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A Comparison Study Between the Fixed Dose Triple Combination of Fluticasone Furoate/ Umeclidinium/ Vilanterol Trifenatate (FF/UMEC/VI) With Budesonide/Formoterol in Subjects With Chronic Obstructive Pulmonary Disease (COPD)

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ClinicalTrials.gov Identifier: NCT02345161
Recruitment Status : Completed
First Posted : January 26, 2015
Results First Posted : July 13, 2018
Last Update Posted : July 13, 2018
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Pulmonary Disease, Chronic Obstructive
Interventions Drug: Triple FF/UMEC/VI
Drug: Placebo to match FF/UMEC/VI
Drug: Budesonide/Formoterol
Drug: Placebo to match Budesonide/Formoterol combination
Drug: Albuterol/salbutamol
Enrollment 1811
Recruitment Details This was a phase IIIa, randomized, double-blind, double-dummy, parallel group multicenter study to evaluate once daily fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI; 100 micrograms [µg]/62.5 µg/25 µg) inhalation versus twice daily budesonide/formoterol (400 µg/12 µg) in participants with chronic obstructive pulmonary disease.
Pre-assignment Details A total of 2121 participants were screened in this study and 1811 were randomized following 2-week run-in. Of those, 1 participant was randomized in error and did not receive randomized treatment. This was followed by a 24-week treatment and 1-week follow-up periods. A sub-set of 430 participants continued in a blinded study treatment for 52 weeks.
Arm/Group Title FF/UMEC/VI 100/62.5/25 µg BUD/FOR 400/12 µg
Hide Arm/Group Description Participants received FF/UMEC/VI 100/62.5/25 µg via the ELLIPTA dry powder inhaler (DPI) once daily in the morning and placebo via the Turbuhaler twice daily (BID) for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study. Participants received BUD/FOR 400/12 µg via the Turbuhaler BID and placebo via the ELLIPTA once daily in the morning for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Period Title: Overall Study
Started 911 899
Completed 866 842
Not Completed 45 57
Reason Not Completed
Withdrawal by Subject             25             33
Adverse Event             16             19
Physician Decision             4             4
Lost to Follow-up             0             1
Arm/Group Title FF/UMEC/VI 100/62.5/25 µg BUD/FOR 400/12 µg Total
Hide Arm/Group Description Participants received FF/UMEC/VI 100/62.5/25 µg via the ELLIPTA dry powder inhaler (DPI) once daily in the morning and placebo via the Turbuhaler twice daily (BID) for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study. Participants received BUD/FOR 400/12 µg via the Turbuhaler BID and placebo via the ELLIPTA once daily in the morning for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study. Total of all reporting groups
Overall Number of Baseline Participants 911 899 1810
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 911 participants 899 participants 1810 participants
64.2  (8.56) 63.7  (8.71) 63.9  (8.64)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 911 participants 899 participants 1810 participants
Female
233
  25.6%
236
  26.3%
469
  25.9%
Male
678
  74.4%
663
  73.7%
1341
  74.1%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 911 participants 899 participants 1810 participants
Amrican Indian or Alaskan Native 16 19 35
Asian-East Asian Heritage 55 49 104
Asian-South East Asian Heritag 1 1 2
Native Hawaiian or other Pacific Islander 0 1 1
White-Arabic/North African Heritage 5 8 13
White-White/Caucasina/Euorpean Heritage 771 759 1530
Mixed Race 63 62 125
1.Primary Outcome
Title Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) at Week 24
Hide Description FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Trough FEV1 at Week 24 was defined as the FEV1 values obtained prior to morning dose of the study treatment. Baseline was defined as the value obtained predose (0 minutes) on Day 1. Change from Baseline was calculated as the pre-dose measurement at Week 24 minus the Baseline value. The analysis was performed using a mixed model repeated measures (MMRM) method including covariates of treatment group, smoking status (screening), geographical region, visit, baseline, baseline by visit and treatment by visit interactions. ITT Population comprised of all randomized subjects excluding those who were randomized in error. Only participants with analyzable data at the given time point were analyzed.
Time Frame Baseline to Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population
Arm/Group Title FF/UMEC/VI 100/62.5/25 µg BUD/FOR 400/12 µg
Hide Arm/Group Description:
Participants received FF/UMEC/VI 100/62.5/25 µg via the ELLIPTA dry powder inhaler (DPI) once daily in the morning and placebo via the Turbuhaler twice daily (BID) for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Participants received BUD/FOR 400/12 µg via the Turbuhaler BID and placebo via the ELLIPTA once daily in the morning for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Overall Number of Participants Analyzed 836 781
Least Squares Mean (Standard Error)
Unit of Measure: Liters (L)
0.142  (0.0083) -0.029  (0.0085)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted LS mean difference
Estimated Value 0.171
Confidence Interval (2-Sided) 95%
0.148 to 0.194
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.0118
Estimation Comments [Not Specified]
2.Primary Outcome
Title Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) at Week 52
Hide Description FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Trough FEV1 at Week 52 was defined as the FEV1 values obtained prior to morning dose of the study treatment. Baseline was defined as the value obtained predose (0 minutes) on Day 1. Change from Baseline was calculated as the pre-dose measurement at Week 24 minus the Baseline value. The analysis was performed using a mixed model repeated measures (MMRM) method including covariates of treatment group, smoking status (screening), geographical region, visit, baseline, baseline by visit and treatment by visit interactions. Extension Population: all participants in the ITT Population who were enrolled into the subset of participants with extension to 52 weeks.
Time Frame Baseline to Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Extension Population; Only participants with analyzable data at the given time point were analyzed.
Arm/Group Title FF/UMEC/VI 100/62.5/25 µg BUD/FOR 400/12 µg
Hide Arm/Group Description:
Participants received FF/UMEC/VI 100/62.5/25 µg via the ELLIPTA dry powder inhaler (DPI) once daily in the morning and placebo via the Turbuhaler twice daily (BID) for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Participants received BUD/FOR 400/12 µg via the Turbuhaler BID and placebo via the ELLIPTA once daily in the morning for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Overall Number of Participants Analyzed 183 171
Least Squares Mean (Standard Error)
Unit of Measure: Liters (L)
0.126  (0.0170) -0.053  (0.0172)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted LS mean difference
Estimated Value 0.179
Confidence Interval (2-Sided) 95%
0.131 to 0.226
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.0242
Estimation Comments [Not Specified]
3.Primary Outcome
Title Change From Baseline in St George's Respiratory Questionnaire-Chronic Obstructive Pulmonary Disease (COPD; SGRQ) Total Score for COPD Participants at Week 24
Hide Description The SGRQ-C is a disease-specific questionnaire designed to measure the impact of respiratory disease and its treatment on a COPD participant's health-related quality of life (HRQoL). SGRQ-C total score was converted to SGRQ total score (ranging from 0-100) according to manual. In addition to an overall summary (total) score, scores for the individual domains of Symptoms, Activity, and Impacts (each ranging from 0-100) are produced. A decrease in score indicated improvement in quality of life. The minimum clinically important difference (MCID) for this instrument is a 4-point improvement (decrease from Baseline). Baseline was defined as the value obtained predose on Day 1. Change from Baseline was calculated as total score at Week 24 minus the Baseline value. The analysis for SGRQ total score was performed using a MMRM method including covariates of treatment group, smoking status (screening), geographical region, visit, baseline, baseline by visit and treatment by visit interactions
Time Frame Baseline to Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population; Only participants with analyzable data at the given time point were analyzed.
Arm/Group Title FF/UMEC/VI 100/62.5/25 µg BUD/FOR 400/12 µg
Hide Arm/Group Description:
Participants received FF/UMEC/VI 100/62.5/25 µg via the ELLIPTA dry powder inhaler (DPI) once daily in the morning and placebo via the Turbuhaler twice daily (BID) for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Participants received BUD/FOR 400/12 µg via the Turbuhaler BID and placebo via the ELLIPTA once daily in the morning for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Overall Number of Participants Analyzed 846 791
Least Squares Mean (Standard Error)
Unit of Measure: Scores on a scale
-6.6  (0.45) -4.3  (0.46)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted LS mean difference
Estimated Value -2.2
Confidence Interval (2-Sided) 95%
-3.5 to -1.0
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.64
Estimation Comments [Not Specified]
4.Primary Outcome
Title Change From Baseline in St George's Respiratory Questionnaire-COPD; SGRQ Total Score for COPD Participants at Week 52
Hide Description The SGRQ-C is a disease-specific questionnaire designed to measure the impact of respiratory disease and its treatment on a COPD participant's health-related quality of life (HRQoL). SGRQ-C total score was converted to SGRQ total score (ranging from 0-100) according to manual. In addition to an overall summary (total) score, scores for the individual domains of Symptoms, Activity, and Impacts (each ranging from 0-100) are produced. A decrease in score indicated improvement in quality of life. The minimum clinically important difference (MCID) for this instrument is a 4-point improvement (decrease from Baseline). Baseline was defined as the value obtained predose on Day 1. Change from Baseline was calculated as total score at Week 52 minus the Baseline value. The analysis for SGRQ total score was performed using a MMRM method including covariates of treatment group, smoking status (screening), geographical region, visit, baseline, baseline by visit and treatment by visit interactions.
