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: Umeclidinium mcg, Vilanterol mcg, and Umeclidinium/Vilanterol / mcg Study Number: DB2116133 Title: A Randomized, Double-Blind, 3-Way, Cross-Over Study to Evaluate Lung Function Response after Treatment with Umeclidinium mcg, Vilanterol mcg, and Umeclidinium/Vilanterol / mcg Once- Daily in Subjects with Chronic Obstructive Pulmonary Disease (COPD) Rationale: The purpose of this study was to evaluate the lung function response to,, and in individual patients using a cross-over design. This allowed evaluation of response in patients who demonstrated a response 12% and 200 ml to either or to determine if additional benefit was provided by. Phase: IIIb Study Period: 19 Oct 2012-06 Mar 2013 Study Design: This was a multicenter, randomized, double-blind, three-way, complete block, cross-over study. Eligible subjects were randomized to 1 of 6 treatment sequences. The study consisted of 14 clinic visits conducted on an outpatient basis. Subjects signed the informed consent form (ICF) at Visit 0 and were assigned a subject identifier. Subjects who met the eligibility criteria at screening (Visit 1) completed a 5- to 7-day run-in period prior to randomization. The treatment phase comprised three 14-day treatment periods, each separated by a 10- to 14-day washout period starting on Day 15. A follow-up phone call for adverse event (AE) assessment occurred 7 to 9 days after completion of the final clinic visit or premature discontinuation. The total duration of subject participation in the study was approximately 12 weeks. Centres: 16 centers in Germany and 5 centers in Estonia Indication: Chronic Obstructive Pulmonary Disease Treatment: Subjects received each of the following treatments, in random order, taken for 14 days: Inhalation Powder mcg once-daily. Inhalation Powder mcg once-daily. Inhalation Powder / mcg once-daily. Objectives: The primary objective of this study was to evaluate the lung function response following treatment with mcg, mcg, and / mcg administered once-daily via the Novel Dry Powder Inhaler (NDPI) in subjects with COPD Primary Outcome/Efficacy Variable: Weighted mean forced expiratory volume in 1 second (FEV1) over 0-6 hours post-dose on Day 14 of each treatment period Secondary Outcome/Efficacy Variable(s): Proportion of subjects who were responsive to, or according to FEV1 at Day 1 (responsive defined as an increase from baseline of at least 12% and 200mL at any time over 0-6 h post-dose) Proportion of subjects who had a larger change from baseline in 0-6 hour weighted mean FEV1 on Day 14 with compared with and alone Trough FEV1 on Day 15 Statistical Methods: The primary analyses were in the subgroup of subjects who responded to or the subgroup of subjects who responded to, where response was defined as an increase of 12% and 200 ml above baseline for FEV1 during the 0-6 h post-dose period on Day 1. It was anticipated that 50% of subjects would respond to and 50% would respond to. Therefore, approximately 172 subjects were to be randomized to provide 146 completers, which would give sufficient power for comparisons in these subgroups. The following treatment comparisons were initially performed for the primary endpoint of 0-6 hour weighted mean FEV1 on Day 14, for the ITT Population. vs. in subjects who responded to vs. in subjects who responded to To account for multiplicity across treatment comparisons a step-down testing procedure was applied whereby inference for the second treatment comparison was dependent on statistical significance at the 5% level having been achieved for the first comparison. Other treatment comparisons were considered exploratory and no multiplicity 1
