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

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1 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: CRS 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 GSK and lorazepam (comparator) in healthy subjects. Rationale: GSK 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 GSK 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 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 GSK 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 GSK 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 GSK PK variability, dosing on two separate occasions (-90 min for either placebo or GSK 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, 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

2 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 (GSK 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 ( 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 GSK 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 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) ( ) White n (%) 13 (59) Pharmacodynamics (PD) Endpoints: Reaction Time to Task Condition for Each Compound Condition Placebo GSK Lorazepam 10 mg 50 mg 400 mg 1 mg Oval Shapes Angry Fear

3 Happy 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 Left Fusiform Gyrus BA Left Anterior Cingulate BA Right Fusiform Gyrus BA Right Anterior Cingulate BA Left Caudate BA Left Anterior Cigulate BA Right Insula BA Left Insula BA Right Amygdala BA Right Insula BA Left Insula BA Left Precentral Gyrus BA Left Fusiform Gyrus BA Left Insula BA Right Fusiform Gyrus BA Left Amygdala BA Left Fusiform Gyrus BA Left Insula BA Right Anterior Cingulate BA Left Anterior Cingulate BA Right Declive BA Left Fusiform Gyrus BA Left Brodmann area 47 BA Right Superior Temporal Gyrus BA Right Caudate Right Insula BA Left Fusiform Gyrus BA Right Parahippocampal Gyrus BA Right Fusiform Gyrus BA Right Anterior Cingulate BA Left Caudate 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 GSK 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. GSK showed variable effects, with attenuation at the doses of 10 and 400 mg and no change with the dose of 50 mg. ROIs Placebo GSK Lorazepam 10 mg 50 mg 400 mg 1 mg R Amygdala L Amygdala Endocrine effects of GSK and lorazepam administration Parameter Time Comparison Geom. LS mean Test Treat. ACTH (ng/l) 4 h 40 m (post scan) GSK GSK Geom. LS mean Ref Treat. Ratio 95% C.I. p-value (0.75, 1.41) (0.58, 1.02)

4 GSK (0.29, < mg -Placebo 0.53) Lorazepam (0.89, Placebo 1.58) Cortisol 4 h 40 m GSK (0.79, (noml/l) (post scan) mg -Placebo GSK ) (0.56, ) GSK (0.35, < mg -Placebo 0.60) Lorazepam (0.98, Placebo 1.62) Note: Subject # 21in Session 3 was excluded because the subject vomited after drug administration Pharmacokinetics (PK) Endpoints: Summary of Plasma GSK Pharmacokinetic Concentration- Time Data (ng/ml) Treatment N Time N Mean SD Median Min Max GSK mg 20 2 h-pre fmri h-post fmri GSK mg 20 2 h-pre fmri h-post fmri GSK h-pre fmri mg 4.67 h-post fmri 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 GSK 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 GSK mg and lorazepam. One subject was withdrawn due to AEs (crying and depression) which occurred during dosing with lorazepam (Period 2) and 10mg GSK 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 GSK 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 (6) 4 (20) Dizziness 0 2 (10) 0 1 (6) 0 Headache 1 (5) (18) 0 Disturbance in (10) attention Coordination 0 1 (5) abnormal Crying 0 1 (5) (5) Mental impairment (5) Fatigue (6) 1 (5) Catheter site (5) hematoma Feeling abnormal (6) 0 Irritability (5) 4

5 Depressed mood (5) Depression 0 1 (5) (5) Disorientation (5) Insomnia (5) Stress 0 1 (5) Dyspepsia 1 (5) Nausea (6) 0 Vomiting 0 1 (5) Drug hypersensitivity 0 1 (5) Multiple allergies 1 (5) Cough (5) 1 (6) 0 Nasal congestion (5) 0 0 Ear discomfort (5) Influenza 1 (5) Rash (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