Time Frame Baseline to Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Extension Population; Only participants with analyzable data at the given time point were analyzed.
Arm/Group Title FF/UMEC/VI 100/62.5/25 µg BUD/FOR 400/12 µg
Hide Arm/Group Description:
Participants received FF/UMEC/VI 100/62.5/25 µg via the ELLIPTA dry powder inhaler (DPI) once daily in the morning and placebo via the Turbuhaler twice daily (BID) for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Participants received BUD/FOR 400/12 µg via the Turbuhaler BID and placebo via the ELLIPTA once daily in the morning for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Overall Number of Participants Analyzed 182 174
Least Squares Mean (Standard Error)
Unit of Measure: Scores on a scale
-4.6  (1.01) -1.9  (1.03)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.065
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted LS mean difference
Estimated Value -2.7
Confidence Interval (2-Sided) 95%
-5.5 to 0.2
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.44
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Transitional Dyspnea Index (TDI) Focal Score Expressed as Least Square Mean at Week 24
Hide Description The TDI measures change in the participant's dyspnoea from Baseline. The scores in both indexes depend on ratings for three different categories: functional impairment; magnitude of task; and magnitude of effort. Each of these scales had a possible score ranging from -6 (major deterioration) to +6 (major improvement). TDI focal score was calculated as the sum of the three individual scores and then divided by 2 (so the range of the TDI focal score is -9 to +9). TDI was measured at Week 4 and Week 24. Analysis performed using a repeated measures model with covariates of treatment group, smoking status (screening), geographical region, visit, BDI focal score, BDI focal score by visit and treatment by visit interactions.
Time Frame Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population; Only participants with analyzable data at the given time point were analyzed.
Arm/Group Title FF/UMEC/VI 100/62.5/25 µg BUD/FOR 400/12 µg
Hide Arm/Group Description:
Participants received FF/UMEC/VI 100/62.5/25 µg via the ELLIPTA DPI once daily in the morning and placebo via the Turbuhaler BID for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Participants received BUD/FOR 400/12 µg via the Turbuhaler BID and placebo via the ELLIPTA once daily in the morning for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Overall Number of Participants Analyzed 839 788
Least Squares Mean (Standard Error)
Unit of Measure: Scores on a scale
2.29  (0.096) 1.72  (0.099)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Mixed effect repeated measures model
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value 0.57
Confidence Interval (2-Sided) 95%
0.30 to 0.84
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.138
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Transitional Dyspnea Index (TDI) Focal Score Expressed as Least Square Mean at Week 52
Hide Description The TDI measures change in the participant's dyspnoea from Baseline. The scores in both indexes depend on ratings for three different categories: functional impairment; magnitude of task; and magnitude of effort. Each of these scales had a possible score ranging from -6 (major deterioration) to +6 (major improvement). TDI focal score was calculated as the sum of the three individual scores and then divided by 2 (so the range of the TDI focal score is -9 to +9). TDI was measured at Weeks 4, 24 and 52. Analysis performed using a repeated measures model with covariates of treatment group, smoking status (screening), geographical region, visit, BDI focal score, BDI focal score by visit and treatment by visit interactions
Time Frame Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Extension Population; Only participants with analyzable data at the given time point were analyzed.
Arm/Group Title FF/UMEC/VI 100/62.5/25 µg BUD/FOR 400/12 µg
Hide Arm/Group Description:
Participants received FF/UMEC/VI 100/62.5/25 µg via the ELLIPTA dry powder inhaler (DPI) once daily in the morning and placebo via the Turbuhaler twice daily (BID) for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Participants received BUD/FOR 400/12 µg via the Turbuhaler BID and placebo via the ELLIPTA once daily in the morning for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Overall Number of Participants Analyzed 182 174
Least Squares Mean (Standard Error)
Unit of Measure: Scores on a scale
1.74  (0.221) 1.39  (0.226)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.279
Comments [Not Specified]
Method Mixed effect repeated measures model
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value 0.34
Confidence Interval (2-Sided) 95%
-0.28 to 0.97
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.317
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Daily Activity Question Percentage of Days Reporting a Score of 2 up to Week 24
Hide Description Participants were asked to complete the daily activity question as part of the eDiary, which included the following options: 0: fewer activities, 1: no affect on my activities, and 2: more activities than usual. Daily activity question percentage of days with score of 2 over Weeks 1-24 was analysed using an ANCOVA model with covariates of treatment group, smoking status (screening), geographical region and baseline.
Time Frame Up to Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population; Only participants with analyzable data at the given time point were analyzed.
Arm/Group Title FF/UMEC/VI (100 mcg/62.5 mcg/25 mcg) Budesonide/Formoterol (400 mcg/12 mcg)
Hide Arm/Group Description:
Each subject will inhale once from their ELLIPTA DPI and once from the reservoir inhaler in the morning and once from the reservoir inhaler in the evening, for 24 weeks (or 52 weeks for subjects participating in the extension part of the study). Subjects will receive FF/UMEC/VI (100mcg/62.5mcg/25mcg) via the ELLIPTA DPI and placebo via reservoir inhaler.
Each subject will inhale once from their ELLIPTA DPI and once from the reservoir inhaler in the morning and once from the reservoir inhaler in the evening, for 24 weeks (or 52 weeks for subjects participating in the extension part of the study). Subjects will receive Budesonide/formoterol (400mcg/12mcg) via reservoir inhaler and placebo via the ELLIPTA DPI.
Overall Number of Participants Analyzed 909 894
Least Squares Mean (Standard Error)
Unit of Measure: Percentage of days
0.0  (0.38) -0.1  (0.39)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI (100 mcg/62.5 mcg/25 mcg), Budesonide/Formoterol (400 mcg/12 mcg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.817
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value 0.1
Confidence Interval (2-Sided) 95%
-0.9 to 1.1
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.51
Estimation Comments [Not Specified]
8.Secondary Outcome
Title Daily Activity Question Percentage of Days Reporting a Score of 2 up to Week 52
Hide Description Participants were asked to complete the daily activity question as aprt of the eDiary, which included the following options: 0: fewer activities, 1: no affect on my activities, and 2: more activities than usual. Daily activity question percentage of days with score of 2 over Weeks 1-24 was analysed using an ANCOVA model with covariates of treatment group, smoking status (screening), geographical region and baseline.
Time Frame Up to Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Extension Population; Only participants with analyzable data at the given time point were analyzed.
Arm/Group Title FF/UMEC/VI 100/62.5/25 µg BUD/FOR 400/12 µg
Hide Arm/Group Description:
Participants received FF/UMEC/VI 100/62.5/25 µg via the ELLIPTA DPI once daily in the morning and placebo via the Turbuhaler BID for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Participants received BUD/FOR 400/12 µg via the Turbuhaler BID and placebo via the ELLIPTA once daily in the morning for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Overall Number of Participants Analyzed 210 219
Least Squares Mean (Standard Error)
Unit of Measure: Percentage of days
0.0  (0.70) 0.3  (0.69)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.767
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.3
Confidence Interval (2-Sided) 95%
-2.1 to 1.6
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.95
Estimation Comments [Not Specified]
9.Secondary Outcome
Title Mean Annual On-treatment Moderate and/or Severe COPD Exacerbations up to Week 24
Hide Description The mean annual moderate and severe COPD exacerbations during the treatment (trt) period (per participant [par.] per year) was assessed. The event rate for exacerbations was calculated as the number of events x 1000 divided by the total participant exposure during the time-period of interest. An exacerbation of COPD, is defined as the worsening of two or more major symptoms (dyspnea, sputum volume, sputum purulence [color]) for at least two consecutive days; or the worsening of any one major symptom together with any one of the minor symptoms (sore throat, cold, fever without other cause, increased cough, increased wheeze) for at least two consecutive days. Analysis performed using a generalised linear model assuming a negative binomial distribution and covariates of treatment group, exacerbation history (0, 1, >=2 moderate/severe), smoking status (screening), geographical region and post-bronchodilator percent predicted FEV1 (day 1).
