated Sleep Disturbance

Baseline characteristics by cohort

Measure	All Participants in the Intent-to-Treat (ITT) Population n=131 Participants All randomized participants who took at least one dose of study drug and had at least one post-baseline polysomnography (PSG) efficacy assessment
Age Continuous	52.0 Years STANDARD_DEVIATION 12.70 • n=5 Participants
Sex: Female, Male Female	76 Participants n=5 Participants
Sex: Female, Male Male	55 Participants n=5 Participants
Race/Ethnicity, Customized African American/African Heritage	7 participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	2 participants n=5 Participants
Race/Ethnicity, Customized Asian	1 participants n=5 Participants
Race/Ethnicity, Customized White	120 participants n=5 Participants
Race/Ethnicity, Customized Mixed Race	1 participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline, Week 4/10 (representing the last week of each intervention period, i.e. Weeks 4 and 10)

Population: ITT Population: Of the 131 ITT participants, 2 and 6 participants did not take Placebo and GEn 1200 mg, respectively, in the second period. In addition, 6 placebo and 4 GEn 1200 participants did not have PSG data during the second intervention period and were therefore not included in this analysis.

PSG is a comprehensive recording of the bio-physiological changes that occur during sleep. It is also known as a "sleep study" that monitors participants as they sleep or try to sleep. WTDS, defined as the total amount of time spent awake after falling asleep until the last awakening, was measured by PSG. Change from baseline was calculated as the Week 4 and Week 10 values minus the baseline value. Mean change from baseline was adjusted for treatment, pooled center, and period effects.

Outcome measures

Measure	Placebo n=123 Participants Placebo once daily either in first intervention period or second intervention period	GEn 1200 mg n=121 Participants GEn 1200 mg once daily either in first intervention period or second intervention period
Adjusted Mean Change From Baseline in Wake Time During Sleep (WTDS) at Week 4/10 Measured by Polysomnography (PSG) (Sleep Study) Using Last Observation Carried Forward (LOCF)	-6.02 minutes Standard Error 4.986	-32.02 minutes Standard Error 5.020

SECONDARY outcome

Timeframe: Baseline, Week 4/10 (representing the last week of each intervention period, i.e. Weeks 4 and 10)

Population: ITT Population: Of the 131 ITT participants, 2 and 6 participants did not take Placebo and GEn 1200 mg, respectively, in the second period. In addition, 6 placebo and 4 GEn 1200 participants did not have PSG data during the second intervention period and were therefore not included in this analysis.

PLMAI is defined as the number of Periodic Limb Movements (PLMs or involuntary jerks of the legs that cause a participant to arouse from sleep per hour of sleep). Change from baseline was calculated as the Week 4 and Week 10 values minus the baseline value. Mean change from baseline was adjusted for treatment, pooled center, and period effects.

Outcome measures

Measure	Placebo n=123 Participants Placebo once daily either in first intervention period or second intervention period	GEn 1200 mg n=121 Participants GEn 1200 mg once daily either in first intervention period or second intervention period
Adjusted Mean Change From Baseline in Periodic Limb Movements Associated With Arousal (PLMAI) at Week 4/10 as Measured by Polysomnography Using LOCF	-1.52 limb movements per hour Standard Error 0.892	-4.59 limb movements per hour Standard Error 0.899

SECONDARY outcome

Timeframe: Baseline, Week 4/10 (representing the last week of each intervention period, i.e. Weeks 4 and 10)

Population: ITT Population: Of the 131 ITT participants, 2 and 6 participants did not take Placebo and GEn 1200 mg, respectively, in the second period. An additional 4 participants (2 in each treatment group) were excluded from the analysis due to missing/incomplete data.

The IRLS is a measure of RLS disease severity. Ten items (individually scored from 0 to 4) are included that assess the impact of symptoms on participants' mood, daily life, and activities. The total scale score is a sum of all of the individual item scores and ranges from 0-40 points, with 40 being the most severe. The scale assesses symptoms over the week prior to measurement. Change from baseline was calculated as the Week 4 and Week 10 values minus the baseline value. Mean change from baseline was adjusted for treatment, pooled center, and period effects.

Outcome measures

Measure	Placebo n=127 Participants Placebo once daily either in first intervention period or second intervention period	GEn 1200 mg n=123 Participants GEn 1200 mg once daily either in first intervention period or second intervention period
Adjusted Mean Change From Baseline in the International Restless Legs Rating Scale (IRLS) Total Score at Week 4/10 Using LOCF	-8.42 scores on a scale Standard Error 0.713	-14.99 scores on a scale Standard Error 0.725

SECONDARY outcome

Timeframe: Baseline, Week 4/10 (representing the last week of each intervention period, i.e. Weeks 4 and 10)

Population: ITT Population: Of the 131 ITT participants, 2 and 6 participants did not take Placebo and GEn 1200 mg, respectively, in the second period. An additional 4 participants (2 in each treatment group) were excluded from the analysis due to missing/incomplete data.

The IRLS is a measure of RLS disease severity. Item 4 of the IRLS evaluates RLS-related sleep impairment. It asks: "In the past week, how severe was your sleep disturbance due to your RLS symptoms?". The item is participant rated using a 5-point scale, where 0 is the absence of any sleep disturbance and 4 is very severe disturbance. Change from baseline was calculated as the Week 4 and Week 10 values minus the baseline value. Mean change from baseline was adjusted for treatment, pooled center, and period effects.

