synopsis › ctr-gsk-7381 › oxs104094 › fae6de74... · 2018-11-04 · 3 synopsis identifier:...

CONFIDENTIAL VM2007/00075/00 OXS104094

3

SYNOPSIS

Identifier: VM2007/00075/00 Study Number: SB-649868

Title: A double-blind, double-dummy, randomized, placebo controlled, four-way crossover study to investigate the effect of single oral doses of SB-649868 and Zolpidem in a model of noise induced situational insomnia in healthy male volunteers

Investigator: Dr

Study centre: United Kingdom.

Publications: None at the time of this report.

Study period: 09 January 2007 – 05 July 2007.

Phase of development: I.

Objectives and Endpoints

The primary objective was:

To determine the effect of SB-649868 on total sleep time in healthy volunteers undergoing a noise-disturbed sleep model.

Secondary objectives were:

• To study the changes induced by SB-649868 and zolpidem on various polysomnography sleep parameters.

• To investigate the effects of SB-649868 and zolpidem on daytime cognitive functioning on the morning following dosing, including tests of alertness, memory, attention and fine motor control.

• To investigate the effects of SB-649868 and zolpidem on subjective sleep quality, on the morning after dosing and on the following 3 days, using sleep questionnaires.

• To investigate the safety and the pharmacokinetic profile of SB-649868 and zolpidem in healthy volunteers.

• To investigate the effects of SB-649868 and zolpidem on hormones in healthy volunteers.

• To investigate the relationship between plasma concentrations of SB-649868 and zolpidem and all the sleep or cognitive parameters and to develop a pharmacokinetic / pharmacodynamic model

The primary endpoint was total sleep time derived from polysomnographic recording.


3


4

Secondary endpoints were:

• Objective polysomnography measures of sleep continuity including: latency to persistent sleep, wake time after sleep onset, wake during sleep, wake after sleep, number of awakenings during sleep, arousal index of all events and sleep efficiency.

• Objective polysomnography measures of sleep structure: non-rapid eye movement (REM) sleep time, slow-wave sleep time (stage 3 and 4), Stage 2 non-REM sleep time, REM sleep time.

• Electroencaphalograph parameters from Power Spectrum analysis of sleep stages.

• Subjective sleep questionnaire: total sleep time, wake time after sleep onset, sleep onset latency, number of awakenings, and sleep quality to be collected on each morning following polysomnograph recording.

• Daytime cognitive function data on the morning following dosing, including tests of alertness, memory, attention and fine motor control.

• Subjective sleep questionnaire: total sleep time, wake time after sleep onset, sleep onset latency, number of awakenings and sleep quality to be collected on each morning at home during the 3-day period following each 2-night polysomnography session.

• Plasma concentration of SB-649868 and zolpidem.

• Pharmacokinetic/ pharmacodynamic modelling: relationship (if any) between plasma concentrations of SB-649868 and zolpidem and all the sleep or cognitive parameters.

• Safety and tolerability evaluated by adverse event monitoring, physical examination, body temperature, electrocardiogram (ECG), vital signs and laboratory parameters.

Methodology

This was a randomised, double-blind, double dummy, placebo-controlled, four-way crossover study to investigate the effect of single oral doses of SB-649868 and of a positive control (zolpidem) in a model of noise induced situational insomnia in healthy male volunteers. A sufficient number of subjects was to be screened to randomise 52 healthy male volunteers and obtain evaluable data from at least 44 subjects.

Subjects were screened approximately 28 days prior to treatment. The screening process comprised two visits to the unit. During Screening Visit 1, subjects provided informed consent prior to any study procedures, which included routine safety assessments. Only subjects who met the screening criteria at Screening Visit 1 were invited to return for Screening Visit 2. During the period between Screening Visits 1 and 2, subjects wore wrist-mounted Actiwatches and completed sleep questionnaires in the morning after awakening from sleep. Subjects were instructed to adhere to an 8-h sleep schedule (23:00- 07:00) for the duration of the study. Subjects were not eligible for Visit 3 if their sleep-wake schedule was too irregular.


4


5

At Screening Visit 2, subjects remained in the unit for 2 nights for polysomnography screening, during this period subjects also underwent a multiple sleep latency test and training for psychometric and cognitive function tests. Any results falling outside the normal range were repeated at the discretion of the Investigator.

The study consisted of four treatment sessions. Each treatment session consisted of 2 nights. Subjects were admitted to the unit on Day 1 at approximately 16:00 in the afternoon, prior to the first night (Night 1), and underwent admission procedures. At approximately 18:00, subjects were served a standard light snack, and at approximately 21:00 a standardised dinner was served. At approximately 22:30 they retired to bed with lights off at approximately 23:00 and lights on at 07:00. During Night 1, study medication was not administered and subjects underwent polysomnography monitoring only (no noise disturbance).

During the second night (Night 2) for all sessions, after a standard light snack at approximately 18:00 and a standardised dinner at approximately 21:00, randomised subjects were administered two double-blinded doses of study medication. Thirty minutes after a standard dinner, at approximately 21:30, subjects received either placebo or SB-649868 (10 mg or 30 mg); at approximately 22:30 subjects received either placebo or zolpidem (10 mg). Subjects retired to bed at 22:30 with lights off at approximately 23:00.

During Night 2, subjects underwent polysomnography monitoring, blood sampling for pharmacokinetic analysis (before lights off) and underwent noise disturbance. Calibrated noise lasted from lights off (23:00) continuously until lights on (07:00).

