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Clinical Trial Results:
A 24-week treatment, multi-center, randomized, double-blind, double-dummy, parallel group study to compare Umeclidinium/Vilanterol, Umeclidinium, and Salmeterol in subjects with chronic obstructive pulmonary disease (COPD)

Summary
EudraCT number	2016-002513-22
Trial protocol	SE ES DE FR NL IT
Global end of trial date	18 Jun 2018

Results information
Results version number	v1(current)
This version publication date	03 Jul 2019
First version publication date	03 Jul 2019
Other versions

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

201749

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, TW8 9GS

Public contact

GSK Response Center, GlaxoSmithKline, 1 8664357343, GSKClinicalSupportHD@gsk.com

Scientific contact

GSK Response Center, GlaxoSmithKline, 1 8664357343, GSKClinicalSupportHD@gsk.com

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

15 Oct 2018

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

18 Jun 2018

Was the trial ended prematurely?

Main objective of the trial

To compare the effect of Umeclidinium/Vilanterol [(UMEC/VI) 62.5/25 mcg once daily] with Umeclidinium [UMEC (62.5 mcg once daily)] on lung function.

Protection of trial subjects

The protection of trial participants was enhanced by excluding participants with unstable liver and cardiac disease, pneumonia and/or moderate COPD exacerbation that had not resolved at least 14 days prior to screening, had >1 moderate exacerbation in the 12 months prior Screening, or 1 severe exacerbation requiring hospitalisation in the 12 months prior screening or other respiratory tract infections that had not resolved at least 7 days prior to screening. Female participants were only eligible to participate if they were not pregnant (as confirmed by a negative urine human chorionic gonadotrophin [hCG] test) and not lactating. Protocol-defined stopping criteria were put in place to safeguard participants and included: • Elevated liver chemistry • Positive urine pregnancy test. Unstable or life-threatening cardiac events (myocardial infarction, hospitalisation for unstable angina, stroke, and other CV events considered life- or intensively health-threatening by the study physician). • Participants with 2 moderate or 1 severe COPD exacerbation during the study.

Background therapy

Evidence for comparator

Actual start date of recruitment

16 Jun 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 549

Country: Number of subjects enrolled

Australia: 35

Country: Number of subjects enrolled

Canada: 83

Country: Number of subjects enrolled

France: 36

Country: Number of subjects enrolled

Germany: 645

Country: Number of subjects enrolled

Italy: 77

Country: Number of subjects enrolled

Mexico: 35

Country: Number of subjects enrolled

Netherlands: 37

Country: Number of subjects enrolled

South Africa: 63

Country: Number of subjects enrolled

Spain: 78

Country: Number of subjects enrolled

Sweden: 109

Country: Number of subjects enrolled

United States: 678

Worldwide total number of subjects

2425

EEA total number of subjects

982

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)

1198

From 65 to 84 years

1208

85 years and over

Subject disposition

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Recruitment details

In this randomized, double-blind, double dummy, 3-arm parallel group study, eligible participants received Umeclidinium/Vilanterol (UMEC/VI) 62.5/25 microgram (mcg) once daily via the ELLIPTA dry powder inhaler (DPI), or UMEC 62.5 mcg once daily via ELLIPTA DPI, or Salmeterol (SAL) 50 mcg twice daily via the DISKUS DPI (1:1:1) for 24 weeks.

Screening details

A total of 3591 participants who met the eligibility criteria were screened; 2431 participants were randomized and 2425 comprised the Intent to Treat (ITT) population (6 participants randomized in error and did not receive any treatment).The study consisted of a run-in period (4 weeks), treatment period (24 weeks) and follow up period (7+/-3 days).

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

UMEC/VI 62.5/25 mcg+ Placebo

Arm description

Participants with COPD received UMEC/VI 62.5/25 mcg once daily via the ELLIPTA DPI along with placebo twice daily via the DISKUS DPI for 24 weeks. In addition albuterol/salbutamol was provided to participants to use on an as-needed basis for relief of COPD symptoms throughout the study. Participants were followed up 7 days after the last dose of study medication.

