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: GW685698+GSK573719 () Study Number: 200699 Title: A Clinical Study to Evaluate Four Doses of Umeclidinium Bromide in Combination with Fluticasone Furoate in COPD Subjects with an Asthmatic Component Rationale: In order to provide a treatment option for COPD patients with an asthmatic component., the combination of a once-daily inhaled corticosteroid (FF, GW685698) and a once-daily long-acting muscarinic antagonist (UMEC, GSK573719) is being studied, and its effect compared to FF alone and to the combination of FF and the once-daily long acting beta2- agonist vilanterol (VI, GW642444). Phase: IIb Study Period: 15-July-2014-18 July 2015 Study Design: Multicenter, randomized, double-blind, parallel-group dose-ranging study to evaluate the dose-response of four doses of UMEC in combination with FF (,,, and 0 mcg), compared with mcg monotherapy in COPD subjects with an asthmatic component. Centres: 55 centers in seven countries (5 in Argentina, 6 in Germany, 7 in Poland, 10 in Romania, 10 Russia, 7 in Ukraine, and 10 in the United States) Indication: COPD with an asthmatic component Treatment: Four-week run-in with fluticasone/salmeterol 250/50 mcg combination, after which subjects were randomized to receive one of 24 possible treatment sequences. Eligible subjects were randomized in Phase A (in a 1:1:1:1:2:2 ratio) to mcg, mcg, mcg, mcg, 0 mcg, or mcg, respectively. After 4 weeks of treatment, subjects entered Phase B and received either 0 mcg or /VI 0/25 mcg for 1 week. Subjects then entered Phase C where they received either the same treatment in Phase B or the same treatment minus the UMEC component for 1 week. Objectives: The primary objective of this study was to evaluate the dose-response of once-daily UMEC (15.6, 62.5, 125 and 250 mcg) in combination with, compared to mcg monotherapy over a 4-week treatment period (i.e. Phase A) in COPD subjects with an asthmatic component. Primary Outcome (Endpoints)/Efficacy : Change from Baseline in trough FEV1 at the end of Phase A (Visit 6) Secondary Outcome (Endpoints)/Efficacy: Mean change from baseline in rescue medication use at the end of Treatment Phase A Mean change from baseline in EXACT-RS score at the end of Treatment Phase A Change from baseline in daily morning (AM) PEF (pre-dose and pre-rescue bronchodilator) measured at home and averaged over the last 21 days of Treatment Phase A Change from trough in FEV1 at 3 hours post-study treatment at Visit 5 Change in clinic FEV1 following 2 puffs of albuterol/salbutamol given 3 hours post-study treatment dose at Visit 5 Statistical Methods: The primary comparisons of interest were between each of the four doses of and FF alone for the primary endpoint of change from baseline in clinic trough FEV1 at the end of Phase A (Visit 6) for the Intent-to-treat (ITT) Population. Sample size was determined based on the simulation results for the probability of observing a difference of at least 150 ml from for each dose of and the precision of estimations for these treatment comparisons. A total of 10,000 simulations were run for a variety of scenarios based on the treatment effect sizes observed in GSK study ILA115938. Each simulation assumed that the standard deviation of change in trough FEV1 was 350 ml; six treatment arms were included in the study (FF100, 15.6 or 31.25, 62.5, 125, 250, and ), and the number randomized to each treatment arm was varied with twice as many assigned to the 250 and arms (i.e., 1:1:1:1:2:2 allocation ratio, respectively). The increase in precision for the treatment comparisons appeared to be small when n>40 per arm. The covariates included in the final dose response model to assess their effect on the primary