Time Frame Up to Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population; Only participants with analyzable data at the given time point were analyzed.
Arm/Group Title FF/UMEC/VI 100/62.5/25 µg BUD/FOR 400/12 µg
Hide Arm/Group Description:
Participants received FF/UMEC/VI 100/62.5/25 µg via the ELLIPTA dry powder inhaler (DPI) once daily in the morning and placebo via the Turbuhaler twice daily (BID) for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Participants received BUD/FOR 400/12 µg via the Turbuhaler BID and placebo via the ELLIPTA once daily in the morning for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Overall Number of Participants Analyzed 907 892
Mean (95% Confidence Interval)
Unit of Measure: Exacerbations per participant per year
0.22
(0.18 to 0.28)
0.34
(0.28 to 0.42)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.002
Comments [Not Specified]
Method Generalized linear modeL
Comments Generalized linear model assuming a negative binomial distribution
Method of Estimation Estimation Parameter Rate ratio
Estimated Value 0.65
Confidence Interval (2-Sided) 95%
0.49 to 0.86
Estimation Comments [Not Specified]
10.Secondary Outcome
Title Mean Annual On-treatment Moderate and/or Severe COPD Exacerbations up to Week 52
Hide Description The mean annual moderate and severe COPD exacerbations during the treatment (trt) period (per participant [par.] per year) was assessed. The event rate for exacerbations was calculated as the number of events x 1000 divided by the total participant exposure during the time-period of interest. An exacerbation of COPD, is defined as the worsening of two or more major symptoms (dyspnea, sputum volume, sputum purulence [color]) for at least two consecutive days; or the worsening of any one major symptom together with any one of the minor symptoms (sore throat, cold, fever without other cause, increased cough, increased wheeze) for at least two consecutive days. Analysis performed using a generalised linear model assuming a negative binomial distribution and covariates of treatment group, exacerbation history (0, 1, >=2 moderate/severe), smoking status (screening), geographical region and post-bronchodilator percent predicted FEV1 (day 1).
Time Frame Up to Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Extension Population; Only participants with analyzable data at the given time point were analyzed.
Arm/Group Title FF/UMEC/VI 100/62.5/25 µg BUD/FOR 400/12 µg
Hide Arm/Group Description:
Participants received FF/UMEC/VI 100/62.5/25 µg via the ELLIPTA DPI once daily in the morning and placebo via the Turbuhaler BID for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Participants received BUD/FOR 400/12 µg via the Turbuhaler BID and placebo via the ELLIPTA once daily in the morning for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study
Overall Number of Participants Analyzed 210 219
Mean (95% Confidence Interval)
Unit of Measure: Exacerbations per participant per year
0.20
(0.15 to 0.28)
0.36
(0.28 to 0.47)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.006
Comments [Not Specified]
Method Generalized Linear model
Comments Generalized linear model assuming a negative binomial distribution
Method of Estimation Estimation Parameter Rate ratio
Estimated Value 0.56
Confidence Interval (2-Sided) 95%
0.37 to 0.85
Estimation Comments [Not Specified]
11.Secondary Outcome
Title Assessment of Respiratory Symptoms by Change From Baseline in 4-weekly Mean Exacerbations of Chronic Pulmonary Disease Tool (EXACT)-RS Scores up to Week 24
Hide Description The EXACT-PRO is a 14 item instrument designed to capture information on the occurrence, frequency, severity, and duration of exacerbations of disease in participants with COPD. EXACT-RS consists of 11 items from the 14 item EXACT-PRO instrument and has a scoring range of 0-40. Three subscales are used to describe different symptoms; dyspnoea (range 0-17), cough and sputum (range 0-11) and chest symptoms (range 0-12). Baseline was defined as the mean value during the period between Visits 1 and 2. Mean scores were calculated for each four weekly period and change from Baseline was calculated as four weekly score minus the Baseline value. Four weekly intervals were analyzed using a MMRM method with covariates of treatment group, smoking status (screening), geographical region, time period, baseline, baseline by time period and treatment by time period interactions. Only participants with data available at the analysis time point were analyzed (represented as n=X, X in category title).
Time Frame Baseline to Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population
Arm/Group Title FF/UMEC/VI 100/62.5/25 µg BUD/FOR 400/12 µg
Hide Arm/Group Description:
Participants received FF/UMEC/VI 100/62.5/25 µg via the ELLIPTA dry powder inhaler (DPI) once daily in the morning and placebo via the Turbuhaler twice daily (BID) for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Participants received BUD/FOR 400/12 µg via the Turbuhaler BID and placebo via the ELLIPTA once daily in the morning for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Overall Number of Participants Analyzed 911 899
Least Squares Mean (Standard Error)
Unit of Measure: Scores on a scale
Week 1-4, n=870,859 Number Analyzed 870 participants 859 participants
-1.45  (0.106) -0.50  (0.106)
Week 5-8, n=851,830 Number Analyzed 851 participants 830 participants
-2.00  (0.129) -0.77  (0.130)
Week 9-12, n=841,813 Number Analyzed 841 participants 813 participants
-2.23  (0.141) -1.05  (0.143)
Week 13-16, n=831,802 Number Analyzed 831 participants 802 participants
-2.42  (0.150) -1.09  (0.151)
Week 17-20, n=828,788 Number Analyzed 828 participants 788 participants
-2.43  (0.156) -1.02  (0.159)
Week 21-24, n=825,783 Number Analyzed 825 participants 783 participants
-2.31  (0.157) -0.96  (0.160)
Breathlessness score, Week 1-4, n=870,859 Number Analyzed 870 participants 859 participants
-0.71  (0.057) -0.20  (0.057)
Breathlessness score, Week 5-8, n=851,830 Number Analyzed 851 participants 830 participants
-0.95  (0.069) -0.26  (0.070)
Breathlessness score, Week 9-12, n=841,813 Number Analyzed 841 participants 813 participants
-1.03  (0.076) -0.34  (0.076)
Breathlessness score, Week 13-16, n=831, 802 Number Analyzed 831 participants 802 participants
-1.11  (0.080) -0.36  (0.081)
Breathlessness score, Week 17-20, n=828,788 Number Analyzed 828 participants 788 participants
-1.10  (0.084) -0.31  (0.085)
Breathlessness score, Week 21-24, n=825,783 Number Analyzed 825 participants 783 participants
-1.07  (0.085) -0.30  (0.087)
Cough, sputum score, Week 1-4, n=870,859 Number Analyzed 870 participants 859 participants
-0.41  (0.031) -0.24  (0.031)
Cough, sputum score, Week 5-8, n=851,830 Number Analyzed 851 participants 830 participants
-0.59  (0.037) -0.39  (0.038)
Cough, sputum score, Week 9-12, n=841,813 Number Analyzed 841 participants 813 participants
-0.67  (0.041) -0.50  (0.041)
Cough, sputum score, Week 13-16, n=831,802 Number Analyzed 831 participants 802 participants
-0.74  (0.043) -0.53  (0.043)
Cough, sputum score, Week 17-20, n=828,788 Number Analyzed 828 participants 788 participants
-0.77  (0.045) -0.53  (0.045)
Cough, sputum score, Week 21-24, n=825,783 Number Analyzed 825 participants 783 participants
-0.72  (0.046) -0.50  (0.046)
Chest score, Week 1-4, n=870,859 Number Analyzed 870 participants 859 participants
-0.33  (0.034) -0.06  (0.035)
Chest score, Week 5-8, n=851,830 Number Analyzed 851 participants 830 participants
-0.46  (0.042) -0.12  (0.043)
Chest score, Week 9-12, n=841,813 Number Analyzed 841 participants 813 participants
-0.54  (0.046) -0.20  (0.047)
Chest score, Week 13-16, n=831,802 Number Analyzed 831 participants 802 participants
-0.58  (0.048) -0.20  (0.048)
Chest score, Week 17-20, n=828,788 Number Analyzed 828 participants 788 participants
-0.57  (0.050) -0.17  (0.050)
Chest score, Week 21-24, n=825,783 Number Analyzed 825 participants 783 participants
-0.53  (0.050) -0.17  (0.051)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.95
Confidence Interval (2-Sided) 95%
-1.25 to -0.66
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.150
Estimation Comments EXACT-RS Scores, Week 1-4
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -1.23
Confidence Interval (2-Sided) 95%
-1.59 to -0.87
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.183
Estimation Comments EXACT-RS Scores, Week 5-8
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -1.18
Confidence Interval (2-Sided) 95%
-1.57 to -0.78
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.201
Estimation Comments EXACT-RS Scores, Week 9-12
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -1.33
Confidence Interval (2-Sided) 95%
-1.75 to -0.91
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.213
Estimation Comments EXACT-RS Scores, Week 13-16
Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -1.41
Confidence Interval (2-Sided) 95%
-1.85 to -0.97
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.223
Estimation Comments EXACT-RS Scores, Week 17-20
Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter Mixed Model Repeated Measures
Estimated Value -1.35
Confidence Interval (2-Sided) 95%
-1.79 to -0.91
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.224
Estimation Comments EXACT-RS Scores, Week 21-24
Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.52
Confidence Interval (2-Sided) 95%
-0.67 to -0.36
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.080
Estimation Comments Breathlessness EXACT-RS Score, Week 1-4
Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.69
Confidence Interval (2-Sided) 95%
-0.88 to -0.50
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.098
Estimation Comments Breathlessness EXACT-RS Score, Week 5-8
Hide Statistical Analysis 9
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.69
Confidence Interval (2-Sided) 95%
-0.90 to -0.48