Outcome measures

Measure	Placebo n=127 Participants Placebo once daily either in first intervention period or second intervention period	GEn 1200 mg n=123 Participants GEn 1200 mg once daily either in first intervention period or second intervention period
Adjusted Mean Change From Baseline in the Item 4 (Sleep Disturbance) Scores of the IRLS Rating Scale at Week 4/10 Using LOCF	-1.47 scores on a scale Standard Error 0.092	-2.27 scores on a scale Standard Error 0.093

SECONDARY outcome

Timeframe: Baseline, Week 4/10 (representing the last week of each intervention period, i.e. Weeks 4 and 10)

Population: ITT Population: Of the 131 ITT participants, 2 and 6 participants did not take Placebo and GEn 1200 mg, respectively, in the second period. In addition, 6 placebo and 4 GEn 1200 participants did not have PSG data during the second intervention period and were therefore not included in this analysis.

Stage N1 is considered "light sleep," during which participants drift in and out of sleep and can be awakened easily. In this stage, the eyes move slowly and muscle activity slows. This stage is sometimes referred to as "somnolence" or "drowsy sleep." Sudden twitches and hypnic jerks may be associated with the onset of sleep during N1. Change from baseline was calculated as the Week 4 and Week 10 values minus the baseline value. Mean change from baseline was adjusted for treatment, pooled center, and period effects.

Outcome measures

Measure	Placebo n=123 Participants Placebo once daily either in first intervention period or second intervention period	GEn 1200 mg n=121 Participants GEn 1200 mg once daily either in first intervention period or second intervention period
Adjusted Mean Change From Baseline in Time Spent in N1 Sleep as Measured by Polysomnography at Week 4/10 Using LOCF	-0.95 minutes Standard Error 1.508	-6.19 minutes Standard Error 1.517

SECONDARY outcome

Timeframe: Baseline, Week 4/10 (representing the last week of each intervention period, i.e. Weeks 4 and 10)

Population: ITT Population: Of the 131 ITT participants, 2 and 6 participants did not take Placebo and GEn 1200 mg, respectively, in the second period. In addition, 6 placebo and 4 GEn 1200 participants did not have PSG data during the second intervention period and were therefore not included in this analysis.

Percentage of stage N1 sleep time was defined as the time spent in stage N1 sleep divided by total sleep time. Change from baseline was calculated as the Week 4 and Week 10 values minus the baseline value. Mean change from baseline was adjusted for treatment, pooled center, and period effects.

Outcome measures

Measure	Placebo n=123 Participants Placebo once daily either in first intervention period or second intervention period	GEn 1200 mg n=121 Participants GEn 1200 mg once daily either in first intervention period or second intervention period
Adjusted Mean Change From Baseline in the Percentage of Total Sleep Time Spent in the N1 Sleep Stage at Week 4/10 Using LOCF	-0.23 percentage of total sleep time Standard Error 0.507	-2.55 percentage of total sleep time Standard Error 0.511

SECONDARY outcome

Timeframe: Baseline, Week 4/10 (representing the last week of each intervention period, i.e. Weeks 4 and 10)

Population: ITT Population: Of the 131 ITT participants, 2 and 6 participants did not take Placebo and GEn 1200 mg, respectively, in the second period. In addition, 6 placebo and 4 GEn 1200 participants did not have PSG data during the second intervention period and were therefore not included in this analysis.

In stage N2 of sleep, eye movement stops and brain waves become slower, with only an occasional burst of rapid brain waves. Participants may also experience spontaneous periods of muscle tone mixed with periods of muscle relaxation. During this stage, muscular activity, and conscious awareness of the external environment disappears. Change from baseline was calculated as the Week 4 and Week 10 values minus the baseline value. Mean change from baseline was adjusted for treatment, pooled center, and period effects.

Outcome measures

Measure	Placebo n=123 Participants Placebo once daily either in first intervention period or second intervention period	GEn 1200 mg n=121 Participants GEn 1200 mg once daily either in first intervention period or second intervention period
Adjusted Mean Change From Baseline in Time Spent in the N2 Sleep Stage as Measured by Polysomnography at Week 4/10 Using LOCF	2.78 minutes Standard Error 4.528	22.95 minutes Standard Error 4.563

SECONDARY outcome

Timeframe: Baseline, Week 4/10 (representing the last week of each intervention period, i.e. Weeks 4 and 10)

Population: ITT Population: Of the 131 ITT participants, 2 and 6 participants did not take Placebo and GEn 1200 mg, respectively, in the second period. In addition, 6 placebo and 4 GEn 1200 participants did not have PSG data during the second intervention period and were therefore not included in this analysis.

Percentage of stage N2 sleep time was defined as the time spent in stage N2 sleep divided by total sleep time. Change from baseline was calculated as the Week 4 and Week 10 values minus the baseline value. Mean change from baseline was adjusted for treatment, pooled center, and period effects.

