The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not

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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. GSK Medicine:Gepotidacin mesylate () Study Number: BTZ Title: A Phase I, Randomized, Double-Blinded, Placebo- and Moxifloxacin-Controlled, 4-Period Crossover Study to Evaluate the Effect of on Cardiac Conduction as Assessed by 12-Lead Electrocardiogram in Healthy Volunteers Rationale: In order to comply with the International Conference on Harmonisation guidance, that the effect of on cardiac repolarization parameters should be assessed, a thorough QT (TQT) study was conducted. This single-dose study evaluated the effects of a therapeutic (1000 mg) and a supratherapeutic (1800 mg) dose of, together with a positive control (moxifloxacin 400 mg) and placebo on the QT interval corrected for heart rate (QTc) interval. Moxifloxacin hydrochloride (administered as branded Avelox ) was used as a positive control in order to validate the sensitivity of the study in detecting QTc change. Moxifloxacin has been shown to prolong the QT interval in some patients and the QTc prolongation has been well quantified (Avelox, 2008). For, a potential for QT prolongation was identified during in vitro studies, and although in vitro prolongation potentials were not realized in in vivo dog studies, slight prolongations in QTc (4% to 9%) were observed in an in vivo intravenous (IV) cardiovascular study in monkeys. Prolongations of QTc have been observed in higher doses of IV. Based on these findings, cardiovascular monitoring is performed in subjects receiving. To date, there have been no clinically significant findings in electrocardiogram (ECG) monitoring. Phase: I Study Period: 06-OCT-2014 to 02-MAR-2015 Study Design: This was a 4-period, randomized, active- and placebo-controlled, double-blinded, crossover study to evaluate the effect of on cardiac conduction as assessed by using a 24-hour continuous 12-lead Holter monitor from the morning of Day 1 of Period 1 and from 1 hour before dosing in Periods 2, 3, and 4, to 48 hours after dosing in each treatment period. Subjects were randomized to a sequence of 4 treatments ( 1000 mg and 1800 mg, placebo control, and positive control) in 4 separate periods. Subjects were screened within 30 days before entry to the clinic. Subjects reported to the clinical unit on Day 2 of Period 1 and on Day 1 in subsequent periods. Subjects remained confined until check-out procedures were completed on Day 3 (i.e., 5 days confinement in Period 1 and 4 days in the following 3 periods). There was a washout of at least 7 days between doses. The Follow-up Visit occurred 7 to 10 days after the final dose. The duration of the study (from Screening to the Follow-up Visit) was approximately 60 days. Center: This study was conducted at a single center in the United States (PPD Phase I Clinic, 7551 Metro Center Drive, Suite 200, Austin, TX). Indication: Antibiotic for conventional gram-positive and biothreat infections. Treatment: Treatment A: 1000-mg IV over 120 minutes 1 dose and moxifloxacin placebo tablet administered orally 1 dose Treatment B: 1800-mg IV over 120 minutes 1 dose and moxifloxacin placebo tablet administered orally 1 dose Treatment C (placebo control): placebo IV over 120 minutes 1 dose and moxifloxacin placebo tablet administered orally 1 dose Treatment D (positive control): Moxifloxacin 400-mg tablet administered orally 1 dose and placebo IV over 120 minutes 1 dose Objectives: The primary objective of this study was to estimate the effect on QTc from single 2-hour IV doses of 1000 mg (therapeutic dose) and 1800 mg (highest therapeutic dose) as determined by the baseline-adjusted, maximum time-matched QTc using the Fridericia formula (QTcF) compared with placebo. The secondary objectives were to estimate the effect of single dose IV (1000 mg and 1800 mg) on the corrected QTc interval using the Bazett formula (QTcB), QT/RR pairs from