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CONFIDENTIAL GM2008/00324/00 GT1109727

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Synopsis

Identifier: GM2008/00324/00 Study Number: GT1109727

Title: Single-Blind, Randomised, Placebo-Controlled First Time in Human Study to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Oral Escalating Doses of GSK1018921 in Healthy Volunteers and to assess the effect of a single dose of GSK1018921 on Quantitative EEG and Mismatch Negativity in a separate cohort of healthy volunteers.

Investigator(s): Germany

Study center(s):

Publication(s): None at the time of this report.

Study period: 10 August 2007 to 12 July 2008

Phase of development: I

Objectives:

Part A

The primary objectives of Part A were:

• To investigate the safety and tolerability of single escalating oral doses of GSK1018921 in healthy male and female (of non-child bearing potential) volunteers.

• To investigate the pharmacokinetics (PK) of single escalating oral doses of GSK1018921 in healthy male and female (of non-child bearing potential) volunteers.

The secondary objectives of Part A were:

• To characterise the single dose pharmacodynamics (PD) of GSK1018921 in healthy male and female (of non-child bearing potential) volunteers.

• To explore the PK-PD relationships of GSK1018921 in healthy male and female (of non-child bearing potential) volunteers.

Part B

The primary objectives of Part B were:

• To assess the PD effects of single doses of GSK1018921 and nicotine (active comparator) on Quantititative Electro EncephaloGraphy (qEEG) and MisMatch Negativity (MMN) in healthy volunteers who were smokers.


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• To investigate the PK/PD relationship between GSK1018921 plasma concentrations and metrics of systemic exposure with the effects on MMN and qEEG parameters in healthy volunteers who were smokers.

The secondary objectives of Part B were:

• To explore the effects of GSK1018921 on Loudness Dependant Auditory Evoked Potential (LDAEP).

• To investigate the safety and tolerability of single dose of GSK1018921 in healthy volunteers who were smokers.

• To estimate the effect of moderate fat/calorie meal on the relative bioavailability of GSK1018921 in healthy volunteers who were smokers.

Methodology:

This is the First Time in Human Study (FTIH) with GSK1018921 to evaluate the safety and tolerability, the PK profile and PD effects of GSK1018921 in healthy male and female (of non-childbearing potential) volunteers.

This study was conducted in two parts, Parts A and B, in a single hospital-based centre.

Part A: Single Dose Escalation Study

This was a randomised single-blind placebo-controlled, single oral escalating dose, five period cross-over study.

Healthy male and female (non-childbearing potential) subjects were randomised into two cohorts with alternate panel design with 11 subjects in each cohort. Eight subjects were randomised to GSK1018921 and 3 subjects were randomised to placebo within each session. Cohort 1 received GSK1018921 doses of 0.5mg, 5mg, 120mg and 280mg; Cohort 2 received doses of 2mg, 25 mg, 70mg and 200mg.

Each subject received no more than 4 doses of GSK1018921 in a maximum of 5 dosing sessions. Each dosing session was staggered over 2 or 3 days and there were at least one subject on placebo on each dosing day. Within each cohort, each session was separated by a washout period of at least 7 days.

If a subject was withdrawn from the study, the subject was replaced as necessary with another subject assigned to the same treatment sequence with respect to active and placebo doses. Further subjects were dosed at a given level if additional data were necessary to establish safety and tolerability prior to dose escalation. Subjects were in the unit for up to 48 hrs post-dose and they came back for the 72 hr post dose PK sample. Dosing was in the morning around the same time for all sessions. Subjects returned for a follow-up visit approximately 7 – 14 days following the last dose of study medication. Each subject’s participation in the study was approximately 11 weeks.

The decision to proceed from one dose level to the next was made by the clinical study team (the investigator, the medical monitor and the project’s clinical pharmacokineticist) based on the evaluation of all available PK, safety and tolerability data. Dose was to be


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increased until maximum tolerated dose was reached or exposure was predicted to exceed the toxicokinetic limits for Cmax or AUC of 907 ng/mL or 12746 ng*hr/mL, respectively.

Standard safety monitoring (clinical laboratory assessment, electrocardiograms [ECGs], cardiac telemetry, vital signs, etc.) was performed. No more than 500 ml of blood in total was taken from each subject over the duration of the study. The exception to this was if additional safety blood samples were needed to be collected for safety reasons.

A summary of study administration is presented in Attachment 1 and time and events schedule in Attachment 2.

Part B: Pharmacodynamic study

This was a randomised, investigator and subject blinded, placebo controlled, four or five way crossover study in a separate cohort of healthy male and female (non-child bearing potential) volunteers, who were smokers. The objective of this study was to test the effects of GSK1018921, nicotine lozenge (active comparator) and placebo on Quantitative EEG (qEEG) and MMN parameters. A further open-label period was included in a subgroup of subjects who received a single dose of GSK1018921 with food.

All Subjects attended up to four dosing sessions, separated by a washout period of at least 7 days. The first 14 subjects were included in the food effect part and therefore attended an additional open-label dosing session. On these dosing occasions they received in a randomized manner, either 80 mg or 200 mg GSK1018921 + placebo lozenge (fasted), a nicotine lozenge + placebo tablet, or placebo lozenge + placebo tablet. The doses of GSK1018921 were based on preliminary analysis of data from Part A which showed 80 mg and 200 mg doses to be well tolerated. Nicotine or matching placebo was administered 1 hr after GSK1018921 or matching placebo to account for the differences in Tmax between the 2 compounds. After the final 7-day washout, a subgroup of subjects who had previously received GSK1018921 (n=14) attended an additional open-label dosing session and received a single 80 mg dose of GSK1018921 with a standardised moderate fat/calorie meal. Although a standard moderate fat/calorie meal was planned, a high fat/calorie meal (45% fat instead of 30%, 555 calories) was given due to an error in the clinic. No PD assessments were conducted in that period.

On each dosing session, each subject underwent EEG/event related potential (ERP) recordings at time-points which were determined based on the PK results of Part A. On each dosing session, each subject underwent qEEG recordings predose, and at 1.5, 2, 4, 6, 12, and 24 hrs post-dose. MMN and event related potential (ERP) recordings were obtained predose and at peak response, i.e., 2 hrs post-dose.

Subjects were required to stay in the unit for up to 3 days and 2 nights for each of the treatment periods (from evening of Day -1 to Day 2).

All subjects needed to abstain from smoking for at least 4 hrs prior to dosing on each study day and until ERP recordings had been completed (approximately 3 hrs after dosing).


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Subjects returned for a follow-up visit approximately 7-14 days following the last dose of study medication. Each subject’s participation in the study was approximately 9 weeks.

Standard safety monitoring (clinical laboratory assessment, ECGs, cardiac telemetry, vital signs, etc.) as well as cognitive tests was performed.

No more than 500 ml of blood in total was taken from each subject over the duration of the study. The exception to this was if additional blood samples needed to be collected for safety reasons.

All EEGs were performed and stored in a digital form. The digital information was stored on the hard drive of the machine, sent to a medical data server, and a copy transferred to a FTP server via secure connection. Reporting of the EEG graphs was carried out by a consultant neurophysiologist, who was blinded to treatment.

A summary of study administration is presented in Attachment 1 and time and events schedule in Attachment 2.