Arm type

Experimental

Investigational medicinal product name

UMEC/VI

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder

Routes of administration

Inhalation use

Dosage and administration details

Participants received UMEC/VI, 62.5 mcg/25 mcg inhalation powder via ELLIPTA, once daily in the morning.

Investigational medicinal product name

Placebo via DISKUS

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder

Routes of administration

Inhalation use

Dosage and administration details

Participants received placebo inhalation powder via DISKUS, one dose in the morning and one in the evening.

Investigational medicinal product name

Albuterol/salbutamol

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder

Routes of administration

Inhalation use

Dosage and administration details

Participants received albuterol/salbutamol as a rescue medication via metered-dose inhaler (MDI) with a spacer which was used when needed during the study

UMEC 62.5 mcg + Placebo

Arm description

Participants with COPD received UMEC 62.5mcg once daily via the ELLIPTA DPI along with placebo twice daily via DISKUS DPI for 24 weeks. In addition albuterol/salbutamol was provided to participants to use on an as-needed basis for relief of COPD symptoms throughout the study. Participants were followed up 7 days after the last dose of study medication.

Arm type

Experimental

Investigational medicinal product name

UMEC

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder

Routes of administration

Inhalation use

Dosage and administration details

Participants received UMEC 62.5 mcg inhalation powder via ELLIPTA, once daily in the morning.

Investigational medicinal product name

Placebo via DISKUS

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder

Routes of administration

Inhalation use

Dosage and administration details

Participants received placebo inhalation powder via DISKUS, one dose in the morning and one in the evening.

Investigational medicinal product name

Albuterol/salbutamol

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder

Routes of administration

Inhalation use

Dosage and administration details

Participants received albuterol/salbutamol as a rescue medication via metered-dose inhaler (MDI) with a spacer which was used when needed during the study

Salmeterol 50 mcg+Placebo

Arm description

Participants with COPD received salmeterol 50 mcg twice daily via the DISKUS DPI along with placebo once daily via ELLIPTA DPI for 24 weeks. In addition albuterol/salbutamol was provided to participants to use on an as-needed basis for relief of COPD symptoms throughout the study. Participants were followed up 7 days after the last dose of study medication.

Arm type

Experimental

Investigational medicinal product name

Salmeterol

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder

Routes of administration

Inhalation use

Dosage and administration details

Participants received salmeterol 50 mcg administered one dose in the morning and one in the evening via DISKUS

Investigational medicinal product name

Placebo via ELLIPTA

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder

Routes of administration

Inhalation use

Dosage and administration details

Participants received placebo inhalation powder via ELLIPTA, once daily in the morning.

Investigational medicinal product name

Albuterol/salbutamol

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder

Routes of administration

Inhalation use

Dosage and administration details

Participants received albuterol/salbutamol as a rescue medication via metered-dose inhaler (MDI) with a spacer which was used when needed during the study

Number of subjects in period 1	UMEC/VI 62.5/25 mcg+ Placebo	UMEC 62.5 mcg + Placebo	Salmeterol 50 mcg+Placebo
Started	812	804	809
Completed	717	650	683
Not completed	95	154	126
Adverse event, serious fatal	5	2	2
Consent withdrawn by subject	29	46	41
Physician decision	1	5	2
Adverse event, non-fatal	24	30	20
Protocol Deviation	2	14	7
Protocol-defined withdrawal criteria met	19	26	29
Site closed	2	2	4
Lost to follow-up	5	13	3
Lack of efficacy	8	16	18