the defined time points at which subjects were supinely resting (QTci), individually corrected QT interval (QTcI), QT interval, heart rate (HR), PR interval, and the complex of 3 of the graphical deflections seen on a typical ECG (QRS interval) compared with placebo; to estimate the effect of a single oral dose of moxifloxacin (400 mg) on QTcF, QTcB, QTci, QTcI, QT, HR, PR, and QRS compared with placebo; to describe the single-dose pharmacokinetics of IV 1000 mg and 1800 mg; to describe the single-dose pharmacokinetics of oral moxifloxacin; to characterize the pharmacodynamic (PK)/pharmacodynamic (PD) relationship between plasma concentrations and changes in QTcF for and moxifloxacin; to estimate the 1

2 urinary excretion of unchanged ; and to evaluate the safety and tolerability of IV after a single 1000-mg and 1800-mg dose. Primary Outcome/Endpoint: Change from baseline ( ) in QTcF for at each time point (average of up to ten 12-lead Holter ECG replicates per time point) as compared with time-matched placebo. Secondary Outcomes/Endpoints Change from baseline in QTcB, QTci, QTcI, QT, HR, PR, and QRS interval. Categorical outliers for QTc, HR, PR, and QRS interval. Change from baseline in QTcF, QTcB, QTci, QTcI, QT, HR, PR, and QRS interval. Plasma concentrations and selected PK parameters of. Plasma concentrations and selected PK parameters of moxifloxacin. Plasma concentrations and change in QTcF for and moxifloxacin. Amount excreted in urine of unchanged, fraction of the dose excreted in urine, and renal clearance, as data permitted. Safety and tolerability of as assessed by 12-lead safety ECG readings, change from baseline in vital sign measurements (blood pressure and pulse rate), monitoring of adverse events (AEs), and toxicity grading of clinical laboratory test results. Statistical Methods: Analysis Populations: The Enrolled Population consisted of all subjects who signed the informed consent. The Safety Population consisted of all subjects who received at least 1 dose of study drug (i.e., 1000 mg or 1800 mg, moxifloxacin 400 mg, or placebo) and had at least 1 postdose safety assessment. The QT/QTc (Pharmacodynamic Population) consisted of all subjects in the Safety Population who had measurements on baseline as well as on-treatment data, with at least 1 time point after dosing in at least 1 period with a valid QTcF value. The Pharmacokinetic Population consisted of all subjects who received at least 1 dose of or moxifloxacin and had evaluable PK data for or moxifloxacin. The Pharmacokinetic/QTc Population consisted of an intersection of the QT/QTc Population and the PK Population. In addition, for the plasma concentration QTc analysis, a time-matched plasma concentration was necessary. Pharmacodynamic Analysis: The primary analysis for was based on a linear mixed-effects model in placebo-corrected change-from-baseline ( ) QTcF (primary endpoint) as the dependent variable, time (categorical), treatment ( 1000 mg and 1800 mg, moxifloxacin 400 mg, and placebo), and time-by-treatment interaction as factors, and baseline QTc as a covariate. Since this study utilized a crossover design, period and sequence terms were also included in the model, if necessary. Subject was included as a random effect for the intercept. Gender effect was added in the full mean model for exploration. If the gender effect was not statistically significant at the alpha level of 0.05, it was excluded from the final model. The least squares mean (90% confidence interval [CI]) was calculated for the contrasts of placebo. Ninety percent (90%) CIs were used to characterize the effects observed and provided a range of plausible values for the true QTcF effect. The linear mixed-effects model mentioned previously was also repeated for those QTc methods that had not been selected as the primary endpoint and to QT, HR, PR, and QRS to compute the mean change between and placebo and their CIs. The analysis to show assay sensitivity was based on