The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. Study No: CRS105510 Title : A randomised, placebo-controlled, double-dummy, crossover design study to investigate the changes of fmri BOLD activation induced by emotional activation paradigms following single doses of GSK561679 and lorazepam (comparator) in healthy subjects. Rationale: GSK561679 is a selective corticotropin releasing factor 1 (CRF1) receptor antagonist that was being developed for the treatment for depression and anxiety. In preclinical studies CRF1 antagonists are known to produce anxiolytic-like effects only during emotional arousal or stress exposure, without evidence of sedative or inhibiting effects on spontaneous behavior. Therefore, it was predicted that this similarity of effects would be observed also in humans when administered at single dose. For this study a well-established emotional activation functional magnetic resonance imagining (fmri) paradigm was used to investigate the attenuating effects of the novel CRF1 antagonist GSK561679 in healthy volunteers and provide a pharmacokinetic/ pharmacodynamic (PK/PD) model for predicting dose-response relationship. The expected result was a reduction of fmri blood oxygenation level-dependent (BOLD) signal in amygdala and/or insula of subjects challenged in a proper protocol of emotional activation. Since CRF-1 receptor antagonism may effect hypothalamic-pituitary-adrenal (HPA) axis and levels of stress hormones, plasma levels of cortisol and ACTH were also measured. On this basis, it was proposed that novel compounds with putative anxiolytic-like effects might be studied in this paradigm with the aim to assess their capacity to attenuate the limbic activation associated with processing of negative emotions, an important component of the response to stress and symptoms of anxiety/mood disorders. Phase: I Study Period: 13 SEP 2007-14 MAY 2009 Study Design: This was a placebo-controlled, randomised, double-blind, double-dummy, 4-way cross-over design, followed by an open-label 5 th session where all subjects received GSK561679 400 mg. Following an initial telephone screening, subjects participated in a pre-study screening visit. There were five dosing sessions. Given the long half-life of the compound seen at higher doses, the highest dose of GSK561679 was given always in Session 5 to avoid any carry-over effect. No carry-over was anticipated with the lower two doses therefore, Sessions 1-4 were conducted in a randomized double-blinded fashion, whereas Session 5 was single-blinded. Subjects received a single dose of medication in each session (i.e. placebo, 1 mg lorazepam, 10, 50 or 400 mg GSK561679) followed by a washout of at least seven days. All subjects were required to return for a follow-up visit at approximately 28 days after the last dose of study medication. Each session consisted of medical assessments, baseline measurements, a snack during drug administration to reduce the GSK561679 PK variability, dosing on two separate occasions (-90 min for either placebo or GSK561679 and -45 min with either placebo or lorazepam), safety assessments, an fmri session with a planned series of activation challenge, PK sampling and recording of adverse events. Blood oxygen level dependent (BOLD) fmri data were collected during the task using a Signa EXCITE 3.0 Tesla-GE scanner with sequences described in the University of California San Diego (UCSD) report. Centres: The University of California at San Diego, 8950 Villa La Jolla Drive, La Jolla, California, United States, 92037. Indication: None. Treatment: Subjects were assigned to study