Number of subjects:

Part A: the study population for Part A consisted of a total of 25 healthy volunteer subjects who received single dose escalations of GSK1018921. The doses studied were 0.5 mg, 2 mg, 5 mg, 25 mg, 70 mg, 120 mg, 200 mg and 280 mg. Table 1 summarises the actual number of subjects exposed to each dose level. Nine to eleven subjects were exposed to each dose level except for 280 mg for which two volunteers were excluded because they were predicted to exceed the PK stopping limits based on Cmax (907 ng/mL).

Table 1 Number of Subjects Who Received Each Treatment Regimen (Single Doses of GSK1018921) (Part A)

Dose Level of GSK1018921 Number of Subjectsa 0.5 mg 11 2 mg 11 5 mg 10 25 mg 10 70 mg 9 120 mg 10 200mg 10 280mg 8 Placebo 21 a. Total of 25 subjects.

Part B: the study population for Part B consisted of 23 healthy volunteer subjects who were regular smokers (at least 10 cigarettes per day for the previous six months). Doses of 80 mg and 200 mg GSK1018921 were compared with nicotine lozenge (Active comparator) and placebo. The effect of food was assessed in the first 14 subjects who had received 80 mg GSK1018921.


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Subject Disposition and Demographics:

Table 2 Summary of Subject Disposition and Demographic Characteristics

Number of Subjects Part A Part B Number of subjects randomised, N: 25 23 Number of subjects included in All subjects (safety) population, n (%):

25 (100) 23 (100)

Number of subjects included in the PK population, n (%) 23 (92) 22 (96)a Number of subjects completed as planned, n (%): 20 (80) 20 (87) Number of subjects withdrawn (any reason), n (%): 5 (20) 3 (13) Number of subjects withdrawn for AE, n (%): 2 (8)b 1 (4)c Other reasons for subject withdrawal, n (%) 3 (12)d 2 (9)e Demographics Part A

N=25 Part B N=23

Age in Years, Mean (Range) 43.8 (20-55) 32.3 (19-45) Sex, n (%)

Female: 3 (12) 1 (4) Male: 22 (88) 22 (96)

BMI in kg/m2, Mean (Range) 25.16 (20.1-30.6) 23.78 (18.5-29.2) Height in cm, Mean (Range) 175.3 (165-190) 177.2 (155-193) Weight in kg, Mean (Range) 77.46 (64.5-101.3) 74.48 (55.5-100.2) Ethnicity, n (%)

Not Hispanic or Latino: 25 (100) 23 (100) Race, n (%)

White – Arabic/North African Heritage 1 (4) 0 White – White/Caucasian/European Heritage 24 (96) 23 (100)

Data source: Table 9.1, Table 9.2, Table 9.5, Table 9.6, Table 9.7, Table 9.10. a. A subset of 13 subjects were included PK food effect comparison. b. Two subjects withdrew due to AEs of ventricular tachycardia c. One subject withdrew due to an AE of joint injury d. Two subjects withdrew due to PK data predicted to exceed Cmax limit; one subject withdrew due to low heart rate e. Two subjects withdrew due to non-compliance: one subject concealment of an important medical history

diagnosis, and one subject alcohol intake.

Diagnosis and main criteria for inclusion:

Part A: Healthy male or female subjects (non-child bearing potential) aged 18 to 55 years were recruited into Part A of the study.

Part B: Healthy male or female subjects (non-child bearing potential) aged 18 to 45 years who were regular smokers (at least 10 cigarettes per day for at least 6 months) were recruited into Part B of the study.

TREATMENT ADMINISTRATION:

Details of GSK1018921 used in Part A and Part B are summarised in Table 3.


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Table 3 Details of Investigational Product

Investigational Product Batch Number GSK1018921 0.5 mg tablets 071138987 GSK1018921 5 mg tablets 071138988 GSK1018921 10 mg tablets 071138989 GSK1018921 40 mg tablets 071139212 GSK1018921 Placebo tablets 071138986 Nicotine 4 mg tablets 081158666 Nicotine Placebo tablets 081159072

Criteria for evaluation:

Part A

The primary endpoints of Part A were:

• Safety and tolerability endpoints consisting of: adverse events (AEs); 12-lead ECG; vital signs (blood pressure, heart rate and respiration rate); clinical laboratory evaluations (haematology, clinical chemistry, urinalysis), cognitive tests.

• Pharmacokinetic parameters of GSK1018921: Cmax, AUC(0- ∞), AUC(0-t), t1/2, Tmax, Ae(0-t), CLR.

The secondary endpoints of Part A were

• Assessment of the Bond-Lader Visual Analogue Scale (VAS), Profile of Moods State (POMS) and glycine levels.

• Relationship between plasma concentrations and metrics of systemic exposure of GSK1018921 with Bond-Lader VAS, POMS parameters and glycine levels.

Part B

The primary endpoints of Part B were:

• Amplitude and latency of MMN; effects on deviant associated negativity; and repetition associated positivity.

• Frequency and power of spectral bands of qEEG.

• Relationship between plasma concentrations and metrics of systemic exposure of GSK1018921 (Cmax, AUC) with MMN and qEEG parameters.

• Safety and tolerability of GSK1018921 in smokers. The secondary endpoints of Part B were:

• Safety and tolerability endpoints consisting of: AEs; 12-lead ECG; vital signs (blood pressure, heart rate and respiration rate); clinical laboratory evaluations (haematology, clinical chemistry, urinalysis).

• Changes in the amplitude of the LDAEP N1/P2 at varying tone intensities.


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• Relationship of plasma concentration levels of GSK1018921, LDAEP and glycine levels.

• Assessment of PK of single dose of GSK1018921 in smokers (Cmax, AUC(0-24), Tmax, and if data permit, AUC(0-∞) and t½) with and without food.

Bioanalytical Methods

Human plasma and urine samples were analysed for GSK1018921 by PCD DMPK, GlaxoSmithKline at The Frythe (UK).

Plasma samples were analysed using a validated analytical method based on protein precipitation, followed by HPLC/MS/MS analysis. The lower limit of quantification (LLQ) was 1 ng/mL for GSK1018921, using a 25 µL aliquot of human plasma, and the higher limit of quantification (HLQ) was 1000 ng/mL [GlaxoSmithKline Document Number FD2007/00126/00].

Human urine samples were analysed using a validated analytical method employing HPLC-MS/MS with a TurboIonspray interface and multiple reaction monitoring. Prior to analysis, GSK1018921 was diluted in urine samples using ammonium formate and [2H3

13C]-GSK1018921 as internal standard. The lower limit of quantification (LLQ) was 1 ng/mL for GSK1018921, using a 25 µL aliquot of human urine, and the higher limit of quantification (HLQ) was 1000 ng/mL [GlaxoSmithKline Document Number FD2008/00286/00].

Quality Control samples (QC), prepared at 3 different GSK1018921 concentrations and stored with study samples, were analysed with each batch of samples against separately prepared calibration standards. For the analysis to be acceptable, no more than one-third of the QC results were to deviate from the nominal concentration by more than 15%, and at least 50% of the results from each QC concentration should be within 15% of nominal. All applicable analytical runs met all predefined run acceptance criteria. All data are stored in the GLP Archive, GlaxoSmithKline, Research and Development.

Pharmacokinetic Methods

PK analysis of plasma and urine data of GSK1018921 was conducted by INDAPharma, LLC (Chapel Hill, NC, USA), under the direction of Clinical Pharmacokinetics/Modelling and Simulation, GlaxoSmithKline.