the change from baseline after dosing with moxifloxacin. The same model was used as described for the primary analysis. The analysis results for categorical outliers, T-wave morphology, and U-wave presence were summarized in frequency tables with counts and percentages for both number of subjects and number of time points. Pharmacokinetic/Pharmacodynamic Analyses: The relationship between changes in QTcF and plasma concentrations were investigated using appropriate PD models. Pharmacokinetic Analysis: Plasma and urine concentrations, along with the actual plasma and urine sampling dates and times, were listed by subject and planned sampling time. Plasma and urine analysis was performed under the control of GSK (or designee). Concentrations of and moxifloxacin in plasma and in urine were determined using currently approved bioanalytical methodologies. Safety Analysis: Safety data were presented in tabular and/or graphical format and summarized descriptively according to GSK s Integrated Data Standards Library standards. 2

3 Study Population: Subjects were male or female (nonpregnant, nonlactating), between 18 and 55 years of age, inclusive, and in good health as judged by the absence of clinically significant diseases or clinically significant abnormal laboratory values. Subjects were not eligible for inclusion if they had Screening and baseline ECG results including a QTcF of >450 msec, PR interval of <120 and >220 msec, QRS duration of <70 and >110 msec, or a HR of <40 and >100 beats per minute (bpm; male subjects) and <45 and >100 bpm (female subjects). In addition, if a subject had a history/evidence of any arrhythmia (e.g., second- or third-degree heart block, atrial fibrillation, supraventricular tachycardia, symptomatic sinus bradycardia, junctional rhythm), clinically significant cardiac disease or procedure (mitral valve regurgitation, heart murmur, angina/ischemia, congenital heart abnormalities, coronary artery bypass grafting surgery, or percutaneous transluminal coronary angioplasty), or a history of additional risk factors for torsades de pointes (e.g., heart failure, hypokalemia, and family history of long QT syndrome), they were excluded from enrolling into the study. Other exclusion criteria also included current or chronic history of liver disease or known hepatic or biliary abnormalities (with the exception of Gilbert syndrome or asymptomatic gallstones); any clinically significant central nervous system (e.g., seizures), cardiac, pulmonary, metabolic, renal, hepatic, or gastrointestinal condition(s) or history of such condition(s) that, in the opinion of the investigator, could have placed the subject at an unacceptable risk as a participant in this study or could have interfered with the absorption, distribution, metabolism, or excretion of drugs; a history of photosensitivity to quinolones; use of systemic antibiotic within 30 days of Screening; confirmed lifetime history of Clostridium difficile (C difficile) diarrhoea; and/or a history of spontaneous tendon rupture. Moxifloxacin 400 mg Tablet 1000-mg IV 1800-mg IV Total Treatment Regimen Placebo [1] Number of subjects planned, [N] Number of subjects randomized, [N] Number of subjects included in Safety Population [n (%)] 52 (100) 52 (100) 50 (100) 53 (100) 55 (100) Number of subjects included in PK Population [n (%)] 0 52 (100) 50 (100) 53 (100) 55 (100) Number of subjects included in QT/QTc Population [n (%)] 52 (100) 52 (100) 50 (100) 53 (100) 55 (100) Number of subjects included in PK/QTc Population [n (%)] 0 52 (100) 48 (96) 51 (96) 55 (100) Number of subjects completed as planned [n (%)] 51 (98) 48 (92) 48 (96) 51 (96) 46 (84) Number of subjects withdrawn (any reason) [n (%)] 1 (2) 4 (8) 2 (4) 2 (4) 9 (16) Number of subjects withdrawn for SAE [n (%)] Number of subjects withdrawn for AE 1 (2) 1 (2) 1 (2) 2 (4) 5 (9) [n (%)] Primary reasons for subject withdrawal [n (%)] [2] AEs 1 (2) 1 (2) 1 (2) 2 (4) 5 (9) Withdrew consent 0 2 (4) (4) Protocol deviation 0 1 (2) 1 (2) 0 2 (4) Demographics Total (N=55) Age in Years [Mean (SD)] 30.8 (9.03) Sex [n (%)] Female 27 (49) Male 28 (51) BMI (kg/m 2 ) [Mean (SD)] (3.049) Height (cm) [Mean (SD)] (9.804) Weight (kg) [Mean (SD)] (11.582) 3