All subjects remained in the unit during each of the treatment sessions. Subjects were discharged at the end of each treatment session when all study procedures had been completed at the discretion of the Investigator depending on the nature of any ongoing adverse events. During the study, each single-dose treatment was separated by a 7-day washout period (±1 day) and preferably occurred on the same day of the week, or were consistently held on either workdays or days of rest, for any given subject. Subjects were instructed to maintain a normal pattern of sleep between 23:00 and 07:00 when outside the unit between treatment sessions, and were reminded to wear an Actiwatch continuously for the duration of the study. Subjects were instructed to return to the unit within 7 – 14 days of the last dose of study treatment for the follow up visit.


5


6

Number of subjects

Subject numbers are summarised in Table 1.

Table 1 Summary of subject numbers

Number of Subjects Number of subjects planned, N: 52 Number of subjects randomised, N: 51 Number of subjects included in safety population, n (%): 51 (100) Number of subjects included in SB-649868 pharmacokinetics population, n (%): 49 (96) Number of subjects included in zolpidem pharmacokinetics population, n (%): 45 (88) Number of subjects completed as planned, n (%): 44 (86) Number of subjects withdrawn (any reason), n (%): 7 (14) Number of subjects withdrawn for serious adverse event, n (%): 0 Number of subjects withdrawn for adverse event, n (%): 2 The study populations were as follows:

• The safety population was defined as all subjects who received at least one dose of any investigational product and comprised 51 subjects.

• The pharmacodynamic population was defined as all subjects of the previous population providing post-baseline pharmacodynamic data and comprised 51 subjects.

• The SB-649868 pharmacokinetic concentration population was defined as all subjects for whom a SB-649868 pharmacokinetic sample was obtained and analysed, and comprised 49 subjects.

• The zolpidem pharmacokinetic concentration population was defined as all subjects for whom a zolpidem pharmacokinetic sample was obtained and analysed, and comprised 45 subjects.

Subject Disposition and Demographics

A total of 51 subjects entered the study; 44 subjects completed the study and 7 subjects prematurely discontinued. The following two subjects were prematurely discontinued because of adverse events:

•

•


6


7

Subject disposition is summarised in the Table 2

Table 2 Summary of subject disposition (safety population)

Placebo1 SB-6498681 Zolpidem1 Total1 10 mg 30 mg Completed, n 9 12 12 11 44 Prematurely discontinued, n 1 3 2 1 7 Reasons for subject withdrawal, n

Lost to follow-up 0 0 0 0 0 Adverse events 1 0 1 0 2 Protocol violation 0 1 1 1 3 Subject decided to withdraw 0 2 0 0 2

Source Data: Table 9.3 1. Treatment taken at the time of discontinuation A summary of subject demographics is presented in Table 3.

Table 3 Summary of subject demographics (safety population)

Demographic parameter Safety population (N = 51) Age in Years, Mean (standard deviation) 28.9 (8.77) Sex, n (%)

Male: 51 (100) Body mass index in kg/m2, Mean (standard deviation) 24.08 (2.371) Height in cm, Mean (standard deviation) 177.0 (6.856) Weight in kg, Mean (standard deviation) 75.63 (10.177) Ethnicity, n (%)

Hispanic or Latino: 3 (6) Not Hispanic or Latino: 48 (94)

Race, n (%) White 39 (76) African American/African Heritage 4 (8) American Indian or Alaskan Native 3 (6) Japanese / East Asian / South East Asian Heritage 4 (8) Central / South Asian Heritage 1 (2)

Source Data: Table 9.1

Diagnosis and main criteria for inclusion

Healthy adult males aged 18 – 55 years inclusive with a body weight ≥50 kg and a body mass index within the range 18.5 – 29.9 kg/m2 were eligible for inclusion in the study. Subjects were to have screening circulating levels of luteinising and follicle-stimulating hormones and testosterone within the normal reference range and were to have normal sleep patterns, as defined in the study protocol, on the basis of the evaluation of both polysomnography screening nights. Subjects were to have a history of going to bed from 22:00 to 00:00 on at least 5 –7 nights per week with a reported nightly sleep duration of


7


8

6.5 – 8.5 h over the previous 3 months or more at Screening Visit 1. All subjects provided written informed consent to participate in the study.

Subjects who were not healthy according to protocol-defined criteria were excluded from the study. Also, subjects who had consumed beverages and medications that were prohibited by the protocol were excluded. Other key exclusion criteria included subjects with sleep disturbances, subjects who were shift workers, and subjects who were not prepared to use protocol-specified methods of contraception and sexual abstinence, as appropriate.

Treatment administration

Subjects were assigned to study treatment in accordance with the randomisation schedule prepared by a Statistician in Discovery Biometrics: Psychiatry prior to the start of the study using validated software (Randall).

Fifty-two (52) subjects were allocated to the sequences:

• ADBC.

• BACD.

• CBDA.

• DCAB.

in a 1:1:1:1 ratio, according to Williams square design, where:

• A = placebo.

• B = SB-649868 10 mg.

• C = SB-649868 30 mg.

• D = zolpidem 10 mg. SB-649868 tablets and zolpidem and placebo capsules were swallowed whole with 240 mL of water. Subjects took two tablets (an appropriate combination of SB-649868 5 mg, 25 mg and placebo tablets to achieve the required dose) at approximately 21:30, (approximately 30 minutes after a standardised dinner) and one capsule (zolpidem 10 mg or placebo) around 22:35, immediately after the pharmacokinetic blood sampling, that had to occur exactly 1 h post-dose.

Each subject received up to two active or placebo tablets and one active or placebo capsule once a day. SB-649868 doses were created as follows:

• SB-649868 10 mg = 5 mg + 5 mg.