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.108
Estimation Comments Breathlessness EXACT-RS Score, Week 9-12
Hide Statistical Analysis 10
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.75
Confidence Interval (2-Sided) 95%
-0.97 to -0.52
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.115
Estimation Comments Breathlessness EXACT-RS Score, Week 13-16
Hide Statistical Analysis 11
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.79
Confidence Interval (2-Sided) 95%
-1.03 to -0.56
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.120
Estimation Comments Breathlessness EXACT-RS Score, Week 17-20
Hide Statistical Analysis 12
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.77
Confidence Interval (2-Sided) 95%
-1.01 to -0.54
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.122
Estimation Comments Breathlessness EXACT-RS Score, Week 21-24
Hide Statistical Analysis 13
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.17
Confidence Interval (2-Sided) 95%
-0.26 to -0.09
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.044
Estimation Comments Cough and sputum EXACT-RS Score, Week 1-4
Hide Statistical Analysis 14
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.20
Confidence Interval (2-Sided) 95%
-0.31 to -0.10
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.053
Estimation Comments Cough and sputum EXACT-RS Score, Week 5-8
Hide Statistical Analysis 15
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.004
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.17
Confidence Interval (2-Sided) 95%
-0.28 to -0.05
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.058
Estimation Comments Cough and sputum EXACT-RS Score, Week 9-12
Hide Statistical Analysis 16
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.22
Confidence Interval (2-Sided) 95%
-0.34 to -0.10
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.061
Estimation Comments Cough and sputum EXACT-RS Score, Week 13-16
Hide Statistical Analysis 17
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.24
Confidence Interval (2-Sided) 95%
-0.36 to -0.11
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.064
Estimation Comments Cough and sputum EXACT-RS Score, Week 17-20
Hide Statistical Analysis 18
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.23
Confidence Interval (2-Sided) 95%
-0.35 to -0.10
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.065
Estimation Comments Cough and sputum EXACT-RS Score, Week 21-24
Hide Statistical Analysis 19
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.27
Confidence Interval (2-Sided) 95%
-0.37 to -0.18
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.049
Estimation Comments Chest EXACT-RS Scores, Week 1-4
Hide Statistical Analysis 20
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.34
Confidence Interval (2-Sided) 95%
-0.46 to -0.23
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.060
Estimation Comments Chest EXACT-RS Scores, Week 5-8
Hide Statistical Analysis 21
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.34
Confidence Interval (2-Sided) 95%
-0.47 to -0.21
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.066
Estimation Comments Chest EXACT-RS Scores, Week 9-12
Hide Statistical Analysis 22
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.38
Confidence Interval (2-Sided) 95%
-0.51 to -0.25
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.068
Estimation Comments Chest EXACT-RS Scores, Week 13-16
Hide Statistical Analysis 23
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.40
Confidence Interval (2-Sided) 95%
-0.53 to -0.26
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.071
Estimation Comments Chest EXACT-RS Scores, Week 17-20
Hide Statistical Analysis 24
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.36
Confidence Interval (2-Sided) 95%
-0.50 to -0.22
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.072
Estimation Comments Chest EXACT-RS Scores, Week 21-24
12.Secondary Outcome
Title Assessment of Respiratory Symptoms by Change From Baseline in 4-weekly Mean EXACT-RS Scores up to Week 52
Hide Description The EXACT-PRO is a 14 item instrument designed to capture information on the occurrence, frequency, severity, and duration of exacerbations of disease in participants with COPD. EXACT-RS consists of 11 items from the 14 item EXACT-PRO instrument and has a scoring range of 0-40. Three subscales are used to describe different symptoms; dyspnoea (range 0-17), cough and sputum (range 0-11) and chest symptoms (range 0-12). Baseline was defined as the mean value during the period between Visits 1 and 2. Mean scores were calculated for each four weekly period and change from Baseline was calculated as four weekly score minus the Baseline value. Four weekly intervals were analyzed using a MMRM method with covariates of treatment group, smoking status (screening), geographical region, time period, baseline, baseline by time period and treatment by time period interactions. Only participants with data available at the analysis time point were analyzed (represented as n=X, X in category title).
Time Frame Baseline to Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Extension Population
Arm/Group Title FF/UMEC/VI 100/62.5/25 µg BUD/FOR 400/12 µg
Hide Arm/Group Description:
Participants received FF/UMEC/VI 100/62.5/25 µg via the ELLIPTA dry powder inhaler (DPI) once daily in the morning and placebo via the Turbuhaler twice daily (BID) for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Participants received BUD/FOR 400/12 µg via the Turbuhaler BID and placebo via the ELLIPTA once daily in the morning for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Overall Number of Participants Analyzed 210 220
Least Squares Mean (Standard Error)
Unit of Measure: Scores on a scale
Week 1-4, n=205, 213 Number Analyzed 205 participants 213 participants
-1.24  (0.222) -0.72  (0.218)
Week 5-8, n=203, 208 Number Analyzed 203 participants 208 participants
-1.97  (0.265) -0.90  (0.260)
Week 9-12, n=201, 206 Number Analyzed 201 participants 206 participants
-2.18  (0.298) -1.21  (0.294)
Week 13-16, n=201, 204 Number Analyzed 201 participants 204 participants
-2.53  (0.317) -1.52  (0.313)
Week 17-20, n=201, 199 Number Analyzed 201 participants 199 participants
-2.64  (0.342) -1.53  (0.338)
Week 21-24, n=202, 197 Number Analyzed 202 participants 197 participants
-2.63  (0.341) -1.52  (0.338)
Week 25-28, n=194, 186 Number Analyzed 194 participants 186 participants
-2.48  (0.349) -1.16  (0.347)
Week 29-32, n=192, 181 Number Analyzed 192 participants 181 participants
-2.33  (0.350) -0.90  (0.349)
Week 33-36, n=187, 180 Number Analyzed 187 participants 180 participants
-2.12  (0.367) -0.62  (0.366)
Week 37-40, n=185, 177 Number Analyzed 185 participants 177 participants
-2.34  (0.359) -1.11  (0.358)
Week 41-44, n=180, 174 Number Analyzed 180 participants 174 participants
-2.30  (0.363) -0.81  (0.362)
Week 45-48, n=180, 173 Number Analyzed 180 participants 173 participants
-2.17  (0.371) -0.64  (0.371)
EXACT-RS Scores, Week 49-52, n=179, 171 Number Analyzed 179 participants 171 participants
-2.03  (0.370) -0.61  (0.370)
Breathlessness scores, Week 1-4, n=205, 213 Number Analyzed 205 participants 213 participants
-0.64  (0.120) -0.31  (0.118)
Breathlessness scores, Week 5-8, n=203, 208 Number Analyzed 203 participants 208 participants
-0.93  (0.147) -0.32  (0.145)
Breathlessness scores, Week 9-12, n=201, 206 Number Analyzed 201 participants 206 participants
-1.05  (0.167) -0.44  (0.164)
Breathlessness scores, Week 13-16, n=201, 204 Number Analyzed 201 participants 204 participants
-1.19  (0.175) -0.57  (0.173)
Breathlessness scores, Week 17-20, n=201, 199 Number Analyzed 201 participants 199 participants
-1.17  (0.189) -0.50  (0.186)
Breathlessness scores, Week 21-24, n=202, 197 Number Analyzed 202 participants 197 participants
-1.13  (0.190) -0.50  (0.188)
Breathlessness scores, Week 25-28, n=194, 186 Number Analyzed 194 participants 186 participants
-1.14  (0.195) -0.38  (0.194)
Breathlessness scores, Week 29-32, n=192, 181 Number Analyzed 192 participants 181 participants
-1.11  (0.196) -0.26  (0.194)
Breathlessness scores, Week 33-36, n=187, 180 Number Analyzed 187 participants 180 participants
-1.08  (0.204) -0.14  (0.203)
Breathlessness scores, Week 37-40, n=185, 177 Number Analyzed 185 participants 177 participants
-1.13  (0.203) -0.37  (0.202)
Breathlessness scores, Week 41-44, n=180, 174 Number Analyzed 180 participants 174 participants
-1.06  (0.208) -0.24  (0.208)
Breathlessness scores, Week 45-48, n=180, 173 Number Analyzed 180 participants 173 participants
-0.97  (0.211) -0.11  (0.211)
Breathlessness scores, Week 49-52, n=179, 171 Number Analyzed 179 participants 171 participants
-0.96  (0.207) -0.08  (0.207)
Cough and sputum scores, Week 1-4, n=205, 213 Number Analyzed 205 participants 213 participants
-0.34  (0.065) -0.32  (0.064)
Cough and sputum scores, Week 5-8, n=203, 208 Number Analyzed 203 participants 208 participants
-0.59  (0.076) -0.44  (0.074)
Cough and sputum scores, Week 9-12, n=201, 206 Number Analyzed 201 participants 206 participants
-0.63  (0.083) -0.52  (0.082)
Cough and sputum scores, Week 13-16, n=201, 204 Number Analyzed 201 participants 204 participants
-0.73  (0.088) -0.62  (0.087)
Cough and sputum scores, Week 17-20, n=201, 199 Number Analyzed 201 participants 199 participants
-0.83  (0.095) -0.73  (0.094)
Cough and sputum scores, Week 21-24, n=202, 197 Number Analyzed 202 participants 197 participants
-0.83  (0.098) -0.71  (0.097)
Cough and sputum scores, Week 25-28, n=194, 186 Number Analyzed 194 participants 186 participants
-0.73  (0.097) -0.57  (0.097)
Cough and sputum scores, Week 29-32, n=192, 181 Number Analyzed 192 participants 181 participants
-0.68  (0.096) -0.48  (0.096)
Cough and sputum scores, Week 33-36, n=187, 180 Number Analyzed 187 participants 180 participants
-0.56  (0.099) -0.40  (0.099)
Cough and sputum scores, Week 37-40, n=185, 177 Number Analyzed 185 participants 177 participants