adjustment was applied. The primary analysis of change from baseline in 0-6 hour weighted mean FEV1 on Day 14 was performed using an analysis of covariance (ANCOVA) model. Data from all subjects were used by including a type of response (,, neither) in the model along with other predefined effects including period baseline FEV1, mean baseline FEV1 and period. Subject was fitted as a random effect. The proportion of subjects who were responders according to FEV1 on Day 1 were analysed using a logistic regression model including treatment, period baseline FEV1, mean baseline FEV1 and period fitted as fixed effects and subjects as a random effect. The proportion of subjects who showed a larger change from baseline in 0-6 h weighted mean FEV1 on Day 14 on vs. were tested to see if it was different from 50% using the McNemar/sign test. This analysis was supported by cumulative distribution function plots of the vs. difference in change from baseline in 0-6 h weighted mean FEV1 on Day 14. The analysis and figure were repeated for vs.. Trough FEV1 was reported in the same way as the primary endpoint (on ITT subjects only). Study Population: Male subjects and female subjects of non-childbearing potential or female subjects of childbearing potential who agreed to acceptable contraceptive methods who had an established clinical history of COPD in accordance with the definition by the American Thoracic Society/European Respiratory Society were included if they were 40 years of age at Visit 1. Subjects had a pre- and post-salbutamol FEV1/forced vital capacity (FVC) ratio of <0.70 and a pre- and post-salbutamol FEV1 of 70% of predicted normal values at Visit 1 calculated using Nutrition Health and Examination Survey (NHANES) III reference equations. Subjects were current or former cigarette smokers with a history of cigarette smoking of 10 pack-years at Visit 1. Concurrent use of inhaled corticosteroids (ICS) at a dose of up to 1000 mcg/day of fluticasone propionate or equivalent was permitted during the study provided the dose remained consistent throughout the study. ITT Population Number of Subjects: Planned, N 172 Randomised, N 182 Completed, n (%) 159 (87) Total Number Subjects Withdrawn, N (%) 23 (13) Withdrawn due to Adverse Events n (%) 6 (3) Withdrawn due to Lack of Efficacy n (%) 4 (2) Withdrawn for other reasons n (%) 13 (7) Demographics ITT Population N (ITT) 182 Females: Males 55/127 Mean Age, years (SD) 63.2 (8.19) White, n (%) 182 (100) Mean Height (SD), cm 171.2 (8.59) Mean Weight (SD), kg 81.0 (17.07) Mean Body Mass Index (SD), kg/m 2 27.53 (4.953) Primary Efficacy Results: 0-6 Hour Weighted Mean FEV1 (L) at Day 14 by Response Type / 2
