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.: AC4115321 Title: A randomized, double-blind, placebo controlled, incomplete block, crossover, dose ranging study to evaluate the dose response of GSK573719 administered once or twice daily over 7 days in patients with COPD Rationale: The purpose of this study was to further characterize the dose response curve for umeclidinium (UMEC) at doses of to 125 mcg once-daily (QD) in patients with COPD. Treatment with doses of UMEC administered twice-daily was also included to further evaluate dosing frequency. Treatment with tiotropium () once-daily was included as an active comparator control. A placebo treatment was included in order to evaluate absolute treatment effect of each active regimen. Phase: IIb Study Period: 25 July 2011-27 October 2011 Study Design: This was a multicenter, randomized, double-blind, placebo controlled, 3 way cross-over, incomplete block study to evaluate 4 doses of UMEC Inhalation Powder (,, 62.5 mcg, 125 mcg), hereafter referred to as UMEC, administered once -daily and 2 doses of UMEC ( and ) administered twice-daily via Novel Dry Powder Inhaler (NDPI) over 7 days in subjects with COPD. Treatment with tiotropium () administered once-daily via the HandiHaler was included as an open label active comparator since it is the standard inhaled long-acting muscarinic antagonist (LA) medication for treatment of COPD. A placebo treatment was also included to allow for evaluation of the absolute treatment effect of each active regimen and further characterization of the safety and benefit risk profile of UMEC. Each subject was randomized to receive a sequence of 3 of 8 potential treatments for a total of 3 treatment periods per subject. The treatment phase consisted of three 7-day treatment periods. Treatment Period 1 and Treatment Period 2 were followed by a 10- to 14-day Washout Period. Treatment Period 3 was followed by a 7- to 9-day Washout Period before the follow-up phone call. There were a total of 7 clinic visits conducted on an outpatient basis. Subjects who met eligibility criteria at Screening (Visit 1) completed a 5- to 7-day Run-in Period prior to randomization at Visit 2. A follow-up phone call for assessment of adverse events (AEs) was conducted approximately 7 days after the last treatment period. The total duration of subject participation, including the Follow-Up was approximately 9 weeks. All subjects were provided with a salbutamol metered dose inhaler (MDI) for use on an as-needed basis throughout the Run-in, Treatment and Washout Periods. Subjects were supplied with a paper diary to record their daily use of supplemental salbutamol and to record any medical problems experienced and any medications used. Centres: A total of 15 centers in the United States (US) randomized subjects to treatment. Indication: COPD Treatment: Dry powder formulations of UMEC delivered via NDPI administered once-daily (in the morning) or twice-daily (morning and evening). Matching placebo delivered via NDPI once-daily (in the evening) or twice-daily (morning and evening). During open-label treatment with tiotropium, subjects were provided with tiotropium bromide () (Spiriva) per inhalation via the HandiHaler dry powder inhaler (DPI) administered once-daily in the morning. was delivered via NDPI administered once-daily in the evening. Salbutamol via metered-dose-inhaler (MDI) was issued for spirometry reversibility testing at Visit 1. Salbutamol MDIs for as needed use were provided throughout the study by GlaxoSmithKline (GSK). Objectives: The primary objective of this study was to evaluate the dose response of 4 once-daily dose regimens of GSK573719 (umeclidinium bromide [UMEC]) (,, 62.5 mcg and 125 mcg) over a 7-day treatment period in patients with chronic obstructive pulmonary disease (COPD). Primary Outcome/Efficacy Variable: The primary efficacy endpoint was trough FEV 1 on Day 8, defined as the mean of the FEV1 values obtained 23 and 24 hours after morning dosing on Day 7 of each treatment period. 1