efficacy endpoint were age (years), sex, baseline FEV1, pack-years smoked and age when first treated with an inhaler per randomization stratification. The ITT population consisted of all subjects randomized to treatment and who received at least one dose of study medication. This constituted the primary population for all analyses of efficacy measures and safety measures during Phase A. The Phase B Population comprised all ITT subjects who completed Phase A according the protocol and received at least one dose of Phase B study treatment. This constituted the primary population for all analyses of efficacy measures and safety measures during Phase B. The Phase C Population comprised all ITT subjects who completed Phase B according the protocol and received at least one dose of Phase C study treatment. This constituted the primary population for all analyses of efficacy measures and safety measures during Phase C. The primary dose response analysis included clinic FEV1 data at baseline and trough FEV1 data at the end of treatment Phase A. The 1
dose response models included the null model, the step model, the slope-intercept model, the slope-intercept model on log scale, the Emax model, and the sigmoidal Emax model. The final dose response model was selected based on the minimum value for Akaike information criterion (AIC). Change from baseline in trough FEV1 at the end of Treatment Phase A was analyzed based on the final dose response model using SAS procedure for non-linear mixed effect model. The mean difference between each given dose of (or ) and FF for the change from baseline in trough FEV1 was predicted based on the final selected dose-response model, adjusted for the covariates age (years), sex, baseline FEV1, pack years smoked and age when first treated with an inhaler per randomization stratification. The Analysis of Covariance (ANCOVA) was also performed as a sensitivity analysis for the primary efficacy endpoint, and was the analysis method for all secondary efficacy endpoints of the continuous type variables, adjusted for all covariates mentioned above. The number and percentage of subjects experiencing at least one AE of any type, AEs within each body system and AEs within each preferred term were presented for each treatment group. Separate summaries were provided for all AEs, drug-related AEs, SAEs, and AEs leading to withdrawal, fatal AEs, most frequent AEs and AEs of special interest (relating to potential pharmacological class effects). All SAEs were tabulated and listed by treatment group. Deaths and SAEs were documented in case narrative format. Vital signs (pulse rate, systolic and diastolic blood pressure), ECGs and COPD exacerbations were summarized by treatment group. Study Population: Male and non-pregnant female outpatients (smokers or non-smokers), aged 18 years with a sufficient medical history to diagnose the subject as having COPD in accordance with the American Thoracic Society/European Respiratory Society definitions, with evidence of an asthmatic component as demonstrated by a best post-bronchodilator morning FEV1 50% and 80% of the predicted normal value at Visit 1 and a pre- and post-bronchodilator FEV1/FVC ratio <0.7 at Visit 1. Subjects were also required to demonstrate reversibility of their disease, defined by a 12% and 200 ml increase in FEV1 between 20 and 60 minutes following four inhalations of albuterol/salbutamol at Visit 1. Number of Subjects in Phase A (ITT Population): 0 Total Planned, N 40 40 40 40 80 80 320 Randomised, N 41 42 40 46 85 84 338 (37) Completed, n (% ) 39 (95) 42 (100) 39 (98) 44 (96) 82 (96) 83 (99) 329 (97) Withdrawn, n (%) 1 2 (5) 0 1 (3) 2 (4) 3 (4) 1 (1) 9 (3) Withdrawn: Adverse Events n (%) 0 0 1 (3) 1 (2) 0 0 