Baseline characteristics

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Reporting group title

UMEC/VI 62.5/25 mcg+ Placebo

Reporting group description

Reporting group title

UMEC 62.5 mcg + Placebo

Reporting group description

Reporting group title

Salmeterol 50 mcg+Placebo

Reporting group description

Reporting group values	UMEC/VI 62.5/25 mcg+ Placebo	UMEC 62.5 mcg + Placebo	Salmeterol 50 mcg+Placebo	Total
Number of subjects	812	804	809	2425
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
Adults (18-64 years)	400	398	400	1198
From 65-84 years	402	399	407	1208
85 years and over	10	7	2	19
Age Continuous
Units: Years
arithmetic mean (standard deviation)	64.6 ( 8.37 )	64.9 ( 8.48 )	64.4 ( 8.53 )	-
Sex: Female, Male
Units: Subjects
Female	319	327	342	988
Male	493	477	467	1437
Race/Ethnicity, Customized
Units: Subjects
Black or African American	24	23	25	72
American Indian or Alaska Native	13	12	12	37
Asian - Central/South Asian Heritage	5	0	0	5
Asian - Japanese Heritage	0	1	0	1
Asian - East Asian Heritage	0	0	1	1
White – Arabic/North African Heritage	3	1	1	5
White – White/Caucasian/European Heritage	764	763	765	2292
American Indian or Alaska Native & White	1	0	0	1
Black or African American & White	2	4	4	10
Native Hawaiian or other Pacific Islander & White	0	0	1	1

End points

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Reporting group title

UMEC/VI 62.5/25 mcg+ Placebo

Reporting group description

Reporting group title

UMEC 62.5 mcg + Placebo

Reporting group description

Reporting group title

Salmeterol 50 mcg+Placebo

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 is defined as the mean of the FEV1 values obtained 23 and 24 hours after dosing on the previous day. Baseline trough FEV1 is the mean of the values measured at 30 minutes and 5 minutes pre-dose on Day 1. Change from Baseline was calculated as the trough FEV1 value on Week 24 minus the Baseline value. Analysis was performed using a repeated measures model (MMRM) with covariates of Baseline FEV1, geographical region, stratum (number of bronchodilators per day during run-in), visit, treatment, visit by Baseline and visit by treatment interaction. ITT population comprised of all randomized participants (excluding those who were randomized in error) who received at least one dose of study medication.

End point type

Primary

End point timeframe

Baseline (Pre-dose on Day 1) and Week 24

End point values	UMEC/VI 62.5/25 mcg+ Placebo	UMEC 62.5 mcg + Placebo	Salmeterol 50 mcg+Placebo
Number of subjects analysed	691 ^[1]	621 ^[2]	654 ^[3]
Units: Liters
least squares mean (standard error)	0.122 ( 0.0081 )	0.056 ( 0.0085 )	-0.019 ( 0.0083 )

Notes
[1] - ITT Population. Participants represents those with data available at the time point being presented
[2] - ITT Population. Participants represents those with data available at the time point being presented
[3] - ITT Population. Participants represents those with data available at the time point being presented

Statistical analysis 1

Statistical analysis description

LS Mean difference comparing UMEC/VI versus UMEC at Week 24.

Comparison groups

UMEC/VI 62.5/25 mcg+ Placebo v UMEC 62.5 mcg + Placebo

Number of subjects included in analysis

1312

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

Mixed model repeated measures

Parameter type

Mean difference (net)

Point estimate

0.066

Confidence interval

level

95%

sides

2-sided

lower limit

0.043

upper limit

0.089

Variability estimate

Standard error of the mean

Dispersion value

0.0118

Statistical analysis 2

Statistical analysis description

LS Mean difference comparing UMEC/VI versus salmeterol at Week 24.

Comparison groups

UMEC/VI 62.5/25 mcg+ Placebo v Salmeterol 50 mcg+Placebo

Number of subjects included in analysis

1345

Analysis specification

Pre-specified

Analysis type

P-value

< 0.001

Method

Mixed model repeated measures

Parameter type

Mean difference (net)

Point estimate

0.141

Confidence interval

level

95%

sides

2-sided

lower limit

0.118

upper limit

0.164

Variability estimate

Standard error of the mean

Dispersion value

0.0117

Statistical analysis 3

Statistical analysis description

LS Mean difference comparing UMEC versus salmeterol at Week 24.