Secondary Outcome/Efficacy Variable(s Secondary efficacy endpoints included weighted mean FEV1 over 0 to 24 hours after morning dosing on Day 7 and serial FEV1 at each time point over 24 hours after morning dosing on Day 7 Statistical Methods: The size of the study was determined using Monte-Carlo Mapped Power (MCMP) approach for mixed effects method to provide sufficient precision around the dose response characterization. The dose response characterized in a previous dose-ranging study with UMEC, AC4113073, was used as reference. In addition, the study provided approximately 85% power for the comparison of active treatments with placebo for the primary efficacy endpoint of trough FEV1 on Day 8. This calculation assumed a two-sided 5% significance level, a within-subject standard deviation (SD) of 170 ml (based on Study AC4113073) and a treatment difference from placebo of 130 ml. This difference was selected as it is of similar magnitude to the effect generally seen with tiotropium. Allowing for a 30% dropout rate, approximately 160 subjects were planned to be randomized to ensure that 112 subjects completed all 3 treatment periods. The trough FEV1 data for both the once-daily (QD) and twice-daily UMEC doses were included in a parametric analysis in order to evaluate dose response. Both a Day 8 dataset and a pooled dataset for Day 7 and Day 8 were analyzed and reported. The rationale for pooling Day 7 and Day 8 (post-hoc analysis) was to ensure informative interpretation of FEV1 response as function of dose given the repeated measures for trough FEV 1 response within each subject on different days. After evaluation of various dose response models, the Emax model was found to be optimal. It assumes a parametric form for dose versus response with normally distributed random effects for individuals and for observations within individual subjects. The change from baseline FEV1 to trough FEV1 on Day 8 was analyzed using a mixed model including period baseline FEV1, mean baseline FEV1, treatment and period as fixed effects and subject as a random effect. Estimated treatment differences, 95% confidence intervals (CI) for the difference and p-values were presented for all comparisons of active treatments (once-daily and twice-daily doses of UMEC and tiotropium) with placebo. The analysis of weighted mean FEV1, and trough and weighted mean FVC endpoints used the same methodology specified for trough FEV1. Serial FEV1 was analyzed using a mixed model including period baseline FEV1, mean baseline FEV1, treatment, period, time, time by baseline interaction, time by mean baseline interaction and time by treatment interaction as fixed effects and subject as a random effect. Nominal times of assessment (rather than actual times) were used in this analysis. Serial FVC was analyzed similarly. The mitt population comprised all subjects randomized to treatment who received at least one dose of study medication. Randomized subjects were assumed to have received study medication unless definitive evidence to the contrary exists. This constituted the primary population for all summaries and analyses of efficacy and safety outcomes. Subjects were included in the summary/analysis of a particular outcome if they provided at least one on-treatment assessment of that outcome. Study Population: 62.5 mcg 125 mcg Number (%) of Subjects Started treatment 60 60 57 59 60 Withdrew during treatment period 1 (2) 2 (3) 1 (2) 0 2 (3) Completed treatment period a 59 (98) 58 (97) 56 (98) 59 (100) 58 (97) Withdrew during Washout b 1 (2) 0 0 0 2 (3) Number (%) of Subjects Started treatment 56 58 56 Withdrew during treatment period 1 (2) 2 (3) 0 Completed treatment period a 55 (98) 56 (97) 56 (100) Withdrew during Washout b 0 1 (2) 3 (5) Note: Subject 782 (UMEC 125 mcg once-daily in Period 1; reason for withdrawal=lost to follow-up) and Subject 1158 (UMEC twice-daily in Period 1; reason for withdrawal=withdrew consent) were included in the count for withdrew during treatment period even though they completed a Day 8 trough 2