• SB-649868 30 mg = 25 mg + 5 mg.

• Placebo = two placebo tablets. A summary of batch numbers is presented in Table 4.


8


9

Table 4 Summary of batch numbers

Investigational product Batch number SB-649868 5 mg tablets 051099394 SB-649868 25 mg tablets 051099395 Placebo tablets to match SB-649868 051071857 Zolpidem 10 mg capsules 061121662 Placebo capsules to match zolpidem 051081156

Criteria for evaluation

• Pharmacodynamics: total sleep time, wake time after sleep onset, arousal index and sleep efficiency as measured with polysomnography and subjective sleep questionnaire scores; polysomnography measurements; electroencephalogram; microarousals; Bond-Lader visual analogue scale (VAS), profile of mood states; actigraphy; noise-disturbed sleep model; neurocognitive measurements; and hormones (luteinising hormone, follicle-stimulating hormone and testosterone).

• Pharmacokinetics: observed SB-649868 and zolpidem plasma concentrations.

• Safety: adverse events, vitals signs, 12-lead ECG and clinical laboratory assessments.

Statistical methods

A sample size of 46 subjects completing the study would have provided 80% power to detect a difference between SB-649868 and placebo of at least 22 minutes in total sleep time, assuming a within-subject standard deviation of about 36.8 minutes (data provided by the centre from previous sleep-disturbed model studies). No sample-size re-estimation was planned. However, if the within-subject standard deviation for total sleep time observed at the interim analysis was higher than the expected 36.8 minutes, then it would have been considered a potential sample size adjustment.

An interim analysis was planned and performed when approximately half the subjects (approximately 23) had completed the study and the data were databased. To maintain the blinding an independent unblinded Statistician performed the interim analysis and released only aggregate data to the GlaxoSmithKline Study Team, while these interim results were not communicated to the study site. The GlaxoSmithKline Study Team and the Investigator remained blinded throughout the entire study. The interim analysis showed that no sample size adjustment was required. Within-subject variability (SDw) of total sleep time at the interim was lower than estimated. It was calculated that if total sleep time SDw remained the same until the end of the study, 46 completers would have provided over 99% power to detect a difference between SB-649868 and placebo of at least 22 minutes in total sleep time.

Statistical analysis of polysomnography endpoints was performed. A mixed-effects model was applied, with period and treatment as fixed effects and subject as random effect. Estimates for mean treatment differences of SB-649868 compared with placebo and with zolpidem were derived together with corresponding 95% confidence intervals.


9


10

Similar estimates were provided for zolpidem compared with placebo. Additional analyses were performed to investigate the carry-over effect and the treatment by period interaction. Tests of significance were performed at the 5% level . Summary statistics were produced for micro arousals, hormones (luteinising hormone, follicle-stimulating hormone and testosterone), cognitive/sedative tests and the Subjective Sleep Questionnaire. Electroencephalogram parameters from Power Spectrum analysis of sleep stages were not statistically analysed.

There was no formal statistical analysis of safety data.

The Reporting and Analysis Plan is presented in Attachment 4.

Pharmacokinetic / Pharmacodynamic Methods

Exploratory pharmacokinetic / pharmacodynamic analyses were performed to evaluate the relationship between plasma concentration and polysomnography measurements (latency to persistent sleep, total sleep time, and wake time after sleep onset). Exploratory analysis was based on visual inspection of plots on change from placebo on polysomnography measurement and observed pharmacokinetic concentration (lights-off concentration, the average concentration over lights-off and the lights-on concentration were evaluated). In addition, exploratory analyses based on mean concentration distribution were divided in to three classes of exposure: patients in the lowest 33% of exposure, patients with exposures in the 33°– 67% percentile, and patients above the 67% percentile.

A non-linear mixed effect modelling approach using all the individual polysomnography measurements collected at each visit was applied using NONMEM VI. The population pharmacokinetic / pharmacodynamic modelling was conducted to test formally the hypothesis of a concentration-related effect and assess the SB-649868 population pharmacokinetic / pharmacodynamic parameters and their between-subject variability. A first order conditional estimation method was used.

The analysis was conducted on the untransformed scores and the placebo response was included in the model. Initially, a linear relationship between concentrations and polysomnography measurements was tested; then, an Emax model for characterising the exposure / efficacy relationship was also evaluated.

Initially, placebo and drug-related polysomnography measurements were simultaneously fitted assuming no drug effect. Then, the hypothesis of a concentration effect was evaluated by including concentration related parameters in the model. Concentration effect was assessed by comparing the decrease in the objective function evaluated using the log-likelihood ratio test when the drug-effect parameters were included in the model. A decrease in the objective function greater then 3.841 for the inclusion of a single parameter was considered as significant (p-value < 0.05).


10


11

Summary

Pharmacodynamics

POLYSOMNOGRAPHY: The primary endpoint of this study was total sleep time. A summary of mean total sleep time values is presented in Table 5.

Table 5 Summary of mean (95% confidence interval) total sleep time (minutes)

Treatment n Mean 95% confidence interval Placebo (N = 46) 45 418.9 407.5, 430.4 SB-649868 10 mg (N = 48) 45 435.9 425.7, 446.1 SB-649868 30 mg (N = 48) 45 451.2 444.9, 457.6 Zolpidem 10 mg (N = 45) 43 431.9 422.3, 441.5 Source Data: Table 12.1 Statistically significant increases in total sleep time were observed for SB-649868 10 mg and 30 mg and for zolpidem 10 mg compared with placebo. When compared with zolpidem 10 mg, a statistically significant increase in total sleep time was observed for SB-649868 30 mg, but not SB-649868 10 mg. A summary of the statistical analysis of total sleep time (minutes) is presented in Table 6.