Comparison groups

UMEC 62.5 mcg + Placebo v Salmeterol 50 mcg+Placebo

Number of subjects included in analysis

1275

Analysis specification

Pre-specified

Analysis type

P-value

< 0.001

Method

Mixed model repeated measures

Parameter type

Mean difference (net)

Point estimate

0.075

Confidence interval

level

95%

sides

2-sided

lower limit

0.051

upper limit

0.098

Variability estimate

Standard error of the mean

Dispersion value

0.0119

Secondary: Self administered computerized (SAC) transient dyspnea index (TDI) Focal score at Week 24

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End point title

Self administered computerized (SAC) transient dyspnea index (TDI) Focal score at Week 24

End point description

TDI focal score comprises of 3 individual scales (Functional Impairment, Magnitude of Task, Magnitude of Effort). Each of these scales had a possible score ranging from -6 to +6, lower scores indicates impairment. TDI focal score was calculated as the sum of 3 individual scores (range is -18 to +18). Lower score indicates deterioration of dyspnea. If a score is missing for any of the three scales, then the TDI focal score was set to missing. Analysis was performed using mixed model repeated measures (MMRM) with covariates of SAC BDI focal score, geographical region, stratum (no. of bronchodilators per day during run-in), visit, treatment, visit by SAC BDI and visit by treatment interactions.

End point type

Secondary

End point timeframe

Week 24

End point values	UMEC/VI 62.5/25 mcg+ Placebo	UMEC 62.5 mcg + Placebo	Salmeterol 50 mcg+Placebo
Number of subjects analysed	704 ^[4]	636 ^[5]	673 ^[6]
Units: Scores on a scale
least squares mean (standard error)	1.68 ( 0.109 )	1.30 ( 0.114 )	1.22 ( 0.111 )

Notes
[4] - ITT Population. Participants represents those with data available at the time point being presented
[5] - ITT Population. Participants represents those with data available at the time point being presented
[6] - ITT Population. Participants represents those with data available at the time point being presented

Statistical analysis 1

Statistical analysis description

LS Mean difference comparing UMEC/VI versus UMEC at Week 24.

Comparison groups

UMEC/VI 62.5/25 mcg+ Placebo v UMEC 62.5 mcg + Placebo

Number of subjects included in analysis

1340

Analysis specification

Pre-specified

Analysis type

P-value

= 0.018

Method

Mixed model repeated measures

Parameter type

Mean difference (net)

Point estimate

0.37

Confidence interval

level

95%

sides

2-sided

lower limit

0.06

upper limit

0.68

Variability estimate

Standard error of the mean

Dispersion value

0.157

Statistical analysis 2

Statistical analysis description

LS Mean difference comparing UMEC/VI versus salmeterol at Week 24.

Comparison groups

UMEC/VI 62.5/25 mcg+ Placebo v Salmeterol 50 mcg+Placebo

Number of subjects included in analysis

1377

Analysis specification

Pre-specified

Analysis type

P-value

= 0.004

Method

Mixed model repeated measures

Parameter type

Mean difference (net)

Point estimate

0.45

Confidence interval

level

95%

sides

2-sided

lower limit

0.15

upper limit

0.76

Variability estimate

Standard error of the mean

Dispersion value

0.155

Statistical analysis 3

Statistical analysis description

LS Mean difference comparing UMEC versus salmeterol at Week 24.

Comparison groups

UMEC 62.5 mcg + Placebo v Salmeterol 50 mcg+Placebo

Number of subjects included in analysis

1309

Analysis specification

Pre-specified

Analysis type

P-value

= 0.61

Method

Mixed model repeated measures

Parameter type

Mean difference (net)

Point estimate

0.08

Confidence interval

level

95%

sides

2-sided

lower limit

-0.23

upper limit

0.39

Variability estimate

Standard error of the mean

Dispersion value

0.159

Secondary: Percentage of TDI responders according to SAC TDI Focal score

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End point title

Percentage of TDI responders according to SAC TDI Focal score

End point description

TDI focal score comprises of 3 individual scales (Functional Impairment, Magnitude of Task, Magnitude of Effort). Each of these scales had a possible score ranging from -6 to +6, lower scores indicates impairment. TDI focal score was calculated as the sum of 3 individual scores (range is -18 to +18). Lower score indicates deterioration of dyspnea. If a score is missing for any of the three scales, then TDI focal score was set to missing. A participant was considered as a responder if the on-treatment TDI focal score was at least 1 unit at that visit. Non-response was SAC TDI focal score of less than 1 unit or a missing SAC TDI focal score with no subsequent non-missing on-treatment scores. Analysis was performed using a generalized linear mixed model with treatment as an explanatory variable and visit, SAC BDI focal score, stratum (no. of bronchodilators per day during run-in), geographical region, visit by SAC BDI and visit by treatment interactions included as covariates.