2 (<1) Withdrawn: Lack of Efficacy n (%) 0 0 0 0 1 (1) 0 1 (<1) Withdrawn: subject reached 1 (2) 0 0 1 (2) 0 1 (1) 3 (<1) protocol-defined stopping criteria Withdrawn: by subject n (%) 1 (2) 0 0 0 2 (2) 0 3 (<1) 1. In Phase B, four subjects (1%) were withdrawn; two of these (<1%) due to an AE that occurred while receiving 0. One subject (<1%) receiving 0 was withdrawn due to subject reaching protocol stopping criteria and one subject receiving /VI was withdrawn due to physician decision. In Phase C, 3 subjects (<1%) were withdrawn from treatment: 1 (1%) receiving FF100 (withdrawal by subject), and 2 (3%) receiving /VI 0/25 (one due to AE, one due to physician decision). Demographics in Phase A (ITT population) N 41 42 40 46 85 84 338 Females: Males 21:20 23:19 19:21 18:28 38:47 41:43 160:178 Mean Age, years (SD) 58.4 55.5 56.7 58.2 57.8 57.6 57.5 (8.59) (11.33) (10.14) (10.47) (11.03) (10.95) (10.56) White, n (%) 40 (98) 42 (100) 39 (98) 45 (98) 81 (95) 83 (99) 330 (98) Primary Efficacy Results (ITT Population): Analysis of Change from Baseline in Clinic Trough FEV1 (L) at the End of Phase A (Final Step Model) 0 Final Step Model (Primary) n 42 39 44 81 83 Mean Difference from 0.103 0.103 0.103 0.103 0.073 95% C.I. (0.014,0.193) (0.014,0.193) (0.014,0.193) (0.014,0.193) (-0.027,0.172) p-value 0.024 0.024 0.024 0.024 0.152 2
ANCOVA Analysis of Change from Baseline in Clinic Trough FEV1 (L) at the End of Phase A 0 n 39 42 39 44 81 83 LS mean (SE) 1.714 1.798 1.854 1.834 1.799 1.786 (0.0441) (0.0448) (0.0454) (0.0416) (0.0325) (0.0331) LS mean change (SE) 0.034 0.118 0.174 0.153 0.119 0.106 (0.0441) (0.0448) (0.0454) (0.0416) (0.0325) (0.0331) Column vs. Difference 0.085 0.140 0.120 0.085 0.072 (-0.032, (0.023, (0.006, (-0.016, (-0.029, 0.201) 0.258) 0.234) 0.186) 0.173) p-value 0.153 0.019 0.039 0.099 0.159 Secondary Efficacy Results (ITT Population): Analysis of Change from Baseline in Rescue Medication Use (puffs) at the End of Phase A 0 Daily rescue medication use (puffs) n 39 42 39 43 80 82 LS Mean (SE) 3.4 (0.29) 2.4 (0.29) 2.3 (0.29) 2.7 (0.27) 2.6 (0.21) 2.7 (0.21) LS Mean change (SE) 0.6 (0.29) -0.4 (0.29) -0.5 (0.29) 0.0 (0.27) -0.2 (0.21) -0.1 (0.21) Column vs. Difference -1.0-1.1-0.7-0.8-0.7 (-1.7,-0.2) (-1.9,-0.4) (-1.4,0.1) (-1.5,-0.2) (-1.4,-0.1) Analysis of Change from Baseline in EXACT-RS Scores at the End of Phase A EXACT-RS Total Score 0 n 39 42 39 43 81 83 LS Mean (SE) 11.3 (0.54) 8.2 (0.55) 8.2 (0.56) 9.3 (0.52) 9.3 (0.40) 9.6 (0.41) LS Mean Change (SE) 0.5 (0.54) -2.6 (0.55) -2.5 (0.56) -1.5 (0.52) -1.5 (0.40) -1.1 (0.41) Column vs. Difference -3.1-3.0-2.0-2.0-1.7 (-4.6,-1.7) (-4.5,-1.6) (-3.4,-0.6) (-3.2,-0.7) (-2.9,-0.4) Total score range: 0 to 40, higher scores indicate more severe symptoms Analysis of Change from Baseline in AM PEF (L/min) Averaged Over the Last 21 Days of Phase A AM PEF 0 n 39 42 39 43 81 83 LS Mean (SE) 265.1 (4.62) 283.3 (4.70) 286.9 (4.76) 284.8 (4.40) 289.9 (3.37) 283.7 (3.47) LS Mean Change (SE) -14.2(4.62) 3.9(4.70) 7.6(4.76) 5.5(4.40) 10.5(3.37) 4.3(3.47) Column vs. Difference 18.1 21.8 19.7 24.8 18.5 (5.9, 30.3) (9.4, 34.1) (7.7, 31.7) (14.1, 35.4 (8.0, 29.1) PM PEF 3
n 39 40 39 43 80 83 LS Mean (SE) 276.1 (5.22) 296.6 (5.41) 308.7 (5.38) 300.4 (4.99) 303.8 (3.83) 302.9 (3.92) LS Mean Change (SE) -14.3(5.22) 6.2(5.41) 18.3(5.38) 10.0 (4.99) 13.5 (3.83) 12.5 (3.92) Column vs. Difference 20.5 32.6 24.3 27.7 26.8 6.5, 34.4 18.6, 46.5 10.7, 37.9 15.7, 39.7 14.8, 38.7 Analysis of Change from Trough in Clinic FEV1 (L) at 3 Hours Post-study Treatment at Visit 5 (Day 28) Visit 5 Day 28 0 N=41 N=42 N=40 N=46 N=85 N=84 Trough n 39 42 39 45 82 83 Mean 1.686 1.795 1.870 1.906 1.809 1.764 SD 0.5505 0.3691 0.6491 0.5517 0.5294 0.5474 At 3 hours