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

Transcription

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: fluticasone furoate/vilanterol/umeclidinium bromide Study Number: Title: A Phase III, 24 week, randomized, double-blind, double-dummy, parallel-group study (with an extension to 52 weeks in a subset of subjects) comparing the efficacy, safety and tolerability of the fixed dose triple combination FF/UMEC/VI administered once daily in the morning via a dry powder inhaler with budesonide/formoterol 400mcg/12mcg administered twice-daily via a reservoir inhaler in subjects with chronic obstructive pulmonary disease Rationale: Previous clinical studies have assessed the use of triple therapy with an inhaled corticosteroid (ICS), a long acting beta agonist (LABA), and a long acting muscarinic antagonist (LAMA), administered by multiple inhalers, in patients with moderate to very severe chronic obstructive pulmonary disease (COPD). These studies have reported greater improvements in lung function, health-related quality of life, hospitalisation rates, and rescue medication use, compared with dual therapy (ICS/LABA) or LAMA alone, thus supporting the use of triple therapy in COPD. GSK has developed a once-daily triple ICS/LAMA/LABA therapy of fluticasone furoate/umeclidinium bromide/vilanterol (FF/UMEC/VI) 100/62.5/25 mcg in a single inhaler (ELLIPTA TM ), with the aim of providing a new treatment option for the management of advanced COPD to reduce the exacerbation frequency, allow for a reduced burden of polypharmacy, convenience, and increase the potential for improvement in lung function, health-related quality of life (HRQoL), and symptom control over established dual/monotherapies. Phase: IIIa Study Period: 23 January April 2016 Study Design: This was a randomised, double-blind, double-dummy, parallel-group, multicentre study comparing the efficacy and safety of once-daily FF/UMEC/VI 100/62.5/25 mcg with a twice daily ICS/LABA, budesonide/formoterol (BUD/FOR) 400/12 mcg. The study had three periods: Run-in (2 weeks), Treatment (24 weeks or 52 weeks), and Follow-up (variable duration, could be from 7 days to 52 weeks). All subjects remained on their existing maintenance COPD therapy during the run-in period; eligible subjects were subsequently randomised to one of the two study treatments. All subjects were treated for up to 24 weeks and a subset of approximately 400 subjects was treated for up to 52 weeks. This subset included the first 400 subjects who were randomised and consented to be treated for 52 weeks. Subjects attended clinic visits for screening, randomisation (Day 1), and after 2, 4, 12, and 24 weeks of treatment (and after 36 and 52 weeks of treatment for subjects in the study extension). Subjects who permanently stopped study treatment were not required to withdraw from the study and could continue to have certain safety and efficacy assessments conducted. Centres: A total of 162 centres in 15 countries randomised and treated subjects: 21 centres in Russian Federation, 17 in Ukraine, 17 in Mexico, 16 in Germany, 12 in Greece, 10 in Czech Republic, 10 in Romania, 9 in Bulgaria, 8 in China, 8 in Estonia, 8 in Hungary, 8 in Italy, 6 in Poland, 6 in Republic of Korea, and 6 in Slovakia. Indication: Chronic Obstructive Pulmonary Disease Treatment: Subjects who met the eligibility criteria