4 Ethnicity [n (%)] Hispanic or Latino 26 (47) Not Hispanic or Latino 29 (53) Race [n (%)] Black or African American 11 (20) American Indian or Alaskan Native 1 (2) Asian 1 (2) White 39 (71) White and Black or African American 3 (5) AE = adverse event; PK = pharmacokinetic; QT = QT interval; QTc = QT interval corrected for heart rate; SAE = serious AE; SD = standard deviation [1] Placebo: placebo 2 hour IV and moxifloxacin placebo [2] Subjects could have only 1 primary reason for discontinuation Primary Efficacy Results: Pharmacodynamics The ECG parameters were well balanced across predose baseline time points. The infusion of caused an increase of HR, which peaked at the end of the infusion (2 hours) at 9.0 bpm (90% CI: 7.9 to 10.2) after 1000 mg and at 12.9 bpm (90% CI: 11.8 to 14.1) after 1800 mg. Beyond 4 hours, the diurnal pattern of HR was the same after all treatments. The HR was therefore elevated during and after the infusion of with the largest effect observed at 2 hours (end of infusion) of 6.5 bpm (90% CI: 5.1 to 7.8) and 10.4 bpm (90% CI: 9.1 to 11.7) after 1000 mg and 1800 mg, respectively. Since the largest HR exceeded 8 bpm, QTci and QTcI were constructed. The mean slope of QTcI (0.3219) derived from all QT/RR data during 24 hours on Day 1, was similar to QTcF (0.333), whereas the mean slope of QTci (0.3872) was derived from supinely resting time points on Day 1, and was steeper, and therefore closer to QTcB (0.5), which is known to overcorrect the QT interval at elevated HRs. When the ability of each correction method (QTcF, QTci, and QTcI) to remove the HR dependence of the QT interval was tested using the mean of squared individual slopes (SSS), the lowest SSS by treatment was observed with QTcF and QTcI, with clearly larger values with QTci. The QTcF was selected as the primary endpoint, since it consistently produced somewhat lower values than QTcI ( versus after placebo to versus after 1800 mg). The infusion of caused an increase of QTcF, which evolved during the infusion and peaked immediately after the end of infusion (2 hours) with a QTcF of 12.8 msec (90% CI: 10.8 to 14.8) after 1000 mg and 22.9 msec (90% CI: 20.9 to 24.8) after 1800 mg. The QTcF was also observed at the end of the infusion with the largest value of 12.1 msec (90% CI: 9.5 to 14.8) after the 1000 mg and 22.2 msec (90% CI: 19.6 to 24.9) after 1800 mg at 2 hours. The QTcF rapidly fell after the end of the infusion with a mean QTcF of 11.9 msec 30 minutes later (2.5 hours), 6.1 msec at 3 hours, and all mean values from 4 hours and onwards were below 5 msec after 1800 mg. The infusion of had a small shortening effect on the PR interval, which coincided with the observed HR effect. The largest effect after the infusion of 1800 mg was observed at 2 hours with a mean PR -7.1 msec (90% CI: 9.0 to 5.1). Infusion of did not have a clinically relevant effect on the QRS interval with the largest mean QRS of 1.2 msec at 1.5 and 2 hours (90% CI: 0.8 to 1.5 and 0.9 to 1.6, respectively). There were no PR or QRS outliers. Placebo-Corrected Change-From-Baseline QTcF ( QTcF; Primary Endpoint) Descriptive Statistics Time point (Hour) (Pharmacodynamic Population) 1000-mg IV 1800-mg IV Moxifloxacin 400-mg Tablet Statistics 0.25 LS Mean SE % CI (2.6; 5.7) (5.7; 8.9) ( 0.4; 2.8) 0.5 LS Mean SE % CI (5.4; 9.5) (10.9; 14.9) (4.3; 8.3) 1 LS Mean SE