post-study treatment Visit 5 Day 28 n 38 42 39 45 81 82 LS Mean 1.850 1.895 1.890 1.874 1.854 1.926 Standard Error 0.0307 0.0305 0.0309 0.0279 0.0220 0.0227 LS Mean Change 0.048 0.093 0.088 0.072 0.052 0.124 Standard Error 0.0307 0.0305 0.0309 0.0279 0.0220 0.0227 Treatment vs. Difference 0.045 0.040 0.025 0.005 0.076-0.034, 0.125-0.041, 0.121-0.054, 0.103-0.065, 0.075 0.007, 0.146 Treatment vs. Difference -0.031-0.036-0.051-0.072-0.098, -0.105, -0.118, 0.015-0.127, -0.016 0.036 0.033 Analysis of Change from Pre-Albuterol/Salbutamol in Clinic FEV1 (L) Following Two Puffs of Albuterol/Salbutamol Given 3 Hours Post-study Treatment at Visit 5 (Day 28) Visit 5 (Day 28) 0 n 37 40 38 42 80 80 LS Mean 2.161 2.073 2.070 2.071 2.100 1.998 Standard Error 0.0287 0.0284 0.0284 0.0262 0.0202 0.0209 LS Mean Change 0.249 0.161 0.159 0.160 0.189 0.087 Standard Error 0.0287 0.0284 0.0284 0.0262 0.0202 0.0209 Column vs. FF Difference -0.088-0.091-0.089-0.060-0.163-0.162, -0.165, -0.162, -0.124, 0.004-0.227, -0.014-0.016-0.016-0.099 Column vs. Difference 0.075 0.072 0.073 0.103 0.013, 0.009, 0.012, 0.052, 0.137 0.135 0.135 0.153 Safety Results: Adverse events and SAEs were collected from the start of the run-in period until the follow-up contact. Ontreatment AEs were defined as occurring up to and including 1 day after the last dose of study medication taken. Any SAEs assessed as related to study participation (e.g., study treatment, protocol-mandated procedures, invasive tests, or change in existing therapy) or related to 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 AEs and SAEs were followed until resolution, until the condition stabilized, until the event was otherwise explained, or until the subject was lost to follow up 4
Most Frequent Adverse Events On-Therapy (ITT Population) FF/ UMEC 0 Any AE(s), n(%) 13 (32) 13 (31) 8 (20) 11 (24) 13 (15) 17 (20) Nasopharyngitis 5 (12) 3 (7) 2 (5) 2 (4) 2 (2) 4 (5) Dysgeusia 1 (2) 0 1 (3) 1 (2) 2 (2) 1 (1) Headache 1 (2) 2 (5) 1 (3) 1 (2) 1 (1) 0 Dysphonia 1 (2) 0 1 (3) 3 (7) 0 0 Cough 2 (5) 0 0 1 (2) 0 2 (2) Back pain 0 1 (2) 1 (3) 0 1 (1) 0 Toothache 0 3 (7) 1 (3) 0 0 0 Respiratory tract infection 0 0 0 1 (2) 0 2 (2) Upper respiratory tract 1 (2) 0 0 0 0 2 (2) infection Throat irritation 1 (2) 0 0 0 1 (1) 0 Nasal congestion 0 0 1 (3) 0 0 1 (1) Rhinitis 1 (2) 1 (2) 0 0 0 0 Respiratory tract infection viral 2 (5) 0 0 0 0 0 Oropharyngeal pain 1 (2) 1 (2) 0 0 0 0 Respiratory disorder 0 0 0 1 (2) 0 1 (1) Rash 0 0 0 2 (4) 0 0 Arthropod bite 0 1 (2) 0 0 0 1 (1) Periodontitis 0 0 1 (3) 0 0 0 Bronchitis 0 0 0 0 0 1 (1) Gingivitis 0 0 0 1 (2) 0 0 Influenza 0 0 0 0 1 (1) 0 Oral candidiasis 0 1 (2) 0 0 0 0 Pharyngotonsillitis 0 0 0 0 1 (1) 0 Sinusitis 1 (2) 0 0 0 0 0 Viral upper respiratory tract 0 0 0 1 (2) 0 0 infection Chronic obstructive pulmonary disease 1 (2) 0 0 0 0 0 Pulmonary congestion 1 (2) 0 0 0 0 0 Dizziness 0 0 0 0 1 (1) 0 Abdominal pain upper 0 0 0 0 1 (1) 0 Diarrhoea 0 0 0 0 1 (1) 0 Dry mouth 0 0 0 0 0 1 (1) Inguinal hernia 0 0 0 1 (2) 0 0 Pain in extremity 0 0 0 0 1 (1) 0 Arrhythmia 0 0 0 1 (2) 0 0 Atrial fibrillation 0 1 (2) 0 0 0 0 Palpitations 0 0 0 0 0 1 (1) Pruritus 0 0 0 0 0 1 (1) Chest discomfort 0 0 1 (3) 0 0 0 Non-cardiac chest pain 1 (2) 0 0 0 0 0 Hyperglycaemia 0 0 0 0 1 (1) 0 Hyperkalaemia 0 0 1 (3) 0 0 0 Anxiety 0 0 1 (3) 0 0 0 Insomnia 0 0 0 0 0 1 (1) Vertigo 1 (2) 0 0 0 0 0 Blood glucose increased 0 1 (2) 0 0 0 0 5