PK analysis of plasma GSK1018921 concentration-time data following each single oral dose in Parts A and B of the study was conducted using standard noncompartmental methods with Model 200 of the WinNonlin Professional Edition version 4.1 (Pharsight Corporation, Mountain View, CA) according to the GlaxoSmithKline Guidance for Non-Compartmental Analysis of Pharmacokinetic Data (GUI-CPK-3001, 01-Oct-07). Actual elapsed time from dosing was used to estimate all individual PK parameters. The following PK parameters were estimated for GSK1018921 as data permitted: the maximum observed plasma concentration (Cmax) and the first time to reach Cmax (tmax), the apparent terminal elimination rate constant (λz) and half-life (t1/2), the area under the GSK1018921 concentration-time curve to the last quantifiable concentration


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(AUC(0-t)) and extrapolated to infinity (AUC(0-∞)), the percentage of AUC(0-∞) obtained by extrapolation (%AUCex), and oral clearance (CL/F).

The following urine PK parameters of GSK1018921 were determined as data permitted: Amount Excreted in Urine (Ae), percent of dose excreted in urine (Ae%), and renal clearance (CLR).

In accordance with GSK SOP-NPD-0003 v01, Management of the Sponsor's Clinical Study Documents (Sponsor Study Records), all PK analyses were archived.

Statistical methods:

Sample Size Considerations

A sample size of 11 subjects in each cohort in Part A was consistent with the design of previous FTIH single-dose studies and allowed an allocation ratio of 8 active to 3 placebo per session. No statistical techniques were applicable to calculate this sample size, as no information on residual variability of GSK1018921 PK parameters were available prior to this study and no formal treatment comparisons were performed. Therefore sample size was based on feasibility.

In Part B, Twenty-one subjects were planned to participate in a 4 or 5 period crossover. Although sample size was based on feasibility, inferential tests were applied as exploratory tools. Hence, 21 subjects should provide power of around 86% to detect an effect size of 1 (considered a “Large effect” for the PD parameters being collected); assuming the worst case scenario where within-subject variability in the endpoint investigated is equal to the between-subject variability, with a two-sided alpha of 5%.

Within Part B, the first 14 of the 21 subjects received an additional treatment of 80mg GSK1018921 with food. Sample size calculations were performed using within-subject variability from preliminary PK parameters from doses 25mg – 280mg in Part A of this study to show the precision of the estimate of food effect in Part B using 14 subjects for 12 evaluables.

Within-subject CVs of 19.1%, 20.1% and 29.6% were observed for AUC(0-inf), AUClast and Cmax of GSK1018921 respectively.

Based on a within subject-CV of 19.1% for AUC(0-inf) and a sample size of 12 evaluable subjects, it was estimated that the 90% confidence interval for 80mg GSK1018921, fed: 80mg GSK1018921, fasted would be obtained by dividing/multiplying the point estimates for a factor of approximately 1.15; i.e., if the point estimate of the ratio was 1.0 then the 90% confidence interval would be 0.87 to 1.15, if the point estimate of the ratio was 1.4 then the 90% confidence interval would be 1.22 to 1.60.

Based on a within subject-CV of 29.6% for Cmax and a sample size of 12 evaluable subjects, it was estimated that the 90% confidence interval for 80mg GSK1018921, fed: 80mg GSK1018921, fasted would be obtained by dividing/multiplying the point estimates for a factor of approximately 1.23; i.e., if the point estimate of the ratio was 1.0


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then the 90% confidence interval would be 0.81 to 1.23, if the point estimate of the ratio was 1.4 then the 90% confidence interval would be 1.13 to 1.72.

For Part B, a secondary comparison of interest was between the GSK1018921 PK parameters, AUC(0-∞) or AUC(0-t), Cmax, and tmax with and without food.

Interim Analyses

No interim analysis was performed but a review of preliminary safety and available pharmacokinetic data from Part A was performed after the completion of each dosing session.

Final Analyses

All displays were generated in the HARP (Harmonisation of Analysis and Reporting Program) environment which uses SAS version 9 on a UNIX platform.

Pharmacokinetic

Plasma concentrations of GSK1018921 were summarised descriptively by nominal time and by treatment for Part A and B. Pharmacokinetic parameters of GSK1018921 were summarised descriptively by treatment for Part A and B.

Dose Proportionality: In Part A, preliminary assessment of dose proportionality was made on AUC(0-∞) and Cmax of GSK1018921 over the dose range of 2 to 280 mg using the power model, i.e., loge(Y) = β × loge(dose) + log(α), with a mixed effect model fitting loge-transformed dose as a continuous covariate and subject as a random effect. The slope (β) with 90% confidence interval, on the loge scale, was calculated using the pooled estimate of variance, and used to assess dose proportionality.

Food Effect: In a subset of 14 subjects included in Part B, the effect of food on GSK1018921 PK parameters (AUC(0-t), AUC(0-∞), and Cmax) was assessed with analysis of variance (ANOVA) using a mixed-effect model with regimen as a fixed effect and subject as a random effect. Point estimates and corresponding 90% confidence intervals were constructed for the difference 80 mg GSK1018921, fed – 80 mg GSK1018921, fasted using the residual variance. These were then back-transformed to provide point estimates and corresponding 90% confidence intervals for the geometric LSMean ratio 80 mg GSK1018921, fed: 80 mg GSK1018921, fasted.

Pharmacodynamic:

Bond & Lader VAS and POMS (Part A and B): Bond and Lader VAS factors (Vigilance/Alertness, Anxiety/Calmness & Dysphoria), Profile of Mood State scale factor scores (Tension-Anxiety, Depression-Rejection, Anger-Hostility, Vigour-Activity, Fatigue-Inertia & Confusion-Bewilderment) were summarised (n, mean, SD, median, minimum and maximum) by regimen and time for both Parts of the study separately.


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Glycine Concentration (Part A and B): RBC (Parts A and B separately) and Plasma (Part B) Glycine concentrations (conducted by Quotient Bio Research Ltd, Cambridge, UK) were summarised (n, mean, SD, median, minimum and maximum) by regimen and time. Plots were produced of mean and 95% CI by regimen over time for RBC (Parts A and B separately) and Plasma (Part B) Glycine concentrations. RBC (Parts A and B separately) and Plasma (Part B) Glycine concentrations were listed.

COGSTATE Cognition Tests (Part A and B): A mixed model was fit separately for each part (A and B) for the primary outcome measure from each test which included the terms period-baseline (pre-dose value for relevant period), subject-baseline (mean of pre-dose values across all periods), regimen, time, period as fixed effects, period-baseline*time, mean-baseline*time and regimen*time as interactions and subject as a random effect. The model for Part A also adjusted for cohort as an additional fixed effect. Least square means were calculated for each regimen. Estimates of pair-wise treatment differences were calculated for each dose of GSK1018921 compared to Placebo along with 95% confidence intervals.