-0.65  (0.097) -0.54  (0.097)
Cough and sputum scores, Week 41-44, n=180, 174 Number Analyzed 180 participants 174 participants
-0.66  (0.101) -0.41  (0.102)
Cough and sputum scores, Week 45-48, n=180, 173 Number Analyzed 180 participants 173 participants
-0.66  (0.098) -0.39  (0.099)
Cough and sputum scores, Week 49-52, n=179, 171 Number Analyzed 179 participants 171 participants
-0.61  (0.100) -0.44  (0.100)
Chest scores, Week 1-4, n=205, 213 Number Analyzed 205 participants 213 participants
-0.27  (0.069) -0.09  (0.068)
Chest scores, Week 5-8, n=203, 208 Number Analyzed 203 participants 208 participants
-0.46  (0.084) -0.13  (0.082)
Chest scores, Week 9-12, n=201, 206 Number Analyzed 201 participants 206 participants
-0.51  (0.093) -0.24  (0.092)
Chest scores, Week 13-16, n=201, 204 Number Analyzed 201 participants 204 participants
-0.61  (0.097) -0.31  (0.095)
Chest scores, Week 17-20, n=201, 199 Number Analyzed 201 participants 199 participants
-0.67  (0.104) -0.29  (0.103)
Chest scores, Week 21-24, n=202, 197 Number Analyzed 202 participants 197 participants
-0.68  (0.102) -0.30  (0.101)
Chest scores, Week 25-28, n=194, 186 Number Analyzed 194 participants 186 participants
-0.63  (0.105) -0.21  (0.104)
Chest scores, Week 29-32, n=192, 181 Number Analyzed 192 participants 181 participants
-0.55  (0.107) -0.16  (0.107)
Chest scores, Week 33-36, n=187, 180 Number Analyzed 187 participants 180 participants
-0.48  (0.111) -0.08  (0.111)
Chest scores, Week 37-40, n=185, 177 Number Analyzed 185 participants 177 participants
-0.57  (0.107) -0.20  (0.107)
Chest scores, Week 41-44, n=180, 174 Number Analyzed 180 participants 174 participants
-0.58  (0.108) -0.16  (0.108)
Chest scores, Week 45-48, n=180, 173 Number Analyzed 180 participants 173 participants
-0.57  (0.113) -0.13  (0.113)
Chest scores, Week 49-52, n=179, 171 Number Analyzed 179 participants 171 participants
-0.49  (0.115) -0.08  (0.115)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.094
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.52
Confidence Interval (2-Sided) 95%
-1.13 to 0.09
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.311
Estimation Comments EXACT-RS Scores, Week 1-4
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.004
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -1.07
Confidence Interval (2-Sided) 95%
-1.80 to -0.34
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.371
Estimation Comments EXACT-RS Scores, Week 5-8
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.022
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.97
Confidence Interval (2-Sided) 95%
-1.79 to -0.14
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.419
Estimation Comments EXACT-RS Scores, Week 9-12
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.024
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -1.01
Confidence Interval (2-Sided) 95%
-1.88 to -0.13
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.445
Estimation Comments EXACT-RS Scores, Week 13-16
Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.021
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -1.11
Confidence Interval (2-Sided) 95%
-2.06 to -0.17
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.481
Estimation Comments EXACT-RS Scores, Week 17-20
Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.022
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -1.11
Confidence Interval (2-Sided) 95%
-2.05 to -0.16
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.481
Estimation Comments EXACT-RS Score, Week 21-24
Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.008
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -1.32
Confidence Interval (2-Sided) 95%
-2.29 to -0.35
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.492
Estimation Comments EXACT-RS Scores, Week 25-28
Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.004
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -1.43
Confidence Interval (2-Sided) 95%
-2.40 to -0.46
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.494
Estimation Comments EXACT-RS Scores, Week 29-32
Hide Statistical Analysis 9
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.004
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -1.50
Confidence Interval (2-Sided) 95%
-2.52 to -0.48
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.519
Estimation Comments EXACT-RS Scores, Week 33-36
Hide Statistical Analysis 10
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.016
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -1.23
Confidence Interval (2-Sided) 95%
-2.22 to -0.23
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.507
Estimation Comments EXACT-RS Scores, Week 37-40
Hide Statistical Analysis 11
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.04
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -1.49
Confidence Interval (2-Sided) 95%
-2.50 to -0.48
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.513
Estimation Comments EXACT-RS Scores, Week 41-44
Hide Statistical Analysis 12
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.007
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -1.53
Confidence Interval (2-Sided) 95%
-2.56 to -0.50
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.525
Estimation Comments EXACT-RS Scores, Week 45-49
Hide Statistical Analysis 13
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.007
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -1.42
Confidence Interval (2-Sided) 95%
-2.45 to -0.39
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.524
Estimation Comments EXACT-RS Scores, Week 49-52
Hide Statistical Analysis 14
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.051
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.33
Confidence Interval (2-Sided) 95%
-0.66 to 0.00
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.169
Estimation Comments Breathlessness EXACT-RS score, Week 1-4
Hide Statistical Analysis 15
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.003
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.61
Confidence Interval (2-Sided) 95%
-1.02 to -0.20
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.207
Estimation Comments Breathlessness EXACT-RS score, Week 5-8
Hide Statistical Analysis 16
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.010
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.61
Confidence Interval (2-Sided) 95%
-1.07 to -0.15
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.234
Estimation Comments Breathlessness EXACT-RS score, Week 9-12
Hide Statistical Analysis 17
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.013
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.62
Confidence Interval (2-Sided) 95%
-1.10 to -0.13
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.247
Estimation Comments Breathlessness EXACT-RS score, Week 13-16
Hide Statistical Analysis 18
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.012
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.67
Confidence Interval (2-Sided) 95%
-1.19 to -0.15
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.265
Estimation Comments Breathlessness EXACT-RS score, Week 17-20
Hide Statistical Analysis 19
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.018
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.64
Confidence Interval (2-Sided) 95%
-1.16 to -0.11
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.268
Estimation Comments Breathlessness EXACT-RS score, Week 21-24
Hide Statistical Analysis 20
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.006
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.76
Confidence Interval (2-Sided) 95%
-1.30 to -0.21
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.275
Estimation Comments Breathlessness EXACT-RS score, Week 25-28
Hide Statistical Analysis 21
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.002
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.85
Confidence Interval (2-Sided) 95%
-1.40 to -0.31
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.276
Estimation Comments Breathlessness EXACT-RS score, Week 29-32
Hide Statistical Analysis 22
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.001
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.95
Confidence Interval (2-Sided) 95%
-1.51 to -0.38
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.288
Estimation Comments Breathlessness EXACT-RS score, Week 33-36
Hide Statistical Analysis 23
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.008
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.76
Confidence Interval (2-Sided) 95%
-1.32 to -0.20
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.287
Estimation Comments Breathlessness EXACT-RS score, Week 37-40
Hide Statistical Analysis 24
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.006
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.82
Confidence Interval (2-Sided) 95%
-1.40 to -0.24
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.294
Estimation Comments Breathlessness EXACT-RS score, Week 41-44
Hide Statistical Analysis 25
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.004
Comments [Not Specified]
Method Breathlessness score, Week 41-44
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.85
Confidence Interval (2-Sided) 95%
-1.44 to -0.27
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.299
Estimation Comments Breathlessness EXACT-RS score, Week 45-48
Hide Statistical Analysis 26
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.003
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.87
Confidence Interval (2-Sided) 95%
-1.45 to -0.30
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.294
Estimation Comments Breathlessness EXACT-RS score, Week 49-52EXA
Hide Statistical Analysis 27
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.840
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.02
Confidence Interval (2-Sided) 95%
-0.20 to 0.16
