A Study to Evaluate the Effects of GW679769 on Sleep and Cognitive Function in Subjects With Primary Insomnia

Mean total sleep time (TST) as objective PSG measures of sleep continuity

TST was defined as duration of Rapid Eye Movement (REM) plus non-REM (NREM)(Stage 1, Stage 2, Stages 3/4) sleep from lights off to lights on. It was calculated as number of REM plus NREM (Stage 1, Stage 2, Stages 3/4) epochs from lights off to lights on divided by 2.

Time frame: Night 1 and 2 of each treatment period (Approximately up to 31 days)

Mean latency to persistent sleep (LPS) as objective PSG measures of sleep continuity

LPS was measured from lights off to the first epoch of 20 consecutive non-wake epochs (sleep onset).It was calculated as number of epochs from lights off to the first of 20 consecutive non-wake epochs (sleep onset) divided by 2.

Time frame: Night 1 and 2 of each treatment period (approximately 31 days)

Mean wake during sleep (WDS) as objective PSG measures of sleep continuity

WDS was the duration, in min, of wakefulness from persistent sleep onset to final epoch of sleep (stage 1, 2, 3/4, or REM), and corresponds to WDS. WDS was defined as duration of wakefulness from persistent sleep onset to final epoch of sleep (stage 1, 2, 3/4 or REM) (min). An awakening was defined as a PSG recording of at least one wake epoch, bracketed by an epoch of stage 1, 2, or stage 3/4 of NREM sleep or REM sleep. The score was derived by a central PSG reader and was analyzed as the mean of the PSG WDS recordings obtained on two consecutive nights.

Time frame: Night 1 and 2 of each treatment period (Approximately up to 31 days)

Mean wake after sleep (WAS) as objective PSG measures of sleep continuity

WAS defined as the duration of wakefulness, in min, from final epoch of sleep to lights on The score was derived by a central PSG reader and was analyzed as the mean of the PSG WAS recordings obtained on two consecutive nights. If only one assessment was present for a particular PSG session, the score from that one assessment was used. The overall WAS for night 1 and 2 was reported.

Time frame: Night 1 and 2 of each treatment period (Approximately up to 31 days)

Mean number of 1 minute awakenings during sleep as objective PSG measures of sleep continuity

Number of periods of awakening from persistent sleep onset to lights on were recorded. Number of times after persistent sleep onset that there was a wake entry on the PSG recording of at least 1 minute duration (at least 2 consecutive wake epochs). Pairs of awakenings were separated an epoch of NREM sleep or REM sleep. Two wake entries of at least one minute separated by stage 1 sleep was considered as a single awakening.

Time frame: Night 1 and 2 of each treatment period (Approximately up to 31 days)

Total Time in NREM Stage 1 and stage 2 as objective PSG measures of sleep structure

NREM sleep time was defined as the duration (in min) of NREM sleep during time in bed. The scores were derived by a central PSG reader and was analyzed as the mean of the PSG NREM recordings obtained on two consecutive nights.Total Time in NREM Stage 1 and stage 2 as objective PSG measures of sleep structure were recorded on night 1 and 2 and mean over the two nights was reported.

Time frame: Night 1 and 2 of each treatment period (Approximately up to 31 days)

Total Time in Slow Wave Sleep (SWS) as objective PSG measures of sleep structure

SWS was defined as the duration, in min, of stage 3 or 4 duration during time in bed. Total time in SWS as objective PSG measures of sleep structure was recorded on night 1 and 2 and mean over the two nights was reported.

Time frame: Night 1 and 2 of each treatment period (Approximately up to 31 days)

Total Time in REM as objective PSG measures of sleep structure

REM sleep time was also known as stage REM duration. It was defined as the number of minutes of stage REM during time in bed. Time in REM as objective PSG measures of sleep structure was recorded on night 1 and 2 and mean over the two nights was reported.

Time frame: Night 1 and 2 of each treatment period (Approximately up to 31 days)

Latency to REM as objective PSG measures of sleep structure

Latency to REM as objective PSG measures of sleep structure was recorded on night 1 and 2 and mean over the two nights was reported.