Outcome measures

Measure	Placebo n=123 Participants Placebo once daily either in first intervention period or second intervention period	GEn 1200 mg n=121 Participants GEn 1200 mg once daily either in first intervention period or second intervention period
Adjusted Mean Change From Baseline in the Percentage of Total Sleep Time Spent in the N2 Sleep Stage at Week 4/10	0.16 percentage of total sleep time Standard Error 0.808	0.64 percentage of total sleep time Standard Error 0.815

SECONDARY outcome

Timeframe: Baseline, Week 4/10 (representing the last week of each intervention period, i.e. Weeks 4 and 10)

Population: ITT Population: Of the 131 ITT participants, 2 and 6 participants did not take Placebo and GEn 1200 mg, respectively, in the second period. In addition, 6 placebo and 4 GEn 1200 participants did not have PSG data during the second intervention period and were therefore not included in this analysis.

Stage N3 is referred to as deep sleep; it is very difficult to wake a participant in this stage of sleep. In deep sleep, there is no eye movement or muscle activity. Change from baseline was calculated as the Week 4 and Week 10 values minus the baseline value. Mean change from baseline was adjusted for treatment, pooled center, and period effects.

Outcome measures

Measure	Placebo n=123 Participants Placebo once daily either in first intervention period or second intervention period	GEn 1200 mg n=121 Participants GEn 1200 mg once daily either in first intervention period or second intervention period
Mean Change From Baseline in the Total Time Spent in Stage N3 Sleep Time at Week 4/10 Measured by PSG Using LOCF	2.89 minutes Standard Error 2.351	15.02 minutes Standard Error 2.371

SECONDARY outcome

Timeframe: Baseline, Week 4/10 (representing the last week of each intervention period, i.e. Weeks 4 and 10)

Population: ITT Population: Of the 131 ITT participants, 2 and 6 participants did not take Placebo and GEn 1200 mg, respectively, in the second period. In addition, 6 placebo and 4 GEn 1200 participants did not have PSG data during the second intervention period and were therefore not included in this analysis.

Percentage of stage N3 sleep time was defined as the time spent in stage N3 sleep divided by total sleep time. Change from baseline was calculated as the Week 4 and Week 10 values minus the baseline value. Mean change from baseline was adjusted for treatment, pooled center, and period effects.

Outcome measures

Measure	Placebo n=123 Participants Placebo once daily either in first intervention period or second intervention period	GEn 1200 mg n=121 Participants GEn 1200 mg once daily either in first intervention period or second intervention period
Adjusted Mean Change From Baseline in the Percentage of Total Sleep Time Spent in the N3 Sleep Stage at Week 4/10	0.57 percentage of total sleep time Standard Error 0.559	2.62 percentage of total sleep time Standard Error 0.564

SECONDARY outcome

Timeframe: Baseline, Week 4/10 (representing the last week of each intervention period, i.e. Weeks 4 and 10)

Population: ITT Population: Of the 131 ITT participants, 2 and 6 participants did not take Placebo and GEn 1200 mg, respectively, in the second period. In addition, 6 placebo and 4 GEn 1200 participants did not have PSG data during the second intervention period and were therefore not included in this analysis.

In REM sleep, a participant's breathing becomes more rapid, irregular, and shallow; eyes jerk rapidly; and limb muscles are temporarily paralyzed. Brain waves during this stage increase to levels experienced when a person is awake. This is the stage when most dreams occur. Change from baseline was calculated as the Week 4 and Week 10 values minus the baseline value. Mean change from baseline was adjusted for treatment, pooled center, and period effects.

Outcome measures

Measure	Placebo n=123 Participants Placebo once daily either in first intervention period or second intervention period	GEn 1200 mg n=121 Participants GEn 1200 mg once daily either in first intervention period or second intervention period
Adjusted Mean Change From Baseline in Time Spent in the REM (Rapid Eye Movement) Sleep Stage at Week 4/10 as Measured by Polysomnography Using LOCF	-1.21 minutes Standard Error 2.638	4.22 minutes Standard Error 2.659

SECONDARY outcome

Timeframe: Baseline, Week 4/10 (representing the last week of each intervention period, i.e. Weeks 4 and 10)

Population: ITT Population: Of the 131 ITT participants, 2 and 6 participants did not take Placebo and GEn 1200 mg, respectively, in the second period. In addition, 6 placebo and 4 GEn 1200 participants did not have PSG data during the second intervention period and were therefore not included in this analysis.

Percentage of stage REM sleep time was defined as the time spent in stage REM sleep divided by total sleep time. Change from baseline was calculated as the Week 4 and Week 10 values minus the baseline value. Mean change from baseline was adjusted for treatment, pooled center, and period effects.

Outcome measures

Measure	Placebo n=123 Participants Placebo once daily either in first intervention period or second intervention period	GEn 1200 mg n=121 Participants GEn 1200 mg once daily either in first intervention period or second intervention period
Adjusted Mean Change From Baseline in the Percentage of Total Sleep Time Spent in the REM Sleep Stage at Week 4/10	-0.49 percentage of total sleep time Standard Error 0.582	-0.71 percentage of total sleep time Standard Error 0.586

SECONDARY outcome

Timeframe: Baseline, Week 4/10 (representing the last week of each intervention period, i.e. Weeks 4 and 10)

Population: ITT Population: Of the 131 ITT participants, 2 and 6 participants did not take Placebo and GEn 1200 mg, respectively, in the second period. In addition, 6 placebo and 4 GEn 1200 participants did not have PSG data during the second intervention period and were therefore not included in this analysis.