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.091
Estimation Comments Cough and sputum EXACT-RS score, Week 1-4
Hide Statistical Analysis 28
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.167
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.15
Confidence Interval (2-Sided) 95%
-0.36 to -0.06
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.106
Estimation Comments Cough and sputum EXACT-RS score, Week 5-8
Hide Statistical Analysis 29
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.359
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.11
Confidence Interval (2-Sided) 95%
-0.34 to 0.12
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.117
Estimation Comments Cough and sputum EXACT-RS score, Week 9-12
Hide Statistical Analysis 30
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.360
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.11
Confidence Interval (2-Sided) 95%
-0.36 to 0.13
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.124
Estimation Comments Cough and sputum EXACT-RS score, Week 13-16
Hide Statistical Analysis 31
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.490
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.09
Confidence Interval (2-Sided) 95%
-0.36 to 0.17
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.134
Estimation Comments Cough and sputum EXACT-RS score, Week 17-20
Hide Statistical Analysis 32
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.388
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.12
Confidence Interval (2-Sided) 95%
-0.39 to 0.15
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.138
Estimation Comments Cough and sputum EXACT-RS score, Week 21-24
Hide Statistical Analysis 33
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.218
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.17
Confidence Interval (2-Sided) 95%
-0.44 to 0.10
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.137
Estimation Comments Cough and sputum EXACT-RS score, Week 25-28
Hide Statistical Analysis 34
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.138
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.20
Confidence Interval (2-Sided) 95%
-0.47 to 0.07
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.136
Estimation Comments Cough and sputum EXACT-RS score, Week 29-32
Hide Statistical Analysis 35
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.239
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.17
Confidence Interval (2-Sided) 95%
-0.44 to 0.11
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.140
Estimation Comments Cough and sputum EXACT-RS score, Week 33-36
Hide Statistical Analysis 36
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.417
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.11
Confidence Interval (2-Sided) 95%
-0.38 to 0.16
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.138
Estimation Comments Cough and sputum EXACT-RS score, Week 37-40
Hide Statistical Analysis 37
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.078
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.25
Confidence Interval (2-Sided) 95%
-0.54 to 0.03
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.144
Estimation Comments Cough and sputum EXACT-RS score, Week 41-44
Hide Statistical Analysis 38
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.058
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.27
Confidence Interval (2-Sided) 95%
-0.54 to 0.01
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.140
Estimation Comments Cough and sputum EXACT-RS score, Week 45-48
Hide Statistical Analysis 39
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.231
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.17
Confidence Interval (2-Sided) 95%
-0.45 to 0.11
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.141
Estimation Comments Cough and sputum EXACT-RS score, Week 49-52
Hide Statistical Analysis 40
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.068
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.18
Confidence Interval (2-Sided) 95%
-0.37 to 0.01
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.097
Estimation Comments Chest EXACT-RS score, Week 1-4
Hide Statistical Analysis 41
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.006
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.32
Confidence Interval (2-Sided) 95%
-0.56 to -0.09
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.118
Estimation Comments Chest EXACT-RS score, Week 5-8
Hide Statistical Analysis 42
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.042
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.27
Confidence Interval (2-Sided) 95%
-0.53 to -0.01
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.131
Estimation Comments Chest EXACT-RS score, Week 9-12
Hide Statistical Analysis 43
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.027
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.30
Confidence Interval (2-Sided) 95%
-0.57 to -0.03
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.136
Estimation Comments Chest EXACT-RS score, Week 13-16
Hide Statistical Analysis 44
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.010
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.38
Confidence Interval (2-Sided) 95%
-0.67 to -0.09
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.146
Estimation Comments Chest EXACT-RS score, Week 17-20
Hide Statistical Analysis 45
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.010
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.37
Confidence Interval (2-Sided) 95%
-0.66 to -0.09
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.144
Estimation Comments Chest EXACT-RS score, Week 21-24
Hide Statistical Analysis 46
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.41
Confidence Interval (2-Sided) 95%
-0.70 to -0.12
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.148
Estimation Comments Chest EXACT-RS score, Week 25-28
Hide Statistical Analysis 47
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.011
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.39
Confidence Interval (2-Sided) 95%
-0.68 to -0.09
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.152
Estimation Comments Chest EXACT-RS score, Week 29-32
Hide Statistical Analysis 48
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.011
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.40
Confidence Interval (2-Sided) 95%
-0.71 to -0.09
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.157
Estimation Comments Chest EXACT-RS score, Week 33-36
Hide Statistical Analysis 49
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.014
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.37
Confidence Interval (2-Sided) 95%
-0.67 to -0.07
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.151
Estimation Comments Chest EXACT-RS score, Week 37-40
Hide Statistical Analysis 50
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.007
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.42
Confidence Interval (2-Sided) 95%
-0.72 to -0.12
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.153
Estimation Comments Chest EXACT-RS score, Week 41-44
Hide Statistical Analysis 51
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.006
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.45
Confidence Interval (2-Sided) 95%
-0.76 to -0.13
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.160
Estimation Comments Chest EXACT-RS score, Week 45-48
Hide Statistical Analysis 52
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.013
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.41
Confidence Interval (2-Sided) 95%
-0.73 to -0.09
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.163
Estimation Comments Chest EXACT-RS score, Week 49-52
13.Secondary Outcome
Title Number of Participants With Any On-treatment Adverse Event (AE) and Serious Adverse Event (SAE) in the Treatment Period
Hide Description An AE was any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. These included an exacerbation of a chronic or intermittent pre-existing condition. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; or all events of possible drug-induced liver injury. Abnormal and clinically significant laboratory test results were also recorded as an AE or SAE. COPD exacerbations were an expected disease-related outcome and were not to be recorded as an AE, unless they met the definition of an SAE. Participants were not to be withdrawn from the study due to COPD exacerbations and their evaluation was an efficacy endpoint.
Time Frame Up to Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population
Arm/Group Title FF/UMEC/VI 100/62.5/25 µg BUD/FOR 400/12 µg
Hide Arm/Group Description:
Participants received FF/UMEC/VI 100/62.5/25 µg via the ELLIPTA DPI once daily in the morning and placebo via the Turbuhaler BID for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Participants received BUD/FOR 400/12 µg via the Turbuhaler BID and placebo via the ELLIPTA once daily in the morning for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Overall Number of Participants Analyzed 911 899
Measure Type: Number
Unit of Measure: Participants
Any AE 354 339
Any SAE 49 51
14.Secondary Outcome
Title Number of Participants With Any On-treatment AE/SAEs in the Extension Part of the Study
Hide Description An AE was any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. These included an exacerbation of a chronic or intermittent pre-existing condition. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; or all events of possible drug-induced liver injury. Abnormal and clinically significant laboratory test results were also recorded as an AE or SAE. COPD exacerbations were an expected disease-related outcome and were not to be recorded as an AE, unless they met the definition of an SAE. Participants were not to be withdrawn from the study due to COPD exacerbations and their evaluation was an efficacy endpoint.