Table 6 Summary of statistical analysis of total sleep time: estimated differences from placebo and zolpidem

Treatment LSMean Estimated difference (95% confidence interval)

p-value

Difference from placebo Placebo 419.0 – – SB-649868 10 mg 435.7 46.8 (8.3, 25.2) <0.001 SB-649868 30 mg 449.7 30.7 (22.3, 39.1) <0.001 Zolpidem 10 mg 430.0 11.0 (2.5, 19.5) 0.012 Difference from zolpidem 10 mg Zolpidem 10 mg 430.0 – – SB-649868 10 mg 435.7 5.8 (-2.8, 14.4) 0.185 SB-649868 30 mg 449.7 19.7 (11.2, 28.2) <0.001 Source data: Table 12.2 and Table 12.3 LS = least squares A summary of mean values for selected polysomnography endpoints is presented in Table 7.


11


12

Table 7 Summary of mean (95% confidence interval) values for selected polysomnography endpoints

Endpoint Mean (95% confidence interval)

Placebo N = 46

SB-649868 10 mg N = 48

SB-649868 30 mg N = 48

Zolpidem 10 mg N = 45

Latency to persistent sleep (minutes)

27.2 (20.3, 34.1)

18.8 (13.0, 24.5)

9.0 (5.9, 12.0)

22.3 (19.0, 25.7)

Number of awakenings after sleep onset

21.2 (17.7, 24.6)

20.2 (17.4, 22.9)

22.0 (17.7, 26.4)

18.2 (14.5, 21.9)

Total REM duration (% of sleep period time)

18.3 (17.1, 19.5)

19.2 (17.8, 20.6)

20.8 (19.5, 22.2)

17.1 (15.5, 18.6)

Sleep efficiency (%) 87.2 (84.8, 89.6)

90.7 (88.6, 92.9)

93.9 (92.6, 95.2)

89.9 (87.9, 91.9)

Total Stage 1 duration (% of sleep period time)

10.4 (9.0, 11.8)

10.9 (9.1, 12.7)

10.7 (8.7, 12.7)

10.0 (8.115, 11.9)


50.7 (47.6, 53.9)

50.6 (47.9, 53.3)

51.1 (47.9, 54.3)

49.6 (46.9, 52.3)


5.6 (4.9, 6.3)

5.9 (5.2, 6.6)

5.9 (5.2, 5.7)

6.4 (5.5, 7.3)


7.0 (5.0, 8.9)

7.1 (5.3, 8.8)

7.41 (5.4, 8.7)

11.5 (9.5, 13.6)

Wake after persistent sleep to lights on (minutes)

37.3 (23.2, 45.5)

30.2 (22.2, 38.1)

21.6 (15.6, 27.5)

29.5 (20.4, 38.6)

Source Data: Table 12.1 REM = rapid eye movement Compared with placebo, statistically significant reductions were observed in latency to persistent sleep for the SB-648969 10 mg and 30 mg doses and in wake after persistent sleep to lights on for the SB-648969 30 mg dose. Sleep efficiency showed statistically significant increases compared with placebo for both the SB-648969 10 mg and 30 mg doses, a significant increase was observed for total Stage 1 duration (% of sleep period time) for the SB-649868 10 mg group and total REM duration for the SB-649868 30 mg group. For the zolpidem 10 mg dose compared with placebo, statistically significant increases were observed for sleep efficiency and total Stage 3 and Stage 4 sleep duration (% of sleep period time), and a decrease was observed for total REM duration. A summary of the statistical analysis of selected polysomnography endpoints (estimated difference from placebo) is presented in Table 8.


12


13

Table 8 Summary of statistical analysis of selected polysomnography endpoints: estimated difference from placebo

Endpoint Estimated difference (95% confidence interval) versus placebo (p-value)

SB-649868 10 mg

SB-649868 30 mg

Zolpidem 10 mg


-8.5 (-13.9, -3.0) (0.003)

-17.4 (-22.8, -11.9) (<0.001)

-3.8 (-9.3, 1.8) (0.180)

Number of awakenings after sleep onset

0.1 (-2.6, 2.8) (0.956)

1.4 (-1.2, 4.1) (0.294)

-2.5 (-5.2, 0.2) (0.069)


0.8 (-0.6, 2.3) (0.242)

2.3 (0.9, 3.7) (0.002)

-1.4 (-2.9, -0.0) (0.049)

Sleep efficiency (%) 3.5 (<0.001)

6.4 (<0.001)

2.3 (0.012)


1.1 (0.039)

0.6 (0.290)

0.0 (0.969)


-0.9 (0.396)

0.1 (0.951)

-1.4 (0.161)


0.2 (0.637)

0.2 (0.585)

0.7 (0.046)


0.3 (0.554)

0.2 (0.738)

4.5 (<0.001)


-6.5 (0.102)

-14.7 (<0.001)

-6.8 (0.088)

Source Data: Table 12.2 REM = rapid eye movement The percentage of time spent in REM sleep appeared to increase with SB-649868 dose: 0.8% for SB-649868 10 mg compared with placebo, p = 0.242, and 2.3% for SB-649868 30 mg compared with placebo, p = 0.002. In contrast, a decrease in percentage of time spent in REM sleep was observed with zolpidem 10 mg: -1.4% compared with placebo, p = 0.049. A statistically significant increase was observed in the time spent in Stage 3 + 4 with zolpidem 10 mg (slow wave sleep, 5.2%, p<0.001), while there were no significant changes with either SB-649868 dose.

