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.: HZC12871 Title: HZC12871: A 52-Week Efficacy And Safety Study To Compare The Effect Of Three Dosage Strengths Of Fluticasone Furoate/GW642444 Inhalation Powder With GW642444 On The Annual Rate Of Exacerbations In Subjects With Chronic Obstructive Pulmonary Disease Rationale: This study was conducted to provide data on the safety and efficacy of inhaled doses of fluticasone furoate/vilanterol () versus administered once-daily (OD) from a Novel Dry Powder Inhaler (NDPI) on the annual rate of moderate and severe exacerbations in subjects with COPD over a 52- week treatment period. Phase: III Study Period: SEP29 31OCT211 Study Design: This was a multicenter, randomized, double-blind, parallel-group design evaluating the effects of OD in the morning (AM) treatment with three dosage strengths of (5/, 1/ and 2/ mcg) versus one dosage strength of ( mcg) in subjects with COPD. Following screening to assess eligibility and a 4-week run-in period during which all subjects received open-label fluticasone propionate / salmeterol /5 mcg (FP/SAL /5) twice daily (BD) to establish a stable baseline, subjects were randomized (1:1:1:1) to one of the double-blind treatments ( 5/, 1/, 2/, or ), delivered via NDPI OD in the AM for 52 weeks. The randomisation was stratified based on smoking status. Except for short acting anticholinergics, subjects discontinued their use of previous COPD medications prior to run-in. Subjects attended clinic visits at screening, randomization, and after 2, 4, 8, 12, 2, 28, 36, 44, and 52 weeks of treatment. A safety follow-up phone contact occurred 1 week after completing either randomized treatment or an early withdrawal visit. Subjects were provided with inhaled albuterol/salbutamol for use as rescue medication throughout the study. The total duration of the study was approximately 57 weeks (including the 4-week run-in period, 52-week treatment period and the 1-week follow-up period) for each completed subject. Centres: 167 centers in 15 countries enrolled at least one subject Indication: COPD Treatment: During Run-in, subjects received open-label FP/SAL /5 BD. During the 52-week treatment period, all blinded dry powder formulations of and were administered via NDPI OD in the AM. Objectives: The primary objective of this study was to evaluate safety and efficacy of 5/ mcg, 1/ mcg and 2/ mcg versus mcg on the annual rate of moderate and severe exacerbations in subjects with COPD over a 52-week treatment period. This study evaluated the contribution of the ICS component on reducing the annual rate of moderate-severe exacerbations when used in combination with a fixed dose of the LABA in subjects with COPD. Primary Outcome/Efficacy Variable: Annual rate of moderate and severe exacerbations. Secondary Outcome/Efficacy Variable(s): Time to first moderate or severe exacerbation; Annual rate of exacerbations requiring systemic/oral corticosteroids; Change from baseline in trough FEV 1 at Visit 11. Statistical Methods: A total of 2631 subjects were screened with the aim of achieving evaluable data from 156 randomized subjects (39 subjects per treatment arm). This sample size was based on the primary endpoint, the annual rate of moderate and severe exacerbations and on the comparison of each combination arm compared with the -alone arm. The annual rate of moderate and severe exacerbations in the treatment arm was assumed to be 1.4 based on estimates of 1.4 to 1.59 from the salmeterol arms of fluticasone propionate/salmeterol (FP/SAL) combination studies. Estimates of the dispersion parameter in previous FP/SAL studies have been.7;.46;.48 and.47. As the current study was a multicenter, international study the higher estimate of dispersion was used in the sample size calculation. This study with 39 evaluable subjects per arm had 9% power to detect a % reduction in the annual rate of moderate and severe exacerbations on a combination arm compared with the -alone arm. Calculations were based on a Negative Binomial regression and used a two-sided 5% significance level. In 1