Time Frame Up to Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Extension Population
Arm/Group Title FF/UMEC/VI 100/62.5/25 µg BUD/FOR 400/12 µg
Hide Arm/Group Description:
Participants received FF/UMEC/VI 100/62.5/25 µg via the ELLIPTA DPI once daily in the morning and placebo via the Turbuhaler BID for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Participants received BUD/FOR 400/12 µg via the Turbuhaler BID and placebo via the ELLIPTA once daily in the morning for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Overall Number of Participants Analyzed 210 220
Measure Type: Number
Unit of Measure: Participants
Any AE 100 122
Any SAE 21 28
15.Secondary Outcome
Title Number of Participants With an On-treatment Penumonia Event in the Treatment Period
Hide Description All suspected pneumonias required confirmation as defined by the presence of new infiltrate(s) on chest x-ray and at least 2 of the following signs and symptoms: Increased cough, Increased sputum purulence (colour) or production, Auscultatory findings of adventitious sounds , Dyspnea or tachypnea, Fever (oral temperature > 37.5 °C), Elevated white blood cells (WBC) (>10,000/millimeter [mm^3] or >15 percent immature forms) or Hypoxemia (hemoglobin/oxygen [HbO2] saturation <88 percent or at least 2 percent lower than Baseline value).
Time Frame Up to Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population.
Arm/Group Title FF/UMEC/VI 100/62.5/25 µg BUD/FOR 400/12 µg
Hide Arm/Group Description:
Participants received FF/UMEC/VI 100/62.5/25 µg via the ELLIPTA DPI once daily in the morning and placebo via the Turbuhaler BID for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Participants received BUD/FOR 400/12 µg via the Turbuhaler BID and placebo via the ELLIPTA once daily in the morning for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Overall Number of Participants Analyzed 911 899
Measure Type: Number
Unit of Measure: Participants
20 7
16.Secondary Outcome
Title Number of Participants With an On-treatment Penumonia Event in the Extension Part of the Study
Hide Description All suspected pneumonias required confirmation as defined by the presence of new infiltrate(s) on chest x-ray AND at least 2 of the following signs and symptoms: Increased cough, Increased sputum purulence (colour) or production, Auscultatory findings of adventitious sounds , Dyspnea or tachypnea, Fever (oral temperature > 37.5 °C), Elevated WBC (>10,000/mm3 or >15 percent immature forms) orr Hypoxemia (HbO2 saturation <88 percent or at least 2 percent lower than Baseline value).
Time Frame Up to Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Extension Population
Arm/Group Title FF/UMEC/VI 100/62.5/25 µg BUD/FOR 400/12 µg
Hide Arm/Group Description:
Participants received FF/UMEC/VI 100/62.5/25 µg via the ELLIPTA DPI once daily in the morning and placebo via the Turbuhaler BID for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Participants received BUD/FOR 400/12 µg via the Turbuhaler BID and placebo via the ELLIPTA once daily in the morning for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Overall Number of Participants Analyzed 210 220
Measure Type: Number
Unit of Measure: Participants
4 4
17.Secondary Outcome
Title Number of Participants With Any On-treatment Cardiovascular (CV) Events (Including Supraventricular Arrhythmia and Non Fatal Myocardial Infarction) in the Treatment Period
Hide Description Cardiovascular safety was monitored via AE reporting with categorization and analysis of adverse events of special interest (AESIs) including cardiac arrhythmia, cardiac failure, ischemic heart disease, hypertension, and central nervous system hemorrhages and cerebrovascular conditions. In addition, ECGs and vital signs were measured in all subjects and24-hour Holter monitoring was performed in a predefined subset. Pre-specified MACE analysis was conducted based on adjudicated CV deaths and investigator-reported non-fatal AEs. Number of participants with any of the following MACE events were to be included per the broad and narrow analyses: Broad MACE criteria (ischemic heart disease standardized MedDRA query [SMQ; myocardial infarction SMQ and other ischemic diseases]) and narrow MACE criteria (myocardial infarction [acute myocardial infarction].
Time Frame Up to Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population
Arm/Group Title FF/UMEC/VI 100/62.5/25 µg BUD/FOR 400/12 µg
Hide Arm/Group Description:
Participants received FF/UMEC/VI 100/62.5/25 µg via the ELLIPTA DPI once daily in the morning and placebo via the Turbuhaler BID for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Participants received BUD/FOR 400/12 µg via the Turbuhaler BID and placebo via the ELLIPTA once daily in the morning for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Overall Number of Participants Analyzed 911 899
Measure Type: Number
Unit of Measure: Participants
Any MACE, Narrow definition 4 7
Any MACE, Broad definition 12 11
18.Secondary Outcome
Title Number of Participants With Any On-treatment CV Events (Including Supraventricular Arrhythmia and Non Fatal Myocardial Infarction) in the Extension Part of the Study
Hide Description Cardiovascular safety was monitored via AE reporting with categorization and analysis of adverse events of special interest (AESIs) including cardiac arrhythmia, cardiac failure, ischemic heart disease, hypertension, and central nervous system hemorrhages and cerebrovascular conditions. In addition, ECGs and vital signs were measured in all subjects and24-hour Holter monitoring was performed in a predefined subset. Pre-specified MACE analysis was conducted based on adjudicated CV deaths and investigator-reported non-fatal AEs. Number of participants with any of the following MACE events were to be included per the broad and narrow analyses: Broad MACE criteria (ischemic heart disease standardized MedDRA query [SMQ; myocardial infarction SMQ and other ischemic diseases]) and narrow MACE criteria (myocardial infarction [acute myocardial infarction]
Time Frame Up to Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Extension Population
Arm/Group Title FF/UMEC/VI 100/62.5/25 µg BUD/FOR 400/12 µg
Hide Arm/Group Description:
Participants received FF/UMEC/VI 100/62.5/25 µg via the ELLIPTA DPI once daily in the morning and placebo via the Turbuhaler BID for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Participants received BUD/FOR 400/12 µg via the Turbuhaler BID and placebo via the ELLIPTA once daily in the morning for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Overall Number of Participants Analyzed 210 220
Measure Type: Number
Unit of Measure: Participants
Any MACE, Narrow definition 5 2
Any MACE, Broad definition 7 5
19.Secondary Outcome
Title Change From Baseline in Heart Rate at Week 24
Hide Description A single 12-lead electrocardiogram (ECG) and rhythm strip were recorded after measurement of vital signs and spirometry. Recordings were made at Screening (Visit 1) and approximately 15-45 minutes after dosing on treatment Week 4 and Week 24 or IP Discontinuation Visit. Change from Baseline in ECG heart rate was summarized for each post-Baseline assessment up to Week 24. Change from Baseline was calculated as the individual post-Baseline value at Week 24 minus the Baseline value. Baseline value is defined as the most recent individual value prior to randomization (generally Screening but could be a test repeat). All ECG measurements were made with the participants in a supine position having rested in this position for approximately 5 minutes before each reading.
Time Frame Baseline and Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population; Only participants with analyzable data at the given time point were analyzed.
Arm/Group Title FF/UMEC/VI 100/62.5/25 µg BUD/FOR 400/12 µg
Hide Arm/Group Description:
Participants received FF/UMEC/VI 100/62.5/25 µg via the ELLIPTA DPI once daily in the morning and placebo via the Turbuhaler BID for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Participants received BUD/FOR 400/12 µg via the Turbuhaler BID and placebo via the ELLIPTA once daily in the morning for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Overall Number of Participants Analyzed 840 787
Mean (Standard Deviation)
Unit of Measure: Beats per minute (Bpm)
-1.1  (11.51) -1.2  (10.91)
20.Secondary Outcome
Title Change From Baseline in Heart Rate at Week 52
Hide Description A single 12-lead ECG and rhythm strip were recorded after measurement of vital signs and spirometry. Recordings were made at Screening (Visit 1) and approximately 15-45 minutes after dosing on treatment Week 4, Week 24 and Week 52 or IP Discontinuation Visit. Change from Baseline in ECG heart rate was summarized for each post-Baseline assessment up to Week 24. Change from Baseline was calculated as the individual post-Baseline value at Week 52 minus the Baseline value. Baseline value is defined as the most recent individual value prior to randomization (generally Screening but could be a test repeat). All ECG measurements were made with the participants in a supine position having rested in this position for approximately 5 minutes before each reading.
Time Frame Baseline and Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Extension Population; Only participants with analyzable data at the given time point were analyzed.