For both doses of SB-649868, there was a statistically significant increase in total REM duration and a statistically significant decrease in total Stage 4 duration (% of sleep period time), compared with zolpidem 10 mg. For the SB-649868 10 mg dose alone, there was a statistically significant increase in total Stage 1 duration compared with zolpidem 10 mg. For the SB-649868 30 mg dose alone, there were statistically significant increases in the number of awakenings after sleep onset and in sleep efficiency, and statistically significant decreases in latency to persistent sleep and wake after persistent sleep to lights on, compared with zolpidem 10 mg. A summary of the statistical analysis of selected polysomnography endpoints (estimated difference from zolpidem 10 mg) is presented in Table 9.


13


14

Table 9 Summary of statistical analysis of selected polysomnography endpoints: estimated difference from zolpidem 10 mg

Endpoint Estimated difference (95% CI) versus zolpidem 10 mg (p-value)

SB-649868 10 mg

SB-649868 30 mg

Latency to persistent sleep (minutes) -4.7 (-10.3, 0.9) (0.099)

-13.6 (-19.2, -8.1) (<0.001)

Number of awakenings after sleep onset 2.6 (-0.2, 5.3) (0.064)

3.9 (1.2, 6.6) (0.005)


12.5 (5.8, 19.2) (<0.001)

20.3 (13.7, 26.9) (<0.001)

Sleep efficiency (%) 1.2 (-0.6, 3.0) (0.180)

4.1 (2.3, 5.9) (<0.001)


1.1 (0.0, 2.2) (0.046)

0.5 (-0.5, 1.6) (0.316)


0.6 (-1.5, 2.6) (0.578)

1.5 (-0.5, 3.5) (0.144)


-0.6 (-1.3, 0.2) (0.128)

-0.5 (-1.3, 0.2) (0.142)


-4.2 (-5.2, -3.1) (<0.001)

-4.3 (-5.4, -3.3) (<0.001)


0.4 (-7.6, 8.3) (0.931)

-7.9 (-15.7, -0.0) (0.050)

Source Data: Table 12.3 CI = confidence interval; REM = rapid eye movement Summary statistics for log-transformed polysomnography endpoints are presented in Table 10.

Table 10 Summary statistics of log-transformed polysomnography endpoints

Endpoint Geometric mean (%CVb) Placebo

N = 46

SB-649868 10 mg N = 48

SB-649868 30 mg N = 48



20.9 (83.6) 11.8 (135.9) 4.8 (185.7) 19.4 (66.7)


26.1 (127.0) 21.3 (108.1) 14.9 (113.3) 17.2 (176.0)

Source Data: Table 12.15 %CVb = between-subject coefficient of variation


14


15

For log-transformed endpoints compared with placebo, there were statistically significant increases in latency to persistent sleep for both SB-649868 doses and in wake after persistent sleep to lights on for the SB-649868 30 mg dose alone. A statistically significant reduction in wake after persistent sleep was observed for zolpidem 10 mg compared with placebo. When compared with zolpidem 10 mg, statistically significant increases in latency to persistent sleep were observed for both SB-649868 dose levels.

A summary of the statistical analysis of log-transformed polysomnography endpoints (estimated difference from placebo) is presented in Table 11.

Table 11 Summary of statistical analysis of log-transformed polysomnography endpoints: estimated ratio versus placebo

Endpoint Estimated ratio (95% confidence interval); test : placebo (p-value)

SB-649868 10 mg

SB-649868 30 mg

Zolpidem 10 mg


0.58 (0.42, 0.79) (<0.001)

0.24 (0.18, 0.33) (<0.001)

0.96 (0.70, 1.32) (0.808)


0.84 (0.66, 1.07) (0.159)

0.60 (0.47, 0.77) (<0.001)

0.68 (0.53, 0.88) (0.003)

Source Data: Table 12.4 Statistically significant increases in latency to persistent sleep were observed for both SB-649868 dose levels compared with zolpidem 10 mg. A summary of the statistical analysis of log-transformed polysomnography endpoints (estimated difference from zolpidem 10 mg) is presented in Table 12.

Table 12 Summary of statistical analysis of log-transformed polysomnography endpoints: estimated ratio versus zolpidem 10 mg

Endpoint Estimated ratio (95% CI); test : zolpidem 10 mg (p-value)

SB-649868 10 mg

SB-649868 30 mg

Latency to persistent sleep (minutes) 0.60 (0.44, 0.83) (0.002)

0.25 (0.18, 0.34) (<0.001)


1.23 (0.95, 1.58) (0.110)

0.88 (0.69, 1.13) (0.323)

Source Data: Table 12.5 CI = confidence interval Overall, for both untransformed and log-transformed polysomnography data, no treatment by period interaction or carry over effect was highlighted as statistically significant. Only log-transformed data of latency to persistent sleep showed a significant treatment by period interaction and this may have been due to chance.


15


16

No statistical adjustment for multiple comparisons was planned and performed. Given the nature of this experimental model study; care must be taken in interpreting the statistically significant comparisons for the higher risk of false positive.

HORMONE RESULTS: Slight increases in concentrations of all three hormones (follicle-stimulating hormone, luteinising hormone and testosterone) were observed 12 h after active treatments, compared with the evening pre-dose, however they were generally similar to those observed for placebo. A summary of hormone concentrations is presented in Table 13.