End point type

Secondary

End point timeframe

Week 24

End point values	UMEC/VI 62.5/25 mcg+ Placebo	UMEC 62.5 mcg + Placebo	Salmeterol 50 mcg+Placebo
Number of subjects analysed	806 ^[7]	799 ^[8]	807 ^[9]
Units: Percentage of responders	50	42	41

Notes
[7] - ITT Population. Participants represents those with data available at the time point being presented
[8] - ITT Population. Participants represents those with data available at the time point being presented
[9] - ITT Population. Participants represents those with data available at the time point being presented

Statistical analysis 1

Statistical analysis description

Odds Ratio (responder vs. a non-responder) comparing UMEC/VI versus UMEC at Week 24.

Comparison groups

UMEC/VI 62.5/25 mcg+ Placebo v UMEC 62.5 mcg + Placebo

Number of subjects included in analysis

1605

Analysis specification

Pre-specified

Analysis type

P-value

< 0.001

Method

generalized linear mixed model

Parameter type

Odds ratio (OR)

Point estimate

1.43

Confidence interval

level

95%

sides

2-sided

lower limit

1.17

upper limit

1.75

Statistical analysis 2

Statistical analysis description

Odds Ratio (responder vs. a non-responder) comparing UMEC/VI versus salmeterol at Week 24.

Comparison groups

UMEC/VI 62.5/25 mcg+ Placebo v Salmeterol 50 mcg+Placebo

Number of subjects included in analysis

1613

Analysis specification

Pre-specified

Analysis type

P-value

< 0.001

Method

generalized linear mixed model

Parameter type

Odds ratio (OR)

Point estimate

1.48

Confidence interval

level

95%

sides

2-sided

lower limit

1.21

upper limit

1.81

Statistical analysis 3

Statistical analysis description

Odds Ratio (responder vs. a non-responder) comparing UMEC versus salmeterol at Week 24.

Comparison groups

UMEC 62.5 mcg + Placebo v Salmeterol 50 mcg+Placebo

Number of subjects included in analysis

1606

Analysis specification

Pre-specified

Analysis type

P-value

= 0.755

Method

generalized linear mixed model

Parameter type

Odds ratio (OR)

Point estimate

1.03

Confidence interval

level

95%

sides

2-sided

lower limit

0.84

upper limit

1.27

Secondary: Mean change from Baseline in Evaluating Respiratory Symptoms (E-RS) total score

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End point title

Mean change from Baseline in Evaluating Respiratory Symptoms (E-RS) total score

End point description

The E-RS is intended to capture information related to respiratory symptoms. A daily symptom score for E-RS is derived by summing 11 item-scores. The domains include: respiratory symptoms (RS)-breathlessness (RS-BRL comprised of 5 items, score range [0-17]), RS-cough and sputum (RS-CSP comprised of 3 items, score range [0-11]), and RS-chest symptoms (RS-CSY comprised of 3 items, score range [0-12]). Total score ranged between 0-40 and higher values indicates severe respiratory symptoms. The instrument was completed each night prior to going to bed. Baseline E-RS score is the mean within-participant daily score over 7 days prior to randomization. Change from Baseline is the difference at Week 21-Week 24 value and Baseline value. Analysis was performed using MMRM with covariates of Baseline score, geographical region, stratum (no. of bronchodilators per day during run-in), 4-weekly period, treatment, 4-weekly period by Baseline and 4-weekly period by treatment interactions.