Mismatch Negativity (MMN) (Part B): As an exploratory analysis, for peak amplitude and peak latency, a mixed model was fit to the mean value across electrodes (Cz, Fz, F3, and F4) of the post-baseline value for standard minus deviant. The model fit period-baseline, subject-baseline and log-transformed serum cotinine concentration pre-dose as covariates, regimen and period as fixed effects, and subject as a random effect. Using the pooled estimate of variance in each analysis LS (least square) means and 95% confidence intervals were calculated from the separate models for the difference in amplitudes and latency of 80mg and 200mg fasted GSK1018921 and nicotine versus Placebo. For each endpoint, differences in Least Square (LS) Means with 95% confidence intervals were plotted by treatment comparison across the electrodes.

EEG (Part B): Exploratory statistical analysis of EEG data was performed separately for the two conditions of “eyes closed” and “eyes open”, for each frequency band separately (alpha, beta, theta and delta) and for both absolute (log-transformed) and relative (untransformed) powers using the mean value averaged across the electrode sites by means of separate mixed effects models. Mean values averaged across the electrode sites were derived for Alpha band over the electrodes C3, C4, Cz, O1, O2, P3, Pz, T5 & T6, for Beta band over C3, C4, Cz, F3, F4, F7, F8, Fz, Pz, for Delta band over C3, C4, Cz, F3, F4, Fz, P3, Pz, T3, T4, T5, T6, for Theta band over C3, C4, Cz, F3, F4, F7, F8, Fz, Pz.

The model fit period-baseline and subject-baseline, and log-transformed serum cotinine concentration pre-dose as covariates, regimen and period and time and regimen*time as fixed effects, subject as a random effect. Using the pooled estimate of variance in each analysis GLS/ LS (Geometric least square/ least square) means and 95% confidence intervals were calculated from the models for the difference in absolute power and relative power respectively of 80mg & 200mg GSK1018921 and nicotine versus Placebo by condition (eyes open or eyes closed), frequency band (delta, theta, alpha beta) and across electrode sites. T-values for the ratios/differences against Placebo were plotted for each endpoint by condition and band (delta, theta, alpha, beta) across the electrodes for each time-point.


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A further separate mixed model was similarly fit to absolute power data from the Total band averaged across the electrodes by condition (eyes open and eyes closed).

Loudness Dependent Auditory Evoked Potential (LDAEP) (Part B): A mixed model was fit to the N1/P2 value (P2-N1) for amplitude with period-baseline and subject-baseline, log-transformed serum cotinine pre-dose value as a covariate, regimen and period as fixed effect factors and terms loudness intensity and loudness intensity*regimen, where loudness intensity (in decibels) was fit as a continuous covariate and subject as a random effect. The slope of N1/P2 value was calculated over loudness intensity by regimen with 95% confidence intervals. The treatment differences from Placebo in slopes along with their 95% CI were estimated.

Changes in conduct of the study or planned analyses

Differences in the statistical analyses compared to the RAP

The calculation of POMS-Brief domains was as follows (RAP had slight incorrect derivations).

Tension-Anxiety: Q1+Q6+Q12+Q16+Q20 Depression-Rejection: Q7+Q11+Q15+Q17+Q21 Anger-Hostility: Q2+Q9+Q14+Q25+Q28 Vigor-Activity: Q4+Q8+Q10+Q27+Q30 Fatigue-Inertia: Q3+Q13+Q19+Q22+Q23 Confusion-Bewildement: Q5+Q18+Q24+Q26R+Q29

R = reverse scoring value on item (item subtracted from 4).

For Cogstate analysis for Part A, the model adjusted for cohort as an additional fixed effect, rather than doing it separately by cohort as specified in the RAP.

The MMN data collected were the derived differences of standard minus deviant. So the mixed model applied to the data was simplified compared to that described in the RAP (see Section 8.2.3 for details on the mixed model actually used).

For EEG, the specific electrodes to average for the different bands were clarified prior to DBF/unblinding.

For LDAEP, intensity baselines were adjusted for as covariates in the mixed model.

Serum cotinine at pre-dose was log-transformed prior to inclusion in analysis models as a covariate, as deemed appropriate on the basis of the results observed.

Summary:

Pharmacokinetics

Part A: A total of 8 to 11 subjects completed PK evaluation at each of the dose levels of 0.5 mg to 280 mg. After the 0.5 mg dose, plasma GSK1018921 concentrations were only measurable (≥1 ng/mL) in two samples of one subject. At 2 mg and 5 mg dose levels,


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plasma GSK1018921 concentrations were low and measurable for a relatively short period in many subjects, which precluded the assessment of t½ or AUC(0-∞). Thus, not all PK parameters of GSK1018921 could be estimated at doses lower than 25 mg and were excluded from the dose-proportionality assessment.

Median pharmacokinetic profiles are included in Figure 1. GSK1018921 was rapidly absorbed following single oral tablet doses under fasting conditions, achieving peak plasma concentration between 1 and 3 hrs post dose across dose levels. After tmax, plasma concentration vs. time profiles of GSK1018921 exhibited apparent bi- or tri-exponential decay, with mean terminal half-life of 16-19 hrs across dose levels of 70-280 mg. The concentration-time profiles declined in parallel between different doses administered, especially at doses ≥70 mg, indicating similar apparent elimination half-lives between dose levels.

Figure 1 Median Plasma GSK1018921 Concentration-Time Plots (Pharmacokinetic Population-Part A)

Data Source: Figure 11.9 Note: LLQ=1ng/ml Note: 0.5 mg is not plotted as only two quantifiable samples were available for one subject Pharmacokinetic parameters for GSK1018921 following single oral doses of GSK1018921 administered under fasting conditions are summarised in Table 4.


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Table 4 Pharmacokinetic Parameters1 for GSK1018921 in Non-Smokers Following Single Oral Escalating Doses of GSK1018921 (Pharmacokinetic Population-Part A)

Dose/ Fasted

AUC(0-∞) (h.ng/mL)

AUC(0-t) (h.ng/mL)

Cmax (ng/mL)

tmax (h)

t½ (h)

CL/F (L/h)

0.5 mg (n=1)2

na na 1.14 1.50 na na

2 mg (n=11)

na 7.78 (79.0)

2.95 (54.5)

1.50 (1.00-3.00)

na na

5 mg (n=10)

na 32.35 (122.9)

8.17 (97.3)

1.50 (1.00-3.00)

na na

25 mg (n=10)

249.62 (64.5)

224.84 (67.3)

33.55 (41.4)

1.75 (1.00-3.03)

10.97 (68.6)

100.15 (64.5)

70 mg (n=9)

813.75 (46.4)

768.77 (47.4)

104.71 (34.2)

1.50 (1.00-3.00)

15.60 (40.9)

86.02 (46.4)

120 mg (n=10)

2151.53 (35.6)

2031.44 (33.4)

255.40 (57.1)

1.75 (1.00-6.00)

18.46 (36.7)

55.77 (35.6)

200 mg (n=10)

2563.73 (49.8)

2461.00 (51.4)

289.48 (62.2)

1.50 (1.00-4.00)

16.79 (38.9)

78.01 (49.8)

280 mg (n=8)

4263.57 (30.5)

4114.96 (30.1)

447.41 (38.1)

1.75 (1.48-3.02)

16.32 (22.8)

65.67 (30.5)

Source Data: Table 11.3 and Table 11.4. na: information not available due to the limited number of quantifiable samples 1. Values are geometric mean (%CVb) for each parameter, except for tmax which are median (range). 2. Concentrations non-quantifiable bar 1 out of 11 subjects at 0.5mg dose. AUC and Cmax values of GSK1018921 generally increased in a dose related manner. No subject exceeded the toxicokinetic limit for Cmax (907 ng/mL) with individual Cmax values ranging up to 758 ng/mL. Two subjects were excluded from dosing at 280 mg since their exposure was predicted to exceed the toxicokinetic limit for Cmax. The maximum AUC(0-24) observed was 5344 ng*hr/mL, 2.4-fold lower than the toxicokinetic limit set for AUC (12746 ng*hr/mL).