Table 13 Summary statistics of hormone concentrations

Mean (95% confidence interval) Placebo

N = 46

SB-649868 10 mg N = 48

SB-649868 30 mg N = 48


Follicle stimulating hormone (IU/L) Day 1 3.07

(2.66, 3.48) 3.02 (2.64, 3.40)

3.02 (2.64, 3.41)

3.06 (2.62, 3.50)

12 h 3.19 (2.78, 3.61)

3.10 (2.71, 3.50)

3.13 (2.75, 3.52)

3.30 (2.84, 3.76)

Luteinising hormone (IU/L) Day 1 4.18

(3.63, 4.72) 4.06 (3.44, 4.67)

3.78 (3.36, 4.20)

3.82 (3.42, 4.22)

12 h 4.39 (3.80, 4.97)

4.18 (3.63, 4.73)

4.41 (3.86, 4.96)

4.38 (3.91, 4.84)

Total testosterone (nmol/L) Day 1 13.58

(12.33, 14.83)

13.80 (12.44, 15.16)

14.29 (12.92, 15.66)

14.74 (13.32, 16.16)

12 h 17.56 (16.14, 18.98)

18.14 (16.48, 19.80)

18.22 (16.82, 19.62)

18.05 (16.69, 19.41)

Source Data: Table 12.8 SUBJECTIVE SLEEP QUESTIONNARES: Subjective evaluations of total sleep time (“How long did you sleep last night?”), wake time after persistent sleep onset (“Total duration of nights awakenings?”), sleep onset latency (“How long to fall asleep?”), number of awakenings (“How many times did you wake up?”) were collected each morning at home during the 3-day period following each night polysomnography session. Treatment effects on the night of noise for total sleep time (‘How long did you sleep last night’) and sleep onset latency (‘How long to fall asleep’) were quite variable, although a stronger hypnotic signal could be detected with the SB-649868 30 mg dose (Table 12.11).

COGNITIVE TEST RESULTS: Changes in cognitive / sedation results and Bond-Lader VAS factors for all three active treatments were generally comparable with those for placebo.


16


17

Subjective sleep questionnaire results showed that, on average, total sleep time and sleep onset latency showed a common worsening on the night of noise post-treatment. The worsening in subjective sleep perception was soon and fully recovered over the following nights. Treatment effects on the night of noise were quite variable, although a stronger hypnotic signal was detected with SB-649868 30 mg.

Daytime cognitive functioning was assessed on the morning after dosing, using tests of alertness, memory, attention and fine motor control. Cognitive function was assessed 10 h post-dose, beginning approximately 30 minutes after waking and ending approximately 90 minutes later. A wide range of tests was used including multiple assessments of reaction time, motor control and tracking, alertness and sustained attention, working, immediate and delayed memory and discrimination, task switching and decision making as well as subjective assessments of mood and well-being.

Performance across all tests was consistently high, indicating that participants were well motivated and understood the requirements of each task. Where tests included increasing levels of difficulty these showed the expected reduction in performance. Moreover, performance levels on tests that had previously been used to evaluate residual effects of zolpidem, which were also included in the current test battery, showed comparable levels of performance.

There were no indications of a different pattern of performance after zolpidem administration than after placebo, and performance after both doses of SB-649868 was similarly unaffected. Although the study was not statistically powered on the basis of anticipated effects in cognitive performance, and no inferential statistics have been calculated, this very detailed assessment of cognitive function suggested that residual effects of SB-649868 were unlikely to be greater than those observed with placebo or zolpidem.

A brief overview of daytime function assessments in this study is presented in Attachment 5.

PHARMACO-ELECTROENCEPHALOGRAPHY RESULTS: Pharmaco-electroencephalography results will be the subject of a separate report.

Pharmacokinetics

Blood samples were collected for quantitative pharmacokinetic analysis of SB-649868 and zolpidem on each night 1 at 1, 1.5, 9.5, and 10 h post-dose. SB-649868 plasma concentrations are summarized in Table 14.


17


18

Table 14 Summary statistics of plasma SB-649868 concentration (ng/mL)

SB-649868 dose

Time (hrs)

n Mean SD Median Min Max

1 48 222.549 184.978 170.415 0.00 550.13 1.5 48 301.128 172.1695 328.825 12.77 578.37 9.5 48 128.375 75.2077 117.695 27.96 402.59

10 mg

10 48 123.813 73.9807 117.775 26.96 390.75 1 48 454.999 431.8341 320.84 0.00 1494.93

1.5 48 682.729 487.9328 782.675 12.95 1657.88 9.5 48 494.325 209.443 520.98 84.35 1100.09

30 mg

10 47 487.177 215.214 512.19 82.69 908.79 Data Source: Table 11.1 SD = standard deviation

Overall, SB-649868 concentrations measured in this study were comparable with those observed in other studies in healthy volunteers.

SB-649868 plasma concentration variability appeared to be higher during the absorption phase (1 and 1.5 h) than the distribution-elimination phase (probably due to the solubility limitations of the current formulation).

Pharmacokinetics / Pharmacodynamic

Exploratory Analysis

Scatter plots of change from placebo for the total sleep time, latency to persistent sleep and wake time after sleep onset as a function of the individual pharmacokinetics concentration are presented in Figure 1, Figure 2 and Figure 3.

The analysis on total sleep time values showed that the difference from placebo in total sleep time clearly increased with increasing SB-649868 concentration. The best correlation was found using the SB-649868 average concentrations over lights-off (p <0.01). A scatter plot of change from placebo for the total sleep time as a function of the individual pharmacokinetics concentrations is presented in Figure 1.