End point type

Secondary

End point timeframe

Baseline (Pre-dose on Day 1) and Week 21 to Week 24

End point values	UMEC/VI 62.5/25 mcg+ Placebo	UMEC 62.5 mcg + Placebo	Salmeterol 50 mcg+Placebo
Number of subjects analysed	677 ^[10]	621 ^[11]	653 ^[12]
Units: Scores on a scale
least squares mean (standard error)	-1.52 ( 0.148 )	-0.99 ( 0.152 )	-0.69 ( 0.150 )

Notes
[10] - ITT Population. Participants represents those with data available at the time point being presented
[11] - ITT Population. Participants represents those with data available at the time point being presented
[12] - ITT Population. Participants represents those with data available at the time point being presented

Statistical analysis 1

Statistical analysis description

LS Mean difference comparing UMEC/VI versus UMEC at Week 21 to Week 24

Comparison groups

UMEC/VI 62.5/25 mcg+ Placebo v UMEC 62.5 mcg + Placebo

Number of subjects included in analysis

1298

Analysis specification

Pre-specified

Analysis type

P-value

= 0.013

Method

Mixed model repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.53

Confidence interval

level

95%

sides

2-sided

lower limit

-0.95

upper limit

-0.11

Variability estimate

Standard error of the mean

Dispersion value

0.213

Statistical analysis 2

Statistical analysis description

LS Mean difference comparing UMEC/VI versus salmeterol at Week 21 to Week 24

Comparison groups

UMEC/VI 62.5/25 mcg+ Placebo v Salmeterol 50 mcg+Placebo

Number of subjects included in analysis

1330

Analysis specification

Pre-specified

Analysis type

P-value

< 0.001

Method

Mixed model repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.83

Confidence interval

level

95%

sides

2-sided

lower limit

-1.25

upper limit

-0.42

Variability estimate

Standard error of the mean

Dispersion value

0.211

Statistical analysis 3

Statistical analysis description

LS Mean difference comparing UMEC versus Salmeterol at Week 21 to Week 24

Comparison groups

UMEC 62.5 mcg + Placebo v Salmeterol 50 mcg+Placebo

Number of subjects included in analysis

1274

Analysis specification

Pre-specified

Analysis type

P-value

= 0.159

Method

Mixed model repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-0.72

upper limit

0.12

Variability estimate

Standard error of the mean

Dispersion value

0.214

Secondary: Mean change from Baseline in E-RS Subscale Score

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End point title

Mean change from Baseline in E-RS Subscale Score

End point description

End point type

Secondary

End point timeframe

Baseline (Pre-dose on Day 1) and Week 21 to Week 24

End point values	UMEC/VI 62.5/25 mcg+ Placebo	UMEC 62.5 mcg + Placebo	Salmeterol 50 mcg+Placebo
Number of subjects analysed	677 ^[13]	621 ^[14]	653 ^[15]
Units: Scores on a scale
least squares mean (standard error)
RS-BRL	-0.67 ( 0.080 )	-0.40 ( 0.082 )	-0.22 ( 0.081 )
RS-CSP	-0.45 ( 0.044 )	-0.38 ( 0.045 )	-0.32 ( 0.044 )
RS-CSY	-0.39 ( 0.049 )	-0.22 ( 0.050 )	-0.15 ( 0.049 )

Notes
[13] - ITT Population. Participants represents those with data available at the time point being presented
[14] - ITT Population. Participants represents those with data available at the time point being presented
[15] - ITT Population. Participants represents those with data available at the time point being presented

Statistical analysis 1

Statistical analysis description

LS Mean difference comparing UMEC/VI versus UMEC at Week 21 to Week 24

Comparison groups

UMEC/VI 62.5/25 mcg+ Placebo v UMEC 62.5 mcg + Placebo

Number of subjects included in analysis

1298

Analysis specification

Pre-specified

Analysis type

P-value

= 0.016 ^[16]

Method

Mixed model repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.27

Confidence interval

level

95%

sides

2-sided

lower limit

-0.5

upper limit

-0.05

Variability estimate

Standard error of the mean

Dispersion value

0.114

Notes
[16] - E-RS Breathlessness Score

Statistical analysis 2

Statistical analysis description

LS Mean difference comparing UMEC/VI versus salmeterol at Week 21 to Week 24

Comparison groups

UMEC/VI 62.5/25 mcg+ Placebo v Salmeterol 50 mcg+Placebo

Number of subjects included in analysis

1330

Analysis specification

Pre-specified

Analysis type

P-value

< 0.001 ^[17]