assessment. This was because they did not complete an Early Withdrawal visit and actually withdrew during the Washout in Period 1. a. A subject was considered to have completed the treatment period if they completed a Day 7 v isit. b. Subjects who withdrew during Washout were counted under the last treatment taken Demographics, mitt population Total (N=163) Age (y) Mean (SD) 59.5 (9.21) Range 41-80 Sex n (%) Female 85 (52) Male 78 (48) Ethnicity n (%) Hispanic/Latino 1 (<1) Not Hispanic/Latino 162 (>99) Race n (%) White 145 (89) African American/African heritage 16 (10) African American/African heritage and White 1 (<1) American Indian or Alaskan Native 1 (<1) Body Mass Index (kg/m 2 ) Mean (SD) 27.36 (5.115) Range 14.7-35.3 Primary Efficacy Results: Final Dose-Response Model Parameters for Trough FEV 1, mitt population Value for Pooled Day 7 and 8 Parameters Value for Day 8 Only 95%CI (% RSE) Emax (L) 0.185 0.154-0.216 (9) 0.156 ED 50 (C 50 - mcg) 37.4 17.8-57.0 (28) 38.2 S0 (L) 1.24 1.21 1.27 (1) 1.24 -FEV1MB-S0 0.691 (p<1e- 0.65 0.73 0.686 (p<1e-010) 010) a (3) a E max 47% 40 48% 60 ED50 50% 54 72% 36 S0 34% 9 33% 8 Residual ( ) Proportional 33% 5 32% 4 95%CI (% RSE) 0.123-0.189 (11) 14.7 61.7 (32) 1.21-1.27 (1) 0.65 0.73 (3) a. Wald Test Abbreviations: -FEV1MB-S0=mean baseline trough FEV1 (forced expiratory volume in one second) response; =residual variability; : Inter-subject variability; ED 50 (C 50)= dose that yields 50% of E max ; E max=maximum predicted FEV 1 response; RSE: Relative Standard Error Note: 95%CI for Fixed-Effect parameter: ±1.96*SE. 3
Trough FEV1 on Day 8 (a secondary analysis of the primary efficacy endpoint), mitt population Trough FEV 1 (L) 62.5 mcg 125 mcg n 59 58 56 59 59 LS mean (SE) 1.342 (0.022) 1.455 (0.022) 1.443 (0.023) 1.466 (0.022) 1.525 (0.022) LS mean change (SE) -0.074 (0.022) 0.038 (0.022) 0.027 (0.023) 0.049 (0.022) 0.109 (0.022) Difference from placebo N/A 0.113 0.101 0.124 0.183 95% CI N/A (0.058,0.168) (0.045,0.158) (0.068,0.179) (0.127,0.239) p-value N/A <0.001 <0.001 <0.001 <0.001 Trough FEV 1 (L) n 55 57 56 LS mean (SE) 1.467 (0.023) 1.481 (0.023) 1.443 (0.023) LS mean change (SE) 0.051 (0.023) 0.065 (0.023) 0.027 (0.023) Difference from 0.125 0.139 0.101 placebo 95% CI (0.069,0.182) (0.083,0.196) (0.045,0.157) p-value <0.001 <0.001 <0.001 Note: Analysis performed using a mix ed model w ith cov ariates of mean baseline, period baseline, treatment and period as fix ed effects and subject as a random effect. Secondary Outcome Variable(s): Secondary Endpoint: Weighted Mean 0-24 hr after morning dosing on Day 7, mitt population 0 to 24 hour Weighted Mean FEV1 62.5 mcg 125 mcg (L) n 54 56 51 54 56 LS mean (SE) 1.327 (0.018) 1.443 (0.018) 1.445 (0.019) 1.459 (0.018) 1.500 (0.018) LS mean change (SE) -0.074 (0.018) 0.043 (0.018) 0.045 (0.019) 0.059 (0.018) 0.100 (0.018) Difference from placebo NA 0.116 0.118 0.132 0.173 95% CI NA (0.072,0.160) (0.073,0.163) (0.087,0.178) (0.129,0.217) 0 to 24 hour Weighted Mean FEV1 (L) n 52 55 53 LS mean (SE) 1.462 (0.018) 1.469 (0.018) 1.484 (0.018) LS mean change (SE) 0.062 (0.018) 0.068 (0.018) 0.084 (0.018) Difference from placebo 0.136 0.142 0.157 95% CI (0.091,0.181) (0.098,0.186) (0.113,0.202) Note: Analysis performed using a mixed model with covariates of trough mean baseline, trough period baseline, treatment and period as fixed effects and subject as a random effect. 4
Secondary Endpoint: Serial FEV1 at each time point over 24 hr after morning dosing on Day 7, mitt population LS Mean Change from Baseline FEV1 (L) over time on Day 7 () QD () QD () 62.5 mcg QD () Dose time Planned relative time n Mean SE Predose 59-0.007 0.021 1 h 59-0.006 0.023 3 h 59-0.013 0.024 6 h 59-0.054 0.022 9 h 59-0.072-0.022 12 h 59-0.086 0.023 13 h 59-0.085 0.024 15 h 59-0.112 0.023 23 h 59-0.101 0.024 24 h 59-0.065 0.024 Predose 58 0.068 0.021 1 h 59 0.086 0.023 3 h 59 0.082 0.024 6 h 59 0.056 0.022 9 h 59 0.040 0.022 12 h 59 0.022 0.023 13 h 59-0.001 0.024 15 h 58-0.008 0.023 23 h 57 0.006 0.025 24 h 58 0.070 0.024 Predose 55 0.067 0.021 1 h 56 0.112 0.023 3 h 56 0.132 0.024 6 h 55 0.067 0.022 9 h 56 0.050 0.022 12 h 56 0.028 0.023 13 h 56-0.003 0.024 15 h 56 0.004 0.023 23 h 56-0.006 0.025 24 h 56 0.065 0.024 Predose 59 0.065 0.021 1 h 59 0.107 0.023 3 h 59 0.082 0.024 6 h 59 0.056 0.022 9 h 59 0.084 0.022 12 h 59 0.043 0.023 13 h 59 0.026 0.024 15 h 58 0.022 0.023 23 h 59 0.012 0.024 24 h 59 0.067 0.023 125 mcg QD () Predose 60 0.122 0.021 1 h 60 0.167 0.023 3 h 59 0.176 0.024 6 h 59 0.088 0.022 9 h 58 0.132 0.022 5