18


19

Figure 1 SB-649868 concentration (X-axis) plotted against the change from placebo in total sleep time (Y-axis)

Exploratory analysis of the change from placebo in latency to persistent sleep revealed a highly significant correlation between latency to persistent sleep improvements and individual SB-649868 concentrations. As expected, the best correlation was found with the concentration measured immediately prior to lights-off (i.e., at 1.5 h post-dose). Also in this case the slope was highly significantly different from 0 (p <0.01). A scatter plot of change from placebo for latency to persistent sleep as a function of the individual pharmacokinetics concentrations is presented in Figure 2.

Figure 2 SB-649868 concentration (X-axis) plotted against the change from placebo in latency to persistent sleep (Y-axis)


19


20

The analysis on wake time after sleep onset showed no statistically significant linear relationship with the exposure, although a more pronounced tendency was observed when looking at SB-649868 concentration immediately after lights-on (i.e., at 9.5 h post dose). A scatter plot of change from placebo for wake time after sleep onset as a function of the individual pharmacokinetics concentrations is presented in Figure 3.

Figure 3 SB-649868 concentration (X-axis) plotted against the change from placebo in wake time after sleep onset (Y-axis)

Population Pharmacokinetic / Pharmacodynamic Results

According to the log-likelihood ratio test, a statistically significant difference was found when including the concentration effect and the best results were obtained with the Emax model (see below). In addition, the most predictive concentrations were those computed over lights-off (i.e., average SB-649868 exposure during the sleeping period).

( )CONCEC

CONCTSTTSTTST PLA

PLA +⋅−

+=50

480

.

Where TST = total sleep time and EC50 = median effective concentration. Here, the theoretical maximal SB-649868 effect was estimated to be equal to the difference between the placebo response (TSTPLA) and the maximal time available for sleep during the study night (i.e., 480 minutes). SB-649868 population pharmacokinetic / pharmacodynamic parameters for the final total sleep time model are reported in Table 15.


20


21

Table 15 Final population parameter estimates for total sleep time

TSTPLA (minutes) EC50 (ng/mL) Estimate 416 411 SE 5.8 75 BSV% 8% 54% Source Data: Table 11.7 TSTPLA = total sleep time after receiving placebo, EC50 = median effective concentration; SE = standard error; BSV% = between-subject variation With respect to latency to persistent sleep modelling, the log-likelihood ratio test showed a statistically significant difference when including the concentration effect and the Emax model (see below) performed better than the linear one; SB-649868 concentration immediately prior to lights-off was found to be the best predictor of improvements in latency to persistent sleep (LPS).

CONCECCONCLPS

LPSLPS PLAPLA +

⋅−=

50 ,

where the maximal effect (LPSPLA) corresponded to the placebo response. SB-649868 population pharmacokinetic / pharmacodynamic parameters for the final latency to persistent sleep model are reported in Table 16.

Table 16 Final Population Parameter Estimates for latency to persistent sleep

LPSPLA (minutes) EC50 (ng/mL) Estimate 21.8 240 SE 2.5 64 BSV% 57% 96% Source Data: Table 11.7 LPSPLA = latency to persistent sleep after receiving placebo, EC50 = median effective concentration; SE = standard error; BSV% = between-subject variation Finally, with respect to wake time after sleep onset modelling, the log-likelihood ratio test showed a statistically significant difference when including the concentration effect and that the Emax model (see below) performed better than the linear one; SB-649868 concentration immediately after lights-on (i.e., 9.5 hrs post dose) was found to be the best predictor of improvements in wake time after sleep onset (WASO).

( )CONCEC

CONCDeltaWASOWASOWASO PLA

PLA +⋅−

−=50 .

This meant that, regardless of SB-649868 concentration, it was not possible to reduce wake time after sleep onset to less than a minimum threshold (Delta), which in this healthy population was estimated to be approximately 5 minutes.

SB-649868 population pharmacokinetic / pharmacodynamic parameters for the final wake time after sleep onset model are reported in Table 17.


21


22

Table 17 Final population parameter estimates for wake time after sleep onset

WASOPLA (minutes) Delta (minutes) EC50 (ng/mL) Estimate 26.5 4.8 347 SE 3.3 2.0 105 BSV% 83% 161% 126% Source Data: Table 11.7 WASOPLA = wake time after sleep onset after receiving placebo, EC50 = median effective concentration; SE = standard error; BSV% = between-subject variation Pharmacokinetic / pharmacodynamic conclusion

The exploratory pharmacokinetic / pharmacodynamic analyses showed that SB-649868 exposure was highly significantly correlated with improvements in total sleep time, latency to persistent sleep and, to a lesser extent, to wake time after sleep onset.

Population pharmacokinetic / pharmacodynamic analysis demonstrated a consistent and highly statistically significant concentration-response relationship for total sleep time, latency to persistent sleep and wake time after sleep onset, that could be well characterised with population Emax models.

Total sleep time improvements were best correlated with the average concentration during the lights-off period; latency to persistent sleep was best correlated with the SB-649868 concentration collected immediately before retiring to bed; wake time after sleep onset was best correlated with concentration at the end of the lights-off period. Comparing the different EC50 estimates obtained for total sleep time, latency to persistent sleep and wake time after sleep onset with the corresponding SB-649868 plasma concentrations, it can be noted that a 12 mg SB-649868 dose was predicted to deliver a 50% reduction in the latency to persistent sleep, while a 26 mg SB-649868 dose would be required to obtain a comparable reduction of the wake time after sleep onset. It is therefore predicted that even doses below 10 mg SB-649868 can still provide significant benefits for sleep induction but not for sleep maintenance: significant wake time after sleep onset benefits are predicted to occur for doses greater or equal to the 20 mg SB-649868 dose with the current formulation.

