Study No: Title : Rationale: Phase: Study Period: Study Design: Centres: Indication: Treatment: Objectives: Statistical Methods:

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1 Study No: MNK Title : A healthy volunteer repeat dose study to evaluate; the safety, tolerability, pharmacokinetics, effects on the pharmacokinetics of midazolam and the neurokinin-1 (NK1) receptor occupancy of GSK Rationale: The study described in the present protocol consisted of two parts. Part A was a multiple ascending dose study to evaluate the safety, tolerability and pharmacokinetics of ascending doses of GSK and to investigate the potential CYP3A4-inhibiting activity of GSK after multiple dosing on the pharmacokinetics of oral midazolam (substrate). The study design was single-blind, randomised, placebo-controlled in healthy male and female (of non-childbearing potential) subjects. Part B was an open-label design in healthy male subjects to assess the GSK NK1 receptor occupancy after repeat oral dosing by positron emission tomography (PET) scanning with [ 11 C]-GR Phase: 1 Study Period: 01 JUL OCT 2009 Study Design: Part A was a parallel group, single-blind, randomised, placebo-controlled design in healthy male and female (of non-childbearing potential) subjects to evaluate the safety, tolerability and PK of multiple ascending doses of GSK Part B was an open-label assessment in four subjects, of NK1 receptor occupancy by GSK in the living human brain, following multiple daily doses of GSK Establishing the NK1 receptor occupancy at steady state will be important information when selecting doses for efficacy studies. For this purpose, positron emission tomography (PET) with the NK1 radiotracer [11C]GR was employed. GSK was provided as a liquid solution and administered orally. Centres: Dr. Maura Fallon Parexel International Clinical Pharmacology Research Unit (CPRU) Level 7 Northwick Park Hospital Watford Road Harrow HA1 3UJ United Kingdom Indication: Schizophrenia, Depression Treatment: GSK doses up to 200 mg (administered as three split doses of 75 mg [37.5%], 62.5 mg [31.25%] and 62.5 mg [31.25%]) Objectives: Part A: To investigate the safety and tolerability of multiple ascending oral doses of GSK in healthy male and female (of non-childbearing potential) subjects. To investigate the pharmacokinetics of multiple ascending oral doses of GSK in healthy male and female (of non-childbearing potential) subjects. To investigate the potential CYP3A4-inhibiting activity of GSK after multiple dosing on the pharmacokinetics of oral midazolam (substrate) in healthy male and female (of non-childbearing potential) subjects. Part B: To investigate the NK1 receptor occupancy (NK1 RO) in the brain at the time of plasma steady state for GSK , at approximately 24 hours post-last-dose of GSK in healthy male subjects. Statistical Methods: Sample Size: The planned sample size for Part A depended primarily on logistic feasibility, however, an estimate on how the targeted sample size would affect the width of the 90% confidence intervals (CIs) of the main PK parameters estimates ('accumulation ratio' and 'time invariance') was provided in the protocol. The study planned to recruit up to 6 subjects (plus 6 replacements) into Part B. Only four subjects were recruited into the study as data from these subjects was considered sufficient to define the GSK plasma concentration versus NK1 receptor occupancy curve at steady state. Part A - Safety Analyses: No formal statistical analysis of safety data was planned or performed. Part A - Pharmacokinetic Analyses: All 33 subjects (29 subjects from Part A and four subjects from Part B) who received a dose of GSK and who provided at least one PK sample were included in the 'PK population'. Plasma concentration versus time data for GSK and midazolam were evaluated by standard noncompartmental analysis using appropriate software. Individual plasma GSK and midazolam concentration versus time profiles for each subject and mean and median plasma concentration versus time profiles by dose were generated.the following PK parameters for GSK and midazolam were log-transformed prior to statistical analysis: AUC0-t, AUC0-τ (GSK only), AUC0-, Cmax, and t½. 1

2 The following PK parameters were determined for each subject Part A for from the plasma concentration time profiles after single dose for both GSK and midazolam on each PK profile day: Cmax, tmax, AUC0-t, AUC0-, %AUCex, λz, t½, tlag.the following PK parameters were determined for each subject from the plasma concentration time profiles after repeat dosing with GSK : Cmax, tmax, and AUC0-τ.For each of these parameters (except tmax, λz, tlag, and %AUCex), the following summary statistics was calculated and tabulated by treatment: n, arithmetic mean, 95% CI (confidence interval) for the arithmetic mean, standard deviation, minimum, median, maximum, geometric mean, 95%CI for the geometric mean, and standard deviation of loge-transformed data. Between-subject coefficient of variation (%CVb) was also calculated.for tmax,tlag and %AUCex, n, median, minimum, maximum, arithmetic mean, 95% CI for the arithmetic means and standard deviation was calculated. Accumulation Ratio:Statistical analysis of AUC0-24 was performed after a log-transformation of the data from all active treatments. For each cohort separately, a mixed-effect model was fitted with day as fixed effect and subject as a random effect. Days 7, 14 and 28 (where applicable) was compared with Day 1 (single dose) for each dose level.the accumulation ratio was calculated by back-transforming the difference between the least-squares means (LSmeans). Using the estimate of variance, 90% CIs was calculated for the difference and back-transformed. Time Invariance:Statistical analysis of AUC0- after single dose and of AUC0-24 after repeat dosing were performed after a log-transformation of the data from all active treatments. The same analysis was performed as for the accumulation ratio. Achievement of Steady State:To evaluate whether steady state was achieved, statistical analysis of Cτ levels were separately performed around Days 7, 14 and 28 (where applicable) of multiple daily dosing after a log-transformation of the data from all active treatment groups.the assessment around Day 7 was specifically performed including predose values collected on Days 5, 6, 7, and 8. Similarly the assessment around Day 14 included pre-dose values collected on Days 12, 13, 14, and 15 and the assessment around Day 28 was based on pre-dose values collected on Days 26, 27, 28, and 29. A mixed effect model was fitted for each treatment group separately and for each assessment (around Day 7, 14 or 28) with day as a continuous covariate and, subject as a random effect. The coefficient of the slope of the day effect on the log-scale for each treatment group was used to investigate whether steady state was achieved around Days 7, 14 and 28. Using the estimate of variance, the 90% CIs for the slopes were calculated. Effect of Repeat Doses of GSK on Midazolam (Part A, Cohort 3) Following log-transformation, midazolam AUC0- and Cmax were analysed by a mixed effect analysis of variance (ANOVA) model with day as fixed effect and subject as random effect. Point estimates and corresponding 90% CIs were computed for the differences, Day 29 (Treatment Period 3) Day 1 (Treatment Period 1) using the residual error from the ANOVA (MSE). The point and interval estimates on the log-scale were then exponentially back transformed to give estimates of the ratios of geometric means and 90% CIs. Data for subjects treated with placebo were listed and summarised but they were excluded from the analysis described above. Dose Proportionality (GSK ) An analysis of dose proportionality was performed taking into account AUC0-24 values on Day 7 and the AUC0-24 at the end of treatment (Day 14 [Cohorts 1 and 2], Day 28 [Cohort 3]). It was based on application of the following power model: log(y) = α + βlog(dose) where y denotes the PK parameter and α is an intercept term. Dose proportionality in this model equates to β=1. A point estimate and 90% CI were derived for β. Effect of GSK on 6- β-hydrocortisol/cortisol Ratio In each cohort separately following log-transformation the 6-β-hydroxycortisol/cortisol ratio, was analysed by a mixed effect ANOVA model with day as fixed effect and subject as random effect. Point estimates and corresponding 90% CIs were computed for the differences, Day 14 (Cohorts 1 and 2) or Day 28 (Cohort 3) Baseline (Day -1) using the residual error from the ANOVA (MSE). The point and interval estimates on the log-scale were then exponentially back transformed to give estimates of the ratios of geometric means and 90% CIs. Differently from what stated in the RAP the analysis was performed also on subjects treated with placebo, grouping together the post-dose assessments (that is, pooling Day 14 and Day 28 data). Part A - Pharmacodynamic Analysis For the subjects whose starting dose was reduced for any reason during the repeated dose period, any cognitive test result observed after the dose modification was excluded from summary statistics or statistical analysis. Results of cognitive tests (primary outcome for each Cogstate task) were summarised by treatment, day and time. Plots reporting mean values (±standard deviation) by treatment and time for the main outcomes were provided. In Table 1 the list of tasks and the relevant outcome considered in the analyses. Table 1 Cogstate Tasks and Main Outcome 2

3 Code Groton Maze Learning Task One Card Learning Task Detection Task Identification Task Main Outcome Total error rate Accuracy of performance = arcsine transformation of the proportion of correct responses Speed of performance = mean of the log10 transformed reaction times for correct responses Speed of performance = mean of the log10 transformed reaction times for correct responses Each outcome was analysed using a mixed effect model including the terms baseline (screening), time (pre-dose, 1, 2, 8 hours for Day 2 and pre-dose for Day 13), treatment, treatment*time and, baseline*time as fixed effects and subject as a random effect. Least-squares means were evaluated for each treatment regimen. Estimates of treatment differences from placebo were calculated together with 95% CIs. Change from baseline (and 95% CI limits) at each time-point for Cogstate individual tests, were standardised into effect sizes (that is, estimate of treatment difference / standard deviation) using the between-subject standard deviation corresponding to each time-point. The estimates of the between-subject standard deviation for each time-point were tabulated. Part B Safety and PK Analyses: Due to the small sample size the analysis, safety and PK data were listed and no summary statistics were provided. Part B - PK/PD Analysis: The relationship between GSK plasma concentrations with the NK1 receptor occupancy was evaluated using suitable modelling techniques. Analyses of NK1 Receptor Occupancy Images were reconstructed with scatter and attenuation correction. For each subject, the dynamic PET data were corrected for motion and realigned to the subjects corresponding structural T1 weighted magnetic resonance imaging (MRI) data. A target region of interest (frontal cortex) and reference region (cerebellum) were delineated on the structural MRI images and applied to the dynamic PET data to generate regional time activity curves. An arterial plasma-metabolite corrected plasma input function was derived and used as an input function to a two tissue compartmental model in order to derive regional estimates of the total PET distribution volume (VT). Population metabolite data was used to correct the for radio-labelled metabolites in plasma. The binding potential (BPND) was then calculated from the VT of the region of interest and a reference region (in this case the cerebellum) as below: Equation: Error! Objects cannot be created from editing field codes. The BPND values from baseline and post-dose scans were used to estimate the occupancy by GSK of NK1 receptors at each scan. PK Methods: Plasma concentration versus time data for GSK and midazolam were evaluated by standard noncompartmental analysis. Study Population: Male or female aged between 18 and 55 years (inclusive) for Part A, or male aged between 25 and 55 years (inclusive) for Part B. Number of Subjects: Part A Part B Planned N 37 6 Dosed N 37 4 Completed n (%) 36 (97) 3 (75) Total Number Subjects Withdrawn N (%) 1 (3) 1 (25) Withdrawn due to Adverse Events n (%) 1 (3) 0 Withdrawn due to Lack of Efficacy n (%) 0 0 Withdrawn for Other Reasons n (%) 0 1 (25) Demographics Part A Part B N (ITT) 37 4 Females: Males 0 : 37 0:4 Mean Age in Years Mean Weight in Kg White n (%) 26 (70) 2 (50) 1 Range stated due to the small N 3

4 Pharmacokinetics (PK),pharmacodynamics (PD), PK/PD Endpoints: Accumulation Ratio; A summary of the results of the statistical analysis is reported below. Treatment Comparison LS Geo.Mean Test LS Geo.Mean Ref. Ratio 90% CI GSK mg Day 7 / Day (1.23, 2.15) Day 14 / Day (1.58, 2.58) GSK mg Day 7 / Day (1.11, 1.66) Day 14 / Day (1.14, 1.71) GSK mg Day 7 / Day (1.57, 2.11) Day 28 / Day (1.54, 2.27) Time Invariance: A summary of the results of the statistical analysis is reported below. Treatment Comparison LS Geo.Mean Test LS Geo.Mean Ref. Ratio 90% CI GSK mg Day 7 / Day (1.06, 1.59) Day 14 / Day (1.32, 1.96) GSK mg Day 7 / Day (0.94, 1.35) Day 14 / Day (0.97, 1.38) GSK mg Day 7 / Day (1.05, 1.32) Day 28 / Day (0.98, 1.56) Achievement of Steady State: A summary of the results of the statistical analysis applied on log transformed GSK is reported below. Treatment Days Back-Transformed Slope 90% CI GSK mg Days ( 1.010, 1.070) Days ( 1.065, 1.214) GSK mg Days ( 0.983, 1.070) Days ( 0.970, 1.071) GSK mg Days ( 0.982, 1.028) Days ( 0.952, 0.989) Days ( 0.955, 1.024) Dose Proportionality:. A summary of the results of the statistical analysis for GSK is reported below. Parameter Adjusted Mean Slope Standard Error 90% CI (Lower,Upper) Day 7 AUC0-24 (ng*hr/ml) ( 1.075, 1.457) End of treatment AUC0-24 (ng*hr/ml) ( 0.920, 1.357) Effect of GSK on Midazolam Pharmacokinetics: A summary of the results is reported below. Parameter Comparison LS Geo.Mean Test LS Geo.Mean Ref. Ratio 90% CI AUC0- Mid+GSK / Midazolam alone (1.62, 2.23) Cmax Mid+GSK / Midazolam alone (1.40, 2.10) Effect of GSK on 6-β-hydroxycortisol/cortisol Ratio: Results are summarised below. Treatment Comparison LS Geo.Mean Test LS Geo.Mean Ref. Ratio 90% CI Placebo Post / Pre (1.01, 1.89) GSK Post / Pre (1.08, 1.70) GSK Post / Pre (1.03, 1.26) 4

5 GSK Post / Pre (1.05, 1.39) Part B VT and BPND data are presented below. Subject ID Oral dose of GSK (number of daily doses in treatment period) Scan time post last dose (hrs) Scan time post first dose (hrs) GSK VT frontal plasma cortex concentration at start of scan (ng/ml) VT cerebellum Results frontal cortex 2001 Baseline mg (8 doses) % BPND Receptor occupancy 2002 Baseline mg (7 doses) % 9 mg (6 doses) % 2003 Baseline mg (7 doses) % 50 mg (7 doses ) % 2004 Baseline mg (7 doses ) % 50 mg (7 doses ) % BPND: binding potential; VT: volume of distribution (ml/cm 3 ). Pharmacokinetics/Pharmacodynamics Part B The EC50 for NK1 RO was estimated as 0.97 ng/ml (95% ) from an Emax model assuming full occupancy could be achieved (using receptor occupancy results from all doses with GSK plasma concentrations). This was consistent with the EC50 predicted from the single dose occupancy study (EC50 = 0.88 ng/ml). The relationship between the plasma concentration and NK1 receptor occupancy is consistent with a direct model. In addition, based on EC50 values the concentration required to approach >95% NK1 RO is estimated as 18.4 ng/ml (95% ). Based on an anticipated 10-fold lower affinity for NK3 receptors as compared to NK1 receptors, the EC50 for NK3 RO is estimated to be ~ 9.7 ng/ml. Safety results: The most frequent AEs in Part A were headache and somnolence while the most frequent AE in Part B was catheter site haematoma. Although no clear dose-related trend was visible in the number of subjects reporting AEs overall, nervous system disorders and gastrointestinal disorders were reported by more subjects following the 200 mg dose of GSK , than following the 30 mg and 90 mg doses. One subject was withdrawn due to an AE. The subject was withdrawn due to atrial fibrillation following a vasovagal syncope after blood collection via syringe. The event occurred on Day 1 in Treatment Period 1, following administration of a single dose of 45 mg GSK Subjects receiving 200 mg GSK tended to show greater reductions in free and total testosterone levels on Day 14 and Day 30 when compared to placebo. Adverse Events: Part A Part B N (ITT) 37 4 No. subjects with AEs n (%) 27 (73%) 4 (100%) Most Frequent AEs Headache Catheter site haematoma Somnolence Dizziness postural Diarrhoea Epigastric discomfort Application site irritation Fatigue 5

6 Serious Adverse Events, n (%) [n considered by the investigator to be related, possibly related, or probably related to study medication]: None Publications: None. 6