order to account for multiplicity across treatment comparisons and key endpoints, a step-down testing procedure was employed, whereby inference for the primary efficacy endpoint for the 1/ combination strength versus was dependent upon statistical significance at the 5% level having first been achieved for the primary efficacy endpoint for 2/ versus comparison. Similarly, inference for the primary efficacy endpoint for the 5/ versus comparison was dependent upon statistical significance having first been achieved for the primary efficacy endpoint for 1/ versus comparison. For a given combination strength, the secondary endpoints were nested under the primary endpoint. Secondary efficacy endpoints were (in order): time to first moderate or severe exacerbation, the annual rate of exacerbations requiring treatment with systemic/oral corticosteroids and trough FEV 1 at 52 weeks. Hence, in order to make inferences on the secondary endpoints at a given strength, statistical significance at the 5% level had to have been demonstrated for the primary efficacy endpoint for that combination strength. A 2-sided 5% risk associated with incorrectly rejecting the null hypothesis (significance level) was considered acceptable for this study. The ITT population, defined as all subjects who had been randomized to and received at least one dose of randomized double blind study medication in the treatment period, was the population of primary interest for all efficacy and safety endpoints. Study Population: Number of Subjects: Planned, N Total 156 randomized subjects (39 subjects per treatment arm) Randomised, N 1626 Completed, n (%) (Subjects were considered to have 1222 (75) completed the study if they completed the treatment period and a safety follow-up phone contact 1 week later) Completed the treatment period (Subjects were considered to have completed the treatment period if they attended the last treatment visit (Visit 11). 123 (76) Withdrawn 4 () Primary /Sub-reason for withdrawal, n (%) 5/ 1/ 2/ N=49 N=48 N=43 N=42 Adverse Event 22 (5) (6) 29 (7) 31 (8) Withdrew consent 34 (8) 18 (4) 17 (4) 22 (5) Lack of efficacy 24 (6) 16 (4) 11 (3) 18 (4) Exacerbation 15 (4) 1 (2) 4 (<1) 13 (3) Withdrawn for other reasons 35 (9) 34 (8) 34 (8) 3 (7) Demographics, n (%) N (ITT) 49 48 43 42 Gender n Females Males Age n Mean Age, years SD Race n White African American/ African 49 17 (42) 239 (58) 49 63.6 9.43 48 331 (81) 9 (2) 48 163 (4) 245 (6) 48 63.6 9.6 48 334 (82) 8 (2) 43 172 (43) 231 (57) 43 63.6 9.6 43 332 (82) 6 (1) 42 153 (38) 249 (62) 42 63.8 9.3 41 324 (81) 9 (2) 2
Heritage Asian Other (includes the following races and racial combinations: American Indian or Alaska Native; American Indian or Alaska Native & White; Asian & White) COPD history at screening, n (%) Duration of COPD n <1 year >=1 to <5 years >=5 to <1 years >=1 to <15 years >=15 to <2 years >=2 to < years >= years COPD type (subjects could select 'Chronic bronchitis', 'Emphysema' or both for COPD type) n Chronic bronchitis Emphysema 39 (1) 29 (7) 49 2 (5) 136 (33) 134 (33) 68 (17) 24 (6) 2 (5) 7 (2) 49 262 (64) 229 (56) 37 (9) 29 (7) 48 27 (7) 167 (41) 12 (29) 5 (12) 2 (5) 13 (3) 11 (3) 45 7 (63) 238 (59) 37 (9) 28 (7) 43 23 (6) 134 (33) 123 (31) 62 (15) 36 (9) 14 (3) 11 (3) 41 266 (66) 228 (57) 41 (1) 27 (7) 42 18 (4) 156 (39) 132 (33) 54 (13) 24 (6) 12 (3) 6 (1) 4 265 (66) 243 (61) 3
Screening lung function All results were taken at the Screening/Rescreening Visit except Baseline FEV1 which was taken at pre-dose Day 1. Measure N=49 5/ N=48 1/ N=43 2/ N=42 Pre-bronchodilator FEV 1 (L) Post-bronchodilator FEV 1 (L) Percent predicted post-bronchodilator FEV 1 (%) Post-bronchodilator FEV 1 /FVC (%) Percent reversibility FEV 1 (%) FEV 1 reversibility (ml) Reversibility at Screening Baseline FEV 1 (L) Measured at pre-dose Day 1 n 46 44 42 398 Mean 1.12 1.159 1.151 1.141 SD.4632.4639.4564.4668 Min-Max.34-2.9.32-2.63.27-2.96.34-2.77 n 45 46 4 398 Mean 1.6 1.295 1.297 1.278 SD.4641.495.4742.4818 Min-Max.41-2.92.34-2.95.32-3.16.44-2.92 n 45 46 4 398 Mean 44.3 45.6 45.7 45.1 SD 13.22 13.69 12.89 13.77 Min-Max 16-7 12-7 13-7 16-73 n 45 46 4 398 Mean 44.7 46.2 46.2 45.1 SD 11.67 11.93 11.71 11.4 Min-Max 2-7 2-7 19-81 19-7 n 44 43 4 396 Mean 15.2 13.8 14.8 14.4 SD 18.54 14.69 16.14 15.1 Min-Max -65-212 -51-85 -4-135 -35-84 n 44 43 4 396 Mean 135.6 138.6 144.8 138.8 SD 192.55 155.16 156.23 154.17 Min-Max -189-91 -87-68 -64-112 -92-78 n 47 43 4 396 Reversible 1 (31) 116 (29) 121 (3) 16 (27) Non- Reversible 282 (69) 287 (71) 279 (7) 29 (73) n 47 44 41 398 Mean 1.24 1.234 1.217 1.2 SD.567.573.476.5155 Min-Max.41-3.2.3-3.55.35-3.33.39-3.28 4