Dose Proportionality: Table 5 contains a summary of the results from the power model statistical analysis of dose proportionality of GSK1018921, for doses of 25mg to 280mg for AUC(0-∞) and doses of 2mg to 280mg for Cmax, from Part A. There were data from 22 subjects in total for analysis.

Table 5 Summary of Assessment of Dose Proportionality as Assessed by the Power Model for Plasma GSK1018921 (Pharmacokinetic Population-Part A)

Parameter Adjusted Mean Slope (SE)

90% CI for Slope CV within %

AUC (0-∞) (ng*h/ml) 1.106 (0.048) (1.027, 1.185) 28.9 Cmax (ng/ml) 1.013 (0.024) (0.972, 1.053) 37.4 Data Source: Table 11.10


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The adjusted mean slope was very close to 1.0 for Cmax suggesting dose proportionality over the 2 mg to 280 mg dose range. For AUC(0-inf), the adjusted mean slope was 1.106, suggestive of a slightly more than proportional increase of AUC(0-inf) with increasing doses over the 25 mg to 280 mg dose range.

The estimated increase in dose required to double each parameter is given by 2(1/β) where β represents the adjusted mean slope (similarly for the confidence interval limits). For AUC(0-∞) the estimated increase is 1.87 (90% CI: 1.79 to 1.96). That is, an increase in dose of 87% would result in the doubling of AUC(0-∞) over the dose range 2 mg-280 mg. Similarly, an increase in dose of 98% would result in the doubling of Cmax (estimated increase 1.98 [90% CI: 1.93 to 2.04]).

The criteria defined for concluding statistically confirmed dose proportionality for AUC(0-∞) and Cmax of GSK1014802 across doses 2 mg-280 mg would be that the 90% CI for the adjusted mean slope had to fall completely within the range of 0.95 to 1.05 (According to GSK SOP-BMD-4002, where r=high dose/low dose =140). The 90% CI for AUC(0-∞) and Cmax slopes were not within this range. However, the study was not powered to demonstrate dose proportionality.

The within-subject variability (CV within %) in AUC(0-∞) and Cmax of GSK1018921 were 28.9% for AUC(0-∞) and 37.4% for Cmax.

The relationship between AUC and Cmax as a function of log transformed GSK1018921 dose is shown in Figure 2 and Figure 3, respectively.


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Figure 2 Plot of AUC (0-∞) of GSK1018921 against Dose on Log-Transformed Axes (Pharmacokinetic Population-Part A)

Data Source: Figure 11.3


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Figure 3 Plot of Cmax of GSK1018921 against Dose on Log-Transformed Axes (Pharmacokinetic Population-Part A)

Data Source: Figure 11.4 NB: Non-quantifiable concentrations (Cmax=0) at 0.5mg dose presented as Cmax=0.1 for display purposes.

Urinary Excretion: Urinary excretion data of GSK1018921 following single oral doses of GSK1018921 administered under fasting conditions in Part A of the study are summarised in Table 6.


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Table 6 Summary of Urinary Excretion Data1 of GSK1018921 (Pharmacokinetic Population-Part A)

Dose/ Fasted Ae(0-48) (mg)

Ae% (% dose)

CLR (mL/h)

0.5 mg (n=10)

0.004 (0.003-0.005)

0.775 (0.528-1.02)

nc

2 mg (n=10)

0.015 (0.001-0.027)

0.752 (0.052-1.33)

nc

5 mg (n=10)

0.052 (0.033-0.105)

1.034 (0.653-2.11)

nc

25 mg (n=10)

0.232 (0.139-0.552)

0.926 (0.555-2.21)

943.55 (67.8)

70 mg (n=9)

1.178 (0.707-1.57)

1.683 (1.01-2.25)

1389.70 (50.9)

120 mg (n=10)

2.161 (0.716-4.20)

1.801 (0.596-3.50)

928.92 (73.7)

200 mg (n=10)

2.760 (1.70-4.35)

1.380 (0.850-2.18)

1125.02 (64.9)

280 mg (n=8)

6.873 (0.990-13.5)

2.454 (0.354-4.81)

1142.06 (109.1)

Source Data: Table 11.7 and Table 11.8. 1. Values are geometric mean (%CVb) for CLR, median (range) for Ae(0-48) and Ae%. nc: not calculated since AUC(0-∞) was missing. Ae: Amount excreted unchanged CLR: Renal Clearance Rate Overall, 0.8 to 2.5% of a single oral dose of GSK1018921 was excreted as unchanged GSK1018921 in urine over a 0 to 48 hr collection interval across dose levels, indicating that renal excretion is a minor elimination pathway for the parent compound, GSK1018921.

Part B: Pharmacokinetic parameters for GSK1018921 80 and 200 mg administered in smokers and for GSK1018921 80 mg administered with food are summarised in Table 7.

Table 7 Pharmacokinetic Parameters1 for GSK1018921 in Smokers Following Doses of GSK1018921 (Pharmacokinetic Population-Part B)

Dose/ Treatment

AUC(0-∞) (h.ng/mL)

AUC(0-t) (h.ng/mL)

Cmax (ng/mL)

tmax (h)

t½ (h)

CL/F (L/h)

80 mg Fasted (n=21)

965.07 (44.6)

905.20 (46.4)

121.47 (59.5)

1.50 (0.85-6.00)

16.61 (37.2)

82.90 (44.6)

200 mg Fasted (n=21)

2509.90 (33.9)

2397.72 (33.8)

253.20 (42.8)

2.43 (0.98-4.00)

15.90 (39.4)

79.68 (33.9)

80 mg Fed2 (n=13)

1148.06 (52.4)

1081.09 (52.8)

114.63 (51.8)

2.00 (0.50-4.00)

17.58 (27.2)

69.68 (52.4)

Source Data: Table 11.13 and Table 11.14. 1. Values are geometric mean (%CVb) for each parameter, except for tmax which are median (range). 2. Evaluated in a subset of subject only (Period 5)


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Pharmacokinetic parameter estimates of GSK1018921 following oral doses of GSK1018921 80 and 200 mg under fasted conditions in healthy smokers (Part B) were generally similar to those in healthy non-smokers (Part A).

Following administration of GSK1018921 with food in a subset of subjects, the median tmax was prolonged slightly from 1.5 to 2.0 hrs. A summary of the statistical analysis of food effect on Cmax and AUC is presented in Table 8.

