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

View this study on Beta.ClinicalTrials.gov

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

Participant Flow

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
Arm/Group Description	Participants received FF/UMEC/VI 10...	Participants received BUD/FOR 400/1...
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

Baseline Characteristics

Arm/Group Title		FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg	Total
Arm/Group Description		Participants received FF/UMEC/VI 10...	Participants received BUD/FOR 400/1...	Total of all reporting groups
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
Baseline Analysis Population Description		[Not Specified]
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

Outcome Measures

1.Primary Outcome


Title	Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) at Week 24
Description	FEV1 is a measure of lung function and is defined as the maximal amoun...
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

Outcome Measure Data

Analysis Population Description

ITT Population


Arm/Group Title	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Arm/Group Description:	Participants received FF/UMEC/VI 10...	Participants received BUD/FOR 400/1...
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)

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
Description	FEV1 is a measure of lung function and is defined as the maximal amoun...
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

Outcome Measure Data

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
Arm/Group Description:	Participants received FF/UMEC/VI 10...	Participants received BUD/FOR 400/1...
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)

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
Description	The SGRQ-C is a disease-specific questionnaire designed to measure the...
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

Outcome Measure Data

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
Arm/Group Description:	Participants received FF/UMEC/VI 10...	Participants received BUD/FOR 400/1...
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)

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
Description	The SGRQ-C is a disease-specific questionnaire designed to measure the...
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

Outcome Measure Data

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
Arm/Group Description:	Participants received FF/UMEC/VI 10...	Participants received BUD/FOR 400/1...
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)

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
Description	The TDI measures change in the participant's dyspnoea from Baseline. T...
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

Outcome Measure Data

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
Arm/Group Description:	Participants received FF/UMEC/VI 10...	Participants received BUD/FOR 400/1...
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)

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
Description	The TDI measures change in the participant's dyspnoea from Baseline. T...
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

Outcome Measure Data

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
Arm/Group Description:	Participants received FF/UMEC/VI 10...	Participants received BUD/FOR 400/1...
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)

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
Description	Participants were asked to complete the daily activity question as par...
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

Outcome Measure Data

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)
Arm/Group Description:	Each subject will inhale once from ...	Each subject will inhale once from ...
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)

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
Description	Participants were asked to complete the daily activity question as apr...
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

Outcome Measure Data

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
Arm/Group Description:	Participants received FF/UMEC/VI 10...	Participants received BUD/FOR 400/1...
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)

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
Description	The mean annual moderate and severe COPD exacerbations during the trea...
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

Outcome Measure Data

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
Arm/Group Description:	Participants received FF/UMEC/VI 10...	Participants received BUD/FOR 400/1...
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)

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
Description	The mean annual moderate and severe COPD exacerbations during the trea...
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

Outcome Measure Data

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
Arm/Group Description:	Participants received FF/UMEC/VI 10...	Participants received BUD/FOR 400/1...
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)

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
Description	The EXACT-PRO is a 14 item instrument designed to capture information ...
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

Outcome Measure Data

Analysis Population Description

ITT Population


Arm/Group Title		FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Arm/Group Description:		Participants received FF/UMEC/VI 10...	Participants received BUD/FOR 400/1...
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
Week 1-4, n=870,859		-1.45 (0.106)	-0.50 (0.106)
Week 5-8, n=851,830	Number Analyzed	851 participants	830 participants
Week 5-8, n=851,830		-2.00 (0.129)	-0.77 (0.130)
Week 9-12, n=841,813	Number Analyzed	841 participants	813 participants
Week 9-12, n=841,813		-2.23 (0.141)	-1.05 (0.143)
Week 13-16, n=831,802	Number Analyzed	831 participants	802 participants
Week 13-16, n=831,802		-2.42 (0.150)	-1.09 (0.151)
Week 17-20, n=828,788	Number Analyzed	828 participants	788 participants
Week 17-20, n=828,788		-2.43 (0.156)	-1.02 (0.159)
Week 21-24, n=825,783	Number Analyzed	825 participants	783 participants
Week 21-24, n=825,783		-2.31 (0.157)	-0.96 (0.160)
Breathlessness score, Week 1-4, n=870,859	Number Analyzed	870 participants	859 participants
Breathlessness score, Week 1-4, n=870,859		-0.71 (0.057)	-0.20 (0.057)
Breathlessness score, Week 5-8, n=851,830	Number Analyzed	851 participants	830 participants
Breathlessness score, Week 5-8, n=851,830		-0.95 (0.069)	-0.26 (0.070)
Breathlessness score, Week 9-12, n=841,813	Number Analyzed	841 participants	813 participants
Breathlessness score, Week 9-12, n=841,813		-1.03 (0.076)	-0.34 (0.076)
Breathlessness score, Week 13-16, n=831, 802	Number Analyzed	831 participants	802 participants
Breathlessness score, Week 13-16, n=831, 802		-1.11 (0.080)	-0.36 (0.081)
Breathlessness score, Week 17-20, n=828,788	Number Analyzed	828 participants	788 participants
Breathlessness score, Week 17-20, n=828,788		-1.10 (0.084)	-0.31 (0.085)
Breathlessness score, Week 21-24, n=825,783	Number Analyzed	825 participants	783 participants
Breathlessness score, Week 21-24, n=825,783		-1.07 (0.085)	-0.30 (0.087)
Cough, sputum score, Week 1-4, n=870,859	Number Analyzed	870 participants	859 participants
Cough, sputum score, Week 1-4, n=870,859		-0.41 (0.031)	-0.24 (0.031)
Cough, sputum score, Week 5-8, n=851,830	Number Analyzed	851 participants	830 participants
Cough, sputum score, Week 5-8, n=851,830		-0.59 (0.037)	-0.39 (0.038)
Cough, sputum score, Week 9-12, n=841,813	Number Analyzed	841 participants	813 participants
Cough, sputum score, Week 9-12, n=841,813		-0.67 (0.041)	-0.50 (0.041)
Cough, sputum score, Week 13-16, n=831,802	Number Analyzed	831 participants	802 participants
Cough, sputum score, Week 13-16, n=831,802		-0.74 (0.043)	-0.53 (0.043)
Cough, sputum score, Week 17-20, n=828,788	Number Analyzed	828 participants	788 participants
Cough, sputum score, Week 17-20, n=828,788		-0.77 (0.045)	-0.53 (0.045)
Cough, sputum score, Week 21-24, n=825,783	Number Analyzed	825 participants	783 participants
Cough, sputum score, Week 21-24, n=825,783		-0.72 (0.046)	-0.50 (0.046)
Chest score, Week 1-4, n=870,859	Number Analyzed	870 participants	859 participants
Chest score, Week 1-4, n=870,859		-0.33 (0.034)	-0.06 (0.035)
Chest score, Week 5-8, n=851,830	Number Analyzed	851 participants	830 participants
Chest score, Week 5-8, n=851,830		-0.46 (0.042)	-0.12 (0.043)
Chest score, Week 9-12, n=841,813	Number Analyzed	841 participants	813 participants
Chest score, Week 9-12, n=841,813		-0.54 (0.046)	-0.20 (0.047)
Chest score, Week 13-16, n=831,802	Number Analyzed	831 participants	802 participants
Chest score, Week 13-16, n=831,802		-0.58 (0.048)	-0.20 (0.048)
Chest score, Week 17-20, n=828,788	Number Analyzed	828 participants	788 participants
Chest score, Week 17-20, n=828,788		-0.57 (0.050)	-0.17 (0.050)
Chest score, Week 21-24, n=825,783	Number Analyzed	825 participants	783 participants
Chest score, Week 21-24, n=825,783		-0.53 (0.050)	-0.17 (0.051)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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
Description	The EXACT-PRO is a 14 item instrument designed to capture information ...
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

Outcome Measure Data

Analysis Population Description

Extension Population


Arm/Group Title		FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Arm/Group Description:		Participants received FF/UMEC/VI 10...	Participants received BUD/FOR 400/1...
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
Week 1-4, n=205, 213		-1.24 (0.222)	-0.72 (0.218)
Week 5-8, n=203, 208	Number Analyzed	203 participants	208 participants
Week 5-8, n=203, 208		-1.97 (0.265)	-0.90 (0.260)
Week 9-12, n=201, 206	Number Analyzed	201 participants	206 participants
Week 9-12, n=201, 206		-2.18 (0.298)	-1.21 (0.294)
Week 13-16, n=201, 204	Number Analyzed	201 participants	204 participants
Week 13-16, n=201, 204		-2.53 (0.317)	-1.52 (0.313)
Week 17-20, n=201, 199	Number Analyzed	201 participants	199 participants
Week 17-20, n=201, 199		-2.64 (0.342)	-1.53 (0.338)
Week 21-24, n=202, 197	Number Analyzed	202 participants	197 participants
Week 21-24, n=202, 197		-2.63 (0.341)	-1.52 (0.338)
Week 25-28, n=194, 186	Number Analyzed	194 participants	186 participants
Week 25-28, n=194, 186		-2.48 (0.349)	-1.16 (0.347)
Week 29-32, n=192, 181	Number Analyzed	192 participants	181 participants
Week 29-32, n=192, 181		-2.33 (0.350)	-0.90 (0.349)
Week 33-36, n=187, 180	Number Analyzed	187 participants	180 participants
Week 33-36, n=187, 180		-2.12 (0.367)	-0.62 (0.366)
Week 37-40, n=185, 177	Number Analyzed	185 participants	177 participants
Week 37-40, n=185, 177		-2.34 (0.359)	-1.11 (0.358)
Week 41-44, n=180, 174	Number Analyzed	180 participants	174 participants
Week 41-44, n=180, 174		-2.30 (0.363)	-0.81 (0.362)
Week 45-48, n=180, 173	Number Analyzed	180 participants	173 participants
Week 45-48, n=180, 173		-2.17 (0.371)	-0.64 (0.371)
EXACT-RS Scores, Week 49-52, n=179, 171	Number Analyzed	179 participants	171 participants
EXACT-RS Scores, Week 49-52, n=179, 171		-2.03 (0.370)	-0.61 (0.370)
Breathlessness scores, Week 1-4, n=205, 213	Number Analyzed	205 participants	213 participants
Breathlessness scores, Week 1-4, n=205, 213		-0.64 (0.120)	-0.31 (0.118)
Breathlessness scores, Week 5-8, n=203, 208	Number Analyzed	203 participants	208 participants
Breathlessness scores, Week 5-8, n=203, 208		-0.93 (0.147)	-0.32 (0.145)
Breathlessness scores, Week 9-12, n=201, 206	Number Analyzed	201 participants	206 participants
Breathlessness scores, Week 9-12, n=201, 206		-1.05 (0.167)	-0.44 (0.164)
Breathlessness scores, Week 13-16, n=201, 204	Number Analyzed	201 participants	204 participants
Breathlessness scores, Week 13-16, n=201, 204		-1.19 (0.175)	-0.57 (0.173)
Breathlessness scores, Week 17-20, n=201, 199	Number Analyzed	201 participants	199 participants
Breathlessness scores, Week 17-20, n=201, 199		-1.17 (0.189)	-0.50 (0.186)
Breathlessness scores, Week 21-24, n=202, 197	Number Analyzed	202 participants	197 participants
Breathlessness scores, Week 21-24, n=202, 197		-1.13 (0.190)	-0.50 (0.188)
Breathlessness scores, Week 25-28, n=194, 186	Number Analyzed	194 participants	186 participants
Breathlessness scores, Week 25-28, n=194, 186		-1.14 (0.195)	-0.38 (0.194)
Breathlessness scores, Week 29-32, n=192, 181	Number Analyzed	192 participants	181 participants
Breathlessness scores, Week 29-32, n=192, 181		-1.11 (0.196)	-0.26 (0.194)
Breathlessness scores, Week 33-36, n=187, 180	Number Analyzed	187 participants	180 participants
Breathlessness scores, Week 33-36, n=187, 180		-1.08 (0.204)	-0.14 (0.203)
Breathlessness scores, Week 37-40, n=185, 177	Number Analyzed	185 participants	177 participants
Breathlessness scores, Week 37-40, n=185, 177		-1.13 (0.203)	-0.37 (0.202)
Breathlessness scores, Week 41-44, n=180, 174	Number Analyzed	180 participants	174 participants
Breathlessness scores, Week 41-44, n=180, 174		-1.06 (0.208)	-0.24 (0.208)
Breathlessness scores, Week 45-48, n=180, 173	Number Analyzed	180 participants	173 participants
Breathlessness scores, Week 45-48, n=180, 173		-0.97 (0.211)	-0.11 (0.211)
Breathlessness scores, Week 49-52, n=179, 171	Number Analyzed	179 participants	171 participants
Breathlessness scores, Week 49-52, n=179, 171		-0.96 (0.207)	-0.08 (0.207)
Cough and sputum scores, Week 1-4, n=205, 213	Number Analyzed	205 participants	213 participants
Cough and sputum scores, Week 1-4, n=205, 213		-0.34 (0.065)	-0.32 (0.064)
Cough and sputum scores, Week 5-8, n=203, 208	Number Analyzed	203 participants	208 participants
Cough and sputum scores, Week 5-8, n=203, 208		-0.59 (0.076)	-0.44 (0.074)
Cough and sputum scores, Week 9-12, n=201, 206	Number Analyzed	201 participants	206 participants
Cough and sputum scores, Week 9-12, n=201, 206		-0.63 (0.083)	-0.52 (0.082)
Cough and sputum scores, Week 13-16, n=201, 204	Number Analyzed	201 participants	204 participants
Cough and sputum scores, Week 13-16, n=201, 204		-0.73 (0.088)	-0.62 (0.087)
Cough and sputum scores, Week 17-20, n=201, 199	Number Analyzed	201 participants	199 participants
Cough and sputum scores, Week 17-20, n=201, 199		-0.83 (0.095)	-0.73 (0.094)
Cough and sputum scores, Week 21-24, n=202, 197	Number Analyzed	202 participants	197 participants
Cough and sputum scores, Week 21-24, n=202, 197		-0.83 (0.098)	-0.71 (0.097)
Cough and sputum scores, Week 25-28, n=194, 186	Number Analyzed	194 participants	186 participants
Cough and sputum scores, Week 25-28, n=194, 186		-0.73 (0.097)	-0.57 (0.097)
Cough and sputum scores, Week 29-32, n=192, 181	Number Analyzed	192 participants	181 participants
Cough and sputum scores, Week 29-32, n=192, 181		-0.68 (0.096)	-0.48 (0.096)
Cough and sputum scores, Week 33-36, n=187, 180	Number Analyzed	187 participants	180 participants
Cough and sputum scores, Week 33-36, n=187, 180		-0.56 (0.099)	-0.40 (0.099)
Cough and sputum scores, Week 37-40, n=185, 177	Number Analyzed	185 participants	177 participants
Cough and sputum scores, Week 37-40, n=185, 177		-0.65 (0.097)	-0.54 (0.097)
Cough and sputum scores, Week 41-44, n=180, 174	Number Analyzed	180 participants	174 participants
Cough and sputum scores, Week 41-44, n=180, 174		-0.66 (0.101)	-0.41 (0.102)
Cough and sputum scores, Week 45-48, n=180, 173	Number Analyzed	180 participants	173 participants
Cough and sputum scores, Week 45-48, n=180, 173		-0.66 (0.098)	-0.39 (0.099)
Cough and sputum scores, Week 49-52, n=179, 171	Number Analyzed	179 participants	171 participants
Cough and sputum scores, Week 49-52, n=179, 171		-0.61 (0.100)	-0.44 (0.100)
Chest scores, Week 1-4, n=205, 213	Number Analyzed	205 participants	213 participants
Chest scores, Week 1-4, n=205, 213		-0.27 (0.069)	-0.09 (0.068)
Chest scores, Week 5-8, n=203, 208	Number Analyzed	203 participants	208 participants
Chest scores, Week 5-8, n=203, 208		-0.46 (0.084)	-0.13 (0.082)
Chest scores, Week 9-12, n=201, 206	Number Analyzed	201 participants	206 participants
Chest scores, Week 9-12, n=201, 206		-0.51 (0.093)	-0.24 (0.092)
Chest scores, Week 13-16, n=201, 204	Number Analyzed	201 participants	204 participants
Chest scores, Week 13-16, n=201, 204		-0.61 (0.097)	-0.31 (0.095)
Chest scores, Week 17-20, n=201, 199	Number Analyzed	201 participants	199 participants
Chest scores, Week 17-20, n=201, 199		-0.67 (0.104)	-0.29 (0.103)
Chest scores, Week 21-24, n=202, 197	Number Analyzed	202 participants	197 participants
Chest scores, Week 21-24, n=202, 197		-0.68 (0.102)	-0.30 (0.101)
Chest scores, Week 25-28, n=194, 186	Number Analyzed	194 participants	186 participants
Chest scores, Week 25-28, n=194, 186		-0.63 (0.105)	-0.21 (0.104)
Chest scores, Week 29-32, n=192, 181	Number Analyzed	192 participants	181 participants
Chest scores, Week 29-32, n=192, 181		-0.55 (0.107)	-0.16 (0.107)
Chest scores, Week 33-36, n=187, 180	Number Analyzed	187 participants	180 participants
Chest scores, Week 33-36, n=187, 180		-0.48 (0.111)	-0.08 (0.111)
Chest scores, Week 37-40, n=185, 177	Number Analyzed	185 participants	177 participants
Chest scores, Week 37-40, n=185, 177		-0.57 (0.107)	-0.20 (0.107)
Chest scores, Week 41-44, n=180, 174	Number Analyzed	180 participants	174 participants
Chest scores, Week 41-44, n=180, 174		-0.58 (0.108)	-0.16 (0.108)
Chest scores, Week 45-48, n=180, 173	Number Analyzed	180 participants	173 participants
Chest scores, Week 45-48, n=180, 173		-0.57 (0.113)	-0.13 (0.113)
Chest scores, Week 49-52, n=179, 171	Number Analyzed	179 participants	171 participants
Chest scores, Week 49-52, n=179, 171		-0.49 (0.115)	-0.08 (0.115)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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
Description	An AE was any untoward medical occurrence in a participant or clinical...
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