were randomised (1:1) at Visit 2 (Day 1). The randomisation was stratified based on smoking status. Subjects received one of the following double-blind treatments administered via oral inhalation for 24 weeks (or 52 weeks in a subset of subjects): FF/UMEC/VI 100/62.5/25 mcg via the ELLIPTA once daily (OD) in the morning and placebo via the Turbuhaler twice daily (BID) OR BUD/FOR 400/12 mcg via the Turbuhaler BID and placebo via the ELLIPTA OD in the morning Objectives: The primary objective was to evaluate the effects of FF/UMEC/VI on lung function and HRQoL compared with BUD/FOR after 24 weeks of treatment. Primary Outcome (Endpoints)/Efficacy: The co-primary endpoints were change from baseline in trough forced expiratory volume in one second (FEV1) at Week 24 and change from baseline in St. George's' Respiratory Questionnaire (SGRQ) Total Score at Week 24. Supporting the co-primary endpoints were the proportion of subjects achieving an increase in trough FEV1 of at least 100 ml from baseline at Week 24 and the proportion of SGRQ responders based on a decrease from baseline of at least 4 units in SGRQ Total Score at Week 24. Secondary Outcome (Endpoints)/Efficacy: Secondary efficacy endpoints included: annual rate of moderate or severe COPD exacerbations (on-treatment), change from baseline in Exacerbations of Chronic Pulmonary Disease Tool- Respiratory Symptoms (EXACT-RS) Score and subscale (breathlessness, cough and sputum, and chest symptoms) scores, Transitional Dyspnoea Index (TDI) Focal Score at Week 24, and percentage of days with a Daily Activity Question score of 2 (did more activities than usual) over Weeks Supporting the secondary analyses were the proportion of EXACT-RS, EXACT-RS Breathlessness, EXACT-RS Cough and Sputum, and EXACT-RS Chest Symptoms responders based on each scale score and the proportion of TDI responders based on TDI focal 1

2 score. Statistical Methods: The Intent-to-Treat (ITT) Population and the Extension (EXT) Population were used for analysis of efficacy and safety data. The ITT Population comprised all randomised subjects, excluding those who were randomised in error who did not receive a dose of study treatment, and included all subjects treated for up to 24 weeks. The EXT Population comprised all subjects in the ITT Population who were enrolled into the subset of subjects (approximately 400) with extension to 52 weeks. Co-primary efficacy endpoints (change from baseline in trough FEV1 and SGRQ Total Score at Week 24) were analysed for the ITT Population using a mixed model repeated measures (MMRM) analysis based on a two-sided hypothesis testing approach. Covariates of treatment group, smoking status (screening), geographical region, visit, baseline value, and baseline-by-visit and treatment group-by-visit interactions were included in the model. To account for multiplicity of the co-primary comparisons, the Hochberg method was used to control overall type I error at α=0.05. Analyses supporting the co-primary endpoints were the proportion of subjects achieving an increase in trough FEV1 of >=100 ml from baseline and the proportion of SGRQ responders based on a pre-defined decrease from baseline >=4 units in SGRQ Total Score. These endpoints were analysed using a generalised linear mixed model with a logit link function using the same covariates as the primary analyses. Secondary