treatment in accordance with the randomization schedule provided by a GSK statistician. Objectives: To measure fmri BOLD response in the amygdala and insula elicited by Matching Emotional Face Expression paradigm following single oral doses of GSK561679, Lorazepam or placebo. Statistical Methods: Sample Size- The power calculation was performed on the basis of results from a previous cross-over study assessing the effect of two doses of lorazepam on amygdala and insula and using the same paradigm. In that study, ratios of effect/( standard deviation [SD] within subjects) >1 were observed for the comparison between Lorazepam 1 mg and placebo. Assuming a ratio effect/sd within subjects of at least 1, it was calculated that 17 evaluable subjects would have provided 80% power. This assumed a two-tailed test with alpha=5%. The following analysis populations were defined; 1
All subjects population: All subjects who received at least one dose of any study drug. Pharmacodynamic (PD) population: All subjects who received at least one dose of any study drug and who provide at least one post-treatment PD datum. Modified PD population: All sessions of the previous population excluding data collected on the last period (GSK651679 400 mg). Pharmacokinetic (PK) Population: All subjects for whom a pharmacokinetic sample was obtained and analyzed. Interim analysis and randomization- No formal interim analysis was planned or carried-out. However, in order to accelerate the analysis of imaging data, after the last patient last visit but before the data base was frozen, the random code was sent to the investigator. Treatment groups were anonymously described as X,W,Y,Z,U and were not communicated to those still involved in the cleaning process. fmri data Statistical analyses of fmri BOLD data were the responsibility of the investigator. Appropriate models for cross-over trials were applied to the imaging data. The analysis was run in two steps: a first analysis as described in the Method session (Session 1 to 5) performed in 15 subjects by applying Analysis of Variance (ANOVA). This analysis showed no effects of treatments. A second analysis was performed on all data available for all subjects using linear mixed effects (LME) models in R (www.cran.org) with parameters estimated using Maximum Likelihood Estimation (MLE). Cortisol and ACTH - Log-transformed Cortisol and ACTH values were analyzed using a mixed effect model including terms for treatment, period, pre-dose, baseline, time (pre fmri, post fmri and prior to leaving the clinic), treatment*time, pre-dose*time, baseline*time as fixed effects, and subject as a random effect. This model was applied to the data collected over the first four periods. Baseline is defined as the mean values (of the log-transformed values) over the pre-dose values in the 4 different periods. Results of the treatment comparisons at each occasion (expressed as least squares geometric means, ratio between least squares geometric means, 95% confidence interval. of the ratios and p-values) were reported. Values measured in the last period (with GSK561679 400 mg) were compared vs. the other treatment groups separately, using a model not including the period effect. Visual Analogue Scales (VAS) Scales - The analysis followed the same approach described above for Cortisol and ACTH values, but in this case was based on the original values without any transformation of the data. Changes in conduct of the study or planned analyses - Subject #21, in Session 3, vomited after the drug administration, data from this session were excluded from any PD and PK statistical