Responder to Only n 90 90 88 LS mean (SE) 1.494 (0.0166) 1.479 (0.0167) 1.614 (0.0166) LS mean change (SE) 0.216 (0.0166) 0.201 (0.0167) 0.337 (0.0166) / vs Column Difference 0.121 0.135 95% CI (0.085,0.157) (0.100,0.171) p-value <0.001 <0.001 Responder to Only n 99 102 100 LS mean (SE) 1.467 (0.0150) 1.511 (0.0147) 1.609 (0.0148) LS mean change (SE) 0.189 (0.0150) 0.233 (0.0147) 0.331 (0.0148) / vs Column Difference 0.142 0.098 95% CI (0.110,0.174) (0.067,0.130) p-value <0.001 <0.001 Responder to Neither n 36 37 36 LS mean (SE) 1.355 (0.0243) 1.335 (0.0240) 1.407 (0.0243) LS mean change (SE) 0.077 (0.0243) 0.057 (0.0240) 0.130 (0.0243) / vs Column Difference 0.052 0.073 95% CI (0.001,0.104) (0.021,0.124) p-value 0.047 0.006 0-6 Hour Weighted Mean FEV1 (L) at Day 14 (Entire ITT Population) / Day 14 n 165 169 168 LS mean (SE) 1.452 (0.0135) 1.464 (0.0134) 1.567 (0.0134) LS mean change (SE) 0.171 (0.0135) 0.183 (0.0134) 0.286 (0.0134) / vs Column Difference 0.115 0.103 95% CI (0.090,0.139) (0.078,0.127) p-value <0.001 <0.001 Secondary Outcome Results: Proportion of Subjects Who Were Responsive According to FEV1 at Day 1 / 3
n 171 171 173 Responder, n (%) 92 (54) 104 (61) 124 (72) Non-Responder, n (%) 79 (46) 67 (39) 49 (28) / vs Column Odds Ratio 2.24 1.45 95% CI (1.40, 3.58) (0.90, 2.32) Proportion of Subjects Who Had a Larger Change from Baseline in 0-6 Hour Weighted Mean FEV1 at Day 14 with Compared with and Alone n 162 163 Improved on, n (%) 113 (70) 121 (74) Not Improved, n (%) 49 (30) 42 (26) Trough FEV1 at Day 15 by Response Type / Responder n 90 89 87 LS mean (SE) 1.433 (0.0178) 1.409 (0.0180) 1.517 (0.0179) LS mean change (SE) 0.159 (0.0178) 0.134 (0.0180) 0.242 (0.0179) / vs Column Difference 0.083 0.108 95% CI (0.043,0.124) (0.067,0.148) Responder n 99 101 99 LS mean (SE) 1.409 (0.0160) 1.436 (0.0158) 1.543 (0.0159) LS mean change (SE) 0.135 (0.0160) 0.161 (0.0158) 0.268 (0.0159) / vs Column Difference 0.133 0.107 95% CI (0.097,0.170) (0.071,0.142) Responder to Neither n 35 37 36 LS mean (SE) 1.335 (0.0263) 1.310 (0.07) 1.366 (0.0260) LS mean change (SE) 0.060 (0.0263) 0.035 (0.07) 0.092 (0.0260) / vs Column Difference 0.031 0.057 95% CI (-0.027,0.090) (-0.001,0.114) Trough FEV1 at Day 15 (Entire ITT Population) / Day 15 n 164 168 168 LS mean (SE) 1.405 (0.0132) 1.403 (0.0131) 1.497 (0.0131) LS mean change (SE) 0.124 (0.0132) 0.122 (0.0131) 0.217 (0.0131) / vs Column Difference 0.093 0.095 95% CI (0.065,0.120) (0.067,0.122) Safety Results: An on therapy adverse event (AE) was defined as an AE with onset on or after the start date of study medication but not later than the last contact date. AEs with onset during the wash-out or follow-up periods were 4
considered on-treatment and were assigned to the treatment received in the previous period. An on therapy serious adverse event (SAE) was defined as a SAE with onset on or after the start date of study medication and up to the last contact date. / Most Frequent Adverse Events On-Therapy n (%) n (%) n (%) 5