endpoint comparisons were not adjusted for multiplicity. The annual rate of moderate/severe COPD exacerbation was analysed using a generalised linear model assuming a negative binomial distribution with time on treatment as an offset variable. Average scores for the EXACT-RS and the three subscales (breathlessness, cough and sputum, and chest symptoms) over 4-week intervals and TDI Focal Score at Week 24 were analysed using a MMRM analysis. The percentage of days with score of 2 on the Daily Activity Question was analysed using an analysis of covariance (ANCOVA) model. The proportions of EXACT-RS responders (decrease from baseline >=2.0), EXACT-RS Breathlessness responders (decrease from baseline >=1.0), EXACT-RS Cough and Sputum responders (decrease from baseline >=0.7), EXACT-RS Chest Symptoms responders (decrease from baseline >=0.7), and TDI responders (score >=1 unit) were analysed using a generalised linear mixed model with a logit link function. Study Population: Male and non-pregnant female subjects at least 40 years of age who were current or former cigarette smokers (at least 10 pack-years at screening) diagnosed with COPD were eligible. Subjects had to demonstrate at screening: A score of >=10 on the COPD Assessment Test (CAT) A post-bronchodilator FEV1 <50% predicted normal OR A post-bronchodilator FEV1 <80% predicted normal and a documented history of >=2 moderate exacerbations or one severe (hospitalised) exacerbation in the previous 12 months A post-salbutamol FEV1/forced vital capacity (FVC) ratio of <0.70. Subjects must also have been receiving daily maintenance treatment for their COPD for at least 3 months prior to screening. Subjects who had a current diagnosis of asthma, COPD caused by α1-antitrypsin deficiency, other significant respiratory disorders (e.g., tuberculosis, lung cancer, pulmonary hypertension, etc), lung resection within 12 months of screening, or other clinically significant diseases in the opinion of the investigator, were not eligible. FF/UMEC/VI 100/62.5/25 BUD/FOR 400/12 Number of Subjects Planned, N Randomised, N ITT Population, N Completed Treatment, n (%) 840 (92) 782 (87) Total Number Subjects Prematurely Discontinued Treatment, n (%) 71 (8) 117 (13) Discontinued due to Adverse Events n (%) 34 (4) 28 (3) Discontinued due to Lack of Efficacy n (%) 10 (1) 37 (4) Discontinued for other reasons n (%) 27 (3) 52 (6) Completed Study, n (%) 866 (95) 842 (94) Total Number Subjects Withdrawn from Study, n (%) 45 (5) 57 (6) Withdrawn due to Adverse Events n (%) 16 (2) 19 (2) Withdrawn due to Lack of Efficacy n (%) 0 0 Withdrawn for other reasons n (%) 29 (3) 38 (4) 2

3 Demographics (ITT Population) FF/UMEC/VI BUD/FOR N Females: Males 233: :663 Mean Age, years (SD) 64.2 (8.56) 63.7 (8.71) White, n (%) 776 (85) 767 (85) Demographics (EXT Population) FF/UMEC/VI BUD/FOR N Females: Males 53:157 58:162 Mean Age, years (SD) 63.7 (7.76) 63.3 (8.43) White, n (%) 210 (100) 219 (>99) Co-Primary Efficacy Results (ITT Population): Trough FEV1 at Week 24 FF/UMEC/VI BUD/FOR n with analysable data at >=1 timepoint n with analysable data at Week LS Mean Change from Baseline (SE) (0.0083) (0.0085) Difference (SE) (0.0118) 95% CI 0.148, Adjusted p-value <0.001 SGRQ Total Score at Week 24 FF/UMEC/VI BUD/FOR n with analysable data at >=1 timepoint n with analysable data at Week LS Mean change from Baseline (SE) -6.6 (0.45) -4.3 (0.46) Difference (SE) -2.2 (0.64) 95% CI -3.5, -1.0 Adjusted p-value <0.001 Supporting Co-Primary Efficacy Results (Week 24): Proportion of subjects with >=100 ml increase in trough FEV1 FF/UMEC/VI BUD/FOR n Increase, n (%) 453 (50) 184 (21) No increase, n (%) 454 (50) 708 (79) Odds ratio % CI 3.27, 4.97 SGRQ Total Score Responders FF/UMEC/VI BUD/FOR n Responder (>=4 unit decrease in score), n (%) 448 (50) 368 (41) Non-responder, n (%) 456 (50) 525 (59) Odds ratio % CI 1.16, 1.70 Secondary Outcome Results (ITT Population): Annual Rate of Moderate or Severe Exacerbations (up to Week 24) FF/UMEC/VI BUD/FOR n Mean annualised exacerbation rate Ratio % CI 0.49, 0.86 % reduction in annualised rate 35 EXACT-RS Score (Weeks 21-24) FF/UMEC/VI BUD/FOR n with analysable data at >=1 timepoint n with analysable data at timepoint LS Mean change from Baseline (SE) (0.157) (0.160) 3

4 Difference (SE) (0.224) 95% CI -1.79, EXACT-RS Responders (Weeks 21-24) n Responder (>=2 unit decrease in score), n (%) 413 (47) 317 (37) Non-responder, n (%) 457 (53) 543 (63) Odds ratio % CI 1.30, 1.94 EXACT-RS Breathlessness Score (Weeks 21-24) FF/UMEC/VI BUD/FOR n with analysable data at >=1 timepoint n with analysable data at timepoint LS Mean change from Baseline (SE) (0.085) (0.087) Difference (SE) (0.122) 95% CI -1.01, EXACT-RS Breathlessness Responders (Weeks 21-24) n Responder (>=1 unit decrease in score), n (%) 410 (47) 294 (34) Non-responder, n (%) 460 (53) 566 (66) Odds ratio % CI 1.42, 2.11 EXACT-RS Cough & Sputum Score (Weeks 21-24) FF/UMEC/VI BUD/FOR n with analysable data at >=1 timepoint n with analysable data at timepoint LS Mean change from Baseline (SE) (0.046) (0.046) Difference (SE) (0.065) 95% CI -0.35, EXACT-RS Cough & Sputum Responders (Weeks 21-24) n Responder (>=0.7 unit decrease in score), n (%) 406 (47) 325 (38) Non-responder, n (%) 464 (53) 535 (62) Odds ratio % CI 1.23, 1.84 EXACT-RS Chest Symptoms Score (Weeks 21-24) FF/UMEC/VI BUD/FOR n with analysable data at >=1 timepoint n with analysable data at timepoint LS Mean change from Baseline (SE) (0.050) (0.051) Difference (SE) (0.072) 95% CI -0.50, EXACT-RS Chest Symptoms Responders (Weeks 21-24) n Responder (>=0.7 unit decrease in score), n (%) 346 (40) 267 (31) Non-responder, n (%) 524 (60) 593 (69) Odds ratio % CI 1.27, 1.94 TDI Focal Score at Week 24 FF/UMEC/VI BUD/FOR n with analysable data at >=1 timepoint n with analysable data at timepoint LS Mean (SE) 2.29 (0.096) 1.72 (0.099) 4

5 Difference (SE) 0.57 (0.138) 95% CI 0.30, 0.84 TDI Responders (Week 24) n Responder (score of >=1 unit), n (%) 553 (61) 455 (51) Non-responder, n (%) 350 (39) 433 (49) Odds ratio % CI 1.33, 1.95 Daily Activity Question -% days reporting score of 2 (Wks 1-24) FF/UMEC/VI BUD/FOR n LS Mean change from Baseline (SE) 0.0 (0.38) -0.1 (0.39) Difference (SE) 0.1 (0.51) 95% CI -0.9, 1.1 Secondary Outcome Results (EXT Population): Trough FEV1 (L) at Week 52 FF/UMEC/VI BUD/FOR n with analysable data at >=1 timepoint n with analysable data at Week LS Mean Change from Baseline (SE) (0.0170) (0.0172) Difference (SE) (0.0242) 95% CI 0.131, Proportion of subjects with >=100 ml increase in trough FEV1 FF/UMEC/VI BUD/FOR n Increase, n (%) 96 (46) 34 (16) No increase, n (%) 114 (54) 185 (84) Odds ratio % CI 3.02, 7.61 SGRQ Total Score at Week 52 FF/UMEC/VI BUD/FOR n with analysable