5 90% CI (6.1; 10.7) (14.6; 19.2) (7.4; 12.1) 1.5 LS Mean SE % CI (7.9; 12.9) (16.9; 21.9) (7.3; 12.3) 2 LS Mean SE % CI (9.5; 14.8) (19.6; 24.9) (7.6; 12.9) 2.5 LS Mean SE % CI (3.0; 7.9) (9.5; 14.3) (9.3; 14.1) 3 LS Mean SE % CI (2.4; 6.3) (4.2; 8.0) (10.7; 14.6) 4 LS Mean SE % CI (0.5; 4.4) (2.7; 6.6) (10.5; 14.3) 6 LS Mean SE % CI (0.3; 4.3) (2.5; 6.4) (7.2; 11.1) 8 LS Mean SE % CI (0.7; 4.1) (1.4; 4.7) (8.3; 11.6) 12 LS Mean SE % CI ( 2.8; 1.5) ( 0.8; 3.4) (4.4; 8.7) 24 LS Mean SE % CI ( 0.1; 3.2) (0.5; 3.8) (4.4; 7.7) 48 LS Mean SE % CI (0.1; 3.9) (0.3; 4.0) (0.1; 3.7) CI = confidence interval; LS = least squares; SE = standard error Note: Results from the linear mixed effects model. Secondary Outcome Results: Pharmacodynamics/Pharmacokinetics: A concentration-dependent effect of on the QTcF interval was identified with a slope of the relationship of msec per ng/ml (90% CI: 1.30 to 1.61) and an intercept of 0.55 msec (Model 1). Predicted ΔΔQTcF Interval at Geometric Mean Peak Concentration (Pharmacokinetic/QTc Population) Dose Geometric Mean (90% CI) of Cmax ( 10 3 ng/ml) Predicted ΔΔQTcF (msec) 90% CI of ΔΔQTcF (msec) 1000-mg IV 7.33 (7.02; 7.66) 11.2 (10.0; 12.4) 2 hour 1800-mg IV 13.3 (12.7; 13.8) 19.9 (18.0; 21.7) 2 hour CI = confidence interval; ΔΔQTcF = placebo-corrected change-from-baseline QTc corrected for heart rate by the Fridericia method Note: Linear mixed-effects modeling approach, using the following equation: QTcFij = Intercepti + slopei Concij = εij, where QTcFij was the time-matched, placebo-corrected change-from-baseline for QTcF for subject i at time j with concentration Concij. The residual ij was assumed to be identical, independent, normally distributed (iidn) with mean 0 and variance 2. Prediction was based on Model 1 (linear model with an intercept). The 90% CI of the geometric mean was calculated in the logarithmic domain and presented after back-transformation to the original concentration domain. 5

6 Pharmacokinetics: After the 2 hour IV infusion of 1000 mg or 1800 mg, the median plasma concentrations of increased steadily until the end of the infusions, and then declined in a multi-exponential fashion. The concentrations were generally detectable in plasma up to 48 hours after the start of infusion. After the oral administration of moxifloxacin 400 mg, the median plasma concentrations of moxifloxacin increased rapidly and then declined in a mono-exponential fashion. Moxifloxacin concentrations were detectable in plasma up to 48 hours after dosing. Geometric Mean (CVb%) of Plasma Pharmacokinetic Parameters by Treatment Group (Log-Transformed) (Pharmacokinetic Population) AUC(0-t) AUC(0- ) Cmax t1/2 CL Vss Treatment N (ng hr/ml) (ng hr/ml) (ng/ml) (hr) (L/hr) (L) 1000 mg (17.3) (17.2) (18.2) (30.2) (17.2) (24.4) 1800 mg [1] [1] 37.5 [1] 144 [1] 52 (18.2) (17.6) (22.1) (13.1) (17.6) (23.8) CVb = between-subject coefficient of variation [1] n = 50 Arithmetic Mean (SD) of Plasma Pharmacokinetic Parameters by Treatment Group (Untransformed) (Pharmacokinetic Population) tmax [1] %AUCex Treatment N (hr) (%) 1000 mg ( ) (0.265) 1800 mg [2] ( ) (0.211) SD = standard deviation [1] Median (range) [2] n = 50 Geometric Mean (CVb%) of Moxifloxacin Plasma Pharmacokinetic Parameters by Treatment Group (Log-Transformed) (Pharmacokinetic Population) AUC(0-t) AUC(0- ) Cmax t1/2 CL/F Vz/F Treatment N (ng hr/ml) (ng hr/ml) (ng/ml) (hr) (L/hr) (L) Moxifloxacin 400-mg oral [1] [1] 11.8 [1] 208 [1] 52 tablet single dose Day 1 (24.7) (20.5) (28.4) (14.7) (20.5) (22.5) CVb = between-subject coefficient of variation [1] n = 51 Arithmetic Mean (SD) of Moxifloxacin Plasma Pharmacokinetic Parameters by Treatment Group (Untransformed) (Pharmacokinetic Population) tmax [1] %AUCex Treatment N (hr) (%) Moxifloxacin 400-mg oral tablet [2] 52 single dose Day 1 ( ) (2.736) SD = standard deviation [1] Median (range) [2] n = 51 6