Safety

ADVERSE EVENTS: Overall, the frequency of adverse events was similar for the active treatment groups and placebo. Generally, for individual adverse events, frequencies were similar for the three active treatments and placebo, although the incidence of somnolence appeared to be greater for the SB-649868 30 mg group than placebo: 14 (29%) subjects compared with 2 (4%) subjects. The most frequently reported adverse events were fatigue and somnolence. A summary of the most frequently reported adverse events (reported by more than one subject) is presented in Table 18.


22


23

Table 18 Summary of most frequent adverse events

Preferred term Placebo N = 46 n (%)

SB-649868 10 mg N = 48 n (%)

SB-649868 30 mg N = 48 n (%)

Zolpidem 10 mg N = 45 n (%)

Any event 27 (59) 23 (48) 30 (63) 23 (51) Fatigue 9 (20) 6 (13) 10 (21) 11 (24) Somnolence 2 (4) 4 (8) 14 (29) 3 (7) Insomnia 4 (9) 6 (13) 1 (2) 3 (7) Hypoglycaemia 3 (7) 2 (4) 5 (10) 4 (9) Vessel puncture site 3 (7) 2 (4) 4 (8) 4 (9) Headache 4 (9) 1 (2) 2 (4) 1 (2) Dizziness 2 (4) 0 2 (4) 1 (2) Disturbance in attention 1 (2) 0 3 (6) 1 (2) Poor quality sleep 1 (2) 1 (2) 0 2 (4) Nausea 2 (4) 0 1 (2) 0 Nasal congestion 1 (2) 2 (4) 0 0 Dyspepsia 2 (4) 0 0 0 Arthralgia 1 (2) 1 (2) 0 0 Vessel puncture site pain 1 (2) 1 (2) 0 0 Dysgeusia 1 (2) 0 1 (2) 0 Mouth ulceration 1 (2) 0 1 (2) 0 Nightmare 1 (2) 0 1 (2) 0 Pharyngolaryngeal pain 0 0 1 (2) 1 (2) Source Data: Table 10.1 Most of the adverse events were mild or moderate in intensity. Only one subject experienced an adverse event of severe intensity (severe somnolence after receiving SB-649868 30 mg that was judged by the Investigator to be related to investigational product). Two subjects had adverse events in clinical laboratory parameters: one subject had decreased blood glucose of mild intensity that was judged related to investigational product (SB-649868 10 mg), and one subject had increased hepatic enzymes of mild intensity was judged related to investigational product (SB-649868 30 mg). There were no serious adverse events in the study. There were no clinically relevant abnormalities in urinalysis, 12-lead ECG and vital signs parameters.

CLINICAL LABORATORY RESULTS: There were no notable changes in mean haematology and clinical chemistry parameters. Two subjects had adverse events in clinical laboratory parameters:

•

The adverse event was mild in intensity and resolved after approximately 10 days. The Investigator judged the decreased blood glucose to be related to investigational product.


23


24

•

The Investigator judged the event to be of mild intensity and to be related to investigational product. The adverse event resolved after approximately 25 days.

There were no notable abnormalities in urinalysis dipstick test results.

VITAL SIGNS RESULTS: There were no notable changes in mean vital signs parameters.

TWELVE-LEAD ELECTROCARDIOGRAM RESULTS: There were no clinically significant 12-lead ECG results.

Conclusions

• Statistically significant increases were observed in the primary endpoint, total sleep time, for both the SB-649868 10 mg and 30 mg doses compared with placebo. A statistically significant increase was also observed for zolpidem 10 mg.

• SB-649868 10 mg and 30 mg exerted statistically significant reductions in latency to persistent sleep and statistically significant increases in sleep efficiency. A statistically significant reduction in wake after persistent sleep to lights on was observed for SB-649868 30 mg. Percentage of time in REM sleep increased with SB-649868 30mg.

• Slight increases were observed in concentrations of luteinising hormone, follicle-stimulating hormone and testosterone for all active treatments and they were generally similar to those observed for placebo.

• Daytime cognitive function data summarised by means of 66 different endpoints and Bond-Lader VAS factors measured on the morning following dosing showed a worsening of performance common across all treatments; this was mainly due to the night of noise-disturbed sleep.

• Treatment effects on the night of noise for total sleep time (‘How long did you sleep last night’) and sleep onset latency (‘How long to fall asleep’) were quite variable, although a stronger hypnotic signal could be detected with the SB-649868 30 mg dose.

• Exploratory and population pharmacokinetic / pharmacodynamic analyses showed that SB-649868 exposure was highly significantly correlated with improvements in total sleep time, latency to persistent sleep and, to a lesser extent, to wake time after sleep onset. According to the different median effective concentration (EC50) estimates obtained for total sleep time, latency to persistent sleep and to wake time after sleep onset with the corresponding SB-649868 plasma concentrations, doses below SB-649868 10 mg provided significant benefits for sleep induction but not for


24


25

sleep maintenance: significant wake time after sleep onset benefits are predicted to occur for doses greater or equal to the SB-649868 20 mg dose with the current formulation.

• SB-649868 was generally well tolerated. Most adverse events were mild or moderate in intensity, with only one severe adverse event. The frequency of adverse events was generally similar for all treatments compared with placebo, although the incidence of somnolence appeared to be higher for SB-649868 30 mg. Two subjects experienced laboratory abnormalities that were reported as adverse events: decreased blood glucose and increased hepatic enzymes. There were no serious adverse events and no clinically relevant abnormalities in 12-lead ECG or vital signs parameters.

Date of Report: February 2008


25

synopsis › ctr-gsk-7381 › oxs104094 › fae6de74... · 2018-11-04 · 3 synopsis identifier:...

Documents