Table 8 Summary of Statistical Analysis of Effect of Food on 80 mg GSK1018921 (Pharmacokinetic Population-Part B, Period 5)

Parameter GLSM Test (Fed) GLSM Ref. (Fasted)

Ratio (Fed:Fasted)

90% CI for ratio

AUC(0-∞) (ng*hr/mL) 1148.060 964.768 1.190 (0.912, 1.553) AUC(0-t) (ng*hr/mL) 1081.089 893.784 1.210 (0.918, 1.594) Cmax (ng/mL) 114.632 122.687 0.934 (0.683, 1.279) Sources: Table 11.16 GLSM: Geometric Least Square Mean

Based on the point estimates for the Geometric Least Square Mean (GLSM) parameter ratio, fed vs. fasted, a high fat/calorie meal caused on average 19% and 21% increases in AUC(0-∞) and AUC(0-t) values and about 7% decrease on average in Cmax value. The 90% CI indicates that the true difference for AUC(0-∞) lies between a 9% decrease and a 55% increase. The 90% CI indicates that the true difference for Cmax lies between an 8% decrease and a 59% increase.

Preliminary assessment of food effect was conducted in a subset of subjects. The 90% confidence interval for each parameter ratio contained 1.0; however, the 90% CI had a very wide range. However, this study was not powered to demonstrate lack of food effect within bioequivalence limits. Nevertheless, based on the point estimates for the ratio, the magnitude of the effect of a high fat/calorie meal on Cmax of GSK1018921 is almost negligible, and on AUC values is unexpected to be clinically meaningful.

Individual values of log-transformed AUC(0-∞) and log-transformed Cmax with and without food are displayed in Figure 4 and Figure 5, respectively. The plot of AUC(0-t) displayed similar results to AUC(0-∞).


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Figure 4 Stick plot of AUC(0-∞) of GSK1018921 for 80 mg GSK1018921 fed and fasted (Pharmacokinetic Population-Part B)

Data source: Figure 11.13


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Figure 5 Stick plot of Cmax of GSK1018921 for 80 mg GSK1018921 fed and fasted (Pharmacokinetic Population-Part B)

Data source: Figure 11.13

Pharmacodynamics

Bond & Lader VAS.

Part A: There were no remarkable trends in any of the three domains of Alertness, Calmness and Contentedness in placebo, nicotine or active drug regimens (Data source: Figure 12.1-Figure 12.3).

Part B: No remarkable trends were observed in any of the three domains in placebo, nicotine or active drug regimens (Data source: Figure 12.17-Figure 12.19).

POMS.

Part A: There were no noticeable trends for placebo and active treatment regimens in POMS total score and 6 domain scores (Data Source: Figure 12.4-Figure 12.9 and Figure 12.37).

Part B: The fatigue-inertia domain illustrated that all regimens, including placebo, had increases over the first 3 hrs post-dose; GSK1018921 200 mg had a mean score higher than baseline and placebo which was sustained to 6 hrs post-dose. All regimens had similar scores from 12 hrs following dosing (Data Source: Figure 12.24).

Increased scores on Fatigue-Inertia seen with all regimens, including placebo, in smokers (part B) but not in non-smokers (part A) and less pronounced effects with nicotine in part


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B suggests that abstinence from nicotine in smokers may have affected fatigue-inertia scores,

COGSTATE Cognition Tests.

The CogState battery used in the study (Parts A and B) consisted of the Detection Task the Identification task, the One Card Learning Task and the Groton Maze Timed Chase Task. The statistical analysis compared the change from baseline under each active treatment condition to that under placebo at each of the post-dose tests (six in Part A and four in Part B). Data for active treatment was calculated as active-placebo. The magnitude of the difference was plotted as were the 95% confidence intervals.

Part A: Summaries of the COGSTATE analyses versus placebo are presented in Data Source Table 12.14- Table 12.17, and Figure 12.10- Figure 12.13.

Overall, there were no significant changes in relation to dose response. The data for Part A was varied, most likely due to the small number of subjects completing each dose level (ranging from 8 to 11 subjects). In particular, for the top dose administered, 280mg, two of the female subjects felt dizzy and were unable to perform the task and this further reduced the number of subjects completing the battery test. In the 280mg cohort, 8 subjects received active treatment but only 6 managed to complete the entire Cogstate battery test. The cognitive testing did not show any significant cognitive deterioration with GSK1018921 in any dose level. A signal of improvement from baseline was seen at 280mg for the detection and identification tasks (Data source: Figure 12.10 and Figure 12.11). Similarly a signal of worsening was seen for the one card learning test at the same dose level (Data Source: Figure 12.12).

Part B: Table 9 summarises the COGSTATE analyses from Part B at the 1.5 and 4 hr time-points.

In this cross-over part of the study, 21 subjects completed the cognitive battery test and each subject received 80 mg, 200 mg and 4 mg nicotine. The same COGSTATE cognitive battery test was used as for Part A.

The 80 mg dose level showed a non-significant signal of improvement at 4 hr in the Detection task (-0.010 (CI: -0.037, 0.017)) (Data Source: Figure 12.25) and Identification Task (-0.022 (-0.046, 0.002)) (Data Source: Figure 12.26). The 200 mg showed a non-significant signal of worsening at 1.5 hours for the Detection task (0.026 (-0.003, 0.054)) (Data Source: Figure 12.25), Identification task (0.020 (-0.004, 0.044)) (Data Source: Figure 12.26) and Accuracy of performance (-0.077 (-0.163, 0.010)) (Data Source: Figure 12.27) at the 1.5 hr time-point.

Overall, data from Part B of the study indicates that 200mg dose showed a non-significant signal of worsening in attention and new learning at 4 hours assessment post dose. The lower dose (80 mg) showed a non-significant trend towards improvement in the same parameters and was in line with the active comparator, nicotine (4mg).


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Table 9 Summary of COGSTATE Analysis (All Subjects-Part B)

Task Endpoint Regimen Difference vs Placebo (95%CI)

Effect Size (Diff/SDb)

1.5h -0.010 (-0.037, 0.017) -0.20 4mg Nicotine Lozenge 4h -0.002 (-0.029, 0.026) -0.03

1.5h 0.001 (-0.027, 0.029) 0.02 80mg GSK1018921, fasted

4h -0.020 (-0.047, 0.008) -0.39

1.5h 0.026 (-0.003, 0.054) 0.50

Detection Task Speed of performance (mins)

200mg GSK1018921, fasted

4h -0.004 (-0.032, 0.024) -0.08

1.5h -0.028 (-0.052, -0.004)

-0.63 4 mg Nicotine Lozenge

4h -0.017 (-0.041, 0.007) -0.38 1.5h -0.016 (-0.040, 0.008) -0.37 80mg

GSK1018921, fasted

4h -0.022 (-0.046, 0.002) -0.49

1.5h 0.020 (-0.004, 0.044) 0.45

Identification Task

Speed of performance (mins)


4h -0.015 (-0.039, 0.009) -0.34

1.5h -0.013 (-0.101, 0.076) -0.08 4 mg Nicotine Lozenge 4h 0.046 (-0.042, 0.134) 0.30

1.5h -0.044 (-0.131, 0.043) -0.28 80mg GSK1018921, fasted

4h 0.021 (-0.066, 0.108) 0.13

1.5h -0.077 (-0.163, 0.010) -0.49

One Card Learning

Accuracy of Performance


4h -0.075 (-0.162, 0.012) -0.48

1.5h 3.481 (-0.469, 7.431) 0.43 4 mg Nicotine Lozenge 4h 0.990 (-2.960, 4.941) 0.12

1.5h -1.959 (-5.951, 2.033) -0.24 80mg GSK1018921, fasted

4h -2.972 (-6.964, 1.020) -0.37

1.5h -1.933 (-5.877, 2.011) -0.24

Groton Maze Learning Test Timed Chase Task

Total no of correct moves per second


4h -1.896 (-5.840, 2.048) -0.23

Data Source: Table 12.18, Table 12.19, Table 12.20, Table 12.21 Effect size=Treatment difference in LSmeans/Overall between subject SD Negative values for the Detection and Identification Tasks are indicative of an improvement over placebo. Positive values for the Groton Maze and One Card Learning Tasks are indicative of an improvement over placebo. Note that a larger magnitude effect size denotes a larger signal.