Serious Adverse Events - On-Therapy n (%) [n considered by the investigator to be related to study medication] Non-fatal on-treatment SAEs FF/ UMEC 0 Hypertensive crisis 0 0 0 0 1 (<1) [0] 0 There were no on-treatment fatal SAEs. Conclusion: For the primary endpoint of trough FEV1 at Visit 6, statistically significant improvements from baseline in trough FEV1 were demonstrated (by modelling) for all four treatments when compared with treatment. The final step model predicted a mean increase of 103 ml in trough FEV1 for each treatment compared with FF alone at Visit 6, (p=0.024). In the ANCOVA analysis of the primary endpoint of trough FEV1 at Visit 6, improvements in trough FEV1 were observed for all treatments, ranging from 85 ml to 140 ml with the treatments and 72 ml with the treatment, with statistically significant LS mean differences over being demonstrated for the and treatments (140 ml and 120 ml, respectively). The improvement in trough FEV1 did not reach 150 ml for any of treatments when compared to. However, the improvement did exceed 50 ml for when compared to the next lower dose of () and to the treatment. In the ITT population, the effect of treatment with compared to reached a plateau at the 62.5 mcg UMEC dose. The LS mean changes in trough FEV1 demonstrated with the treatments were similar to or greater than the change observed with the treatment. The results of the primary endpoint were also supported by the secondary endpoints: LS mean reductions from Baseline in rescue medication use (puffs/day) when compared to ranged from 0.7 to 1.1 puffs for all groups and and were statistically significant for all treatment groups except. Clinically meaningful and statistically significant LS mean changes (decreases) in the EXACT-RS total scores were demonstrated for all of the treatments and the treatment compared with. LS mean improvements in PEF when compared to ranged from 18.1 to 24.8 L/min in groups and 18.5 L/min in group for the AM assessments, and from 20.5 to 32.6 L/min in groups and 26.8 L/min in group for the PM assessments; these improvements were statistically significant. For the secondary endpoint of change from trough in FEV1 at three hours post-study treatment on Visit 5, LS mean increases were observed in all treatments, ranging from 5 to 45 ml in the groups and 76 ml in when compared to FF. These increases were not statistically significant. The secondary endpoint of change in clinic FEV1 following two puffs of albuterol measured albuterol responses on backgrounds of ICS/LABA and ICS/LAMA on Day 28. LS mean changes for the groups when compared to ranged from 73mL to 103 ml; a statistically significant treatment difference was observed in favor of all treatments. The clinical significance of this difference is uncertain. The most commonly reported AEs in the ITT population were nasopharyngitis, viral respiratory tract infection, cough, and dysphonia. Non-serious AEs were reported for each treatment group (by study phase) as follows: Phase A FF/ UMEC 0 Any AE n (%) 13 (32) 13 (31) 8 (20) 11 (24) 13 (15) 17 (20) 0 /VI 0/25 Phase B (N=166) (N=163) Any AE n (%) 15 (9) 9 (6) Phase C (N=79) 0 (N=82) /VI 0/25 (N=80) Any AE n (%) 3 (4) 2 (2) 3 (4) 3 (4) There was one on-treatment, non-fatal SAE in Phase B during treatment with 0 (hypertensive crisis). There were no on-treatment fatal events; however, one post-treatment death was reported for a subject 20 days after they 6
had been withdrawn from the study due to an unspecified AE. The subject experienced the non-fatal SAE of pneumonia 2 days after withdrawal; although this SAE was reported to have resolved, the subject experienced two further SAEs that were reported as having a fatal outcome: transient ischemic attack and pulmonary embolism, which had dates of onset 14 and 17 days, respectively, after the last dose of study medication. Of these two fatal SAEs, the pulmonary embolism was reported to be an underlying cause of death. The investigator considered the SAEs of pneumonia and pulmonary embolism related to treatment. 7