PLMAWI is defined as the number of PLMs (involuntary leg movements) that caused participants to wake up per hour of sleep. It is calculated by dividing the number of PLMs causing awakening by the total number of hours of sleep. Change from baseline was calculated as the Week 4 and Week 10 values minus the baseline value. Mean change from baseline was adjusted for treatment, pooled center, and period effects.

Outcome measures

Measure	Placebo n=123 Participants Placebo once daily either in first intervention period or second intervention period	GEn 1200 mg n=121 Participants GEn 1200 mg once daily either in first intervention period or second intervention period
Adjusted Mean Change From Baseline in Periodic Limb Movements Causing Awakening (PLMAWI) at Week 4/10 as Measured by Polysomnography Using LOCF	-0.08 number of PLMs/total hours of sleep Standard Error 0.047	-0.22 number of PLMs/total hours of sleep Standard Error 0.048

SECONDARY outcome

Timeframe: Week 4/10 (representing the last week of each intervention period, i.e. Weeks 4 and 10)

Population: ITT Population: Of the 131 ITT participants, 2 and 6 participants did not take Placebo and GEn 1200 mg, respectively, in the second period. In addition, 6 placebo and 4 GEn 1200 participants did not have PSG data during the second intervention period and were therefore not included in this analysis.

PLMAI is defined as the number of PLMs associated with arousal per hour of sleep. Participants with <=5 PLMAI were evaluated as responders.

Outcome measures

Measure	Placebo n=123 Participants Placebo once daily either in first intervention period or second intervention period	GEn 1200 mg n=121 Participants GEn 1200 mg once daily either in first intervention period or second intervention period
Number of PLMAI Responders at Week 4/10 Using LOCF	44 participants	64 participants

SECONDARY outcome

Timeframe: Baseline, Week 4/10 (representing the last week of each intervention period, i.e. Weeks 4 and 10)

Population: ITT Population: The number of participants assessed varied due to missing/incomplete diary data.

Each day upon awakening, participants rated their overall sleep quality for the previous night on an 11-point scale (0=poor to 10=excellent) using the SPSD. Response to sleep quality was calculated for each visit by averaging the last 7 available diary days. Only participants with at least 4 days of diary data available (not in consecutive order) at any visit were included in the analysis. Change from baseline was calculated as the Week 4 and Week 10 values minus the baseline value. Mean change from baseline was adjusted for treatment, pooled center, and period effects.

Outcome measures

Measure	Placebo n=116 Participants Placebo once daily either in first intervention period or second intervention period	GEn 1200 mg n=109 Participants GEn 1200 mg once daily either in first intervention period or second intervention period
Adjusted Mean Change From Baseline in Sleep Quality at Week 4/10 as Measured by the Subjective Post Sleep Diary (SPSD) Using LOCF	0.85 scores on a scale Standard Error 0.141	1.95 scores on a scale Standard Error 0.145

SECONDARY outcome

Timeframe: Baseline, Week 4/10 (representing the last week of each intervention period, i.e. Weeks 4 and 10)

Population: ITT Population: The number of participants assessed varied due to missing/incomplete diary data.

Each day upon awakening, participants rated how rested they felt upon awakening on an 11-point scale (0=poor to 10=excellent) using the SPSD. Response to feeling rested upon awakening was calculated for each visit by averaging the last 7 available diary days. Only participants with at least 4 days of diary data available (not in consecutive order) at any visit were included in the analysis. Change from baseline was calculated as the Week 4 and Week 10 values minus the baseline value. Mean change from baseline was adjusted for treatment, pooled center, and period effects.

Outcome measures

Measure	Placebo n=116 Participants Placebo once daily either in first intervention period or second intervention period	GEn 1200 mg n=109 Participants GEn 1200 mg once daily either in first intervention period or second intervention period
Adjusted Mean Change From Baseline in Participant's Ratings of Feeling Rested Upon Awakening as Measured by the Subjective Post Sleep Diary (SPSD) at Week 4/10 Using LOCF.	0.83 scores on a scale Standard Error 0.142	1.68 scores on a scale Standard Error 0.146

SECONDARY outcome

Timeframe: Baseline, Week 4/10 (representing the last week of each intervention period, i.e. Weeks 4 and 10)

Population: ITT Population: Of the 131 ITT participants, 2 and 6 participants did not take Placebo and GEn 1200 mg, respectively, in the second period. In addition, 6 placebo and 4 GEn 1200 participants did not have PSG data during the second intervention period and were therefore not included in this analysis.

The number of awakenings was measured by PSG and is defined as the number of wake periods lasting at least 1 minute. Change from baseline was calculated as the Week 4 and Week 10 values minus the baseline value. Mean change from baseline was adjusted for treatment, pooled center, and period effects.

Outcome measures

Measure	Placebo n=123 Participants Placebo once daily either in first intervention period or second intervention period	GEn 1200 mg n=121 Participants GEn 1200 mg once daily either in first intervention period or second intervention period
Adjusted Mean Change From Baseline in the Number of Awakenings Measured Objectively by Polysomnography at Week 4/10 Using LOCF	-0.56 awakenings Standard Error 0.411	-3.04 awakenings Standard Error 0.414

SECONDARY outcome

Timeframe: Baseline, Week 4/10 (representing the last week of each intervention period, i.e. Weeks 4 and 10)

Population: ITT Population: The number of participants assessed varied due to missing/incomplete diary data.