analysis. Study Population: Healthy non-smoking males or females aged 18-50 years inclusive, with a Speilberger Trait Anxiety Inventory (STAI) score of >40 and with a STAI-state score <50 th percentile of the normal population were eligible to participate. Left handed subjects and subjects with any history of psychiatric illness or endocrine disorder were excluded. Number of Subjects: Total planned, N: 20 randomized, N 22 completed as planned, n (%) 17 (77) Number of subjects included in All subjects (safety) population, n 22 (100) (%) Number of subjects included in PK population, n (%) 22 (100) Number of Subjects Withdrawn (any reason), n (%) 5 (23) Withdrawn due to Adverse Events n (%) 1 (5) Withdrawn for Other Reasons n (%) 4 (18) Demographics Age in Years, Mean (Range) 29.3 (19-50) Females: Males 10: 12 Mean Weight in Kg (Range) 73.90 (51.7-98.0) White n (%) 13 (59) Pharmacodynamics (PD) Endpoints: Reaction Time to Task Condition for Each Compound Condition Placebo GSK561679 Lorazepam 10 mg 50 mg 400 mg 1 mg Oval Shapes 853.31 867.30 894.46 812.60 941.43 Angry 1258.51 1252.06 1339.90 1244.58 1490.60 Fear 1321.13 1344.48 1404.76 1409.70 1619.15 2
Happy 1054.15 1001.78 1059.82 1028.17 1249.45 fmri data analysis: Overall drug effects. Brain regions whose BOLD activation was modified by drug treatment ROI Number Volume x y z Brain Area BA 1 3392-36 -49-12 Left Fusiform Gyrus BA 37 2 3264-4 28-8 Left Anterior Cingulate BA 32 3 3072 36-50 -11 Right Fusiform Gyrus BA 37 4 2816 10 40 9 Right Anterior Cingulate BA 32 5 1792-7 9 1 Left Caudate BA 25 6 1408-12 36 10 Left Anterior Cigulate BA 32 7 1152 41 0-6 Right Insula BA 13 8 896-41 -27 16 Left Insula BA 13 9 704 23-8 -12 Right Amygdala BA 34 10 704 44-17 -3 Right Insula BA 22 11 704-33 6 14 Left Insula BA 13 12 640-46 -7 6 Left Precentral Gyrus BA 6 13 576-38 -77-14 Left Fusiform Gyrus BA 19 14 576-42 5-5 Left Insula BA 13 15 512 46-6 -25 Right Fusiform Gyrus BA 20 16 512-24 -7-17 Left Amygdala BA 34 17 512-21 -89-12 Left Fusiform Gyrus BA 18 18 512-33 21 11 Left Insula BA 13 19 512 10 20 20 Right Anterior Cingulate BA 24 20 448-1 5-10 Left Anterior Cingulate BA 25 21 384 51-52 -20 Right Declive BA 37 22 384-27 -66-9 Left Fusiform Gyrus BA 19 23 384-36 20-1 Left Brodmann area 47 BA 47 24 384 52-35 16 Right Superior Temporal Gyrus BA 13 25 384 16-12 23 Right Caudate - 26 384 42-19 20 Right Insula BA 13 27 320-52 -10-25 Left Fusiform Gyrus BA 20 28 320 27-1 -17 Right Parahippocampal Gyrus BA 34 29 320 42-77 -12 Right Fusiform Gyrus BA 19 30 320 17 38-6 Right Anterior Cingulate BA 10 31 320-15 -9 24 Left Caudate - 32 256 39 20 2 Right Insula BA 13 Note: BA = Brodmann areal. Significant clusters are presented at the one-sided p=0.01 level and an extent threshold of 256µL, X = 1 mg Lorazepam, Y = 10 mg GSK561679, Z = 50mg GSK561679, ROI = Region of Interest. fmri primary endpoint analysis: The LME analysis revealed a unilateral attenuation of activation in the right amygdala region with Lorazepam. Left amygdala BOLD response to emotional faces was attenuated by GSK561679 10 mg while at the dose of 50 and 400 mg increased amygdala responsivity to facial emotional expressions. BOLD response in insula was not attenuated by lorazepam, at variance with expected outcome. GSK561679 showed variable effects, with attenuation at the doses of 10 and 400 mg and no change with the dose of 50 mg. ROIs Placebo GSK561679 Lorazepam 10 mg 50 mg 400 mg 1 mg R Amygdala 0.07-0.02 0.15 0.05-0.025 L Amygdala 0.1-0.1 0.08 0.15-0.025 Endocrine effects of GSK5616679 and lorazepam administration Parameter Time Comparison Geom. LS mean Test Treat. ACTH (ng/l) 4 h 40 m (post scan) GSK561679 10 GSK561679 50 Geom. LS mean Ref Treat. Ratio 95% C.I. p-value 12.4 12.0 1.03 (0.75, 1.41) 9.2 12.0 0.77 (0.58, 1.02) 0.856 0.072 3