Primary Efficacy Results: Annual rate of moderate and severe exacerbations N=49 5/ N=48 1/ N=43 2/ N=42 n 47 44 41 398 LS mean annual rate 1.5.92.7.9 Column vs. Ratio.87.66.85 95% CI (.72, 1.6) (.54,.81) (.7, 1.4) p-value.181 <.1.19 Percent Reduction 13 34 15 95% CI (-6, 28) (19, 46) (-4, 3) Analysis performed using a negative binomial regression model with covariates of treatment, smoking status at screening (stratum), baseline disease severity (pre-dose Day 1 % predicted FEV1) and center grouping and with logarithm of time on treatment as an offset variable. Secondary Outcome Variable(s): Time to first moderate or severe exacerbation N=49 5/ N=48 1/ N=43 2/ N=42 n 47 44 41 398 Column vs. Hazard Ratio.92.72.85 95% CI (.76, 1.13) (.59,.89) (.69, 1.4) Hazard ratios, CIs and p-values are from a Cox proportional hazards model with covariates of treatment, smoking status at screening (stratum), baseline disease severity (pre-dose Day 1 % predicted FEV1) and center grouping. Annual rate of exacerbations requiring systemic/oral corticosteroids N=49 5/ N=48 1/ N=43 2/ N=42 n 47 44 41 398 LS mean annual rate.84.71.52.68 Column vs. Ratio.84.62.81 95% CI (.67, 1.5) (.49,.78) (.64, 1.1) Percent reduction 16 38 19 95% CI (-5, 33) (22, 51) (-1, 36) Analysis performed using a negative binomial regression model with covariates of treatment, smoking status at screening (stratum), baseline disease severity (pre-dose Day 1 % predicted FEV1) and center grouping and with logarithm of time on treatment as an offset variable. 5
Change from baseline in trough FEV 1 at Visit 11. N=49 5/ N=48 1/ N=43 2/ N=42 n a 392 395 388 387 n b 291 38 31 289 LS Mean (SE) 1.18 (.114) 1.22 (.112) 1.238 (.112) 1.244 (.114) LS Mean Change (SE) -.4 (.114). (.112).18 (.112).24 (.114) Column vs. Difference.41.58.64 95% CI (.9,.72) (.27,.9) (.33,.96) Analysis performed using a repeated measures model with covariates of treatment, smoking status at screening (stratum), baseline (pre-dose Day 1), center grouping, Week, Week by baseline and Week by treatment interactions. a. Number of subjects with analyzable data for one or more time points. b. Number of subjects with analyzable data at the given time point. Safety Results: An adverse event (AE) was defined as any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AEs were collected from the start of open-label ADVAIR DISKUS /5 run-in period (Visit 1) and until the follow up contact. A serious adverse event (SAE) was defined as any untoward medical occurrence that, at any dose, resulted in death, was life-threatening, required hospitalisation or prolongation of existing hospitalisation (complications that occurred during hospitalisation were AEs; complications that prolonged hospitalisation or fulfilled any other serious criteria, were an SAE), resulted in disability/incapacity to conduct normal life functions, or was a congenital anomaly/birth defect. SAEs were collected over the same time period as stated above for AEs. However, any SAEs assessed as related to study participation (e.g., investigational product, protocol-mandated procedures, invasive tests, or change in existing therapy) or related to a GSK concomitant medication, were recorded from the time a subject consents to participate in the study up to and including any follow up contact. Overview of Adverse Events n (%) N=49 5/ N=48 1/ N=43 2/ N=42 During run-in 77 (19) 78 (19) 91 (23) 86 (21) On-treatment 281 (69) 34 (75) 31 (75) 288 (72) Post-treatment 14 (3) 22 (5) 12 (3) 12 (3) On-treatment drug-related 5 (12) 85 (21) 64 (16) 6 (15) Post-treatment drug-related 5 (1) 3 (<1) Leading to permanent discontinuation of study drug or withdrawal from study a 22 (5) 26 (6) 29 (7) 3 (7) a. Includes both on-treatment and post-treatment adverse events 6