Each day upon awakening, participants recorded, using the SPSD, the total number of hours spent awake the previous night due to RLS. Response to number of hours awake was calculated for each visit by averaging the last 7 available diary days. Only participants with at least 4 days of diary data available (not in consecutive order) at any visit were included in the analysis. Change from baseline was calculated as the Week 4 and Week 10 values minus the baseline value. Mean change from baseline was adjusted for treatment, pooled center, and period effects.

Outcome measures

Measure	Placebo n=116 Participants Placebo once daily either in first intervention period or second intervention period	GEn 1200 mg n=109 Participants GEn 1200 mg once daily either in first intervention period or second intervention period
Adjusted Mean Change From Baseline in the Self-reported Number of Hours Spent Awake During the Night (SPSD) Due to RLS at Week 4/10 Using LOCF	-0.45 hours Standard Error 0.064	-0.56 hours Standard Error 0.065

SECONDARY outcome

Timeframe: Week 4/10 (representing the last week of each intervention period, i.e. Weeks 4 and 10)

Population: ITT Population: The number of participants assessed varied due to missing/incomplete diary data.

Each day upon awakening, participants recorded, using the SPSD, the number of awakenings due to RLS they experienced the previous night. Number of awakenings was calculated for each visit by averaging the last 7 available diary days. Only participants with at least 4 days of diary data available (not in consecutive order) at any visit were included in the analysis.

Outcome measures

Measure	Placebo n=125 Participants Placebo once daily either in first intervention period or second intervention period	GEn 1200 mg n=115 Participants GEn 1200 mg once daily either in first intervention period or second intervention period
Number of Participants With no Self-reported Awakenings (SPSD) Due to RLS at Week 4/10 Using LOCF	68 participants	87 participants

SECONDARY outcome

Timeframe: Baseline, Week 4/10 (representing the last week of each intervention period, i.e. Weeks 4 and 10)

Population: ITT Population: Of the 131 ITT participants, 2 and 6 participants did not take Placebo and GEn 1200 mg, respectively, in the second period. In addition, 6 placebo and 4 GEn 1200 participants did not have PSG data during the second intervention period and were therefore not included in this analysis.

Total sleep time is the number of minutes participants slept on average during the 8-hour polysomnography. Scoring of PSG data to yield measure of total sleep time was conducted at a central site in the United States. Change from baseline was calculated as the Week 4 and Week 10 values minus the baseline value. Mean change from baseline was adjusted for treatment, pooled center, and period effect.

Outcome measures

Measure	Placebo n=123 Participants Placebo once daily either in first intervention period or second intervention period	GEn 1200 mg n=121 Participants GEn 1200 mg once daily either in first intervention period or second intervention period
Adjusted Mean Change From Baseline in the Total Sleep Time Measured by Polysomnography (PSG) at Week 4/10 Using LOCF	3.62 minutes Standard Error 5.572	36.32 minutes Standard Error 5.615

SECONDARY outcome

Timeframe: Baseline, Week 4/10 (representing the last week of each intervention period, i.e. Weeks 4 and 10)

Population: ITT Population: Of the 131 ITT participants, 2 and 6 participants did not take Placebo and GEn 1200 mg, respectively, in the second period. In addition, 6 placebo and 4 GEn 1200 participants did not have PSG data during the second intervention period and were therefore not included in this analysis.

Sleep efficiency is a percentage that is calculated by dividing total sleep time by the amount of time the participant was in bed during the PSG. Change from baseline was calculated as the Week 4 and Week 10 values minus the baseline value. Mean change from baseline was adjusted for treatment, pooled center, and period effect.

Outcome measures

Measure	Placebo n=123 Participants Placebo once daily either in first intervention period or second intervention period	GEn 1200 mg n=121 Participants GEn 1200 mg once daily either in first intervention period or second intervention period
Adjusted Mean Change From Baseline in the Sleep Efficiency Measured by Polysomnography (PSG) at Week 4/10 Using LOCF	0.76 minutes/hour Standard Error 1.161	7.57 minutes/hour Standard Error 1.170

SECONDARY outcome

Timeframe: Baseline, Week 4/10 (representing the last week of each intervention period, i.e. Weeks 4 and 10)

Population: ITT Population: Of the 131 ITT participants, 2 and 6 participants did not take Placebo and GEn 1200 mg, respectively, in the second period. In addition, 6 placebo and 4 GEn 1200 participants did not have PSG data during the second intervention period and were therefore not included in this analysis.

Wake After Sleep Onset (WASO) is defined as the total amount of time spent awake after falling asleep until the end of PSG recording. This endpoint is measured objectively by PSG. Change from baseline was calculated as the Week 4 and Week 10 values minus the baseline value. Mean change from baseline was adjusted for treatment, pooled center, and period effects

Outcome measures

Measure	Placebo n=123 Participants Placebo once daily either in first intervention period or second intervention period	GEn 1200 mg n=121 Participants GEn 1200 mg once daily either in first intervention period or second intervention period
Adjusted Mean Change From Baseline in the Wake After Sleep Onset (WASO) Measured by Polysomnography (PSG) at Week 4/10 Using LOCF.	-3.76 minutes Standard Error 4.964	-32.24 minutes Standard Error 5.002

SECONDARY outcome

Timeframe: Baseline, Week 4/10 (representing the last week of each intervention period, i.e. Weeks 4 and 10)

Population: ITT Population: The number of participants assessed varied due to missing/incomplete data.