7 Arithmetic Mean (SD) Urine Pharmacokinetic Parameters by Treatment Group (Untransformed) (Pharmacokinetic Population) Ae %fe CLr Treatment N (mg) (%) (L/hr) 1000 mg 1800 mg SD = standard deviation (172) (17.2) (7.59) (232) (12.9) (4.81) Safety Results: In the Safety Population, AEs and serious AEs (SAEs) were collected from the start of study treatment until the follow-up contact. Summary of Adverse Events by System Organ Class and Preferred Term That Occurred in Subjects in Each Treatment (Safety Population) System Organ Class Preferred Term, n (%) Placebo [1] (N=52) Moxifloxacin 400-mg Tablet (N=52) 1000-mg IV (N=50) 1800-mg IV (N=53) Any event 3 (6) 9 (17) 23 (46) 34 (64) Gastrointestinal disorders 2 (4) 4 (8) 19 (38) 34 (64) Nausea 1 (2) 1 (2) 6 (12) 18 (34) Abdominal pain 1 (2) 1 (2) 6 (12) 13 (25) Abdominal discomfort (14) 8 (15) Diarrhoea 1 (2) 1 (2) 4 (8) 5 (9) Vomiting 0 1 (2) 0 8 (15) Salivary hypersecretion (4) 6 (11) General disorders and administration site conditions 0 3 (6) 4 (8) 11 (21) Feeling hot (4) 8 (15) Nervous system disorders 1 (2) 1 (2) 5 (10) 7 (13) Dizziness 1 (2) 0 2 (4) 5 (9) Respiratory, thoracic, and mediastinal disorders 0 1 (2) 5 (10) 6 (11) Oropharyngeal discomfort (10) 5 (9) Investigations 1 (2) 1 (2) 1 (2) 0 Clostridium difficile test positive 1 (2) 1 (2) 1 (2) 0 Infections and infestations (2) C difficile infection (2) [1] Placebo: placebo 2 hour IV and moxifloxacin placebo tablet Serious Adverse Events - On-Therapy There were no severe AEs, serious AEs, or deaths reported in this study. Clostridium difficile Associated Diarrhoea Four subjects were discontinued due to AEs related to C difficile associated diarrhoea. Subject 9098 (moxifloxacin 400 mg), Subject 9128 ( 1000 mg), and Subject 9155 (placebo) were discontinued due to mild, related AEs of a positive Clostridium tests; and Subject 9162 ( 1800 mg) was discontinued due to a mild, related AE of a C difficile infection. 7

8 Conclusions: Pharmacodynamics: Infusion of at a dose of 1000 mg and 1800 mg over 2 hours caused a mild HR effect of approximately 6 bpm to 10 bpm and QT prolongation measured as QTcF of 12 msec to 22 msec. The QT prolongation evolved during the infusion and was quickly reversed over 2 hours after the end of the infusion. did not have a clinically relevant effect on cardiac conduction (PR and QRS intervals). Pharmacodynamics/Pharmacokinetics: A statistically significant effect on the QTcF interval was demonstrated with a slope of the relationship between plasma concentrations for and QTcF of msec per ng/ml (90% CI: 1.30 to 1.61) and an intercept of 0.55 msec. has an effect on the QT interval, which exceeded 10 msec (based on the 90% CI) within the studied plasma concentration range. Pharmacokinetics: Cmax and AUC(0- ) were approximately dose proportional when the 2 hour IV dose was increased from 1000 mg to 1800 mg. Estimates of tmax, t½, CL, CLr, and the Vss remained unchanged between the two 2 hour IV doses. Moxifloxacin Following oral administration of moxifloxacin 400 mg, moxifloxacin was rapidly absorbed with a median tmax of 2.07 hours and an elimination half-life of 12.3 hours. Safety: There was a dose-dependent increase in reported AEs with the increasing dose of during this study that were consistent with increased cholinergic tone and were expected based on previous Phase 1 studies with 1800 mg 2 hour IV doses in healthy subjects. However, the administration of single 2 hour IV doses of 1000 mg, 1800 mg; and single oral doses of moxifloxacin 400 mg and placebo were safe and generally tolerated in the healthy subjects in this study. There were no severe AEs, SAEs, or deaths reported during this study. There were 5 subjects that were discontinued due to AEs. One subject was discontinued due to an AE of throat tightness and 4 subjects were discontinued due to AEs related to C difficile associated diarrhoea. After 1800 mg, more subjects experienced out-of-range QTcB and QTcF results in the safety ECGs, as compared with after 1000 mg, moxifloxacin 400 mg, or placebo. These findings were similar to the observed outliers in the PD population. However, no clinically significant changes were reported as AEs for safety ECGs. No treatment-related trends in mean safety vital sign measurements were observed. No clinically significant mean changes from baseline or treatment-related differences were observed in clinical laboratory values during the study. 8