data at >=1 timepoint n with analysable data at Week LS Mean change from Baseline (SE) -4.6 (1.01) -1.9 (1.03) Difference (SE) -2.7 (1.44) 95% CI -5.5, 0.2 SGRQ Total Score Responders (Week 52) FF/UMEC/VI BUD/FOR n Responder (>=4 unit decrease in score), n (%) 91 (44) 73 (33) Non-responder, n (%) 118 (56) 146 (67) Odds ratio % CI 1.01, 2.24 Annual Rate of Moderate or Severe Exacerbations (up to Week 52) FF/UMEC/VI BUD/FOR n Mean annualised exacerbation rate Ratio % CI 0.37, 0.85 % reduction in annualised rate 44 EXACT-RS Score (Weeks 49-52) FF/UMEC/VI BUD/FOR n with analysable data at >=1 timepoint n with analysable data at timepoint

6 LS Mean change from Baseline (SE) (0.370) (0.370) Difference (SE) (0.524) 95% CI -2.45, EXACT-RS Responders (Weeks 49-52) n Responder (>=2 unit decrease in score), n (%) 87 (42) 68 (32) Non-responder, n (%) 118 (58) 145 (68) Odds ratio % CI 1.03, 2.32 EXACT-RS Breathlessness Score (Weeks 49-52) FF/UMEC/VI BUD/FOR n with analysable data at >=1 timepoint n with analysable data at timepoint LS Mean change from Baseline (SE) (0.207) (0.207) Difference (SE) (0.294) 95% CI -1.45, EXACT-RS Breathlessness Responders (Weeks 49-52) n Responder (>=1 unit decrease in score), n (%) 87 (42) 59 (28) Non-responder, n (%) 118 (58) 154 (72) Odds ratio % CI 1.23, 2.80 EXACT-RS Cough & Sputum Score (Weeks 49-52) FF/UMEC/VI BUD/FOR n with analysable data at >=1 timepoint n with analysable data at timepoint LS Mean change from Baseline (SE) (0.100) (0.100) Difference (SE) (0.141) 95% CI -0.45, 0.11 EXACT-RS Cough & Sputum Responders (Weeks 49-52) n Responder (>=0.7 unit decrease in score), n (%) 92 (45) 62 (29) Non-responder, n (%) 113 (55) 151 (71) Odds ratio % CI 1.26, 2.94 EXACT-RS Chest Symptoms Score (Weeks 49-52) FF/UMEC/VI BUD/FOR n with analysable data at >=1 timepoint n with analysable data at timepoint LS Mean change from Baseline (SE) (0.115) (0.115) Difference (SE) (0.163) 95% CI -0.73, EXACT-RS Chest Symptoms Responders (Weeks 49-52) n Responder (>=0.7 unit decrease in score), n (%) 76 (37) 63 (30) Non-responder, n (%) 129 (63) 150 (70) Odds ratio % CI 0.98, 2.33 TDI Focal Score at Week 52 FF/UMEC/VI BUD/FOR n with analysable data at >=1 timepoint

7 n with analysable data at timepoint LS Mean (SE) 1.74 (0.221) 1.39 (0.226) Difference (SE) 0.34 (0.317) 95% CI -0.28, 0.97 TDI Responders (Week 52) n Responder (score of >=1 unit), n (%) 110 (53) 101 (46) Non-responder, n (%) 99 (47) 117 (54) Odds ratio % CI 0.91, 1.99 Daily Activity Question -% days reporting score of 2 (Weeks 1-52) FF/UMEC/VI BUD/FOR n LS Mean change from Baseline (SE) 0.0 (0.70) 0.3 (0.69) Difference (SE) -0.3 (0.95) 95% CI -2.1, 1.6 Safety Results: Adverse Events (AE) information was collected from Day 1 (Randomisation Visit) until the Follow-up Visit/telephone contact was completed or until the Week 24 Visit or Week 52 Visit for subjects who discontinued study treatment but were scheduled to continue in the study until those visits. Additionally, Serious Adverse Events (SAEs) assessed as related to study participation 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. Number (%) of Subjects Most Frequent Adverse Events On-Therapy FF/UMEC/VI BUD/FOR ITT Population (up to Week 24), N Subjects with any AE(s), n (%) 354 (39) 339 (38) Nasopharyngitis 64 (7) 43 (5) Headache 44 (5) 53 (6) Upper respiratory tract infection 20 (2) 19 (2) COPD 15 (2) 23 (3) Back pain 19 (2) 18 (2) Arthralgia 17 (2) 13 (1) Pneumonia 19 (2) 7 (<1) Pharyngitis 15 (2) 9 (1) Abdominal Pain Upper 9 (<1) 12 (1) Rhinitis 10 (1) 11 (1) Cough 10 (1) 10 (1) Hypertension 8 (<1) 12 (1) Oropharyngeal pain 9 (<1) 10 (1) Influenza 10 (1) 8 (<1) Diarrhoea 9 (<1) 7 (<1) Rhinorrhoea 3 (<1) 12 (1) Blood pressure increased 4 (<1) 8 (<1) EXT Population (up to Week 52), N Subjects with any AE(s), n (%) 100 (48) 122 (55) 7