Time frame: Night 1 and 2 of each treatment period (Approximately up to 31 days)

Total sleep time (TST) as parameter of subjective post-sleep questionnaire

TST was the duration in min of REM plus NREM (Stage 1, Stage 2, Stages 3/4) sleep from lights off to lights on obtained on two consecutive nights of each PSG session. It was calculated as the number of REM plus NREM (Stage 1, Stage 2, Stages 3/4) epochs from lights off to lights on that is during Time in Bed (TIB). TST as parameter of subjective post-sleep questionnaire was recorded in response to the question, How long (total hours and minutes) do you think you slept last night? The questionnaire was reported by the participants on the next day of the PSG nights 1 and 2 and mean over the two nights was reported.

Time frame: Day 1 and 2 post PSG of each treatment period (Approximately up to 31 days)

WASO as parameter of subjective post-sleep questionnaire

WASO was defined as the amount of time awake after persistent sleep onset to lights on. An awakening was defined as a PSG recording of at least one wake epoch, bracketed by an epoch of stage 1, 2, or stage 3/4 of NREM sleep or REM sleep. WASO was calculated as summation of number of WAS and number of WDS. WASO as parameter of subjective post-sleep questionnaire was assessed from response of the question Did you wake up during the night? The questionnaire was reported by the participants on the next day of the PSG nights 1 and 2 and mean over the two nights was reported.

Time frame: Day 1 and 2 post PSG of each treatment period (Approximately up to 31 days)

Sleep onset latency (SOL) as parameter of subjective post-sleep questionnaire

SOL is the time required to fall asleep. SOL as parameter of subjective post-sleep questionnaire was recorded in response to the question, How long do you think it took you to fall asleep last night? The questionnaire was reported by the participants on the next day of the PSG nights 1 and 2 and mean over the two nights was reported.

Time frame: Day 1 and 2 post PSG of each treatment period (Approximately up to 31 days)

Number of awakenings as parameter of subjective post-sleep questionnaire

Number of awakenings was subjective (participant-rated) measurement of number of awakening after sleep onset. Number of awakenings as parameter of subjective post-sleep questionnaire was recorded in response to the question, How many times do you think you woke up? The questionnaire was reported by the participants on the next day of the PSG nights 1 and 2 and mean over the two nights was reported.

Time frame: Day 1 and 2 post PSG of each treatment period (Approximately up to 31 days)

Sleep quality (SQ) as parameter of subjective post-sleep questionnaire

SQ as parameter of subjective post-sleep questionnaire was recorded in response to the question, How would you describe the quality of your sleep last night? The responses from participants were recorded as very poor = 1, poor = 2, average= 3,good= 4, very good= 5 indicating the SQ. The questionnaire was reported by the participants on the next day of the PSG nights 1 and 2 and mean over the two nights was reported.

Time frame: Day 1 and 2 post PSG of each treatment period (Approximately up to 31 days)

Digit symbol substitution test (DSST) as a measure of daytime cognitive function

DSST was a widely used measure of performance impairment. It is a typical test of association involved in substituting symbols for digits over a period of time. The number of correct signs substituted was taken as the score. Participants marked a geometric pattern associated with one of the digits displayed on a computer screen. Participants had 90 seconds to match as many geometric patterns as possible. The dependent measure were the number of patterns the participant were able to mark correctly (i.e., number of trials correct). Minimum possible score is 0= impaired cognitive function, there was no upper limit of the score. Higher the score indicated betterment in the daytime cognitive function. Mean DSST was calculated from the observations recorded on days followed by first and second PSG nights and mean over the two nights was reported.

Time frame: Day 1 and 2 post PSG of each treatment period (Approximately up to 31 days)

Mean Hopkins Verbal Learning Test-Revised (HVLT-R) score including total recall and delayed recall as a measure of Daytime Cognitive Function

HVLT-R assesses verbal learning and memory. It comprised of four subscales including total recall, delayed recall, retention score, and recognition discrimination index. The total recall score was the number of correctly reported words in each of the 3 learning trials and the score ranged from 0 to 36. The delayed recall score was the number of correctly reported words in the delayed recall test and the score ranged from 0 to 12. The retention score represented the score on the delayed recall test divided by the higher of the recall scores from learning trials 2 and 3, multiplied by 100. It was practically ranged from 0 to 100. Higher score indicated betterment in the daytime cognitive function. The recognition discrimination index (RDI) was calculated by subtracting the total false positives score (semantically-related plus semantically un-related) from the total true-positives score obtained in the delayed recognition test).