During the SIT, participants sat in bed with legs extended for 1 hour and were asked to rate their leg discomfort on a 100 millimeters visual analog scale every 5 minutes (score of 0-100, 0=none, higher numbers indicate more discomfort) and PLMs were assessed. The SIT-PLM Index is defined as the number of PLMs per hour during the SIT. Mean change from baseline was adjusted for treatment, pooled center, and period effects. Only results from SITs performed before a PSG assessment and of at least 60 minutes in length are included in the analysis.

Outcome measures

Measure	Placebo n=119 Participants Placebo once daily either in first intervention period or second intervention period	GEn 1200 mg n=117 Participants GEn 1200 mg once daily either in first intervention period or second intervention period
Adjusted Mean Change From Baseline in the Suggested Immobilization Test (SIT) PLM Index at Week 4/10	-3.73 number of PLMs per hour Standard Error 7.394	-30.52 number of PLMs per hour Standard Error 7.436

SECONDARY outcome

Timeframe: Baseline, Week 4/10 (representing the last week of each intervention period, i.e. Weeks 4 and 10)

Population: ITT Population: The number of participants assessed varied due to missing/incomplete data.

During the SIT, participants sat in bed with legs extended for 1 hour and rated their leg discomfort on a visual analog scale every 5 minutes (range 0-100, 0=none, higher numbers indicate more discomfort). The SIT MDS is the average rating of leg discomfort during the specified time frame. Change from baseline was calculated as the Week 4 and Week 10 values minus the baseline value. Mean change from baseline was adjusted for treatment, pooled center, and period effects. Only results from SITs performed before a PSG assessment and of at least 60 minutes in length are included in the analysis.

Outcome measures

Measure	Placebo n=118 Participants Placebo once daily either in first intervention period or second intervention period	GEn 1200 mg n=117 Participants GEn 1200 mg once daily either in first intervention period or second intervention period
Adjusted Mean Change From Baseline in the SIT MDS (Mean Leg Discomfort Score), Mean of Scores From 0 to 60 Minutes, at Week 4/10	-8.57 scores on a scale Standard Error 2.136	-21.24 scores on a scale Standard Error 2.145

SECONDARY outcome

Timeframe: Week 4/10 (representing the last week of each intervention period, i.e. Weeks 4 and 10)

Population: ITT Population: The number of participants assessed varied due to missing/incomplete data.

Each participant completed the participant-completed Patient Global Impression questionnaire at the end of each Treatment Period (Weeks 4 and 10) or Early Withdrawal. This instrument was developed to capture a participant's subjective assessment of therapy and is composed of the following 4 questions with dichotomous (Yes or No) responses: "Helped me sleep," "Helped me fall asleep faster," "Helped me sleep longer," and "Helped me get a better night's sleep."

Outcome measures

Measure	Placebo n=123 Participants Placebo once daily either in first intervention period or second intervention period	GEn 1200 mg n=118 Participants GEn 1200 mg once daily either in first intervention period or second intervention period
Number of Participants Who Responded Affirmatively to Each of the 4 Items of the Participant-completed Patient Global Impression of Therapy at Week 4/10 Using LOCF Helped me sleep longer	31 participants	80 participants
Number of Participants Who Responded Affirmatively to Each of the 4 Items of the Participant-completed Patient Global Impression of Therapy at Week 4/10 Using LOCF Helped me sleep	53 participants	95 participants
Number of Participants Who Responded Affirmatively to Each of the 4 Items of the Participant-completed Patient Global Impression of Therapy at Week 4/10 Using LOCF Helped me fall asleep faster	39 participants	77 participants
Number of Participants Who Responded Affirmatively to Each of the 4 Items of the Participant-completed Patient Global Impression of Therapy at Week 4/10 Using LOCF Helped me get a better night's sleep	50 participants	89 participants

SECONDARY outcome

Timeframe: Baseline, Week 4/10 (representing the last week of each intervention period, i.e. Weeks 4 and 10)

Population: ITT Population: The number of participants assessed varied due to missing/incomplete data.

The CGI-S scale allows the investigator to rate the severity of participants' illness considering their total clinical experience with the participant population being studied and based on all information available at the time of rating. The scale is rated from 1-7 (1=Normal, not at all ill; 7=Among the most extremely ill patients). Change from baseline was calculated as the Week 4 and Week 10 values minus the baseline value. Mean change from baseline was adjusted for treatment, pooled center, and period effects.

Outcome measures

Measure	Placebo n=121 Participants Placebo once daily either in first intervention period or second intervention period	GEn 1200 mg n=118 Participants GEn 1200 mg once daily either in first intervention period or second intervention period
Adjusted Mean Change From Baseline in the Clinical Global Impression of Illness - Severity (CGI-S) Score at Week 4/10 Using LOCF	-1.18 scores on a scale Standard Error 0.119	-2.43 scores on a scale Standard Error 0.121

SECONDARY outcome

Timeframe: Week 4/10 (representing the last week of each intervention period, i.e. Weeks 4 and 10)

Population: ITT Population: The number of participants assessed varied due to missing/incomplete data.

The CGI-I scale allows the investigator to rate the participant's global improvement or worsening compared with the condition at baseline (i.e., Day 1), and whether or not the change is thought to be due to treatment with study medication. The scale is rated from 1-7 (1=Very much improved to 7=Very much worse). Participants with a score of 1 ("Very much improved") or 2 ("Much improved") are considered to be responders.

Outcome measures

Measure	Placebo n=127 Participants Placebo once daily either in first intervention period or second intervention period	GEn 1200 mg n=123 Participants GEn 1200 mg once daily either in first intervention period or second intervention period
Number of Participants Who Were Defined as Clinical Global Impression of Illness (CGI-I) Scale "Responders" at Week 4/10 Using LOCF	46 participants	91 participants

SECONDARY outcome

Timeframe: Week 4/10 (representing the last week of each intervention period, i.e. Weeks 4 and 10)

Population: ITT Population: The number of participants assessed varied due to missing/incomplete data.

Participant satisfaction with RLS medication was captured on a seven-point ordinal scale. The scale asked "Overall, how satisfied are you with the medication you received for the treatment of your RLS symptoms during the study." The participant responses ranged from 1 ("Very satisfied") to 7 ("Very dissatisfied"). A "satisfied" response was scored a 2.

Outcome measures

Measure	Placebo n=122 Participants Placebo once daily either in first intervention period or second intervention period	GEn 1200 mg n=118 Participants GEn 1200 mg once daily either in first intervention period or second intervention period
Number of Participants Who Self-reported "Very Satisfied" or "Satisfied" With the Investigational Product at Week 4/10 Using LOCF Very Satisfied	22 participants	38 participants
Number of Participants Who Self-reported "Very Satisfied" or "Satisfied" With the Investigational Product at Week 4/10 Using LOCF Satisfied	23 participants	35 participants

Adverse Events

Placebo

Serious events: 0 serious events

Other events: 27 other events

Deaths: 0 deaths

GEn 1200 mg

Serious events: 2 serious events

Other events: 54 other events

Deaths: 0 deaths

Serious adverse events

Measure	Placebo n=132 participants at risk Participants who took at least one dose of placebo in either the first intervention period or the second intervention period. Of the 136 participants in the Safety Population, 132 took at least one dose of placebo.	GEn 1200 mg n=127 participants at risk Participants who took at least one dose of GEn 1200 mg in either the first intervention period or the second intervention period. Of the 136 participants in the Safety Population, 127 took at least one dose of GEn 1200 mg.
Infections and infestations Cellulitis	0.00% 0/132 • Adverse event (AE) and serious adverse event (SAE) collection started immediately following informed consent and continued throughout the study (up to Week 12). AEs and SAEs were presented for the Safety Population, defined as all participants who were randomized and took at least one dose of investigational product. Participants were assigned to a treatment group within the Safety Population if they took at least one dose of that treatment (i.e., in that treatment period).	0.79% 1/127 • Number of events 1 • Adverse event (AE) and serious adverse event (SAE) collection started immediately following informed consent and continued throughout the study (up to Week 12). AEs and SAEs were presented for the Safety Population, defined as all participants who were randomized and took at least one dose of investigational product. Participants were assigned to a treatment group within the Safety Population if they took at least one dose of that treatment (i.e., in that treatment period).
Nervous system disorders Transient ischaemic attack	0.00% 0/132 • Adverse event (AE) and serious adverse event (SAE) collection started immediately following informed consent and continued throughout the study (up to Week 12). AEs and SAEs were presented for the Safety Population, defined as all participants who were randomized and took at least one dose of investigational product. Participants were assigned to a treatment group within the Safety Population if they took at least one dose of that treatment (i.e., in that treatment period).	0.79% 1/127 • Number of events 1 • Adverse event (AE) and serious adverse event (SAE) collection started immediately following informed consent and continued throughout the study (up to Week 12). AEs and SAEs were presented for the Safety Population, defined as all participants who were randomized and took at least one dose of investigational product. Participants were assigned to a treatment group within the Safety Population if they took at least one dose of that treatment (i.e., in that treatment period).