8 Nasopharyngitis 23 (11) 22 (10) Headache 17 (8) 22 (10) COPD 5 (2) 22 (10) URTI 6 (3) 10 (5) Hypertension 7 (3) 6 (3) Arthralgia 5 (2) 6 (3) Back pain 4 (2) 5 (2) Pneumonia 4 (2) 4 (2) Rhinitis 3 (1) 5 (2) Dizziness 1 (<1) 6 (3) Oropharyngeal pain 6 (3) 1 (<1) Pharyngitis 5 (2) 1 (<1) Respiratory tract infection viral 3 (1) 3 (1) Abdominal pain upper 1 (<1) 3 (1) Blood pressure increased 0 4 (2) Dyspnoea 0 4 (2) Vertigo 0 4 (2) Candida infection 0 3 (1) Gastrooesophageal reflux disease 0 3 (1) Oral fungal infection 0 2 (<1) Serious Adverse Events - On-Therapy Number (%) of Subjects [n subjects with events considered by the investigator to be related to study medication] Subjects with non-fatal SAEs, n (%) [n related] FF/UMEC/VI BUD/FOR ITT Population (up to Week 24), N Any non-fatal SAE, n (%) [n related] 45 (4.9) [2] 47 (5.2) [1] COPD 12 (1.3) 21 (2.3) Pneumonia 8 (0.9) [1] 3 (0.3) Myocardial infarction 0 2 (0.2) Lung neoplasm malignant 0 2 (0.2) Ankle fracture 2 (0.2) 0 Constipation 2 (0.2) 0 Angina pectoris 1 (0.1) 1 (0.1) Transient ischaemic attack 1 (0.1) 1 (0.1) Haemoptysis 0 1 (0.1) Pneumothorax 0 1 (0.1) Pulmonary embolism 0 1 (0.1) Pulmonary oedema 1 (0.1) 0 Appendicitis 1 (0.1) 0 Cellulitis 0 1 (0.1) Infected dermal cyst 1 (0.1) 0 Infective exacerb. of chronic obstruct. airways 0 1 (0.1) disease Lung infection 1 (0.1) [1] 0 Osteomyelitis 1 (0.1) 0 Respiratory tract infection 0 1 (0.1) Tuberculosis 1 (0.1) 0 Urinary tract infection 1 (0.1) 0 Acute coronary syndrome 1 (0.1) 0 Atrial fibrillation 0 1 (0.1) Atrial flutter 0 1 (0.1) [1] Cardiac failure 1 (0.1) [1] 0 Cyanosis 0 1 (0.1) Bladder cancer 1 (0.1) 0 8

9 Brain neoplasm 0 1 (0.1) Brain neoplasm malignant 0 1 (0.1) Lung neoplasm 1 (0.1) 0 Metastases to lung 1 (0.1) 0 Squamous cell carcinoma of lung 0 1 (0.1) Hip fracture 1 (0.1) 0 Humerus fracture 0 1 (0.1) Procedural haemorrhage 1 (0.1) 0 Radius fracture 0 1 (0.1) Gastric ulcer 0 1 (0.1) Intestinal mass 1 (0.1) 0 Epilepsy 0 1 (0.1) Postictal paralysis 0 1 (0.1) Anxiety 1 (0.1) 0 Psychotic disorder 1 (0.1) 0 Haemorrhage urinary tract 1 (0.1) 0 Neprolithiasis 0 1 (0.1) Ureterolithiasis 0 1 (0.1) Coronary artery bypass 1 (0.1) 0 Heart valve replacement 1 (0.1) 0 Inguinal hernia repair 1 (0.1) 0 Deafness 0 1 (0.1) Cataract 0 1 (0.1) Non-cardiac chest pain 0 1 (0.1) Cholecystitis chronic 1 (0.1) 0 Electrocardiogram ST segment elevation 1 (0.1) 0 Intervertebral disc protrusion 1 (0.1) 0 Dermatitis 0 1 (0.1) Peripheral arterial occlusive disease 1 (0.1) 0 EXT Population (up to Week 52), N Any non-fatal SAE, n (%) [n related] 19 (9.0) [0] 27 (12.3) [1] COPD 5 (2.4) 20 (9.1) Pneumonia 4 (1.9) 4 (1.8) [1] Transient ischaemic attack 1 (0.5) 1 (0.5) Lung neoplasm 1 (0.5) 1 (0.5) Pneumothorax 0 1 (0.5) Colon cancer 1 (0.5) 0 Metastases to central nervous system 1 (0.5) 0 Metastases to lung 1 (0.5) 0 Small cell lung cancer 1 (0.5) 0 Acute myocardial infarction 1 (0.5) 0 Atrial fibrillation 1 (0.5) 0 Atrioventricular block complete 1 (0.5) 0 Myocardial ischaemia 0 1 (0.5) Epilepsy 0 1 (0.5) Postictal paralysis 0 1 (0.5) Presyncope 0 1 (0.5) Humerus fracture 0 1 (0.5) Meniscus injury 1 (0.5) 0 Intervertebral disc protrusion 1 (0.5) 0 Osteonecrosis 1 (0.5) 0 Gastric ulcer 1 (0.5) 0 Anxiety 1 (0.5) 0 Inguinal hernia repair 1 (0.5) 0 Subjects with fatal SAEs, n (%) [n related] FF/UMEC/VI BUD/FOR 9