Arm/Group Title FF/UMEC/VI 100/62.5/25 µg BUD/FOR 400/12 µg
Hide Arm/Group Description:
Participants received FF/UMEC/VI 100/62.5/25 µg via the ELLIPTA DPI once daily in the morning and placebo via the Turbuhaler BID for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Participants received BUD/FOR 400/12 µg via the Turbuhaler BID and placebo via the ELLIPTA once daily in the morning for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Overall Number of Participants Analyzed 181 169
Mean (Standard Deviation)
Unit of Measure: Bpm
0.2  (11.30) -1.0  (10.77)
21.Secondary Outcome
Title Change From Baseline in Corrected QT Interval Using Fridericia's Correction (QTcF) and PR Interval at Week 24
Hide Description A single 12-lead ECG and rhythm strip were recorded after measurement of vital signs and spirometry. Recordings were made at Screening (Visit 1) and approximately 15-45 minutes after dosing on treatment Week 4 and Week 24 or IP Discontinuation Visit. Change from Baseline in ECG QTcF and PR interval was summarized for each post-Baseline assessment up to Week 24. Change from Baseline was calculated as the individual post-Baseline value at Week 24 minus the Baseline value. Baseline value is defined as the most recent individual value prior to randomization (generally Screening but could be a test repeat). Only participants with data available at the analysis time point were analyzed (represented as n=X, X in category title). All ECG measurements were made with the participants in a supine position having rested in this position for approximately 5 minutes before each reading.
Time Frame Baseline and Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population
Arm/Group Title FF/UMEC/VI 100/62.5/25 µg BUD/FOR 400/12 µg
Hide Arm/Group Description:
Participants received FF/UMEC/VI 100/62.5/25 µg via the ELLIPTA DPI once daily in the morning and placebo via the Turbuhaler BID for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Participants received BUD/FOR 400/12 µg via the Turbuhaler BID and placebo via the ELLIPTA once daily in the morning for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Overall Number of Participants Analyzed 911 899
Least Squares Mean (Standard Error)
Unit of Measure: Milliseconds (msec)
QTcF, n=840,787 Number Analyzed 840 participants 787 participants
2.5  (0.56) 0.6  (0.58)
PR, n=812,766 Number Analyzed 812 participants 766 participants
-0.1  (0.54) 0.5  (0.56)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.023
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value 1.8
Confidence Interval (2-Sided) 95%
0.3 to 3.4
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.81
Estimation Comments For QTcF
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.471
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value -0.6
Confidence Interval (2-Sided) 95%
-2.1 to 1.0
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.78
Estimation Comments For PR interval
22.Secondary Outcome
Title Change From Baseline in QTcF and PR Interval at Week 52
Hide Description Single 12-lead ECG and rhythm strip were recorded after measurement of vital signs and spirometry. Recordings were made at Screening (Visit 1) and approximately 15-45 minutes after dosing on treatment Week 4, Week 24 and Week 52 or IP Discontinuation Visit. Change from Baseline in ECG QTcF and PR interval was summarized for each post-Baseline assessment up to Week 24. Change from Baseline was calculated as the individual post-Baseline value at Week 52 minus the Baseline value. Baseline value is defined as the most recent individual value prior to randomization (generally Screening but could be a test repeat). Only participants with data available at the analysis time point were analyzed (represented as n=X, X in category title).
Time Frame Baseline and Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Extension Population
Arm/Group Title FF/UMEC/VI 100/62.5/25 µg BUD/FOR 400/12 µg
Hide Arm/Group Description:
Participants received FF/UMEC/VI 100/62.5/25 µg via the ELLIPTA DPI once daily in the morning and placebo via the Turbuhaler BID for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Participants received BUD/FOR 400/12 µg via the Turbuhaler BID and placebo via the ELLIPTA once daily in the morning for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Overall Number of Participants Analyzed 210 220
Least Squares Mean (Standard Error)
Unit of Measure: Msec
QTcF, n=181,169 Number Analyzed 181 participants 169 participants
1.4  (1.27) 2.4  (1.31)
PR, n=174,160 Number Analyzed 174 participants 160 participants
1.6  (1.09) 1.4  (1.13)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.564
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value -1.1
Confidence Interval (2-Sided) 95%
-4.7 to 2.5
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.83
Estimation Comments For QTcF
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.908
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value 0.2
Confidence Interval (2-Sided) 95%
-2.9 to 3.3
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.57
Estimation Comments For PR interval
23.Secondary Outcome
Title Change From Baseline in QT Interval Corrected for Heart Rate According to Bazett's Formula (QTcB) at Week 24
Hide Description A single 12-lead ECG and rhythm strip were recorded after measurement of vital signs and spirometry. Recordings were made at Screening (Visit 1) and approximately 15-45 minutes after dosing on treatment Week 4 and Week 24 or IP Discontinuation Visit. Change from Baseline in QTcB was summarized for each post-Baseline assessment up to Week 24. Change from Baseline was calculated as the individual post-Baseline value at Week 24 minus the Baseline value. Baseline value is defined as the most recent individual value prior to randomization (generally Screening but could be a test repeat). All ECG measurements were made with the participants in a supine position having rested in this position for approximately 5 minutes before each reading.
Time Frame Baseline and Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population; Only participants with analyzable data at the given time point were analyzed.
Arm/Group Title FF/UMEC/VI 100/62.5/25 µg BUD/FOR 400/12 µg
Hide Arm/Group Description:
Participants received FF/UMEC/VI 100/62.5/25 µg via the ELLIPTA DPI once daily in the morning and placebo via the Turbuhaler BID for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Participants received BUD/FOR 400/12 µg via the Turbuhaler BID and placebo via the ELLIPTA once daily in the morning for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Overall Number of Participants Analyzed 840 787
Mean (Standard Deviation)
Unit of Measure: Msec
1.5  (21.00) -0.7  (20.48)
24.Secondary Outcome
Title Change From Baseline in QTcB at Week 52
Hide Description A single 12-lead ECG and rhythm strip were recorded after measurement of vital signs and spirometry. Recordings were made at Screening (Visit 1) and approximately 15-45 minutes after dosing on treatment Week 4, Week 24, and Week 52 or IP Discontinuation Visit. Change from Baseline in QTcB was summarized for each post-Baseline assessment up to Week 52. Change from Baseline was calculated as the individual post-Baseline value at Week 52 minus the Baseline value. Baseline value is defined as the most recent individual value prior to randomization (generally Screening but could be a test repeat). All ECG measurements were made with the participants in a supine position having rested in this position for approximately 5 minutes before each reading.
Time Frame Baseline and Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Extension Population; Only participants with analyzable data at the given time point were analyzed.
Arm/Group Title FF/UMEC/VI 100/62.5/25 µg BUD/FOR 400/12 µg
Hide Arm/Group Description:
Participants received FF/UMEC/VI 100/62.5/25 µg via the ELLIPTA DPI once daily in the morning and placebo via the Turbuhaler BID for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Participants received BUD/FOR 400/12 µg via the Turbuhaler BID and placebo via the ELLIPTA once daily in the morning for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Overall Number of Participants Analyzed 181 169
Mean (Standard Deviation)
Unit of Measure: Msec
0.9  (21.30) 2.2  (22.46)
25.Secondary Outcome
Title Change From Baseline in Systolic and Diastolic Blood Pressures (BP) at Week 24
Hide Description Vital signs were obtained at the Screening Visit and prior to taking the morning dose of study treatment and prior to conducting spirometry at Week 4 and Week 24 or at the Study Treatment Discontinuation Visit. A single set of blood pressure (systolic and diastolic) measurements were collected taken after the participant had rested for 5 minutes in the sitting position. Change from Baseline values for systolic and diastolic BP (SBP and DBP) at Week 24 were summarised and these data were analyzed using MMRM analysis. Baseline was defined as the values from most recent assessment prior to randomization which records both systolic and diastolic BP (generally Screening but could be a test repeat).
Time Frame Baseline and Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population; Only participants with analyzable data at the given time point were analyzed.
Arm/Group Title FF/UMEC/VI 100/62.5/25 µg BUD/FOR 400/12 µg
Hide Arm/Group Description:
Participants received FF/UMEC/VI 100/62.5/25 µg via the ELLIPTA DPI once daily in the morning and placebo via the Turbuhaler BID for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Participants received BUD/FOR 400/12 µg via the Turbuhaler BID and placebo via the ELLIPTA once daily in the morning for 24 weeks in the treatment period and 52 weeks for participants in the extension part of the study.
Overall Number of Participants Analyzed 855 805
Least Squares Mean (Standard Error)
Unit of Measure: Millimeter of mercury (mmHg)
SBP -1.0  (0.39) -1.1  (0.40)
DBP -0.3  (0.27) -0.5  (0.27)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FF/UMEC/VI 100/62.5/25 µg, BUD/FOR 400/12 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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Statistical Test of Hypothesis P-Value 0.849
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation