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Clinical Trial Results:
Phase III, 24 week, randomized, double blind, double dummy, parallel group study (with an extension to 52 weeks in a subset of subjects) comparing the efficacy, safety and tolerability of the fixed dose triple combination FF/UMEC/VI administered once daily in the morning via a dry powder inhaler with budesonide/formoterol 400mcg/12mcg administered twice-daily via a reservoir inhaler in subjects with chronic obstructive pulmonary disease.

Summary
EudraCT number	2013-003073-10
Trial protocol	IT SK GR DE CZ PL BG EE HU
Global end of trial date	07 Apr 2016

Results information
Results version number	v2(current)
This version publication date	12 Jul 2018
First version publication date	21 Dec 2016
Other versions	v1
Version creation reason

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

116853

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

GlaxoSmithKline

Sponsor organisation address

980 Great West Road, Brentford, Middlesex, United Kingdom,

Public contact

GSK Response Center, GlaxoSmithKline, 1 866-435-7343,

Scientific contact

GSK Response Center, GlaxoSmithKline, 1 866-435-7343,

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

07 Apr 2016

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

07 Apr 2016

Was the trial ended prematurely?

Main objective of the trial

To evaluate the effects of FF/UMEC/VI on lung function and health related quality of life compared with budesonide/formoterol after 24 weeks of treatment

Protection of trial subjects

N/A

Background therapy

Evidence for comparator

Actual start date of recruitment

23 Jan 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Bulgaria: 134

Country: Number of subjects enrolled

China: 70

Country: Number of subjects enrolled

Czech Republic: 109

Country: Number of subjects enrolled

Germany: 278

Country: Number of subjects enrolled

Greece: 115

Country: Number of subjects enrolled

Hungary: 117

Country: Number of subjects enrolled

Italy: 89

Country: Number of subjects enrolled

Korea, Republic of: 63

Country: Number of subjects enrolled

Mexico: 245

Country: Number of subjects enrolled

Estonia: 147

Country: Number of subjects enrolled

Russian Federation: 227

Country: Number of subjects enrolled

Romania: 112

Country: Number of subjects enrolled

Ukraine: 240

Country: Number of subjects enrolled

Slovakia: 46

Country: Number of subjects enrolled

Poland: 129

Worldwide total number of subjects

2121

EEA total number of subjects

1276

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

1033

From 65 to 84 years

1076

85 years and over

Subject disposition

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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.

Screening 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.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Subject

Are arms mutually exclusive

Yes

FF/UMEC/VI 100/62.5/25 µg

Arm 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.

Arm type

Experimental

Investigational medicinal product name

FF/UMEC/VI

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder

Routes of administration

Inhalation use

Dosage and administration details

The combination was provided as inhalation via an ELLIPTA DPI having 30 doses (2 strips with 30 blisters per strip). It consisted of 100 µg of FF (blended with lactose) per blister, 62.5 µg of UMEC (blended with lactose and magnesium stearate) per blister and 25 µg of VI (blended with lactose) per blister; administered once daily in the morning

Investigational medicinal product name

Placebo to match FF/UMEC/VI

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder

Routes of administration

Inhalation use

Dosage and administration details

The placebo (Lactose) was provided as inhalation via an ELLIPTA DPI having 30 doses (2 strips with 30 blisters per strip); administered twice daily

BUD/FOR 400/12 µg

Arm description

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.

Arm type

Experimental

Investigational medicinal product name

BUD/FOR

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder

Routes of administration

Inhalation use

Dosage and administration details

The combination (400 µg Budesonide/12 µg Formoterol) was provided as inhalation via TURBOHALER with 60 doses; administered once daily in the morning

Investigational medicinal product name

Placebo to match BUD/FOR

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder

Routes of administration

Inhalation use

Dosage and administration details

The placebo (Lactose) was provided as inhalation via TURBOHALER with 60 doses; administered twice daily

Number of subjects in period 1 ^[1]	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Started	911	899
Completed	866	842
Not completed	45	57
Consent withdrawn by subject	25	33
Physician decision	4	4
Adverse event, non-fatal	16	19
Lost to follow-up	-	1

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: 1811 were randomized following 2 week run-in. Of those, 1 subject was randomized in error and did not receive randomized treatment.

Baseline characteristics

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Reporting group title

FF/UMEC/VI 100/62.5/25 µg

Reporting group description

Reporting group title

BUD/FOR 400/12 µg

Reporting group description

Reporting group values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg	Total
Number of subjects	911	899
Age categorical
Units: Subjects
Age continuous
Age continuous description
Units: years
arithmetic mean (standard deviation)	64.2 ( 8.56 )	63.7 ( 8.71 )	-
Gender categorical
Gender categorical description
Units: Subjects
Female	233	236	469
Male	678	663	1341
Race/Ethnicity, Customized
Units: Subjects
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

End points

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Reporting group title

FF/UMEC/VI 100/62.5/25 µg

Reporting group description

Reporting group title

BUD/FOR 400/12 µg

Reporting group description

Primary: Change from Baseline in trough forced expiratory volume in one second (FEV1) at Week 24

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End point title

Change from Baseline in trough forced expiratory volume in one second (FEV1) at Week 24

End point 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. Only participants with analyzable data at the given time point were analyzed.

End point type

Primary

End point timeframe

Baseline to Week 24

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	836 ^[1]	781
Units: Liters (L)
least squares mean (standard error)	0.142 ( 0.0083 )	-0.029 ( 0.0085 )

Notes
[1] - ITT Population comprised of all randomized subjects excluding those who were randomized in error.

Statistical analysis 1

Comparison groups

BUD/FOR 400/12 µg v FF/UMEC/VI 100/62.5/25 µg

Number of subjects included in analysis

1617

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed Model Repeated Measures

Parameter type

Adjusted LS mean difference

Point estimate

0.171

Confidence interval

level

95%

sides

2-sided

lower limit

0.148

upper limit

0.194

Variability estimate

Standard error of the mean

Dispersion value

0.0118

Primary: Change from Baseline in trough forced expiratory volume in one second (FEV1) at Week 52

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End point title

Change from Baseline in trough forced expiratory volume in one second (FEV1) at Week 52

End point 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. Only participants with analyzable data at the given time point were analyzed.

End point type

Primary

End point timeframe

Baseline to Week 52

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	183 ^[2]	171
Units: Liters (L)
least squares mean (standard error)	0.126 ( 0.0170 )	-0.053 ( 0.0172 )

Notes
[2] - Extension Population

Statistical analysis 1

Comparison groups

BUD/FOR 400/12 µg v FF/UMEC/VI 100/62.5/25 µg

Number of subjects included in analysis

354

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed Model Repeated Measures

Parameter type

Adjusted LS mean difference

Point estimate

0.179

Confidence interval

level

95%

sides

2-sided

lower limit

0.131

upper limit

0.226

Variability estimate

Standard error of the mean

Dispersion value

0.0242

Primary: Change from Baseline in St George's Respiratory Questionnaire-Chronic Obstructive Pulmonary Disease (COPD; SGRQ) Total Score for COPD participants at Week 24

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End point title

Change from Baseline in St George's Respiratory Questionnaire-Chronic Obstructive Pulmonary Disease (COPD; SGRQ) Total Score for COPD participants at Week 24

End point 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). In addition to an overall summary (total) score, scores for the individual domains of Symptoms, Activity, and Impacts 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. SGRQ-C total score was converted to SGRQ total score according to manual. 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

End point type

Primary

End point timeframe

Baseline to Week 24

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	846 ^[3]	791
Units: Score on a scale
least squares mean (standard error)	-6.6 ( 0.45 )	-4.3 ( 0.46 )

Notes
[3] - ITT Population; Only participants with analyzable data at the given time point were analyzed.

Statistical analysis 1

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

1637

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed Model Repeated Measures

Parameter type

Adjusted LS mean difference

Point estimate

-2.2

Confidence interval

level

95%

sides

2-sided

lower limit

-3.5

upper limit

-1

Variability estimate

Standard error of the mean

Dispersion value

0.64

Primary: Change from Baseline in St George's Respiratory Questionnaire-COPD; SGRQ Total Score for COPD participants at Week 52

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End point title

Change from Baseline in St George's Respiratory Questionnaire-COPD; SGRQ Total Score for COPD participants at Week 52

End point 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). In addition to an overall summary (total) score, scores for the individual domains of Symptoms, Activity, and Impacts 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. SGRQ-C’ total score was converted to SGRQ total score according to manual’.The analysis for SGRQ total score was performed using a MMRM method including covariates of treatment group, smoking status (score).

End point type

Primary

End point timeframe

Baseline to Week 52

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	182 ^[4]	174
Units: Scores on a scale
least squares mean (standard error)	-4.6 ( 1.01 )	-1.9 ( 1.03 )

Notes
[4] - Extension Population; Only participants with analyzable data at the given time point were analyzed.

Statistical analysis 1

Comparison groups

BUD/FOR 400/12 µg v FF/UMEC/VI 100/62.5/25 µg

Number of subjects included in analysis

356

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.065

Method

Mixed Model Repeated Measures

Parameter type

Adjusted LS mean difference

Point estimate

-2.7

Confidence interval

level

95%

sides

2-sided

lower limit

-5.5

upper limit

0.2

Variability estimate

Standard error of the mean

Dispersion value

1.44

Secondary: Transitional Dyspnea Index (TDI) focal score expressed as least square mean at Week 24

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End point title

Transitional Dyspnea Index (TDI) focal score expressed as least square mean at Week 24

End point 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. Only participants with analyzable data at the given time point were analyzed.

End point type

Secondary

End point timeframe

Week 24

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	839 ^[5]	788
Units: Scores on a scale
least squares mean (standard error)	2.29 ( 0.096 )	1.72 ( 0.099 )

Notes
[5] - ITT Population

Statistical analysis 1

Comparison groups

BUD/FOR 400/12 µg v FF/UMEC/VI 100/62.5/25 µg

Number of subjects included in analysis

1627

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed effect repeated measures model

Parameter type

LS Mean difference

Point estimate

0.57

Confidence interval

level

95%

sides

2-sided

lower limit

0.3

upper limit

0.84

Variability estimate

Standard error of the mean

Dispersion value

0.138

Secondary: Transitional Dyspnea Index (TDI) focal score expressed as least square mean at Week 52

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End point title

Transitional Dyspnea Index (TDI) focal score expressed as least square mean at Week 52

End point 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. Only participants with analyzable data at the given time point were analyzed.

End point type

Secondary

End point timeframe

Week 52

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	182 ^[6]	174
Units: Scores on a scale
least squares mean (standard error)	1.74 ( 0.221 )	1.39 ( 0.226 )

Notes
[6] - Extension Population

Statistical analysis 1

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

356

Analysis specification

Pre-specified

Analysis type

P-value

= 0.279

Method

Mixed effect repeated measures model

Parameter type

LS Mean difference

Point estimate

0.34

Confidence interval

level

95%

sides

2-sided

lower limit

-0.28

upper limit

0.97

Variability estimate

Standard error of the mean

Dispersion value

0.317

Secondary: Daily activity question percentage of days reporting a score of 2 up to Week 24

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End point title

Daily activity question percentage of days reporting a score of 2 up to Week 24

End point 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. Only participants with analyzable data at the given time point were analyzed.

End point type

Secondary

End point timeframe

Up to Week 24

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	909 ^[7]	894
Units: Percentage
least squares mean (standard error)	0.0 ( 0.38 )	-0.1 ( 0.39 )

Notes
[7] - ITT Population

Statistical analysis 1

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

1803

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.817

Method

ANCOVA

Parameter type

LS Mean difference

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.9

upper limit

1.1

Variability estimate

Standard error of the mean

Dispersion value

0.51

Secondary: Daily activity question percentage of days reporting a score of 2 up to Week 52

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End point title

Daily activity question percentage of days reporting a score of 2 up to Week 52

End point 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. Only participants with analyzable data at the given time point were analyzed.

End point type

Secondary

End point timeframe

Up to Week 52

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	210 ^[8]	219
Units: Percentage
least squares mean (standard error)	0.0 ( 0.70 )	0.3 ( 0.69 )

Notes
[8] - Extension Population

Statistical analysis 1

Comparison groups

BUD/FOR 400/12 µg v FF/UMEC/VI 100/62.5/25 µg

Number of subjects included in analysis

429

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.767

Method

ANCOVA

Parameter type

LS Mean difference

Point estimate

-0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-2.1

upper limit

1.6

Variability estimate

Standard error of the mean

Dispersion value

0.95

Secondary: Mean annual on-treatment moderate and/or severe COPD exacerbations up to Week 24

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End point title

Mean annual on-treatment moderate and/or severe COPD exacerbations up to Week 24

End point 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). 99999 indicates that data were not available.

End point type

Secondary

End point timeframe

Up to Week 24

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	907 ^[9]	892
Units: Exacerbations per participant per year
arithmetic mean (standard deviation)	0.22 ( 99999 )	0.34 ( 99999 )

Notes
[9] - ITT population; Only participants with analyzable data at the given time point were analyzed.

Statistical analysis 1

Statistical analysis description

Percentage reduction in annual exacerbation rate (95%CI): 35% (14%, 51%)

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

1799

Analysis specification

Pre-specified

Analysis type

superiority ^[10]

P-value

= 0.002

Method

Generalized linear modeL

Parameter type

Rate ratio

Point estimate

0.65

Confidence interval

level

95%

sides

2-sided

lower limit

0.49

upper limit

0.86

Notes
[10] - Generalized linear model assuming a negative binomial distribution

Secondary: Mean annual on-treatment moderate and/or severe COPD exacerbations up to Week 52

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End point title

Mean annual on-treatment moderate and/or severe COPD exacerbations up to Week 52

End point description

End point type

Secondary

End point timeframe

Up to Week 52

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	210 ^[11]	219
Units: Exacerbations per participant per year
arithmetic mean (standard deviation)	0.20 ( 99999 )	0.36 ( 99999 )

Notes
[11] - Extension Population; Only participants with analyzable data at the given time point were analyzed.

Statistical analysis 1

Statistical analysis description

Percentage reduction in annual exacerbation rate (95%CI): 44% (15%, 63%)

Comparison groups

BUD/FOR 400/12 µg v FF/UMEC/VI 100/62.5/25 µg

Number of subjects included in analysis

429

Analysis specification

Pre-specified

Analysis type

superiority ^[12]

P-value

= 0.006

Method

Generalized Linear model

Parameter type

Rate ratio

Point estimate

0.56

Confidence interval

level

95%

sides

2-sided

lower limit

0.37

upper limit

0.85

Notes
[12] - Generalized linear model assuming a negative binomial distribution

Secondary: Assessment of respiratory symptoms by 4-weekly mean Exacerbations of Chronic Pulmonary Disease Tool (EXACT)-RS scores up to Week 24

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End point title

Assessment of respiratory symptoms by 4-weekly mean Exacerbations of Chronic Pulmonary Disease Tool (EXACT)-RS scores up to Week 24

End point description

The EXACT-PRO is a 14 item participant reported outcome instrument designed to capture information on the occurrence, frequency, severity, and duration of exacerbations of disease in participants with COPD. The total score for EXACT-PRO ranges from 0-100. EXACT-RS consists of 11 items from the 14 item EXACT-PRO instrument. The EXACT-RS has a scoring range of 0-40. Three subscales of the EXACT-RS are used to describe different symptoms; dyspnoea, cough and sputum and chest symptoms. A clinically meaningful improvement in EXACT-RS score was defined as a decrease in the 4-weekly mean score of >=2 units from Baseline. 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).

End point type

Secondary

End point timeframe

Up to Week 24

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	911 ^[13]	899
Units: Scores on a scale
least squares mean (standard error)
Week 1-4, n=870,859	-1.45 ( 0.106 )	-0.50 ( 0.106 )
Week 5-8, n=851,830	-2.00 ( 0.129 )	-0.77 ( 0.130 )
Week 9-12, n=841,813	-2.23 ( 0.141 )	-1.05 ( 0.143 )
Week 13-16, n=831,802	-2.42 ( 0.150 )	-1.09 ( 0.151 )
Week 17-20, n=828,788	-2.43 ( 0.156 )	-1.02 ( 0.159 )
Week 21-24, n=825,783	-2.31 ( 0.157 )	-0.96 ( 0.160 )
Breathlessness score, Week 1-4, n=870,859	-0.71 ( 0.057 )	-0.20 ( 0.057 )
Breathlessness score, Week 5-8, n=851,830	-0.95 ( 0.069 )	-0.26 ( 0.070 )
Breathlessness score, Week 9-12, n=841,813	-1.03 ( 0.076 )	-0.34 ( 0.076 )
Breathlessness score, Week 13-16, n=831, 802	-1.11 ( 0.080 )	-0.36 ( 0.081 )
Breathlessness score, Week 17-20, n=828,788	-1.10 ( 0.084 )	-0.31 ( 0.085 )
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	-0.41 ( 0.031 )	-0.24 ( 0.031 )
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	-0.67 ( 0.041 )	-0.50 ( 0.041 )
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	-0.77 ( 0.045 )	-0.53 ( 0.045 )
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	-0.33 ( 0.034 )	-0.06 ( 0.035 )
Chest score, Week 5-8, n=851,830	-0.46 ( 0.042 )	-0.12 ( 0.043 )
Chest score, Week 9-12, n=841,813	-0.54 ( 0.046 )	-0.20 ( 0.047 )
Chest score, Week 13-16, n=831,802	-0.58 ( 0.048 )	-0.20 ( 0.048 )
Chest score, Week 17-20, n=828,788	-0.57 ( 0.050 )	-0.17 ( 0.050 )
Chest score, Week 21-24, n=825,783	-0.53 ( 0.050 )	-0.17 ( 0.051 )

Notes
[13] - ITT Population

Statistical analysis 1

Statistical analysis description

Scores, Week 1-4

Comparison groups

BUD/FOR 400/12 µg v FF/UMEC/VI 100/62.5/25 µg

Number of subjects included in analysis

1810

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.95

Confidence interval

level

95%

sides

2-sided

lower limit

-1.25

upper limit

-0.66

Variability estimate

Standard error of the mean

Dispersion value

0.15

Statistical analysis 2

Statistical analysis description

Scores, Week 5-8

Comparison groups

BUD/FOR 400/12 µg v FF/UMEC/VI 100/62.5/25 µg

Number of subjects included in analysis

1810

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-1.23

Confidence interval

level

95%

sides

2-sided

lower limit

-1.59

upper limit

-0.87

Variability estimate

Standard error of the mean

Dispersion value

0.183

Statistical analysis 3

Statistical analysis description

Scores, Week 9-12

Comparison groups

BUD/FOR 400/12 µg v FF/UMEC/VI 100/62.5/25 µg

Number of subjects included in analysis

1810

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-1.18

Confidence interval

level

95%

sides

2-sided

lower limit

-1.57

upper limit

-0.78

Variability estimate

Standard error of the mean

Dispersion value

0.201

Statistical analysis 4

Statistical analysis description

Scores, Week 13-16

Comparison groups

BUD/FOR 400/12 µg v FF/UMEC/VI 100/62.5/25 µg

Number of subjects included in analysis

1810

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-1.33

Confidence interval

level

95%

sides

2-sided

lower limit

-1.75

upper limit

-0.91

Variability estimate

Standard error of the mean

Dispersion value

0.213

Statistical analysis 5

Statistical analysis description

Scores, Week 17-20

Comparison groups

BUD/FOR 400/12 µg v FF/UMEC/VI 100/62.5/25 µg

Number of subjects included in analysis

1810

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-1.41

Confidence interval

level

95%

sides

2-sided

lower limit

-1.85

upper limit

-0.97

Variability estimate

Standard error of the mean

Dispersion value

0.223

Statistical analysis 6

Statistical analysis description

Scores, Week 21-24

Comparison groups

BUD/FOR 400/12 µg v FF/UMEC/VI 100/62.5/25 µg

Number of subjects included in analysis

1810

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed Model Repeated Measures

Parameter type

Mixed Model Repeated Measures

Point estimate

-1.35

Confidence interval

level

95%

sides

2-sided

lower limit

-1.79

upper limit

-0.91

Variability estimate

Standard error of the mean

Dispersion value

0.224

Statistical analysis 7

Statistical analysis description

Breathlessness score, Week 1-4

Comparison groups

BUD/FOR 400/12 µg v FF/UMEC/VI 100/62.5/25 µg

Number of subjects included in analysis

1810

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.52

Confidence interval

level

95%

sides

2-sided

lower limit

-0.67

upper limit

-0.36

Variability estimate

Standard error of the mean

Dispersion value

0.08

Statistical analysis 8

Statistical analysis description

Breathlessness score, Week 5-8

Comparison groups

BUD/FOR 400/12 µg v FF/UMEC/VI 100/62.5/25 µg

Number of subjects included in analysis

1810

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.69

Confidence interval

level

95%

sides

2-sided

lower limit

-0.88

upper limit

-0.5

Variability estimate

Standard error of the mean

Dispersion value

0.098

Statistical analysis 9

Statistical analysis description

Breathlessness score, Week 9-12

Comparison groups

BUD/FOR 400/12 µg v FF/UMEC/VI 100/62.5/25 µg

Number of subjects included in analysis

1810

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.69

Confidence interval

level

95%

sides

2-sided

lower limit

-0.9

upper limit

-0.48

Variability estimate

Standard error of the mean

Dispersion value

0.108

Statistical analysis 10

Statistical analysis description

Breathlessness score, Week 13-16

Comparison groups

BUD/FOR 400/12 µg v FF/UMEC/VI 100/62.5/25 µg

Number of subjects included in analysis

1810

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.75

Confidence interval

level

95%

sides

2-sided

lower limit

-0.97

upper limit

-0.52

Variability estimate

Standard error of the mean

Dispersion value

0.115

Statistical analysis 11

Statistical analysis description

Breathlessness score, Week 17-20

Comparison groups

BUD/FOR 400/12 µg v FF/UMEC/VI 100/62.5/25 µg

Number of subjects included in analysis

1810

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.79

Confidence interval

level

95%

sides

2-sided

lower limit

-1.03

upper limit

-0.56

Variability estimate

Standard error of the mean

Dispersion value

0.12

Statistical analysis 12

Statistical analysis description

Breathlessness score, Week 21-24

Comparison groups

BUD/FOR 400/12 µg v FF/UMEC/VI 100/62.5/25 µg

Number of subjects included in analysis

1810

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.77

Confidence interval

level

95%

sides

2-sided

lower limit

-1.01

upper limit

-0.54

Variability estimate

Standard error of the mean

Dispersion value

0.122

Statistical analysis 13

Statistical analysis description

Cough and sputum score, Week 1-4

Comparison groups

BUD/FOR 400/12 µg v FF/UMEC/VI 100/62.5/25 µg

Number of subjects included in analysis

1810

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.17

Confidence interval

level

95%

sides

2-sided

lower limit

-0.26

upper limit

-0.09

Variability estimate

Standard error of the mean

Dispersion value

0.044

Statistical analysis 14

Statistical analysis description

Cough and sputum score, Week 5-8

Comparison groups

BUD/FOR 400/12 µg v FF/UMEC/VI 100/62.5/25 µg

Number of subjects included in analysis

1810

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.31

upper limit

-0.1

Variability estimate

Standard error of the mean

Dispersion value

0.053

Statistical analysis 15

Statistical analysis description

Cough and sputum score, Week 9-12

Comparison groups

BUD/FOR 400/12 µg v FF/UMEC/VI 100/62.5/25 µg

Number of subjects included in analysis

1810

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.004

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.17

Confidence interval

level

95%

sides

2-sided

lower limit

-0.28

upper limit

-0.05

Variability estimate

Standard error of the mean

Dispersion value

0.058

Statistical analysis 16

Statistical analysis description

Cough and sputum score, Week 13-16

Comparison groups

BUD/FOR 400/12 µg v FF/UMEC/VI 100/62.5/25 µg

Number of subjects included in analysis

1810

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.22

Confidence interval

level

95%

sides

2-sided

lower limit

-0.34

upper limit

-0.1

Variability estimate

Standard error of the mean

Dispersion value

0.061

Statistical analysis 17

Statistical analysis description

Cough and sputum score, Week 17-20

Comparison groups

BUD/FOR 400/12 µg v FF/UMEC/VI 100/62.5/25 µg

Number of subjects included in analysis

1810

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.24

Confidence interval

level

95%

sides

2-sided

lower limit

-0.36

upper limit

-0.11

Variability estimate

Standard error of the mean

Dispersion value

0.064

Statistical analysis 18

Statistical analysis description

Cough and sputum score, Week 21-24

Comparison groups

BUD/FOR 400/12 µg v FF/UMEC/VI 100/62.5/25 µg

Number of subjects included in analysis

1810

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.23

Confidence interval

level

95%

sides

2-sided

lower limit

-0.35

upper limit

-0.1

Variability estimate

Standard error of the mean

Dispersion value

0.065

Statistical analysis 19

Statistical analysis description

Chest scores, Week 1-4

Comparison groups

BUD/FOR 400/12 µg v FF/UMEC/VI 100/62.5/25 µg

Number of subjects included in analysis

1810

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.27

Confidence interval

level

95%

sides

2-sided

lower limit

-0.37

upper limit

-0.18

Variability estimate

Standard error of the mean

Dispersion value

0.049

Statistical analysis 20

Statistical analysis description

Chest scores, Week 5-8

Comparison groups

BUD/FOR 400/12 µg v FF/UMEC/VI 100/62.5/25 µg

Number of subjects included in analysis

1810

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.34

Confidence interval

level

95%

sides

2-sided

lower limit

-0.46

upper limit

-0.23

Variability estimate

Standard error of the mean

Dispersion value

0.06

Statistical analysis 21

Statistical analysis description

Chest scores, Week 9-12

Comparison groups

BUD/FOR 400/12 µg v FF/UMEC/VI 100/62.5/25 µg

Number of subjects included in analysis

1810

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.34

Confidence interval

level

95%

sides

2-sided

lower limit

-0.47

upper limit

-0.21

Variability estimate

Standard error of the mean

Dispersion value

0.066

Statistical analysis 22

Statistical analysis description

Chest scores, Week 13-16

Comparison groups

BUD/FOR 400/12 µg v FF/UMEC/VI 100/62.5/25 µg

Number of subjects included in analysis

1810

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.38

Confidence interval

level

95%

sides

2-sided

lower limit

-0.51

upper limit

-0.25

Variability estimate

Standard error of the mean

Dispersion value

0.068

Statistical analysis 23

Statistical analysis description

Chest scores, Week 17-20

Comparison groups

BUD/FOR 400/12 µg v FF/UMEC/VI 100/62.5/25 µg

Number of subjects included in analysis

1810

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-0.53

upper limit

-0.26

Variability estimate

Standard error of the mean

Dispersion value

0.071

Statistical analysis 24

Statistical analysis description

Chest scores, Week 21-24

Comparison groups

BUD/FOR 400/12 µg v FF/UMEC/VI 100/62.5/25 µg

Number of subjects included in analysis

1810

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.36

Confidence interval

level

95%

sides

2-sided

lower limit

-0.5

upper limit

-0.22

Variability estimate

Standard error of the mean

Dispersion value

0.072

Secondary: Assessment of respiratory symptoms by 4-weekly mean EXACT-RS scores up to Week 52

Top of page

End point title

Assessment of respiratory symptoms by 4-weekly mean EXACT-RS scores up to Week 52

End point description

End point type

Secondary

End point timeframe

Up to Week 52

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	210 ^[14]	220
Units: Scores on a scale
least squares mean (standard error)
Week 1-4, n=205, 213	-1.24 ( 0.222 )	-0.72 ( 0.218 )
Week 5-8, n=203, 208	-1.97 ( 0.265 )	-0.90 ( 0.260 )
Week 9-12, n=201, 206	-2.18 ( 0.298 )	-1.21 ( 0.294 )
Week 13-16, n=201, 204	-2.53 ( 0.317 )	-1.52 ( 0.313 )
Week 17-20, n=201, 199	-2.64 ( 0.342 )	-1.53 ( 0.338 )
Week 21-24, n=202, 197	-2.63 ( 0.341 )	-1.52 ( 0.338 )
Week 25-28, n=194, 186	-2.48 ( 0.349 )	-1.16 ( 0.347 )
Week 29-32, n=192, 181	-2.33 ( 0.350 )	-0.90 ( 0.349 )
Week 33-36, n=187, 180	-2.12 ( 0.367 )	-0.62 ( 0.366 )
Week 37-40, n=185, 177	-2.34 ( 0.359 )	-1.11 ( 0.358 )
Week 41-44, n=180, 174	-2.30 ( 0.363 )	-0.81 ( 0.362 )
Week 45-48, n=180, 173	-2.17 ( 0.371 )	-0.64 ( 0.371 )
Week 49-52, n=179, 171	-2.03 ( 0.370 )	-0.61 ( 0.370 )
Breathlessness scores, Week 1-4, n=205, 213	-0.64 ( 0.120 )	-0.31 ( 0.118 )
Breathlessness scores, Week 5-8, n=203, 208	-0.93 ( 0.147 )	-0.32 ( 0.145 )
Breathlessness scores, Week 9-12, n=201, 206	-1.05 ( 0.167 )	-0.44 ( 0.164 )
Breathlessness scores, Week 13-16, n=201, 204	-1.19 ( 0.175 )	-0.57 ( 0.173 )
Breathlessness scores, Week 17-20, n=201, 199	-1.17 ( 0.189 )	-0.50 ( 0.186 )
Breathlessness scores, Week 21-24, n=202, 197	-1.13 ( 0.190 )	-0.50 ( 0.188 )
Breathlessness scores, Week 25-28, n=194, 186	-1.14 ( 0.195 )	-0.38 ( 0.194 )
Breathlessness scores, Week 29-32, n=192, 181	-1.11 ( 0.196 )	-0.26 ( 0.194 )
Breathlessness scores, Week 33-36, n=187, 180	-1.08 ( 0.204 )	-0.14 ( 0.203 )
Breathlessness scores, Week 37-40, n=185, 177	-1.13 ( 0.203 )	-0.37 ( 0.202 )
Breathlessness scores, Week 41-44, n=180, 174	-1.06 ( 0.208 )	-0.24 ( 0.208 )
Breathlessness scores, Week 45-48, n=180, 173	-0.97 ( 0.211 )	-0.11 ( 0.211 )
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	-0.34 ( 0.065 )	-0.32 ( 0.064 )
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	-0.63 ( 0.083 )	-0.52 ( 0.082 )
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	-0.83 ( 0.095 )	-0.73 ( 0.094 )
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	-0.73 ( 0.097 )	-0.57 ( 0.097 )
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	-0.56 ( 0.099 )	-0.40 ( 0.099 )
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	-0.66 ( 0.101 )	-0.41 ( 0.102 )
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	-0.61 ( 0.100 )	-0.44 ( 0.100 )
Chest scores, Week 1-4, n=205, 213	-0.27 ( 0.069 )	-0.09 ( 0.068 )
Chest scores, Week 5-8, n=203, 208	-0.46 ( 0.084 )	-0.13 ( 0.082 )
Chest scores, Week 9-12, n=201, 206	-0.51 ( 0.093 )	-0.24 ( 0.092 )
Chest scores, Week 13-16, n=201, 204	-0.61 ( 0.097 )	-0.31 ( 0.095 )
Chest scores, Week 17-20, n=201, 199	-0.67 ( 0.104 )	-0.29 ( 0.103 )
Chest scores, Week 21-24, n=202, 197	-0.68 ( 0.102 )	-0.30 ( 0.101 )
Chest scores, Week 25-28, n=194, 186	-0.63 ( 0.105 )	-0.21 ( 0.104 )
Chest scores, Week 29-32, n=192, 181	-0.55 ( 0.107 )	-0.16 ( 0.107 )
Chest scores, Week 33-36, n=187, 180	-0.48 ( 0.111 )	-0.08 ( 0.111 )
Chest scores, Week 37-40, n=185, 177	-0.57 ( 0.107 )	-0.20 ( 0.107 )
Chest scores, Week 41-44, n=180, 174	-0.58 ( 0.108 )	-0.16 ( 0.108 )
Chest scores, Week 45-48, n=180, 173	-0.57 ( 0.113 )	-0.13 ( 0.113 )
Chest scores, Week 49-52, n=179, 171	-0.49 ( 0.115 )	-0.08 ( 0.115 )

Notes
[14] - Extension Population

Statistical analysis 1

Statistical analysis description

Scores, Week 1-4

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.094

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.52

Confidence interval

level

95%

sides

2-sided

lower limit

-1.13

upper limit

0.09

Variability estimate

Standard error of the mean

Dispersion value

0.311

Statistical analysis 2

Statistical analysis description

Scores, Week 5-8

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.004

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-1.07

Confidence interval

level

95%

sides

2-sided

lower limit

-1.8

upper limit

-0.34

Variability estimate

Standard error of the mean

Dispersion value

0.371

Statistical analysis 3

Statistical analysis description

Scores, Week 9-12

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.022

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.97

Confidence interval

level

95%

sides

2-sided

lower limit

-1.79

upper limit

-0.14

Variability estimate

Standard error of the mean

Dispersion value

0.419

Statistical analysis 4

Statistical analysis description

Scores, Week 13-16

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.024

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-1.01

Confidence interval

level

95%

sides

2-sided

lower limit

-1.88

upper limit

-0.13

Variability estimate

Standard error of the mean

Dispersion value

0.445

Statistical analysis 5

Statistical analysis description

Scores, Week 17-20

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.021

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-1.11

Confidence interval

level

95%

sides

2-sided

lower limit

-2.06

upper limit

-0.17

Variability estimate

Standard error of the mean

Dispersion value

0.481

Statistical analysis 6

Statistical analysis description

Score, Week 21-24

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.022

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-1.11

Confidence interval

level

95%

sides

2-sided

lower limit

-2.05

upper limit

-0.16

Variability estimate

Standard error of the mean

Dispersion value

0.481

Statistical analysis 7

Statistical analysis description

Scores, Week 25-28

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.008

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-1.32

Confidence interval

level

95%

sides

2-sided

lower limit

-2.29

upper limit

-0.35

Variability estimate

Standard error of the mean

Dispersion value

0.492

Statistical analysis 8

Statistical analysis description

Scores, Week 29-32

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.004

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-1.43

Confidence interval

level

95%

sides

2-sided

lower limit

-2.4

upper limit

-0.46

Variability estimate

Standard error of the mean

Dispersion value

0.494

Statistical analysis 9

Statistical analysis description

Scores, Week 33-36

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.004

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-1.5

Confidence interval

level

95%

sides

2-sided

lower limit

-2.52

upper limit

-0.48

Variability estimate

Standard error of the mean

Dispersion value

0.519

Statistical analysis 10

Statistical analysis description

Scores, Week 37-40

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.016

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-1.23

Confidence interval

level

95%

sides

2-sided

lower limit

-2.22

upper limit

-0.23

Variability estimate

Standard error of the mean

Dispersion value

0.507

Statistical analysis 11

Statistical analysis description

Scores, Week 41-44

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.004

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-1.49

Confidence interval

level

95%

sides

2-sided

lower limit

-2.5

upper limit

-0.48

Variability estimate

Standard error of the mean

Dispersion value

0.513

Statistical analysis 12

Statistical analysis description

Scores, Week 45-49

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.004

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-1.53

Confidence interval

level

95%

sides

2-sided

lower limit

-2.56

upper limit

-0.5

Variability estimate

Standard error of the mean

Dispersion value

0.525

Statistical analysis 13

Statistical analysis description

Scores, Week 49-52

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.007

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-1.42

Confidence interval

level

95%

sides

2-sided

lower limit

-2.45

upper limit

-0.39

Variability estimate

Standard error of the mean

Dispersion value

0.524

Statistical analysis 14

Statistical analysis description

Breathlessness score, Week 1-4

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.051

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.33

Confidence interval

level

95%

sides

2-sided

lower limit

-0.66

upper limit

Variability estimate

Standard error of the mean

Dispersion value

0.169

Statistical analysis 15

Statistical analysis description

Breathlessness score, Week 5-8

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.003

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.61

Confidence interval

level

95%

sides

2-sided

lower limit

-1.02

upper limit

-0.2

Variability estimate

Standard error of the mean

Dispersion value

0.207

Statistical analysis 16

Statistical analysis description

Breathlessness score, Week 9-12

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.01

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.61

Confidence interval

level

95%

sides

2-sided

lower limit

-1.07

upper limit

-0.15

Variability estimate

Standard error of the mean

Dispersion value

0.234

Statistical analysis 17

Statistical analysis description

Breathlessness score, Week 13-16

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.013

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.62

Confidence interval

level

95%

sides

2-sided

lower limit

-1.1

upper limit

-0.13

Variability estimate

Standard error of the mean

Dispersion value

0.247

Statistical analysis 18

Statistical analysis description

Breathlessness score, Week 17-20

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.012

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.67

Confidence interval

level

95%

sides

2-sided

lower limit

-1.19

upper limit

-0.15

Variability estimate

Standard error of the mean

Dispersion value

0.265

Statistical analysis 19

Statistical analysis description

Breathlessness score, Week 21-24

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.018

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.64

Confidence interval

level

95%

sides

2-sided

lower limit

-1.16

upper limit

-0.11

Variability estimate

Standard error of the mean

Dispersion value

0.268

Statistical analysis 20

Statistical analysis description

Breathlessness score, Week 25-28

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.006

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.76

Confidence interval

level

95%

sides

2-sided

lower limit

-1.3

upper limit

-0.21

Variability estimate

Standard error of the mean

Dispersion value

0.275

Statistical analysis 21

Statistical analysis description

Breathlessness score, Week 29-32

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.002

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.85

Confidence interval

level

95%

sides

2-sided

lower limit

-1.4

upper limit

-0.31

Variability estimate

Standard error of the mean

Dispersion value

0.276

Statistical analysis 22

Statistical analysis description

Breathlessness score, Week 33-36

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.001

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.95

Confidence interval

level

95%

sides

2-sided

lower limit

-1.51

upper limit

-0.38

Variability estimate

Standard error of the mean

Dispersion value

0.288

Statistical analysis 23

Statistical analysis description

Breathlessness score, Week 37-40

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.008

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.76

Confidence interval

level

95%

sides

2-sided

lower limit

-1.32

upper limit

-0.2

Variability estimate

Standard error of the mean

Dispersion value

0.287

Statistical analysis 24

Statistical analysis description

Breathlessness score, Week 41-44

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.006

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.82

Confidence interval

level

95%

sides

2-sided

lower limit

-1.4

upper limit

-0.24

Variability estimate

Standard error of the mean

Dispersion value

0.294

Statistical analysis 25

Statistical analysis description

Breathlessness score, Week 45-48

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.004

Method

Breathlessness score, Week 41-44

Parameter type

LS Mean difference

Point estimate

-0.85

Confidence interval

level

95%

sides

2-sided

lower limit

-1.44

upper limit

-0.27

Variability estimate

Standard error of the mean

Dispersion value

0.299

Statistical analysis 26

Statistical analysis description

Breathlessness score, Week 49-52

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.003

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.87

Confidence interval

level

95%

sides

2-sided

lower limit

-1.45

upper limit

-0.3

Variability estimate

Standard error of the mean

Dispersion value

0.294

Statistical analysis 27

Statistical analysis description

Cough and sputum score, Week 1-4

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.84

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.2

upper limit

0.16

Variability estimate

Standard error of the mean

Dispersion value

0.091

Statistical analysis 28

Statistical analysis description

Cough and sputum score, Week 5-8

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.167

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.15

Confidence interval

level

95%

sides

2-sided

lower limit

-0.36

upper limit

-0.06

Variability estimate

Standard error of the mean

Dispersion value

0.106

Statistical analysis 29

Statistical analysis description

Cough and sputum score, Week 9-12

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.359

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.11

Confidence interval

level

95%

sides

2-sided

lower limit

-0.34

upper limit

0.12

Variability estimate

Standard error of the mean

Dispersion value

0.117

Statistical analysis 30

Statistical analysis description

Cough and sputum score, Week 13-16

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.36

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.11

Confidence interval

level

95%

sides

2-sided

lower limit

-0.36

upper limit

0.13

Variability estimate

Standard error of the mean

Dispersion value

0.124

Statistical analysis 31

Statistical analysis description

Cough and sputum score, Week 17-20

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.49

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.09

Confidence interval

level

95%

sides

2-sided

lower limit

-0.36

upper limit

0.17

Variability estimate

Standard error of the mean

Dispersion value

0.134

Statistical analysis 32

Statistical analysis description

Cough and sputum score, Week 21-24

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.388

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.12

Confidence interval

level

95%

sides

2-sided

lower limit

-0.39

upper limit

0.15

Variability estimate

Standard error of the mean

Dispersion value

0.138

Statistical analysis 33

Statistical analysis description

Cough and sputum score, Week 25-28

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.218

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.17

Confidence interval

level

95%

sides

2-sided

lower limit

-0.44

upper limit

0.1

Variability estimate

Standard error of the mean

Dispersion value

0.137

Statistical analysis 34

Statistical analysis description

Cough and sputum score, Week 29-32

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.138

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.47

upper limit

0.07

Variability estimate

Standard error of the mean

Dispersion value

0.136

Statistical analysis 35

Statistical analysis description

Cough and sputum score, Week 33-36

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.239

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.17

Confidence interval

level

95%

sides

2-sided

lower limit

-0.44

upper limit

0.11

Variability estimate

Standard error of the mean

Dispersion value

0.14

Statistical analysis 36

Statistical analysis description

Cough and sputum score, Week 37-40

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.417

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.11

Confidence interval

level

95%

sides

2-sided

lower limit

-0.38

upper limit

0.16

Variability estimate

Standard error of the mean

Dispersion value

0.138

Statistical analysis 37

Statistical analysis description

Cough and sputum score, Week 41-44

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.078

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.25

Confidence interval

level

95%

sides

2-sided

lower limit

-0.54

upper limit

0.03

Variability estimate

Standard error of the mean

Dispersion value

0.144

Statistical analysis 38

Statistical analysis description

Cough and sputum score, Week 45-48

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.058

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.27

Confidence interval

level

95%

sides

2-sided

lower limit

-0.54

upper limit

0.01

Variability estimate

Standard error of the mean

Dispersion value

0.14

Statistical analysis 39

Statistical analysis description

Cough and sputum score, Week 49-52

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.231

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.17

Confidence interval

level

95%

sides

2-sided

lower limit

-0.45

upper limit

0.11

Variability estimate

Standard error of the mean

Dispersion value

0.141

Statistical analysis 40

Statistical analysis description

Chest score, Week 1-4

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.068

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.18

Confidence interval

level

95%

sides

2-sided

lower limit

-0.37

upper limit

0.01

Variability estimate

Standard error of the mean

Dispersion value

0.097

Statistical analysis 41

Statistical analysis description

Chest score, Week 5-8

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.006

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.32

Confidence interval

level

95%

sides

2-sided

lower limit

-0.56

upper limit

-0.09

Variability estimate

Standard error of the mean

Dispersion value

0.118

Statistical analysis 42

Statistical analysis description

Chest score, Week 9-12

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.042

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.27

Confidence interval

level

95%

sides

2-sided

lower limit

-0.53

upper limit

-0.01

Variability estimate

Standard error of the mean

Dispersion value

0.131

Statistical analysis 43

Statistical analysis description

Chest score, Week 13-16

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.027

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-0.57

upper limit

-0.03

Variability estimate

Standard error of the mean

Dispersion value

0.136

Statistical analysis 44

Statistical analysis description

Chest score, Week 17-20

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.01

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.38

Confidence interval

level

95%

sides

2-sided

lower limit

-0.67

upper limit

-0.09

Variability estimate

Standard error of the mean

Dispersion value

0.146

Statistical analysis 45

Statistical analysis description

Chest score, Week 21-24

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.01

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.37

Confidence interval

level

95%

sides

2-sided

lower limit

-0.66

upper limit

-0.09

Variability estimate

Standard error of the mean

Dispersion value

0.144

Statistical analysis 46

Statistical analysis description

Chest score, Week 25-28

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.41

Confidence interval

level

95%

sides

2-sided

lower limit

-0.7

upper limit

-0.12

Variability estimate

Standard error of the mean

Dispersion value

0.148

Statistical analysis 47

Statistical analysis description

Chest score, Week 29-32

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.011

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.39

Confidence interval

level

95%

sides

2-sided

lower limit

-0.68

upper limit

-0.09

Variability estimate

Standard error of the mean

Dispersion value

0.152

Statistical analysis 48

Statistical analysis description

Chest score, Week 33-36

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.011

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-0.71

upper limit

-0.09

Variability estimate

Standard error of the mean

Dispersion value

0.157

Statistical analysis 49

Statistical analysis description

Chest score, Week 37-40

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.014

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.37

Confidence interval

level

95%

sides

2-sided

lower limit

-0.67

upper limit

-0.07

Variability estimate

Standard error of the mean

Dispersion value

0.151

Statistical analysis 50

Statistical analysis description

Chest score, Week 41-44

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.007

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.42

Confidence interval

level

95%

sides

2-sided

lower limit

-0.72

upper limit

-0.12

Variability estimate

Standard error of the mean

Dispersion value

0.153

Statistical analysis 51

Statistical analysis description

Chest score, Week 45-48

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.006

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.45

Confidence interval

level

95%

sides

2-sided

lower limit

-0.76

upper limit

-0.13

Variability estimate

Standard error of the mean

Dispersion value

0.16

Statistical analysis 52

Statistical analysis description

Chest score, Week 49-52

Comparison groups

FF/UMEC/VI 100/62.5/25 µg v BUD/FOR 400/12 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.013

Method

Mixed Model Repeated Measures

Parameter type

LS Mean difference

Point estimate

-0.41

Confidence interval

level

95%

sides

2-sided

lower limit

-0.73

upper limit

-0.09

Variability estimate

Standard error of the mean

Dispersion value

0.163

Secondary: Number of participants with any on-treatment adverse event (AE) and serious adverse event (SAE) in the treatment period

Top of page

End point title

Number of participants with any on-treatment adverse event (AE) and serious adverse event (SAE) in the treatment period

End point 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.

End point type

Secondary

End point timeframe

Up to Week 24

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	911 ^[15]	899
Units: Participants
Any AE	354	339
Any SAE	49	51

Notes
[15] - ITT Population

No statistical analyses for this end point

Secondary: Number of participants with any on-treatment AE/SAEs in the extension part of the study

Top of page

End point title

Number of participants with any on-treatment AE/SAEs in the extension part of the study

End point description

End point type

Secondary

End point timeframe

Up to Week 52

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	210 ^[16]	220
Units: Participants
Any AE	100	122
Any SAE	21	28

Notes
[16] - Extension Population

No statistical analyses for this end point

Secondary: Number of participants with an on-treatment penumonia event in the treatment period

Top of page

End point title

Number of participants with an on-treatment penumonia event in the treatment period

End point 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).

End point type

Secondary

End point timeframe

Up to Week 24

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	911 ^[17]	899
Units: Participants	20	7

Notes
[17] - ITT Population

No statistical analyses for this end point

Secondary: Number of participants with an on-treatment penumonia event in the extension part of the study

Top of page

End point title

Number of participants with an on-treatment penumonia event in the extension part of the study

End point 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).

End point type

Secondary

End point timeframe

Up to Week 52

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	210 ^[18]	220
Units: Participants	4	4

Notes
[18] - Extension Population

No statistical analyses for this end point

Secondary: Number of participants with any on-treatment cardiovascular (CV) events (including supraventricular arrhythmia and non fatal myocardial infarction) in the treatment period

Top of page

End point title

Number of participants with any on-treatment cardiovascular (CV) events (including supraventricular arrhythmia and non fatal myocardial infarction) in the treatment period

End point 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].

End point type

Secondary

End point timeframe

Up to Week 24

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	911 ^[19]	899
Units: Participants
Any MACE, Narrow definition	4	7
Any MACE, Broad definition	12	11

Notes
[19] - ITT Population

No statistical analyses for this end point

Secondary: Number of participants with any on-treatment CV events (including supraventricular arrhythmia and non fatal myocardial infarction) in the extension part of the study

Top of page

End point 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

End point description

End point type

Secondary

End point timeframe

Up to Week 52

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	210 ^[20]	220
Units: Participants
Any MACE, Narrow definition	5	2
Any MACE, Broad definition	7	5

Notes
[20] - Extension Population

No statistical analyses for this end point

Secondary: Change from Baseline in heart rate at Week 24

Top of page

End point title

Change from Baseline in heart rate at Week 24

End point 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. Only participants with analyzable data at the given time point were analyzed.

End point type

Secondary

End point timeframe

Baseline and Week 24

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	840 ^[21]	787
Units: Beats per minute (Bpm)
arithmetic mean (standard deviation)	-1.1 ( 11.51 )	-1.2 ( 10.91 )

Notes
[21] - ITT Population

No statistical analyses for this end point

Secondary: Change from Baseline in heart rate at Week 52

Top of page

End point title

Change from Baseline in heart rate at Week 52

End point 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. Only participants with analyzable data at the given time point were analyzed.

End point type

Secondary

End point timeframe

Baseline and Week 52

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	181 ^[22]	169
Units: Bpm
arithmetic mean (standard deviation)	0.2 ( 11.30 )	-1.0 ( 10.77 )

Notes
[22] - Extension Population

No statistical analyses for this end point

Secondary: Change from Baseline in Corrected QT Interval using Fridericia’s Correction (QTcF) and PR interval at Week 24

Top of page

End point title

Change from Baseline in Corrected QT Interval using Fridericia’s Correction (QTcF) and PR interval at Week 24

End point 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.

End point type

Secondary

End point timeframe

Baseline and Week 24

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	911 ^[23]	899
Units: Milliseconds (msec)
least squares mean (standard error)
QTcF, n=840,787	2.5 ( 0.56 )	0.6 ( 0.58 )
PR, n=812,766	-0.1 ( 0.54 )	0.5 ( 0.56 )

Notes
[23] - ITT Population

Statistical analysis 1

Statistical analysis description

For QTcF

Comparison groups

BUD/FOR 400/12 µg v FF/UMEC/VI 100/62.5/25 µg

Number of subjects included in analysis

1810

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.023

Method

Mixed Model Repeated Measures

Parameter type

LS mean difference

Point estimate

1.8

Confidence interval

level

95%

sides

2-sided

lower limit

0.3

upper limit

3.4

Variability estimate

Standard error of the mean

Dispersion value

0.81

Statistical analysis 2

Statistical analysis description

For PR interval

Comparison groups

BUD/FOR 400/12 µg v FF/UMEC/VI 100/62.5/25 µg

Number of subjects included in analysis

1810

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.471

Method

Mixed Model Repeated Measures

Parameter type

LS mean difference

Point estimate

-0.6

Confidence interval

level

95%

sides

2-sided

lower limit

-2.1

upper limit

Variability estimate

Standard error of the mean

Dispersion value

0.78

Secondary: Change from baseline in QTcF and PR interval at Week 52

Top of page

End point title

Change from baseline in QTcF and PR interval at Week 52

End point 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).

End point type

Secondary

End point timeframe

Baseline and Week 52

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	210 ^[24]	220
Units: Msec
least squares mean (standard error)
QTcF, n=181,169	1.4 ( 1.27 )	2.4 ( 1.31 )
PR, n=174,160	1.6 ( 1.09 )	1.4 ( 1.13 )

Notes
[24] - Extension Population

Statistical analysis 1

Statistical analysis description

For QTcF

Comparison groups

BUD/FOR 400/12 µg v FF/UMEC/VI 100/62.5/25 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.564

Method

Mixed Model Repeated Measures

Parameter type

LS mean difference

Point estimate

-1.1

Confidence interval

level

95%

sides

2-sided

lower limit

-4.7

upper limit

2.5

Variability estimate

Standard error of the mean

Dispersion value

1.83

Statistical analysis 2

Statistical analysis description

For PR interval

Comparison groups

BUD/FOR 400/12 µg v FF/UMEC/VI 100/62.5/25 µg

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.908

Method

Mixed Model Repeated Measures

Parameter type

LS mean difference

Point estimate

0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-2.9

upper limit

3.3

Variability estimate

Standard error of the mean

Dispersion value

1.57

Secondary: Change from Baseline in QT Interval Corrected for Heart Rate According to Bazett's Formula (QTcB) at Week 24

Top of page

End point title

Change from Baseline in QT Interval Corrected for Heart Rate According to Bazett's Formula (QTcB) at Week 24

End point 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. Only participants with analyzable data at the given time point were analyzed.

End point type

Secondary

End point timeframe

Baseline and Week 24

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	840 ^[25]	787
Units: Msec
arithmetic mean (standard deviation)	1.5 ( 21.00 )	-0.7 ( 20.48 )

Notes
[25] - ITT Population

No statistical analyses for this end point

Secondary: Change from baseline in QTcB at Week 52

Top of page

End point title

Change from baseline in QTcB at Week 52

End point 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. Only participants with analyzable data at the given time point were analyzed.

End point type

Secondary

End point timeframe

Baseline and Week 52

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	181 ^[26]	169
Units: Msec
arithmetic mean (standard deviation)	0.9 ( 21.30 )	2.2 ( 22.46 )

Notes
[26] - Extension Population

No statistical analyses for this end point

Secondary: Change from Baseline in systolic and diastolic blood pressures (BP) at Week 24

Top of page

End point title

Change from Baseline in systolic and diastolic blood pressures (BP) at Week 24

End point 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). Only participants with analyzable data at the given time point were analyzed.

End point type

Secondary

End point timeframe

Baseline and Week 24

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	855 ^[27]	805
Units: Millimeter of mercury (mmHg)
least squares mean (standard error)
SBP	-1.0 ( 0.39 )	-1.1 ( 0.40 )
DBP	-0.3 ( 0.27 )	-0.5 ( 0.27 )

Notes
[27] - ITT Population

Statistical analysis 1

Statistical analysis description

Week 24, SBP

Comparison groups

BUD/FOR 400/12 µg v FF/UMEC/VI 100/62.5/25 µg

Number of subjects included in analysis

1660

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.849

Method

Mixed Model Repeated Measures

Parameter type

LS mean difference

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

1.2

Variability estimate

Standard error of the mean

Dispersion value

0.56

Statistical analysis 2

Statistical analysis description

Week 24, DBP

Comparison groups

BUD/FOR 400/12 µg v FF/UMEC/VI 100/62.5/25 µg

Number of subjects included in analysis

1660

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.613

Method

Mixed Model Repeated Measures

Parameter type

LS mean difference

Point estimate

0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.6

upper limit

0.9

Variability estimate

Standard error of the mean

Dispersion value

0.38

Secondary: Change from Baseline in systolic and diastolic blood pressures (BP) at Week 52

Top of page

End point title

Change from Baseline in systolic and diastolic blood pressures (BP) at Week 52

End point 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, Week 24, and Week 52 or at the Study Treatment Discontinuation Visit. A single set of blood pressure (systolic and diastolic) measurements were 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 52 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). Only participants with analyzable data at the given time point were analyzed.

End point type

Secondary

End point timeframe

Baseline and Week 52

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	184 ^[28]	175
Units: mmHg
least squares mean (standard error)
SBP	-1.3 ( 0.83 )	0.3 ( 0.85 )
DBP	-0.4 ( 0.52 )	0.4 ( 0.53 )

Notes
[28] - Extension Population

Statistical analysis 1

Statistical analysis description

Week 52, SBP

Comparison groups

BUD/FOR 400/12 µg v FF/UMEC/VI 100/62.5/25 µg

Number of subjects included in analysis

359

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.183

Method

Mixed Model Repeated Measures

Parameter type

LS mean difference

Point estimate

-1.6

Confidence interval

level

95%

sides

2-sided

lower limit

-3.9

upper limit

0.8

Variability estimate

Standard error of the mean

Dispersion value

1.19

Statistical analysis 2

Statistical analysis description

Week 52, DBP

Comparison groups

BUD/FOR 400/12 µg v FF/UMEC/VI 100/62.5/25 µg

Number of subjects included in analysis

359

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.253

Method

Mixed Model Repeated Measures

Parameter type

LS mean difference

Point estimate

-0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-2.3

upper limit

0.6

Variability estimate

Standard error of the mean

Dispersion value

0.75

Secondary: Number of participants with any abnormal holter electrocardiogram (ECG) finding at Week 24

Top of page

End point title

Number of participants with any abnormal holter electrocardiogram (ECG) finding at Week 24

End point description

The 24-hour holter measurements were obtained at Screening and 24 hours prior to Week 24 (Visits 1 and 6). The number of participants with clinically significant change (abnormal) were reported. Holter Monitoring Population: all participants in the ITT Population who had at least one holter monitoring evaluation. Only participants with analyzable data at the given time point were analyzed.

End point type

Secondary

End point timeframe

Up to Week 24

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	212 ^[29]	206
Units: Participants	180	165

Notes
[29] - Holter Monitoring Population

No statistical analyses for this end point

Secondary: Change from Baseline in pulse rate at Week 24

Top of page

End point title

Change from Baseline in pulse rate at Week 24

End point description

Pulse rate was 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. Pulse rate was measured in a sitting position after the participant was kept at rest for at least 5 minutes. Change from Baseline values for pulse rate 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 (generally Screening but could be a test repeat). Only participants with analyzable data at the given time point were analyzed.

End point type

Secondary

End point timeframe

Baseline and Week 24

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	855 ^[30]	805
Units: Bpm
least squares mean (standard error)	-0.5 ( 0.31 )	-0.8 ( 0.32 )

Notes
[30] - ITT Population

Statistical analysis 1

Comparison groups

BUD/FOR 400/12 µg v FF/UMEC/VI 100/62.5/25 µg

Number of subjects included in analysis

1660

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.526

Method

Mixed Model Repeated Measures

Parameter type

LS mean difference

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-0.6

upper limit

1.2

Variability estimate

Standard error of the mean

Dispersion value

0.45

Secondary: Change from Baseline in pulse rate at Week 52

Top of page

End point title

Change from Baseline in pulse rate at Week 52

End point description

Pulse rate was obtained at the Screening Visit and prior to taking the morning dose of study treatment and prior to conducting spirometry at Week 4, Week 24, and Week 52 or at the Study Treatment Discontinuation. Pulse rate was measured in a sitting position after the participant was kept at rest for at least 5 minutes. Change from Baseline values for pulse rate at Week 52 were summarized and these data were analyzed using MMRM analysis. Baseline was defined as the values from most recent assessment prior to randomization (generally Screening but could be a test repeat). Only participants with analyzable data at the given time point were analyzed.

End point type

Secondary

End point timeframe

Baseline and Week 52

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	184 ^[31]	175
Units: Bpm
least squares mean (standard error)	0.7 ( 0.67 )	-1.9 ( 0.69 )

Notes
[31] - Extension Population

Statistical analysis 1

Comparison groups

BUD/FOR 400/12 µg v FF/UMEC/VI 100/62.5/25 µg

Number of subjects included in analysis

359

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.007

Method

Mixed Model Repeated Measures

Parameter type

LS mean difference

Point estimate

2.6

Confidence interval

level

95%

sides

2-sided

lower limit

0.7

upper limit

4.5

Variability estimate

Standard error of the mean

Dispersion value

0.96

Secondary: Change from Baseline in basophils, eosinophils, monocytes, neutrophils, leukocytes, lymphocytes, and platelets at Week 24

Top of page

End point title

Change from Baseline in basophils, eosinophils, monocytes, neutrophils, leukocytes, lymphocytes, and platelets at Week 24

End point description

Hematology laboratory assessments included basophils, eosinophils, lymphocytes, monocytes, neutrophils, total neutrophil, leukocytes, and platelets; parameters were measured at Baseline (BL), Week 12 and Week 24. Change from Baseline was calculated by subtracting the Baseline value from the individual post-dose value at Week 24. Baseline was defined as the most recent individual value prior to randomization (generally Screening but could be a repeat test). Only participants with data available at the analysis time point were analyzed (represented as n=X, X in category title). The maximum post-Baseline values have also been presented.

End point type

Secondary

End point timeframe

Baseline and Week 24

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	911 ^[32]	899
Units: 10^9 per liter (10^9/L)
arithmetic mean (standard deviation)
Week 24, Basophils, n=817,761	-0.001 ( 0.0217 )	-0.001 ( 0.0204 )
Maximum post BL, Basophils, n=876,853	0.005 ( 0.0211 )	0.005 ( 0.0206 )
Week 24, Eosinophils, n=817, 761	-0.008 ( 0.1926 )	-0.015 ( 0.1926 )
Maxmium post BL, Eosinophils, n=876,853	0.034 ( 0.1941 )	0.019 ( 0.1952 )
Category title 5. Week 24, Monocytes, n=817,761	-0.006 ( 0.1977 )	0.004 ( 0.2125 )
Maximum post BL, Monocytes, n=876,853	0.040 ( 0.1985 )	0.048 ( 0.2069 )
Week 24, Neutrophils, n=817,761	0.071 ( 1.7682 )	0.142 ( 1.8552 )
Maximum post BL, Neutrophils, n=876,853	0.481 ( 1.8761 )	0.649 ( 1.9143 )
Week 24, Leukocytes, n=819,761	0.06 ( 1.847 )	0.11 ( 1.915 )
Maximum post BL, Leukocytes, n=877,853	0.52 ( 1.940 )	0.64 ( 1.947 )
Week 24, Platelets, n=810,759	-0.7 ( 43.12 )	-0.7 ( 44.26 )
Maximum post BL, Platelets, n=871,846	10.8 ( 42.50 )	10.2 ( 45.46 )
Week 24, Lymphocytes, n=817,761	0.002 ( 0.5311 )	-0.023 ( 0.5669 )
Maximum post BL, Lymphocytes, n=876,853	0.187 ( 0.5468 )	0.150 ( 0.5767 )

Notes
[32] - ITT Population

No statistical analyses for this end point

Secondary: Change from Baseline in basophils, eosinophils, monocytes, neutrophils, leukocytes, lymphocytes, and platelets at Week 52

Top of page

End point title

Change from Baseline in basophils, eosinophils, monocytes, neutrophils, leukocytes, lymphocytes, and platelets at Week 52

End point description

Hematology laboratory assessments included Basophils, eosinophils, lymphocytes, monocytes,neutrophils, total neutrophil, leukocytes, and platelets; parameters were measured at Baseline (BL), Week 12, Week 24, and Week 52 for the extension part of the study. Change from Baseline was calculated by subtracting the Baseline value from the individual post-dose value at Week 52. Baseline was 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). The maximum post-Baseline values have also been presented.

End point type

Secondary

End point timeframe

Baseline and Week 52

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	210 ^[33]	220
Units: 10^9/L
arithmetic mean (standard deviation)
Week 52, Basophils, n=168,166	0.002 ( 0.0203 )	0.003 ( 0.0241 )
Maximum post BL, Basophils, n=205,212	0.011 ( 0.0196 )	0.010 ( 0.0226 )
Week 52, Eosinophils, n=168,166	0.002 ( 0.1819 )	-0.011 ( 0.2567 )
Maximum post BL, Eosinophils, n=205,212	0.074 ( 0.2460 )	0.057 ( 0.2884 )
Week 52, Monocytes, n=168,166	0.025 ( 0.2382 )	0.028 ( 0.2164 )
Maximum post BL, Monocytes, n=205,212	0.075 ( 0.2359 )	0.072 ( 0.2123 )
Week 52, Neutrophils, n=168,166	0.246 ( 2.1768 )	-0.163 ( 2.3222 )
Maximum post BL, Neutrophils, n=205,212	0.923 ( 2.1444 )	0.835 ( 2.1223 )
Week 52, Leukocytes, n=168,166	0.33 ( 2.243 )	-0.17 ( 2.387 )
Maximum post BL, Leukocytes, n=205,212	0.97 ( 2.163 )	0.87 ( 2.168 )
Week 52, Platelets, n=170,166	-1.8 ( 39.96 )	-2.7 ( 49.22 )
Maximum post BL, Platelets, n=203,210	13.6 ( 40.57 )	13.9 ( 51.61 )
Week 52, Lymphocytes, n=168,166	0.060 ( 0.6850 )	-0.027 ( 0.5714 )
Maximum post BL, Lymphocytes, n=202,212	0.325 ( 0.6299 )	0.295 ( 0.5910 )

Notes
[33] - Extension Population

No statistical analyses for this end point

Secondary: Change from Baseline in erythrocytes at Week 24

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End point title

Change from Baseline in erythrocytes at Week 24

End point description

Hematology laboratory assessments included erythrocytes and was measured at Baseline, Week 12 and Week 24. Change from Baseline was calculated by subtracting the Baseline value from the individual post-dose value at Week 24. Baseline was 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). The maximum post-Baseline values have also been presented.

End point type

Secondary

End point timeframe

Baseline and Week 24

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	911 ^[34]	899
Units: 10^12 per liter (10^12/L)
arithmetic mean (standard deviation)
Week 24, n=822,769	-0.02 ( 0.292 )	-0.04 ( 0.294 )
Maximum post BL, n=880,857	0.06 ( 0.270 )	0.04 ( 0.273 )

Notes
[34] - ITT Population

No statistical analyses for this end point

Secondary: Change from Baseline in erythrocytes at Week 52

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End point title

Change from Baseline in erythrocytes at Week 52

End point description

Hematology laboratory assessments included erythrocytes and was measured at Baseline, Week 12 and Week 24, and Week 52 for the extension part of the study. Change from Baseline was calculated by subtracting the Baseline value from the individual post-dose value at Week 52. Baseline was 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). The maximum post-Baseline values have also been presented.

End point type

Secondary

End point timeframe

Baseline and Week 52

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	210 ^[35]	220
Units: 10^12/L
arithmetic mean (standard deviation)
Week 52, n=174,170	0.02 ( 0.282 )	0.00 ( 0.313 )
Maximum post BL, n=206,212	0.11 ( 0.261 )	0.07 ( 0.289 )

Notes
[35] - Extension Population

No statistical analyses for this end point

Secondary: Change from Baseline in hemoglobin at Week 24

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End point title

Change from Baseline in hemoglobin at Week 24

End point description

Blood samples were collected for the measurement of hemoglobin at Baseline, Week 12, and Week 24. Change from Baseline was calculated as the post-Baseline value at Week 24 minus the Baseline value. Baseline was 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). The maximum post-Baseline values have also been presented.

End point type

Secondary

End point timeframe

Baseline and Week 24

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	911 ^[36]	899
Units: Grams per liter (g/L)
arithmetic mean (standard deviation)
Week 24, n=822,769	-0.9 ( 8.17 )	-1.0 ( 8.65 )
Maximum post BL, n=880,857	1.5 ( 7.55 )	1.5 ( 8.26 )

Notes
[36] - ITT Population

No statistical analyses for this end point

Secondary: Change from Baseline in hemoglobin at Week 52

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End point title

Change from Baseline in hemoglobin at Week 52

End point description

Blood samples were collected for the measurement of hemoglobin at Baseline, Week 12, Week 24, and Week 52 for the extension part of the study. Change from Baseline was calculated as the post-Baseline value at Week 52 minus the Baseline value. Baseline was 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). The maximum post-Baseline values have also been presented.

End point type

Secondary

End point timeframe

Baseline and Week 52

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	210 ^[37]	220
Units: g/L
arithmetic mean (standard deviation)
Week 52, n=174,170	-2.5 ( 8.06 )	-2.5 ( 9.82 )
Maximum post BL, n=206,212	2.2 ( 7.67 )	1.9 ( 8.55 )

Notes
[37] - Extension Population

No statistical analyses for this end point

Secondary: Change from Baseline in hematocrit at Week 24

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End point title

Change from Baseline in hematocrit at Week 24

End point description

Blood samples were collected for the measurement of hematocrit (proportion of red blood cells in blood) at Baseline, Week 12, and Week 24. Change from Baseline was calculated as the post-Baseline value at Week 24 minus the Baseline value. Baseline was 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). The maximum post-Baseline values have also been presented.

End point type

Secondary

End point timeframe

Baseline and Week 24

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	911 ^[38]	899
Units: Fraction of 1
arithmetic mean (standard deviation)
Week 24, n=822,769	0.0024 ( 0.02627 )	0.0024 ( 0.02798 )
Maximum post BL, n=880,857	0.0115 ( 0.02533 )	0.0123 ( 0.02669 )

Notes
[38] - ITT Population

No statistical analyses for this end point

Secondary: Change from Baseline in hematocrit at Week 52

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End point title

Change from Baseline in hematocrit at Week 52

End point description

Blood samples were collected for the measurement of hematocrit (proportion of red blood cells in blood) at Baseline, Week 12, Week 24, and Week 52 for the extension part of the study. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Baseline was defined as 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). The maximum post-Baseline values have also been presented.

End point type

Secondary

End point timeframe

Baseline and Week 52

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	210 ^[39]	220
Units: Fraction of 1
arithmetic mean (standard deviation)
Week 52, n=174,170	-0.0056 ( 0.02468 )	-0.0056 ( 0.03170 )
Maximum post BL, n=206,212	0.0153 ( 0.02552 )	0.0149 ( 0.02793 )

Notes
[39] - Extension Population

No statistical analyses for this end point

Secondary: Change from Baseline in albumin and protein at Week 24

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End point title

Change from Baseline in albumin and protein at Week 24

End point description

Blood samples were collected for the measurement of albumin and protein at Baseline, Week 12 and Week 24. Change from Baseline (BL) was calculated as the post-Baseline value at Week 24 minus the Baseline value. Baseline was defined as the most recent individual value prior to randomization (generally Screening but could be a test repeat). The maximum post BL values have been presented. Only participants with data available at the analysis time point were analyzed (represented as n=X, X in category title). The maximum post-Baseline values have also been presented.

End point type

Secondary

End point timeframe

Baseline and Week 24

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	911 ^[40]	899
Units: g/L
arithmetic mean (standard deviation)
Week 24, Albumin, n=839,787	-0.7 ( 2.55 )	-0.5 ( 2.41 )
Maximum post BL, Albumin, n=888,866	0.1 ( 2.36 )	0.2 ( 2.24 )
Week 24, Protein, n=839,787	-0.6 ( 3.70 )	-1.0 ( 3.64 )
Maximum post BL, Protein, n=888,866	0.4 ( 3.42 )	0.1 ( 3.43 )

Notes
[40] - ITT Population

No statistical analyses for this end point

Secondary: Change from Baseline in albumin and protein at Week 52

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End point title

Change from Baseline in albumin and protein at Week 52

End point description

Blood samples were collected for the measurement of albumin and protein at Baseline, Week 12, Week 24, and Week 52 for the extension part of the study. Change from Baseline was calculated as the post-Baseline value at Week 52 minus the Baseline value. Baseline was 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). The maximum post-Baseline values have also been presented.

End point type

Secondary

End point timeframe

Baseline and Week 52

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	210 ^[41]	220
Units: g/L
arithmetic mean (standard deviation)
Week 52, Albumin, n=181,174	-0.8 ( 2.77 )	-0.7 ( 2.64 )
Maximum post BL,Albumin, n=207,214	0.4 ( 2.45 )	0.2 ( 2.25 )
Week 52, Protein, n=181,174	-1.1 ( 4.04 )	-1.6 ( 3.86 )
Maximum post BL, Protein, n=207,214	0.6 ( 3.57 )	0.0 ( 3.30 )

Notes
[41] - Extension Population

No statistical analyses for this end point

Secondary: Change from Baseline in alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl aminotransferase (GGT), alkaline phosphatase (ALP), and creatine kinase at Week 24

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End point title

Change from Baseline in alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl aminotransferase (GGT), alkaline phosphatase (ALP), and creatine kinase at Week 24

End point description

Blood samples were collected for the measurement of ALP, ALT, AST, CK, and GGT at Baseline, Week 12 and Week 24. Change from Baseline was calculated as the post-Baseline value at Week 24 minus the Baseline value. Baseline was 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). The maximum post-Baseline values have also been presented.

End point type

Secondary

End point timeframe

Baseline and Week 24

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	911 ^[42]	899
Units: International units per liter (IU/L)
arithmetic mean (standard deviation)
Week 24, ALT, n=838,785	1.4 ( 10.81 )	3.8 ( 69.15 )
Maximum post BL, ALT, n=887,864	3.0 ( 11.99 )	5.5 ( 66.01 )
Week 24, AST, n=835,785	1.1 ( 10.30 )	4.0 ( 86.63 )
Maximum post BL, AST, n=887,866	3.2 ( 12.61 )	5.6 ( 82.66 )
Week 24, ALP, n=839,787	1.1 ( 15.42 )	-2.8 ( 12.47 )
Maximum post BL, ALP, n=888,866	4.3 ( 16.46 )	0.8 ( 11.96 )
Week 24, GGT, n=839,787	3.4 ( 31.65 )	0.5 ( 21.84 )
Maximum post BL, GGT, n=888,866	7.5 ( 42.66 )	4.7 ( 27.76 )
Week 24, Creatine Kinase, n=839,787	-3.9 ( 106.48 )	-3.4 ( 191.25 )
Maximum post BL, Creatine Kinase, n=888,866	20.6 ( 138.17 )	20.6 ( 185.06 )

Notes
[42] - ITT Population

No statistical analyses for this end point

Secondary: Change from Baseline in ALT, AST, GGT, ALP, and creatine kinase at Week 52

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End point title

Change from Baseline in ALT, AST, GGT, ALP, and creatine kinase at Week 52

End point description

Blood samples were collected for the measurement of ALP, ALT, AST, CK, and GGT at Baseline, Week 12, Week 24 and Week 52 for the extension part of the study. Change from Baseline was calculated as the post-Baseline value at Week 52 minus the Baseline value. Baseline was 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). The maximum post-Baseline values have also been presented.

End point type

Secondary

End point timeframe

Baseline and Week 52

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	210 ^[43]	220
Units: International units per liter (IU/L)
arithmetic mean (standard deviation)
Week 52, ALT, n=181,173	1.7 ( 10.64 )	1.3 ( 12.38 )
Maximum post BL, ALT, n=207,212	5.4 ( 15.45 )	4.5 ( 12.84 )
Week 52, AST, n=180,174	1.7 ( 9.72 )	0.8 ( 11.16 )
Maximum post BL, AST, n=207,214	5.5 ( 15.55 )	3.7 ( 11.65 )
Week 52, ALP, n=181,174	1.7 ( 13.77 )	-2.7 ( 10.83 )
Maximum post BL, ALP, n=207,214	6.7 ( 12.84 )	1.2 ( 11.73 )
Week 52, GGT, n=181,174	0.2 ( 28.77 )	0.2 ( 26.86 )
Maximum post BL, GGT, n=207,214	7.7 ( 31.33 )	8.9 ( 34.98 )
Week 52, Creatine Kinase, n=181,174	6.1 ( 68.48 )	16.7 ( 97.17 )
Maximum post BL, Creatine Kinase, n=207,214	39.9 ( 79.71 )	46.9 ( 90.78 )

Notes
[43] - Extension Population

No statistical analyses for this end point

Secondary: Change from Baseline in glucose, calcium, carbon dioxide (CO2), chloride, phosphate, potassium, sodium, and urea at Week 24

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End point title

Change from Baseline in glucose, calcium, carbon dioxide (CO2), chloride, phosphate, potassium, sodium, and urea at Week 24

End point description

Blood samples were collected for the measurement of Glucose, calcium, CO2, chloride, phophate, potassium, sodium, and urea at Baseline, Week 12, and Week 24. Change from Baseline was calculated as the post-Baseline value at Week 24 minus the Baseline value. Baseline was 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). The maximum post-Baseline values have also been presented.

End point type

Secondary

End point timeframe

Baseline and Week 24

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	911 ^[44]	899
Units: Millimoles per liter (mmol/L)
arithmetic mean (standard deviation)
Week 24, Calcium, n=835,785	-0.016 ( 0.0887 )	-0.014 ( 0.0931 )
Maximum post BL, Calcium, n=887,866	0.013 ( 0.0817 )	0.012 ( 0.0868 )
Week 24, Chloride, n=838,787	-0.4 ( 2.76 )	-0.7 ( 2.60 )
Maximum post BL, Chloride, n=888,866	0.9 ( 2.53 )	0.6 ( 2.35 )
Week 24, CO2, n=835,785	-0.6 ( 2.54 )	0.0 ( 2.61 )
Maximum post BL, CO2, n=835,785	0.0 ( 2.38 )	0.5 ( 2.48 )
Week 24, Glucose, n=839,787	0.12 ( 1.433 )	0.00 ( 1.449 )
Maximum post BL, Glucose, n=887,866	0.53 ( 1.506 )	0.37 ( 1.463 )
Week 24, Potassium, n=834,785	0.04 ( 0.457 )	-0.03 ( 0.456 )
Maximum post BL, Potassium, n=887,866	0.18 ( 0.428 )	0.13 ( 0.417 )
Week 24, Phosphate, n=839,787	-0.028 ( 0.2373 )	-0.029 ( 0.2728 )
Maximum post BL, Phosphate, n=888,866	0.039 ( 0.2310 )	0.043 ( 0.2576 )
Week 24, Sodium, n=837,787	-0.3 ( 2.35 )	-0.2 ( 2.38 )
Maximum post BL, Sodium, n=888,866	0.6 ( 2.15 )	0.7 ( 2.22 )
Week 24, Urea, n=839,787	0.08 ( 1.591 )	0.04 ( 1.549 )
Maximum post BL, Urea, n=888,866	0.68 ( 1.601 )	0.64 ( 1.604 )

Notes
[44] - ITT Population

No statistical analyses for this end point

Secondary: Change from Baseline in glucose, calcium, CO2, chloride, magnesium, phosphate, potassium, sodium, and urea at Week 52

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End point title

Change from Baseline in glucose, calcium, CO2, chloride, magnesium, phosphate, potassium, sodium, and urea at Week 52

End point description

Blood samples were collected for the measurement of Glucose, calcium, CO2, chloride, magnesium, phophate, potassium, sodium, and urea at Baseline, Week 12, Week 24, and Week 52 for the extension part of the study. Change from Baseline was calculated as the post-Baseline value at Week 52 minus the Baseline value. Baseline was 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). The maximum post-Baseline values have also been presented.

End point type

Secondary

End point timeframe

Baseline and Week 52

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	210 ^[45]	220
Units: Mmol/L
arithmetic mean (standard deviation)
Week 52, Calcium, n=180,174	-0.033 ( 0.0943 )	-0.040 ( 0.0968 )
Maximum post BL,Calcium, n=207,214	0.026 ( 0.0849 )	0.008 ( 0.0868 )
Week 52, Chloride, n=181,174	-0.1 ( 3.00 )	-0.2 ( 2.71 )
Maximum post BL,Chloride, n=207,214	1.4 ( 2.63 )	1.3 ( 2.39 )
Week 52, CO2, n=180,174	-1.2 ( 2.46 )	-1.0 ( 2.58 )
Maximum post BL,CO2, n=207,214	-0.2 ( 2.26 )	0.3 ( 2.28 )
Week 52, Glucose, n=181,174	0.31 ( 1.538 )	0.22 ( 1.546 )
Maximum post BL,Glucose, n=207,214	0.92 ( 1.683 )	0.63 ( 1.738 )
Week 52, Potassium, n=180,174	-0.02 ( 0.443 )	-0.10 ( 0.454 )
Maximum post BL,Potassium, n=207,214	0.29 ( 0.456 )	0.20 ( 0.418 )
Week 52, Phosphate, n=181,174	-0.003 ( 0.1645 )	0.005 ( 0.1800 )
Maximum post BL,Phosphate, n=207,214	0.109 ( 0.1551 )	0.110 ( 0.1770 )
Week 52, Sodium, n=181,174	-0.2 ( 2.34 )	-0.1 ( 2.51 )
Maximum post BL,Sodium, n=207,214	1.1 ( 2.13 )	1.1 ( 2.22 )
Week 52, Urea, n=181,174	0.16 ( 1.625 )	0.12 ( 1.553 )
Maximum post BL, Urea, n=207,214	1.06 ( 1.755 )	1.08 ( 1.629 )

Notes
[45] - Extension Population

No statistical analyses for this end point

Secondary: Change from Baseline in bilirubin, creatinine, and urate at Week 24

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End point title

Change from Baseline in bilirubin, creatinine, and urate at Week 24

End point description

Blood samples were collected for the measurement of bilirubin, creatinine, and urate at Baseline, Week 12, and Week 24. Change from Baseline was calculated as the post-Baseline value at Week 24 minus the Baseline value. Baseline was 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). The maximum post-Baseline values have also been presented.

End point type

Secondary

End point timeframe

Baseline and Week 24

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	911 ^[46]	899
Units: Micromoles per liter
arithmetic mean (standard deviation)
Week 24, Bilirubin, n=839,786	-0.2 ( 3.88 )	0.1 ( 3.77 )
Maximum post BL, Bilirubin, n=888,865	1.1 ( 4.09 )	1.2 ( 3.67 )
Week 24, Creatinine, n=839,787	1.05 ( 9.816 )	1.14 ( 9.580 )
Maximum post BL, Creatinine, n=888,866	4.12 ( 9.711 )	3.99 ( 9.509 )
Week 24, Urate, n=839,787	2.8 ( 60.87 )	1.7 ( 62.96 )
Maximum post BL, Urate, n=888,866	23.7 ( 58.64 )	21.9 ( 59.20 )

Notes
[46] - ITT Population

No statistical analyses for this end point

Secondary: Change from Baseline in bilirubin, creatinine, and urate at Week 52

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End point title

Change from Baseline in bilirubin, creatinine, and urate at Week 52

End point description

Blood samples were collected for the measurement of bilirubin, creatinine, and urate at Baseline, Week 12, Week 24, and Week 52 of the extension part of the study. Change from Baseline was calculated as the post-Baseline value at Week 52 minus the Baseline value. Baseline was defined as the most recent individual value prior to randomization (generally Screening but could be a test repeat).

End point type

Secondary

End point timeframe

Baseline and Week 52

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	210 ^[47]	220
Units: Micromoles per liter
arithmetic mean (standard deviation)
Week 52, Bilirubin, n=181,174	0.3 ( 3.41 )	0.1 ( 3.94 )
Maximum post BL, Bilirubin, n=207,214	2.0 ( 3.88 )	2.3 ( 4.28 )
Week 52, Creatinine, n=181,174	2.95 ( 11.663 )	1.28 ( 11.563 )
Maximum post BL, Creatinine, n=207,214	6.99 ( 11.425 )	6.00 ( 11.392 )
Week 52, Urate, n=181,174	3.6 ( 60.92 )	3.9 ( 64.85 )
Maximum post BL, Urate, n=207,214	42.0 ( 62.06 )	40.0 ( 63.47 )

Notes
[47] - Extension Population

No statistical analyses for this end point

Secondary: Number of participants reporting an adverse event of special interest (AESI) of oropharyngeal origin in the treatment period

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End point title

Number of participants reporting an adverse event of special interest (AESI) of oropharyngeal origin in the treatment period

End point description

Oropharyngeal examinations for clinical evidence of infection (e.g., Candida albicans) were performed at each clinic visit. All suspected cases of candidiasis were reported as AEs. The number of participants with oral candidiasis, Candida infection, oral fungal infection, and oropharyngeal candidiasis were reported.

End point type

Secondary

End point timeframe

Up to Week 24

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	911 ^[48]	899
Units: Participants
Oral candidiasis	2	4
Candida infection	1	4
Oral fungal infection	2	3
Oropharyngeal candidiasis	2	0

Notes
[48] - ITT Population

No statistical analyses for this end point

Secondary: Number of participants reporting an AESI of oropharyngeal origin in the extension part of the study

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End point title

Number of participants reporting an AESI of oropharyngeal origin in the extension part of the study

End point description

Oropharyngeal examinations for clinical evidence of infection (e.g., Candida albicans) were performed at each clinic visit. All suspected cases of candidiasis were reported as AEs. The number of participants with oral candidiasis, candida infection, oral fungal infection, and oropharyngeal candidiasis were reported.

End point type

Secondary

End point timeframe

Up to Week 52

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	210 ^[49]	220
Units: Participants
Candida infection	0	3
Oral fungal infection	0	2

Notes
[49] - Extension Population

No statistical analyses for this end point

Secondary: Number of participants with at least one on-treatment bone fracture incident in the treatment period

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End point title

Number of participants with at least one on-treatment bone fracture incident in the treatment period

End point description

To evaluate the potential for bone systemic corticosteroid effects, the incidence of bone fractures was assessed. It was categorized as an adverse event of special interest.

End point type

Secondary

End point timeframe

Up to Week 24

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	911 ^[50]	899
Units: Participants	4	6

Notes
[50] - ITT Population

No statistical analyses for this end point

Secondary: Number of participants with at least one on-treatment bone fracture incident in the extension part of the study

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End point title

Number of participants with at least one on-treatment bone fracture incident in the extension part of the study

End point description

To evaluate the potential for bone systemic corticosteroid effects, the incidence of bone fractures was assessed. It was categorized as an adverse event of special interest.

End point type

Secondary

End point timeframe

Up to Week 52

End point values	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Number of subjects analysed	210 ^[51]	220
Units: Participants	0	1

Notes
[51] - Extension Population

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

On-treatment serious adverse events (SAEs) and non-serious AEs were collected from start of the study drug until Week 24 and follow-up period for participants in ITT population and up to Week 52 and follow-up for participants in Extension Population

Adverse event reporting additional description

On-treatment SAEs and non-serious AEs are reported for ITT and extension populations

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.0

Reporting group title

FF/UMEC/VI 100/62.5/25 µg

Reporting group description

Reporting group title

BUD/FOR 400/12 µg

Reporting group description

Serious adverse events	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Total subjects affected by serious adverse events
subjects affected / exposed	61 / 911 (6.70%)	64 / 899 (7.12%)
number of deaths (all causes)	6	10
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder cancer
subjects affected / exposed	1 / 911 (0.11%)	0 / 899 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Brain neoplasm
subjects affected / exposed	0 / 911 (0.00%)	1 / 899 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Brian neoplasm malignant
subjects affected / exposed	0 / 911 (0.00%)	1 / 899 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Colon cancer
subjects affected / exposed	1 / 911 (0.11%)	0 / 899 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lung neoplasm
subjects affected / exposed	1 / 911 (0.11%)	1 / 899 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lung neoplasm malignant
subjects affected / exposed	0 / 911 (0.00%)	2 / 899 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Metastases to central nervous system
subjects affected / exposed	1 / 911 (0.11%)	0 / 899 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metastases to liver
subjects affected / exposed	1 / 911 (0.11%)	0 / 899 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Metastases to lung
subjects affected / exposed	1 / 911 (0.11%)	0 / 899 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Small cell lung cancer
subjects affected / exposed	1 / 911 (0.11%)	0 / 899 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Squamous cell carcinoma
subjects affected / exposed	0 / 911 (0.00%)	1 / 899 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Peripheral arterial occlusive disease
subjects affected / exposed	1 / 911 (0.11%)	0 / 899 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures
Coronary artery bypass
subjects affected / exposed	1 / 911 (0.11%)	0 / 899 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Heart valve replacement
subjects affected / exposed	1 / 911 (0.11%)	0 / 899 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Inguinal hernia repair
subjects affected / exposed	1 / 911 (0.11%)	0 / 899 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Catheter site phlebitis
subjects affected / exposed	0 / 911 (0.00%)	1 / 899 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Non-cardiac chest pain
subjects affected / exposed	0 / 911 (0.00%)	1 / 899 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sudden cardiac death
subjects affected / exposed	2 / 911 (0.22%)	0 / 899 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute pulmonary edema
subjects affected / exposed	0 / 911 (0.00%)	1 / 899 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Chronic obstructive pulmonary disease
subjects affected / exposed	16 / 911 (1.76%)	31 / 899 (3.45%)
occurrences causally related to treatment / all	0 / 20	0 / 36
deaths causally related to treatment / all	0 / 0	0 / 0
Chronic respiratory failure
subjects affected / exposed	0 / 911 (0.00%)	1 / 899 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Hemoptysis
subjects affected / exposed	0 / 911 (0.00%)	1 / 899 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 911 (0.00%)	1 / 899 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 911 (0.00%)	1 / 899 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary edema
subjects affected / exposed	1 / 911 (0.11%)	0 / 899 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Anxiety
subjects affected / exposed	1 / 911 (0.11%)	0 / 899 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Psychotic disorder
subjects affected / exposed	1 / 911 (0.11%)	0 / 899 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Electrocardiogram ST segment elevation
subjects affected / exposed	1 / 911 (0.11%)	0 / 899 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Ankle fracture
subjects affected / exposed	2 / 911 (0.22%)	0 / 899 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	1 / 911 (0.11%)	0 / 899 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	0 / 911 (0.00%)	1 / 899 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Meniscus injury
subjects affected / exposed	1 / 911 (0.11%)	0 / 899 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Procedural hemorrhage
subjects affected / exposed	1 / 911 (0.11%)	0 / 899 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	0 / 911 (0.00%)	1 / 899 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Acute coronory syndrome
subjects affected / exposed	1 / 911 (0.11%)	0 / 899 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	1 / 911 (0.11%)	1 / 899 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Angina pectoris
subjects affected / exposed	1 / 911 (0.11%)	1 / 899 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	1 / 911 (0.11%)	1 / 899 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	0 / 911 (0.00%)	1 / 899 (0.11%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atrioventricular block complete
subjects affected / exposed	1 / 911 (0.11%)	0 / 899 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	1 / 911 (0.11%)	2 / 899 (0.22%)
occurrences causally related to treatment / all	1 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 2
Cardiac failure acute
subjects affected / exposed	0 / 911 (0.00%)	1 / 899 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Cyanosis
subjects affected / exposed	0 / 911 (0.00%)	1 / 899 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 911 (0.00%)	2 / 899 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Myocaridal ischemia
subjects affected / exposed	0 / 911 (0.00%)	1 / 899 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Epilepsy
subjects affected / exposed	0 / 911 (0.00%)	1 / 899 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hemorrhagic stroke
subjects affected / exposed	1 / 911 (0.11%)	0 / 899 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Ischemic stroke
subjects affected / exposed	1 / 911 (0.11%)	0 / 899 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Postical paralysis
subjects affected / exposed	0 / 911 (0.00%)	1 / 899 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Presyncope
subjects affected / exposed	0 / 911 (0.00%)	1 / 899 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Transient ischemic attack
subjects affected / exposed	1 / 911 (0.11%)	1 / 899 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ear and labyrinth disorders
Deafness
subjects affected / exposed	0 / 911 (0.00%)	1 / 899 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Cataract
subjects affected / exposed	0 / 911 (0.00%)	1 / 899 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Constipation
subjects affected / exposed	2 / 911 (0.22%)	0 / 899 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric Ulcer
subjects affected / exposed	1 / 911 (0.11%)	1 / 899 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal mass
subjects affected / exposed	1 / 911 (0.11%)	0 / 899 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Upper gastrointestinal hemorrhage
subjects affected / exposed	0 / 911 (0.00%)	1 / 899 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Hepatobiliary disorders
Cholecystitis chronic
subjects affected / exposed	1 / 911 (0.11%)	0 / 899 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Dermatitis
subjects affected / exposed	0 / 911 (0.00%)	1 / 899 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Chronic kideny disease
subjects affected / exposed	0 / 911 (0.00%)	1 / 899 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Hemorrhage urinary tract
subjects affected / exposed	1 / 911 (0.11%)	0 / 899 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	0 / 911 (0.00%)	1 / 899 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ureterolithiasis
subjects affected / exposed	0 / 911 (0.00%)	1 / 899 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Intervertebra; disc protrusion
subjects affected / exposed	1 / 911 (0.11%)	0 / 899 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Osteonecrosis
subjects affected / exposed	1 / 911 (0.11%)	0 / 899 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	1 / 911 (0.11%)	0 / 899 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 911 (0.00%)	1 / 899 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infected dermal cyst
subjects affected / exposed	1 / 911 (0.11%)	0 / 899 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infective exacerbation of chronic onstructive airways diseas
subjects affected / exposed	0 / 911 (0.00%)	1 / 899 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lung infection
subjects affected / exposed	1 / 911 (0.11%)	0 / 899 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	1 / 911 (0.11%)	0 / 899 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	10 / 911 (1.10%)	5 / 899 (0.56%)
occurrences causally related to treatment / all	1 / 11	1 / 5
deaths causally related to treatment / all	0 / 1	0 / 0
Respiratory tract infection
subjects affected / exposed	0 / 911 (0.00%)	1 / 899 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 911 (0.00%)	1 / 899 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Tuberculosis
subjects affected / exposed	1 / 911 (0.11%)	0 / 899 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 911 (0.11%)	0 / 899 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 3%

Non-serious adverse events	FF/UMEC/VI 100/62.5/25 µg	BUD/FOR 400/12 µg
Total subjects affected by non serious adverse events
subjects affected / exposed	105 / 911 (11.53%)	104 / 899 (11.57%)
Nervous system disorders
Headache
subjects affected / exposed	44 / 911 (4.83%)	56 / 899 (6.23%)
occurrences all number	79	85
Infections and infestations
Nasopharyngitis
subjects affected / exposed	72 / 911 (7.90%)	51 / 899 (5.67%)
occurrences all number	89	59

More information

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Were there any global substantial amendments to the protocol? Yes

03 Dec 2014

Amendment 1 applies to China only. This amendment confirms that SAE’s, in China, will be recorded from consent to the follow-up visit/telephone contact or until Visit 6 (telephone contact) for participants who have discontinued IP but continue in the study.

16 Apr 2015

Amendment 2 applies to China only. Due to a new interpretation of Chinese regulations, the main study cannot be initiated until the pharmacogenetic research portion obtained a permit from the Human Genetic Resource Administration of China (HGRAC). This would incur a substantial delay to the start of the study in China and prevent China from being able to recruit a sufficient number of participants into the study. Therefore, China will not participate in the pharmacogenetic research portion of the study.

04 Mar 2016

The following 2 amendments were approved on the same date: Amendment 3 applies to China only: The purpose was to amend the multiplicity adjustment to be applied in the statistical analysis and correct minor discrepancies, make some minor clarifications and update references and citations. The changes made in Amendment 3 are the same as the changes made in Amendment 4 (see below for details) but Amendment 3 incorporates the China- specific amendments 1 and 2. Amendment 4: This country specific protocol amendment applies to all countries except for China, where this amendment has been incorporated into Amendment 3. Amendment 3 purpose is to amend the multiplicity adjustment to be applied in the statistical analysis and correct minor discrepancies, make some minor clarifications and update references and citations.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from Baseline in trough forced expiratory volume in one second (FEV1) at Week 24

Primary: Change from Baseline in trough forced expiratory volume in one second (FEV1) at Week 24

Primary: Change from Baseline in trough forced expiratory volume in one second (FEV1) at Week 52

Primary: Change from Baseline in trough forced expiratory volume in one second (FEV1) at Week 52

Primary: Change from Baseline in St George's Respiratory Questionnaire-Chronic Obstructive Pulmonary Disease (COPD; SGRQ) Total Score for COPD participants at Week 24

Primary: Change from Baseline in St George's Respiratory Questionnaire-Chronic Obstructive Pulmonary Disease (COPD; SGRQ) Total Score for COPD participants at Week 24

Primary: Change from Baseline in St George's Respiratory Questionnaire-COPD; SGRQ Total Score for COPD participants at Week 52

Primary: Change from Baseline in St George's Respiratory Questionnaire-COPD; SGRQ Total Score for COPD participants at Week 52

Secondary: Transitional Dyspnea Index (TDI) focal score expressed as least square mean at Week 24

Secondary: Transitional Dyspnea Index (TDI) focal score expressed as least square mean at Week 24

Secondary: Transitional Dyspnea Index (TDI) focal score expressed as least square mean at Week 52

Secondary: Transitional Dyspnea Index (TDI) focal score expressed as least square mean at Week 52

Secondary: Daily activity question percentage of days reporting a score of 2 up to Week 24

Secondary: Daily activity question percentage of days reporting a score of 2 up to Week 24

Secondary: Daily activity question percentage of days reporting a score of 2 up to Week 52

Secondary: Daily activity question percentage of days reporting a score of 2 up to Week 52

Secondary: Mean annual on-treatment moderate and/or severe COPD exacerbations up to Week 24

Secondary: Mean annual on-treatment moderate and/or severe COPD exacerbations up to Week 24

Secondary: Mean annual on-treatment moderate and/or severe COPD exacerbations up to Week 52

Secondary: Mean annual on-treatment moderate and/or severe COPD exacerbations up to Week 52

Secondary: Assessment of respiratory symptoms by 4-weekly mean Exacerbations of Chronic Pulmonary Disease Tool (EXACT)-RS scores up to Week 24

Secondary: Assessment of respiratory symptoms by 4-weekly mean Exacerbations of Chronic Pulmonary Disease Tool (EXACT)-RS scores up to Week 24

Secondary: Assessment of respiratory symptoms by 4-weekly mean EXACT-RS scores up to Week 52

Secondary: Assessment of respiratory symptoms by 4-weekly mean EXACT-RS scores up to Week 52

Secondary: Number of participants with any on-treatment adverse event (AE) and serious adverse event (SAE) in the treatment period

Secondary: Number of participants with any on-treatment adverse event (AE) and serious adverse event (SAE) in the treatment period

Secondary: Number of participants with any on-treatment AE/SAEs in the extension part of the study

Secondary: Number of participants with any on-treatment AE/SAEs in the extension part of the study

Secondary: Number of participants with an on-treatment penumonia event in the treatment period

Secondary: Number of participants with an on-treatment penumonia event in the treatment period

Secondary: Number of participants with an on-treatment penumonia event in the extension part of the study

Secondary: Number of participants with an on-treatment penumonia event in the extension part of the study

Secondary: Number of participants with any on-treatment cardiovascular (CV) events (including supraventricular arrhythmia and non fatal myocardial infarction) in the treatment period

Secondary: Number of participants with any on-treatment cardiovascular (CV) events (including supraventricular arrhythmia and non fatal myocardial infarction) in the treatment period

Secondary: Number of participants with any on-treatment CV events (including supraventricular arrhythmia and non fatal myocardial infarction) in the extension part of the study

Secondary: Number of participants with any on-treatment CV events (including supraventricular arrhythmia and non fatal myocardial infarction) in the extension part of the study

Secondary: Change from Baseline in heart rate at Week 24

Secondary: Change from Baseline in heart rate at Week 24

Secondary: Change from Baseline in heart rate at Week 52

Secondary: Change from Baseline in heart rate at Week 52

Secondary: Change from Baseline in Corrected QT Interval using Fridericia’s Correction (QTcF) and PR interval at Week 24

Secondary: Change from Baseline in Corrected QT Interval using Fridericia’s Correction (QTcF) and PR interval at Week 24

Secondary: Change from baseline in QTcF and PR interval at Week 52

Secondary: Change from baseline in QTcF and PR interval at Week 52

Secondary: Change from Baseline in QT Interval Corrected for Heart Rate According to Bazett's Formula (QTcB) at Week 24

Secondary: Change from Baseline in QT Interval Corrected for Heart Rate According to Bazett's Formula (QTcB) at Week 24

Secondary: Change from baseline in QTcB at Week 52

Secondary: Change from baseline in QTcB at Week 52

Secondary: Change from Baseline in systolic and diastolic blood pressures (BP) at Week 24

Secondary: Change from Baseline in systolic and diastolic blood pressures (BP) at Week 24

Secondary: Change from Baseline in systolic and diastolic blood pressures (BP) at Week 52

Secondary: Change from Baseline in systolic and diastolic blood pressures (BP) at Week 52

Secondary: Number of participants with any abnormal holter electrocardiogram (ECG) finding at Week 24

Secondary: Number of participants with any abnormal holter electrocardiogram (ECG) finding at Week 24

Secondary: Change from Baseline in pulse rate at Week 24

Secondary: Change from Baseline in pulse rate at Week 24

Secondary: Change from Baseline in pulse rate at Week 52

Secondary: Change from Baseline in pulse rate at Week 52

Secondary: Change from Baseline in basophils, eosinophils, monocytes, neutrophils, leukocytes, lymphocytes, and platelets at Week 24

Secondary: Change from Baseline in basophils, eosinophils, monocytes, neutrophils, leukocytes, lymphocytes, and platelets at Week 24

Secondary: Change from Baseline in basophils, eosinophils, monocytes, neutrophils, leukocytes, lymphocytes, and platelets at Week 52

Secondary: Change from Baseline in basophils, eosinophils, monocytes, neutrophils, leukocytes, lymphocytes, and platelets at Week 52

Secondary: Change from Baseline in erythrocytes at Week 24

Secondary: Change from Baseline in erythrocytes at Week 24

Secondary: Change from Baseline in erythrocytes at Week 52

Secondary: Change from Baseline in erythrocytes at Week 52

Secondary: Change from Baseline in hemoglobin at Week 24

Secondary: Change from Baseline in hemoglobin at Week 24

Secondary: Change from Baseline in hemoglobin at Week 52

Secondary: Change from Baseline in hemoglobin at Week 52

Secondary: Change from Baseline in hematocrit at Week 24