Most Frequent Adverse Events On-Therapy Preferred term, n (%) N=49 5/ N=48 1/ N=43 2/ N=42 281 (69) 34 (75) 31 (75) 288 (72) Nasopharyngitis 54 (13) 58 (14) 6 (15) 76 (19) Upper respiratory tract infection 47 (11) 47 (12) 51 (13) 39 (1) Oral candidiasis 21 (5) 39 (1) 34 (8) 36 (9) Headache 3 (7) 27 (7) (6) 34 (8) COPD 28 (7) 27 (7) 26 (6) 3 (7) Adverse Events of Special Interest On-Therapy The incidence of pneumonia reported as an AE (grouped preferred terms indicative of pneumonia) was 4% in the mcg group vs. 6% to 8% of subjects in the three groups. Overview of Serious Adverse Events n (%) N=49 5/ N=48 1/ N=43 2/ N=42 On-treatment 6 (15) 65 (16) 56 (14) 63 (16) Post-treatment 4 (<1) 6 (1) 5 (1) On-treatment drug-related 5 (1) 7 (2) Post-treatment drug-related On- treatment fatal 4 (<1) 7 (2) 5 (1) 13 (3) Post-treatment fatal 3 (<1) 3 (<1) On- and post-treatment drug-related fatal SAEs 7
Summary of On-Treatment Serious Adverse Events by System Organ Class n (%) N=49 5/ N=48 1/ N=43 2/ N=42 Any serious event 6 (15) 65 (16) 56 (14) 63 (16) Respiratory, thoracic and mediastinal 3 (7) 31 (8) 3 (7) 33 (8) disorders Infections and infestations 1 (2) 19 (5) 21 (5) 21 (5) Cardiac disorders 1 (2) 7 (2) 6 (1) 5 (1) Gastrointestinal disorders 5 (1) 5 (1) 7 (2) Neoplasms benign, malignant, and 6 (1) 3 (<1) 4 (<1) unspecified (including cysts and polyps) Nervous system disorders 4 (<1) 3 (<1) 5 (1) Metabolism and nutrition disorders 3 (<1) Musculoskeletal and connective tissue 3 (<1) 3 (<1) disorders Vascular disorders 3 (<1) Injury, poisoning and procedural 5 (1) complications General disorders and administration 3 (<1) site conditions Renal and urinary disorders 3 (<1) Hepatobiliary disorders Blood and lymphatic disorders Psychiatric disorders Reproductive system and breast disorders Eye disorders Immune system disorders 8
On-treatment Serious Adverse Events considered by the investigator to be related to study medication System Organ Class Preferred term, n (%) 5/ 1/ 2/ N=42 N=49 N=48 N=43 5 (1) 7 (2) Respiratory, thoracic and mediastinal disorders 5 (1) COPD 4 (<1) Acute respiratory failure Asthma Bronchitis chronic Infections and infestations 5 (1) Pneumonia 4 (<1) Lung abscess Cardiac disorders Palpitations General disorders and administration site conditions Non-cardiac chest pain Neoplasms benign, malignant, and unspecified (including cysts and polyps) Metastatic carcinoma of the bladder 9
Fatal Serious Adverse Events (during treatment period and post treatment) System Organ Class Preferred term, n (%) N=49 5/ N=48 1/ N=43 2/ N=42 7 (2) 9 (2) 6 (1) 13 (3) Cardiac disorders Myocardial infarction Acute coronary syndrome Angina unstable Arrhythmia Cardiac arrest Cardiac failure Cardio-respiratory arrest Cardiopulmonary failure Coronary artery thrombosis Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease Acute respiratory failure Respiratory failure Infections and infestations Pneumonia Sepsis Septic shock Urinary tract infection bacterial 4 (<1) Neoplasms benign, malignant and unspecified (incl cysts and polyps) Acute lymphocytic leukaemia Diffuse large B-cell lymphoma Pancreatic carcinoma metastatic Vascular disorders Aortic aneurysm rupture Hypertension Shock haemorrhagic Gastrointestinal disorders Abdominal pain Abdominal pain lower General disorders and administration site conditions Death Nervous system disorders Cerebrovascular accident Loss of consciousness Musculoskeletal and connective tissue disorders Intervertebral disc protrusion 3 (<1) 5 (1) 4 (<1) 6 (1) 6 (1) 1
Conclusion: Once-daily treatment in the morning with 5/, 1/, or 2/ decreased the annual rate of moderate and severe exacerbations with the greatest magnitude of effect noted in the 1/ group (34% reduction with a p<.1). Similar results were observed for secondary endpoint measures (time to first moderate or severe exacerbation, and the annual rate of exacerbations requiring systemic/oral corticosteroids). All strengths of provided changes in trough FEV 1 measures of lung function of 41 to 64 ml compared with at 52 weeks. There was an increased incidence of pneumonia and candidiasis; fatal events of pneumonia were reported for no subjects in the, 5/, and 1/ groups and six subjects in the 2/ group (plus one additional subject with a fatal SAE of COPD exacerbation that was recorded as a fatal pneumonia on the pneumonia ecrf page). 11