Time frame: Day 1 and 2 post PSG of each treatment period (Approximately up to 31 days)

HVLT-R (Retention %) as a measure of daytime Cognitive Function

The HVLT-R offers a brief assessment of verbal learning and memory (recognition and recall) and its use had been validated with brain-disordered populations. Eight distinct forms of the HVLT-R were available, eliminating practice effects on repeated administrations. Each form consists of a list of 12 nouns (targets) with four words drawn from each of three semantic categories. The semantic categories differ across the eight forms, but the forms were very similar in their psychometric properties. The HVLT-R tasks included three learning trials, a delayed recall trial (20-25 minute delay), and a yes/no delayed recognition trial. This latter trial consists of a randomized list that includes the 12 target words and 12 non-target words, 6 of which are drawn from the same semantic categories as the targets. Mean percent retention of the target words was measured as a daytime cognitive function and mean over the three measures recorded at Night 1, Day 1 and 2 are reported.

Time frame: Night 1, Day 1 and 2 post PSG of each treatment period (Approximately up to 31 days)

HVLT-R (Recognition Discrimination Index [RDI]) as a measure of daytime Cognitive Function

The HVLT-R offers a brief assessment of verbal learning and memory (recognition and recall) and its use had been validated with brain-disordered populations. Eight distinct forms of the HVLT-R were available, eliminating practice effects on repeated administrations. Each form consists of a list of 12 nouns (targets) with four words drawn from each of three semantic categories. The semantic categories differ across the eight forms, but the forms were very similar in their psychometric properties. The HVLT-R tasks included three learning trials, a delayed recall trial (20-25 minute delay), and a yes/no delayed recognition trial. This latter trial consists of a randomized list that includes the 12 target words and 12 non-target words, 6 of which are drawn from the same semantic categories as the targets. Recognition Discrimination Index of the target words was measured as a daytime cognitive function and mean over the three measures recorded at Night 1, Day 1 and 2 are reported.

Time frame: Night 1, Day 1 and 2 post PSG of each treatment period (Approximately up to 31 days)

Leeds Sleep Evaluation Questionnaire as scales for sleepiness/alertness

LSEQ had been used to monitor subjectively perceived changes in sleep during psychopharmacological investigation involving a variety of psychoactive agents. The questionnaire contains ten self-rating 100-mm-line analogue questions pertaining to four consecutive aspects of sleep: getting to sleep (GTS), QOS, awakening from sleep (AFS) and behaviour following wakefulness (BFW). Scores on the four LSEQ subscales vary between 100 (the largest possible positive change experienced after drug administration) and 0 (the largest possible negative change experienced after drug administration).

Time frame: Day 1 and 2 post PSG of each treatment period (Approximately up to 31 days)

Stanford Sleepiness Scale as scales for sleepiness/alertness

Stanford Sleepiness Scale was assessed using the sleep evaluation questionnaire on Day 1 and 7 prior to dosing and at approximately 1 hour intervals after dosing until discharge from the clinic. It was rated on a seven point scale (1-7), where lower score indicates active and higher score indicates sleep onset soon; 1: feeling active, vital, alert, or wide awake, 2: functioning at high levels, but not at peak; able to concentrate, 3: awake, but relaxed; responsive but not fully alert, 4: somewhat foggy, let down, 5: foggy; losing interest in remaining awake; slowed down, 6: sleepy, woozy, fighting sleep; prefer to lie down, 7: no longer fighting sleep, sleep onset soon; having dream-like thoughts and X: asleep. The mean over Day 1 and Day 2 post PSG nights are reported.

Time frame: Day 1 and 2 post PSG of each treatment period (Approximately up to 31 days)