Outcome Measure Data

Analysis Population Description

ITT Population


Arm/Group Title	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Arm/Group Description:	Participants received FF/UMEC/VI 10...	Participants received BUD/FOR 400/1...
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
Description	An AE was any untoward medical occurrence in a participant or clinical...
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

Outcome Measure Data

Analysis Population Description

Extension Population


Arm/Group Title	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Arm/Group Description:	Participants received FF/UMEC/VI 10...	Participants received BUD/FOR 400/1...
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
Description	All suspected pneumonias required confirmation as defined by the prese...
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

Outcome Measure Data

Analysis Population Description

ITT Population.


Arm/Group Title	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Arm/Group Description:	Participants received FF/UMEC/VI 10...	Participants received BUD/FOR 400/1...
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
Description	All suspected pneumonias required confirmation as defined by the prese...
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

Outcome Measure Data

Analysis Population Description

Extension Population


Arm/Group Title	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Arm/Group Description:	Participants received FF/UMEC/VI 10...	Participants received BUD/FOR 400/1...
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
Description	Cardiovascular safety was monitored via AE reporting with categorizati...
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

Outcome Measure Data

Analysis Population Description

ITT Population


Arm/Group Title	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Arm/Group Description:	Participants received FF/UMEC/VI 10...	Participants received BUD/FOR 400/1...
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
Description	Cardiovascular safety was monitored via AE reporting with categorizati...
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

Outcome Measure Data

Analysis Population Description

Extension Population


Arm/Group Title	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Arm/Group Description:	Participants received FF/UMEC/VI 10...	Participants received BUD/FOR 400/1...
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
Description	A single 12-lead electrocardiogram (ECG) and rhythm strip were recorde...
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

Outcome Measure Data

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
Arm/Group Description:	Participants received FF/UMEC/VI 10...	Participants received BUD/FOR 400/1...
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
Description	A single 12-lead ECG and rhythm strip were recorded after measurement ...
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

Outcome Measure Data

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
Arm/Group Description:	Participants received FF/UMEC/VI 10...	Participants received BUD/FOR 400/1...
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
Description	A single 12-lead ECG and rhythm strip were recorded after measurement ...
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

Outcome Measure Data

Analysis Population Description

ITT population


Arm/Group Title		FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Arm/Group Description:		Participants received FF/UMEC/VI 10...	Participants received BUD/FOR 400/1...
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
QTcF, n=840,787		2.5 (0.56)	0.6 (0.58)
PR, n=812,766	Number Analyzed	812 participants	766 participants
PR, n=812,766		-0.1 (0.54)	0.5 (0.56)

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

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
Description	Single 12-lead ECG and rhythm strip were recorded after measurement of...
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

Outcome Measure Data

Analysis Population Description

Extension Population


Arm/Group Title		FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Arm/Group Description:		Participants received FF/UMEC/VI 10...	Participants received BUD/FOR 400/1...
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
QTcF, n=181,169		1.4 (1.27)	2.4 (1.31)
PR, n=174,160	Number Analyzed	174 participants	160 participants
PR, n=174,160		1.6 (1.09)	1.4 (1.13)

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

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
Description	A single 12-lead ECG and rhythm strip were recorded after measurement ...
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

Outcome Measure Data

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
Arm/Group Description:	Participants received FF/UMEC/VI 10...	Participants received BUD/FOR 400/1...
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
Description	A single 12-lead ECG and rhythm strip were recorded after measurement ...
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

Outcome Measure Data

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
Arm/Group Description:	Participants received FF/UMEC/VI 10...	Participants received BUD/FOR 400/1...
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
Description	Vital signs were obtained at the Screening Visit and prior to taking t...
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

Outcome Measure Data

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
Arm/Group Description:	Participants received FF/UMEC/VI 10...	Participants received BUD/FOR 400/1...
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)

Statistical Analysis 1

Method of Estimation
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	0.849
	Comments	[Not Specified]
	Method	Mixed Model Repeated Measures
	Comments	[Not Specified]