GSK561679 4.7 12.0 0.39 (0.29, <0.001 400 mg -Placebo 0.53) Lorazepam- 14.2 12.0 1.18 (0.89, 0.252 Placebo 1.58) Cortisol 4 h 40 m GSK561679 10 273.1 264.5 1.03 (0.79, 0.813 (noml/l) (post scan) mg -Placebo GSK561679 50 190.9 264.5 0.72 1.35) (0.56, 0.013 0.93) GSK561679 120.5 264.5 0.46 (0.35, <0.001 400 mg -Placebo 0.60) Lorazepam- 332.6 264.5 1.26 (0.98, 0.076 Placebo 1.62) Note: Subject # 21in Session 3 was excluded because the subject vomited after drug administration Pharmacokinetics (PK) Endpoints: Summary of Plasma GSK561679 Pharmacokinetic Concentration- Time Data (ng/ml) Treatment N Time N Mean SD Median Min Max GSK561679 10 mg 20 2 h-pre fmri 19 23.8 9.7 23.8 11.9 45.9 4.67 h-post fmri 19 12.1 5.0 11.5 5.7 28.4 GSK561679 50 mg 20 2 h-pre fmri 20 114.3 48 102.9 39.9 218.9 4.67 h-post fmri 20 59.5 35 52.1 22.1 182 GSK561679 400 17 2 h-pre fmri 16 1381.3 538.1 1376.8 302.8 2243.6 mg 4.67 h-post fmri 16 630.6 279.8 647.7 158.2 1278.6 Safety results: Adverse event (AE) and serious adverse event (SAE) data were collected and recorded on the case report form (CRF) starting from the first dose of investigational product until the study completion. A total of 40 AEs were reported by 14 (64%) subjects across all treatment groups. Most of the AEs were mild (32 AEs) to moderate (4 AEs) in intensity (3 AEs were not classed by the Investigator), except one subject who experienced a severe episode of headache following dosing with GSK561679 400 mg (Period 5). The event was not considered to be drug-related by the Investigator. The most common AEs (AEs >5% within each treatment group) reported across all treatment groups were somnolence, headache, dizziness, disturbance in attention, fatigue, feeling abnormal, nausea and cough. Eleven subjects experienced 25 AEs, which were considered to be possibly related to the investigational product by the Investigator. The most common drug-related AE was somnolence following dosing with GSK561679 400 mg and lorazepam. One subject was withdrawn due to AEs (crying and depression) which occurred during dosing with lorazepam (Period 2) and 10mg GSK561679 in Period 3 (crying and depression). Both episodes resolved and subject did not experience any AE during Period 4 (50mg GSK561679) and was withdrawn from study prior to Period 5 (400mg GSK561679). Summary of Number of Subjects Reporting All AEs on Treatment Adverse Events Placebo GSK561679 Lorazepam 10 mg 50 mg 400 mg N=20 N=20 N=20 N=17 N=20 Any Event, n (%) 2 (10) 6 (30) 1 (5) 6 (35) 6 (30) Somolence 0 0 0 1 (6) 4 (20) Dizziness 0 2 (10) 0 1 (6) 0 Headache 1 (5) 0 0 3 (18) 0 Disturbance in 0 0 0 0 2 (10) attention Coordination 0 1 (5) 0 0 0 abnormal Crying 0 1 (5) 0 0 1 (5) Mental impairment 0 0 0 0 1 (5) Fatigue 0 0 0 1 (6) 1 (5) Catheter site 0 0 0 0 1 (5) hematoma Feeling abnormal 0 0 0 1 (6) 0 Irritability 0 0 0 0 1 (5) 4
Depressed mood 0 0 0 0 1 (5) Depression 0 1 (5) 0 0 1 (5) Disorientation 0 0 0 0 1 (5) Insomnia 0 0 0 0 1 (5) Stress 0 1 (5) 0 0 0 Dyspepsia 1 (5) 0 0 0 0 Nausea 0 0 0 1 (6) 0 Vomiting 0 1 (5) 0 0 0 Drug hypersensitivity 0 1 (5) 0 0 0 Multiple allergies 1 (5) 0 0 0 0 Cough 0 0 1 (5) 1 (6) 0 Nasal congestion 0 0 1 (5) 0 0 Ear discomfort 0 0 0 0 1 (5) Influenza 1 (5) 0 0 0 0 Rash 0 0 0 0 1 (5) Serious Adverse Events, n (%) [n considered by the investigator to be related, possibly related, or probably related to study medication]: No non-fatal or fatal SAEs were reported during the study. 5