Glycine Concentration.

Part A: There were no remarkable differences between placebo and GSK1018921 doses for RBC Glycine concentrations. The baseline data for all doses was highly variable and therefore no dose response could be seen (Data Source: Table 12.4 and Figure 12.15).


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Part B: The plot of the mean and 95% CI for RBC Glycine concentration for Part B illustrates GSK1018921 80 and 200 mg fasted treatment regimens had decreased concentrations of RBC Glycine whilst Nicotine maintained RBC concentrations similar to those with Placebo (Figure 6). The GSK1018921 200 mg fasted regimen displayed greater decreases in RBC concentration than GSK1018921 80 mg, with concentrations lowest at 12 hrs.

The GSK1018921 80 mg fed regimen maintained higher RBC Glycine concentrations at pre-dose and up to 4 hrs post-dose, similar to placebo and nicotine but concentrations decreased from 4 hrs post-dose, closer to levels at 80mg fasted.

Figure 6 Plot of Mean and 95% Confidence Interval for RBC Glycine Concentration (All Subjects-Part B)


The plot of plasma Glycine concentrations showed all active GSK1018921 regimens (80 mg fasted, 200 mg fasted and 80 mg fed) had increased Glycine concentrations peaking at 2 hrs post-dose with 200 mg showing higher increase compared to 80 mg in the fasted state (Figure 7). Nicotine displayed similar concentrations to placebo throughout all timepoints.


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Figure 7 Plot of Mean and 95% Confidence Interval for Plasma Glycine Concentration (All Subjects-Part B)


MMN (Part B): For amplitude and latency, on average the values for all regimens were lower than those for Placebo (with exception of GSK1018921 80 mg for amplitude, which was very slightly higher) (Data Source: Table 12.9). However, all of the 95% CI for the differences included 0, suggesting there was no evidence of strong signal against placebo with any of the two doses or nicotine. (Data Source: Figure 12.31).

Pharmaco-EEG (Part B): A summary of the mixed model analysis results for Pharmaco-EEG relative power for frequency bands alpha, beta, delta and theta (Data Source: Table 12.8) are provided in Figure 8 in terms of t-values for treatment comparisons against Placebo. T-values >2 give an indication of trend towards statistical significance of the comparisons, although, given that several multiple comparisons were performed, by chance around 5% would be expected to be statistically significant.

Quantitative EEG for nicotine compared to placebo at 1.5 hr, eyes closed, showed a statistically significant decrease in theta band power (p<0.0001) and increased alpha band (p=0.001 relative and p=0.007 absolute power). A similar trend was seen at 2 hr post dose. Subsequent time-points post 2 hr did not display this trend for the same bands.

GSK1018921 80 mg compared with Placebo showed less pronounced differences, both for the absolute and relative power, although in line with the more marked trend observed at the 200 mg dose as shown in Figure 8.


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GSK1018921 200mg compared with Placebo at 1.5 hr shows lower values of alpha (p=0.009) and beta (p=0.002) and signals of increased values of delta and theta bands over the 6 hrs post dose. The peak of the increased theta and delta effects was observed at 4 hours post-dose (p=0.007 and 0.399, respectively).


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Figure 8 Plot of T-Values for Relative Power of Treatment Comparisons vs. Placebo, Eyes closed (All Subjects- Part B)

Nicotine versus Placebo 80 mg GSK1018921 versus Placebo 200 mg GSK1018921 versus Placebo

Data Source: Figure 12.29 fasted 4mg nic=4mg nicotine lozenge; Pl=Placebo; 80mg GSK = 80mg GSK 1018921, fasted; 200mg GSK=200mg GSK1018921.

CO

NFID

ENTIA

LG

M2008/00324/00

GT1109727

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LDAEP (Part B): Overall, there was an apparent non-significant downward trend of N1/P2 Amplitude slope value with increasing loudness (see Source Data Figure 12.32). All of the 95% CIs for the slopes included 0 for each regimen (Data Source: Table 12.10).

PK/PD Relationships

The PK/PD relationship between pharmacologic response and GSK1018921 concentrations was explored for different pharmacodynamic markers. Mean peak responses of different endpoints from the COGSTATE cognition tests were generally observed 1.5 hrs post dose (Part B), corresponding to peak GSK1018921 concentrations. However, given that the magnitude of response was generally small and only observed at that time point, no formal analyses were conducted.

Likewise, dose-related increases in mean plasma glycine were noted following oral GSK1018921 peaking at 2 hr post-dose and decreasing by 4 hrs, in agreement with peak systemic exposure. However, given the variability and the small magnitude of response, no exposure-response analyses were conducted.

Based on time of onset and offset of reports of dizziness (see Safety section for additional details), the fraction of subjects experiencing the AE were calculated at each time point for Study Part A (dose ≥ 70 mg) and Part B (80 and 200 mg dose) and plotted as a function of the mean GSK1018921 concentration (Figure 9). These plots suggest that dizziness is directly related to plasma GSK1018921 concentrations.

Figure 9 Fraction of Subjects Experiencing Dizziness vs. Mean GSK1018921 Concentration at Each Time Points for Study Part A (Left) and Part B (Right)

Mean GSK1018921 Concentrations (ng/mL)

0 100 200 300 400 500

Frac

tion

of S

ubje

cts

Exp

erie

ncin

g A

E

0.0

0.2

0.4

0.6

0.8

1.0

Dose 70 mgDose 120 mgDose 200 mgDose 280 mg

Mean GSK1018921 Concentrations (ng/mL)

0 50 100 150 200 250 300

Frac

tion

of S

ubje

cts

Exp

erie

ncin

g AE

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

Dose 80 mgDose 200 mg

Treatment included subjects receiving ≥ 70 mg for Study Part A and subjects receiving GSK1018921 in a blinded fashion (80 and 200 mg fasting) in Part B; Note that the scale on the Y-axis is different in Part A and B.


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Safety

A total of 21 subjects (84%) experienced an AE in Part A. Dizziness (total of 13 subjects; 52%) was the most common AE reported and was reported at doses of 70 mg and above with an apparent dose relationship (Table 10). Seven out of 8 (88%) subjects reported dizziness following the 280 mg dose. Headache (total of 11 subjects; 44%) was the next most frequently reported AE with a similar incidence across the dose groups. Visual disturbance was only reported following 280 mg (5 subjects, 63%) as well as blurred vision in this group only (1 subject, 13%). Photophobia was also noted at the 200mg dose level (1 subject, 10%). The high incidence of dizziness and visual disturbance following the 280 mg dose indicates that this dose level was not well tolerated.

Twenty-one subjects (84%) experienced AEs judged to be drug-related by the investigator (Data Source: Table 10.2). All episodes of dizziness, headache and visual disturbance were judged to be drug-related.