10 ITT Population (up to Week 24), N Any fatal SAE, n (%) [n related] 4 (0.4) [0] 6 (0.7) a [0] Cardiac failure 0 2 (0.2) Acute myocardial infarction 0 1 (0.1) Cardiac failure acute 0 1 (0.1) a Catheter site phlebitis 0 1 (0.1) Sudden cardiac death 1 (0.1) 0 Pneumonia 1 (0.1) 0 Sepsis 0 1 (0.1) Upper gastrointestinal haemorrhage 0 1 (0.1) Metastases to liver 1 (0.1) 0 Haemorrhagic stroke 1 (0.1) 0 Chronic kidney disease 0 1 (0.1) Acute pulmonary oedema 0 1 (0.1) Chronic respiratory failure 0 1 (0.1) EXT Population (up to Week 52), N Any fatal SAE, n (%) [n related] 2 (1.0) [0] 1 (0.5) a [0] Cardiac failure acute 0 1 (0.5) a Sudden cardiac death 1 (0.5) 0 Ischaemic stroke 1 (0.5) 0 a One subject in the EXT Population (BUD/FOR group) died prior to Week 24 and is counted in both the ITT and EXT Populations. Six subjects in each treatment group had fatal SAEs. Conclusion: For the co-primary endpoints, FF/UMEC/VI produced a greater increase in trough FEV1 and a larger decrease in SGRQ Total Score compared with BUD/FOR at Week 24 in the ITT Population; these differences were statistically significant. In support of the co-primary endpoints, larger proportions of subjects treated with FF/UMEC/VI achieved >=100 ml increase in trough FEV1 and responded based on SGRQ Total Score compared with BUD/FOR. Up to Week 24, the annualised rate of moderate or severe exacerbations was reduced by 35% with FF/UMEC/VI compared with BUD/FOR. Greater reductions in COPD symptoms, as measured by EXACT-RS (and subscales) and TDI were observed with FF/UMEC/VI compared with BUD/FOR at the end of the 24-week treatment period and the proportions of responders were greater with FF/UMEC/VI compared with BUD/FOR. There was no difference between treatment groups in the percentage of days reporting a score of 2 on the Daily Activity Question. In the smaller EXT Population, the efficacy results up to Week 52 followed a similar trend to the ITT Population up to Week 24; the annualised rate of moderate or severe exacerbations was reduced by 44%. In the ITT Population (up to week 24), 39% of subjects treated with FF/UMEC/VI and 38% of subjects treated with BUD/FOR experienced at least one AE. In the EXT Population (up to Week 52); 48% of subjects treated with FF/UMEC/VI and 55% of subjects treated with BUD/FOR experienced at least one AE. The most common AEs in both treatment groups in both populations were nasopharyngitis and headache. In the ITT Population, 5% of subjects in each treatment group (45 subjects FF/UMEC/VI and 47 subjects BUD/FOR) experienced non-fatal SAEs. In the EXT Population, 19 subjects (9%) in the FF/UMEC/VI group and 27 subjects (12%) in the BUD/FOR group experienced non-fatal SAEs. The most common non-fatal SAEs in both treatment groups in both populations were COPD and pneumonia. Six subjects (<1%) in each treatment group had fatal SAEs; none were considered related to study treatment by the investigators. 10