Other adverse events

Measure	Placebo n=132 participants at risk Participants who took at least one dose of placebo in either the first intervention period or the second intervention period. Of the 136 participants in the Safety Population, 132 took at least one dose of placebo.	GEn 1200 mg n=127 participants at risk Participants who took at least one dose of GEn 1200 mg in either the first intervention period or the second intervention period. Of the 136 participants in the Safety Population, 127 took at least one dose of GEn 1200 mg.
Nervous system disorders Dizziness	2.3% 3/132 • Number of events 3 • Adverse event (AE) and serious adverse event (SAE) collection started immediately following informed consent and continued throughout the study (up to Week 12). AEs and SAEs were presented for the Safety Population, defined as all participants who were randomized and took at least one dose of investigational product. Participants were assigned to a treatment group within the Safety Population if they took at least one dose of that treatment (i.e., in that treatment period).	20.5% 26/127 • Number of events 26 • Adverse event (AE) and serious adverse event (SAE) collection started immediately following informed consent and continued throughout the study (up to Week 12). AEs and SAEs were presented for the Safety Population, defined as all participants who were randomized and took at least one dose of investigational product. Participants were assigned to a treatment group within the Safety Population if they took at least one dose of that treatment (i.e., in that treatment period).
Nervous system disorders Headache	6.8% 9/132 • Number of events 9 • Adverse event (AE) and serious adverse event (SAE) collection started immediately following informed consent and continued throughout the study (up to Week 12). AEs and SAEs were presented for the Safety Population, defined as all participants who were randomized and took at least one dose of investigational product. Participants were assigned to a treatment group within the Safety Population if they took at least one dose of that treatment (i.e., in that treatment period).	8.7% 11/127 • Number of events 11 • Adverse event (AE) and serious adverse event (SAE) collection started immediately following informed consent and continued throughout the study (up to Week 12). AEs and SAEs were presented for the Safety Population, defined as all participants who were randomized and took at least one dose of investigational product. Participants were assigned to a treatment group within the Safety Population if they took at least one dose of that treatment (i.e., in that treatment period).
Nervous system disorders Somnolence	1.5% 2/132 • Number of events 2 • Adverse event (AE) and serious adverse event (SAE) collection started immediately following informed consent and continued throughout the study (up to Week 12). AEs and SAEs were presented for the Safety Population, defined as all participants who were randomized and took at least one dose of investigational product. Participants were assigned to a treatment group within the Safety Population if they took at least one dose of that treatment (i.e., in that treatment period).	12.6% 16/127 • Number of events 16 • Adverse event (AE) and serious adverse event (SAE) collection started immediately following informed consent and continued throughout the study (up to Week 12). AEs and SAEs were presented for the Safety Population, defined as all participants who were randomized and took at least one dose of investigational product. Participants were assigned to a treatment group within the Safety Population if they took at least one dose of that treatment (i.e., in that treatment period).
Gastrointestinal disorders Dry mouth	3.8% 5/132 • Number of events 5 • Adverse event (AE) and serious adverse event (SAE) collection started immediately following informed consent and continued throughout the study (up to Week 12). AEs and SAEs were presented for the Safety Population, defined as all participants who were randomized and took at least one dose of investigational product. Participants were assigned to a treatment group within the Safety Population if they took at least one dose of that treatment (i.e., in that treatment period).	4.7% 6/127 • Number of events 6 • Adverse event (AE) and serious adverse event (SAE) collection started immediately following informed consent and continued throughout the study (up to Week 12). AEs and SAEs were presented for the Safety Population, defined as all participants who were randomized and took at least one dose of investigational product. Participants were assigned to a treatment group within the Safety Population if they took at least one dose of that treatment (i.e., in that treatment period).
Gastrointestinal disorders Nausea	3.8% 5/132 • Number of events 5 • Adverse event (AE) and serious adverse event (SAE) collection started immediately following informed consent and continued throughout the study (up to Week 12). AEs and SAEs were presented for the Safety Population, defined as all participants who were randomized and took at least one dose of investigational product. Participants were assigned to a treatment group within the Safety Population if they took at least one dose of that treatment (i.e., in that treatment period).	4.7% 6/127 • Number of events 6 • Adverse event (AE) and serious adverse event (SAE) collection started immediately following informed consent and continued throughout the study (up to Week 12). AEs and SAEs were presented for the Safety Population, defined as all participants who were randomized and took at least one dose of investigational product. Participants were assigned to a treatment group within the Safety Population if they took at least one dose of that treatment (i.e., in that treatment period).
Gastrointestinal disorders Constipation	3.0% 4/132 • Number of events 4 • Adverse event (AE) and serious adverse event (SAE) collection started immediately following informed consent and continued throughout the study (up to Week 12). AEs and SAEs were presented for the Safety Population, defined as all participants who were randomized and took at least one dose of investigational product. Participants were assigned to a treatment group within the Safety Population if they took at least one dose of that treatment (i.e., in that treatment period).	4.7% 6/127 • Number of events 6 • Adverse event (AE) and serious adverse event (SAE) collection started immediately following informed consent and continued throughout the study (up to Week 12). AEs and SAEs were presented for the Safety Population, defined as all participants who were randomized and took at least one dose of investigational product. Participants were assigned to a treatment group within the Safety Population if they took at least one dose of that treatment (i.e., in that treatment period).
Immune system disorders Nasopharyngitis	3.0% 4/132 • Number of events 4 • Adverse event (AE) and serious adverse event (SAE) collection started immediately following informed consent and continued throughout the study (up to Week 12). AEs and SAEs were presented for the Safety Population, defined as all participants who were randomized and took at least one dose of investigational product. Participants were assigned to a treatment group within the Safety Population if they took at least one dose of that treatment (i.e., in that treatment period).	4.7% 6/127 • Number of events 6 • Adverse event (AE) and serious adverse event (SAE) collection started immediately following informed consent and continued throughout the study (up to Week 12). AEs and SAEs were presented for the Safety Population, defined as all participants who were randomized and took at least one dose of investigational product. Participants were assigned to a treatment group within the Safety Population if they took at least one dose of that treatment (i.e., in that treatment period).

Additional Information

XenoPort Call Center

XenoPort, Inc.

Phone: 877-936-6778

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