Table 10 Summary of Most Frequently Occurring Adverse Events (2 or More Subjects in any Group) in Non-Smokers (All Subjects-Part A)

GSK1018921 Preferred term

Placebo Only N=2

Placebo N=19

0.5 mg N=11

2 mg N=11

5 mg N=10

25 mg N=10

70 mg N=9

120 mg N=10

200 mg N=10

280 mg N=8

Total N=25

n (%)

N (%)

N (%)

n (%)

n (%)

n (%)

n (%)

N (%)

n (%)

n (%)

n (%)

Any Event 2 (100)

5 (26)

2 (18)

0 5 (50)

4 (40)

3 (33)

5 (50)

8 (80)

7 (88)

21 (84)

Dizziness 0 0 0 0 0 0 2 (22)

4 (40)

6 (60)

7 (88)

13 (52)

Headache 2 (100)

1 (5)

1 (9)

0 4 (40)

2 (20)

0 3 (30)

1 (10)

2 (25)

11 (44)

Fatigue 1 (50)

2 (11)

0 0 0 0 0 0 2 (20)

0 5 (20)

Visual disturbance

0 0 0 0 0 0 0 0 0 5 (63)

5 (20)

Data source: Table 10.1 NB: Total is total number of subjects experiencing the event not total number of events In Part A, there were no deaths, non-fatal Serious AEs, or pregnancies. Following GSK1018921 doses, there were no abnormalities of potential clinical concern in laboratory values or vital signs (Data Source: Table 10.6; Table 10.7 and Table 10.10). There were no ECG abnormalities of clinical significance. No QTc(B) or QTc(F) intervals were greater than 450 msec (Data Source: Table 10.14).

In Part B a total of 18 subjects (78%) experienced an AE. The most frequently occurring AE was dizziness (12 subjects; 52%) with the greatest incidence occurring in the GSK1018921 200 mg group (Table 11). Headache, gait disturbance, blurred vision, tunnel vision, photopsia and nausea also occurred with a greater frequency in the GSK1018921 200 mg group compared with the other groups.


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Seventeen subjects (74%) experienced AEs judged to be drug-related by the investigator (Data Source: Table 10.16). All episodes of dizziness, gait disturbance, blurred vision tunnel vision, photopsia and nausea were judged to be drug-related.

Table 11 Summary of Most Frequently Occurring Adverse Events (2 or More Subjects in any Group) in Smokers (All Subjects-Part B)

GSK1018921 Preferred Term

Placebo

N=21

Nicotine Lozenge

N=22

80 mg Fasted N=21

200 mg Fasted N=22

80 mg Fed

N=13

Total

N=23

N (%) N (%) n (%) n (%) n (%) n (%) Any Event 9 (43) 8 (36) 9 (43) 15 (68) 4 (31) 18 (78) Dizziness 1 (5) 2 (9) 4 (19) 8 (36) 1 (8) 12 (52) Headache 3 (14) 2 (9) 2 (10) 5 (23) 0 9 (39) Tunnel Vision 0 0 0 3 (14) 0 3 (13) Fatigue 0 1 (5) 2 (10) 2 (9) 1 (8) 6 (26) Gait disturbance 0 0 1 (5) 5 (23) 0 5 (22) Asthenia 0 0 2 (10) 1 (5) 0 2 (9) Blurred Vision 2 (10) 0 1 (5) 5 (23) 0 5 (22) Photopsia 0 0 0 3 (14) 0 3 (13) Polyuria 1 (5) 2 (9) 2 (10) 0 0 5 (22) Nausea 0 1 (5) 0 2 (9) 0 3 (13) Data Source: Table 10.15 NB: Total is total number of subjects experiencing the event not total number of events In Part B, there were no deaths, non-fatal SAEs, or pregnancies. There were no post-dose abnormalities of potential clinical concern in laboratory values or vital signs (Data Source: Table 10.20; Table 10.21 and Table 10.24). One subject on 80mg GSK1018921 fed regimen (pre-dose) and another subject on both 80mg GSK1018921 fasted (3 hrs post-dose) and 200mg GSK1018921 fasted regimen (pre-dose) had QTc(B) or QTc(F) intervals greater than 450 msec (Data Source: Table 10.28). There were no ECG abnormalities that were judged to be clinically significant.

Discussion and Conclusions:

• GSK1018921 was rapidly absorbed following administration of oral tablet doses under fasted conditions, with median tmax occurring at about 1.5 hrs over a wide dose range of 0.5 to 280 mg. Elimination of GSK1018921 from plasma followed an apparent bi- or tri-exponential decay, with mean terminal half life ranging from 16-19 hrs across 70-280 mg dose levels.

• Renal excretion is a minor elimination pathway for the parent compound GSK1018921, with less than 2.5% of the dose, on average, recovered in urine as unchanged GSK1018921.

• AUC(0-∞) of GSK1018921 increased slightly more than dose proportionally over the 25 mg to 280 mg dose range, and Cmax of GSK1018921 increased approximately dose proportionally over the 2 mg to 280 mg dose range.


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• Pharmacokinetic parameter estimates of GSK1018921 appeared to be similar between healthy non-smokers and smokers.

• Administration of food had no clinically significant effects on Cmax and AUC with mean ratio (90% CI) of 0.934 (0.683-1.279) and 1.19 (0.912-1.553), respectively.

• GSK1018921 displayed reduced RBC Glycine concentrations with an apparent dose response, whilst Nicotine maintained RBC glycine concentrations similar to those with placebo. This suggests that GlyT-1 sites on RBC were blocked by GSK1018921 leading to reduced RBC glycine levels.

• Single doses of GSK1018921 increased plasma Glycine concentrations at 2 hrs post-dose with an apparent dose response relationship with the 200 mg regimen displaying higher mean plasma Glycine concentrations. As expected, plasma glycine concentrations on the nicotine regimen did not differ dramatically from placebo.

• Neither GSK1018921 nor nicotine showed any significant modulation of MMN amplitude or latency.

• In healthy smokers, single doses of GSK1018921 showed clear pharmacodynamic effects on quantitative EEG with an apparent dose response. GSK1018921 200 mg showed signals of increased delta and theta band power and decreased alpha and beta band powers with eyes closed over the first 6 hrs post-dose, peaking at 4 hrs post-dose. Benzodiazepines, which impair cognitive performance with single doses, are known to increase beta power. In contrast, decreased beta power with GSK1018921 might suggest potentially beneficial effects on cognition. Enhanced theta, delta bands and reduced alpha band suggests single GSK1018921 200 mg dose might have relaxing effects in smokers as no sedative effects were reported during the study.

• GSK1018921 showed no signals of cognitive effects in healthy smokers except at 1.5 hours post dose. Non-significant signals of impaired attention and new learning tasks noted at 1.5 hours post dose only with GSK1018921 200 mg dose coincided with 36% of subjects experiencing Cmax related dizziness and 23% experiencing blurred vision.

• Single doses of GSK1018921 did not modulate LDAEP in healthy abstained smokers.

• The compound was generally well tolerated up to a dose of 200 mg (maximum tolerated dose). The most common AE was dizziness and was reported at doses of 70 mg and above, with direct relationship to GSK1018921 exposure. In Part A, visual disturbance and blurred vision only occurred following doses of 280 mg. In Part B, gait disturbance, blurred vision, tunnel vision, photopsia and nausea occurred with a greater frequency in the GSK1018921 200 mg group.

Date of Report: July 2009.


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