Subjects with any AE(s), n(%) 28 (16) 30 (18) 32 (18) Nasopharyngitis 5 (3) 11 (6) 7 (4) Headache 3 (2) 2 (1) 6 (3) Dyspnea 2 (1) 1 (<1) 0 Chronic Obstructive Pulmonary Disease 2 (1) 0 0 Pyrexia 2 (1) 2 (1) 1 (<1) Back Pain 2 (1) 0 1 (<1) Rhinitis 1 (<1) 1 (<1) 2 (1) Cough 1 (<1) 1 (<1) 3 (2) Gastroenteritis norovirus 1 (<1) 0 0 Herpes Zoster 1 (<1) 0 0 Otitis Media 1 (<1) 0 0 Oropharyngeal Pain 1 (<1) 1 (<1) 0 Wheezing 1 (<1) 0 0 Radiculitis lumbrosacral 1 (<1) 0 0 Abdominal pain upper 1 (<1) 0 0 Gastritis 1 (<1) 0 0 Gastroesophageal reflux disease 1 (<1) 0 0 Toothache 1 (<1) 0 0 Arthralgia 1 (<1) 0 0 Decreased appetite 1 (<1) 1 (<1) 0 Hyperglycemia 1 (<1) 0 0 Thermal burn 1 (<1) 0 0 Anxiety 1 (<1) 0 0 Cataract 1 (<1) 0 0 Esophageal carcinoma 1 (<1) 0 0 Pancreatic carcinoma 1 (<1) 0 0 Hypertension 1 (<1) 0 0 Diarrhea 0 3 (2) 0 Bronchitis 0 1 (<1) 0 Candidiasis 0 1 (<1) 0 Pneumonia 0 1 (<1) 0 Viral infection 0 1 (<1) 0 Dysphonia 0 1 (<1) 0 Throat irritation 0 1 (<1) 0 Upper respiratory tract inflammation 0 1 (<1) 0 Dizziness 0 1 (<1) 0 Edema peripheral 0 1 (<1) 0 Gout 0 1 (<1) 0 Type 2 diabetes mellitus 0 1 (<1) 0 Sinus tachycardia 0 1 (<1) 0 Tachyarrhythmia 0 1 (<1) 0 Spinal fracture 0 1 (<1) 0 Aggression 0 1 (<1) 0 Depression 0 1 (<1) 0 Photophobia 0 1 (<1) 0 Gamma-glutamyltransferase increased 0 1 (<1) 0 Weight increased 0 1 (<1) 0 Abscess limb 0 0 1 (<1) Gastroenteritis 0 0 1 (<1) Gastroenteritis viral 0 0 1 (<1) Gingivitis 0 0 1 (<1) Oral fungal infection 0 0 1 (<1) Pharyngitis 0 0 1 (<1) Upper respiratory tract infection 0 0 1 (<1) 6
Urinary tract infection 0 0 1 (<1) Epistaxis 0 0 1 (<1) Paresthesia 0 0 1 (<1) Abdominal pain 0 0 1 (<1) Chest pain 0 0 1 (<1) Myalgia 0 0 1 (<1) Osteoarthritis 0 0 1 (<1) Hypercholesterolemia 0 0 1 (<1) Angina pectoris 0 0 1 (<1) Tachycardia 0 0 1 (<1) Contusion 0 0 1 (<1) Bladder cancer 0 0 1 (<1) Serious Adverse Events - On-Therapy n (%) [n considered by the investigator to be related to study medication] / n (%) [related] n (%) [related] n (%) [related] Subjects with any SAE(s), n (%) [number related] 3 (2) [1] 1 (<1) [0] 3 (2) [0] Includes both fatal and non-fatal events Bladder cancer 0 0 1 (<1) [0] Oesophageal carcinoma 1 (<1) [0] 0 0 Pancreatic carcinoma 1 (<1) [0] 0 0 Chronic Obstructive Pulmonary Disease 2 (1) [1] 0 0 Angina pectoris 0 0 1 (<1) [0] Abscess limb 0 0 1 (<1) [0] Spinal fracture 0 1 (<1) [0] 0 / n (%) [related] n (%) [related] n (%) [related] Subjects with fatal SAEs, n (%) [number related] 1 (<1) [0] 0 [0] 0 [0] Oesophageal carcinoma 1 (<1) [0] 0 0 Pancreatic carcinoma 1 (<1) [0] 0 0 Conclusion: Subjects identified as responders to or demonstrated statistically significantly greater improvement in lung function (0-6 hour weighted mean FEV1 and trough FEV1) with / compared with or alone. Non-responders to or also showed greater improvements in lung function with / compared with either component alone. In the ITT Population, treatment differences were greater with / compared with components. In the ITT Population, 16% of subjects had AEs in the treatment period, 18% of subjects had AEs in the treatment period, and 18% of subjects had AEs in the / treatment period. The most commonly reported AEs were nasopharyngitis and headache in the and / periods, and nasopharyngitis and diarrhea in the treatment period. On-treatment SAEs were reported by 2% of subjects in the / treatment period, 2% of subjects in the treatment period and by <1% of subjects during the treatment period. COPD was the only SAE reported in more than one subject. 7
One subject (<1%) had a fatal event (oesophageal carcinoma/pancreatic carcinoma) in the study that occurred during the treatment period that was not considered related to study drug by the investigator. 8