12 h 59 0.103 0.023 13 h 58 0.103 0.024 15 h 59 0.073 0.023 23 h 59 0.073 0.024 24 h 59 0.146 0.024 BD () Predose 54 0.069 0.022 1 h 55 0.128 0.024 3 h 55 0.126 0.025 6 h 55 0.045 0.022 9 h 55 0.070 0.023 12 h/pre-pm 55 0.048 0.023 dose PM 1 h 55 0.063 0.025 3 h 55 0.041 0.024 11 h 55 0.001 0.025 12 h 55 0.083 0.024 BD () Predose 57 0.097 0.021 1 h 57 0.135 0.023 3 h 57 0.120 0.024 6 h 57 0.081 0.022 9 h 56 0.038 0.022 12 h/pre-pm 57 0.048 0.023 dose PM 1 h 57 0.041 0.024 3 h 57 0.047 0.023 11 h 57 0.033 0.025 12 h 57 0.084 0.024 () Predose 54 0.084 0.022 1 h 56 0.176 0.023 3 h 56 0.180 0.025 6 h 56 0.128 0.022 9 h 56 0.094 0.023 12 h 56 0.081 0.023 13 h 56 0.061 0.025 15 h 56 0.037 0.023 23 h 56 0.002 0.025 24 h 56 0.049 0.024 Adverse events (AEs) were evaluated throughout the study beginning from the start of investigational product (Visit 2) through to study completion. Serious adverse events (SAEs) were collected over the same time period as adverse events. However, any SAEs assessed as being related to study participation (e.g., study related procedures or changes in existing therapy) or a GSK concomitant medication were recorded from the time a subject consented to participate in the study up to and including any follow up contact. All SAEs were reported to GSK within 24 hours. 6
Most Frequent (Reported by 3% or More Subjects in Any Treatment Group) Adverse Events On- Therapy (mitt Population) 62.5 mcg 125 mcg Subjects with any AE 5 (8) 6 (10) 3 (5) 3 (5) 11 (18) Headache 2 (3) 1 (2) 0 0 3 (5) Nasopharyngitis 0 1 (2) 0 0 1 (2) Dysgeusia 0 1 (2) 0 0 2 (3) Sinusitis 0 0 0 0 2 (3) Subjects with any AE 4 (7) 7 (12) 2 (4) Headache 4 (7) 1 (2) 0 Nasopharyngitis 0 0 2 (4) Dysgeusia 0 0 0 Sinusitis 0 0 0 Serious Adverse Events - On-Therapy (mitt population) n (%) [n considered by the investigator to be related to study medication] Subjects with non-fatal SAEs, n (%) 62.5 mcg 125 mcg Subjects with any SAE 0 1 (2) [0] 1 (2) [0] 0 0 Myocardial infarction 0 0 1 (2) [0] 0 0 Acute respiratory failure 0 1 (2) [0] 0 0 0 Subjects with any SAE 0 0 0 (any dose) Subjects with fatal SAEs, n (%) 0 (0) [0] 0 (0) [0] (any dose) Conclusion: Based on the population Emax dose response model of trough FEV1 data, UMEC had a geometric mean ED50 of 37 mcg (95%CI: 18, 57) and a predicted maximum intrinsic efficacy at trough of 0.185 L (95%CI: 0.154, 0.216) after once-daily dosing. The results from this study confirm those from two previous dose ranging studies in COPD by demonstrating that treatment with UMEC once-daily results in statistically and clinically significant improvements in lung function over 24 hours. This study extends previous findings by demonstrating a dose ordering over a lower dose range of 15.6 to 125 mcg once-daily. This study further substantiates the findings from a previous study that UMEC has a once-daily duration of action. Adverse events were reported for 8, 10, 5, 5, and 18% of subjects for placebo and doses of 15.6, 31.25, 62.5, and 125mcg once-daily, respectively. Adverse events were reported for 7, 12, and 4% of subjects for doses of 15.6 and 31.25 of UMEC and 18mcg of tiotropium, respectively. Two subjects reported single on-treatment SAEs of acute respiratory failure in the UMEC 15.6mcg once-daily group and myocardial infarction in the UMEC once-daily group. There were no fatalities. Within 1 year after study completion this section will either refer you to a publication or contain text interpreting the trial results. 7