Method

Mixed model repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.46

Confidence interval

level

95%

sides

2-sided

lower limit

-0.68

upper limit

-0.23

Variability estimate

Standard error of the mean

Dispersion value

0.113

Notes
[17] - E-RS Breathlessness Score

Statistical analysis 3

Statistical analysis description

LS Mean difference comparing UMEC versus salmeterol at Week 21 to Week 24

Comparison groups

UMEC 62.5 mcg + Placebo v Salmeterol 50 mcg+Placebo

Number of subjects included in analysis

1274

Analysis specification

Pre-specified

Analysis type

P-value

= 0.115 ^[18]

Method

Mixed model repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.18

Confidence interval

level

95%

sides

2-sided

lower limit

-0.41

upper limit

0.04

Variability estimate

Standard error of the mean

Dispersion value

0.115

Notes
[18] - E-RS Breathlessness Score

Statistical analysis 4

Statistical analysis description

LS Mean difference comparing UMEC/VI versus UMEC at Week 21 to Week 24

Comparison groups

UMEC/VI 62.5/25 mcg+ Placebo v UMEC 62.5 mcg + Placebo

Number of subjects included in analysis

1298

Analysis specification

Pre-specified

Analysis type

P-value

= 0.247 ^[19]

Method

Mixed model repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.07

Confidence interval

level

95%

sides

2-sided

lower limit

-0.2

upper limit

0.05

Variability estimate

Standard error of the mean

Dispersion value

0.063

Notes
[19] - E-RS Cough and Sputum Score

Statistical analysis 5

Statistical analysis description

LS Mean difference comparing UMEC/VI versus salmeterol at Week 21 to Week 24

Comparison groups

UMEC/VI 62.5/25 mcg+ Placebo v Salmeterol 50 mcg+Placebo

Number of subjects included in analysis

1330

Analysis specification

Pre-specified

Analysis type

P-value

= 0.042 ^[20]

Method

Mixed model repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.13

Confidence interval

level

95%

sides

2-sided

lower limit

-0.25

upper limit

Variability estimate

Standard error of the mean

Dispersion value

0.063

Notes
[20] - E-RS Cough and Sputum Score

Statistical analysis 6

Statistical analysis description

LS Mean difference comparing UMEC versus salmeterol at Week 21 to Week 24

Comparison groups

UMEC 62.5 mcg + Placebo v Salmeterol 50 mcg+Placebo

Number of subjects included in analysis

1274

Analysis specification

Pre-specified

Analysis type

P-value

= 0.391 ^[21]

Method

Mixed model repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.05

Confidence interval

level

95%

sides

2-sided

lower limit

-0.18

upper limit

0.07

Variability estimate

Standard error of the mean

Dispersion value

0.063

Notes
[21] - E-RS Cough and Sputum Score

Statistical analysis 7

Statistical analysis description

LS Mean difference comparing UMEC/VI versus UMEC at Week 21 to Week 24

Comparison groups

UMEC/VI 62.5/25 mcg+ Placebo v UMEC 62.5 mcg + Placebo

Number of subjects included in analysis

1298

Analysis specification

Pre-specified

Analysis type

P-value

= 0.014 ^[22]

Method

Mixed model repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.17

Confidence interval

level

95%

sides

2-sided

lower limit

-0.31

upper limit

-0.04

Variability estimate

Standard error of the mean

Dispersion value

0.07

Notes
[22] - E-RS Chest Symptoms Score

Statistical analysis 8

Statistical analysis description

LS Mean difference comparing UMEC/VI versus salmeterol at Week 21 to Week 24

Comparison groups

UMEC/VI 62.5/25 mcg+ Placebo v Salmeterol 50 mcg+Placebo

Number of subjects included in analysis

1330

Analysis specification

Pre-specified

Analysis type

P-value

< 0.001 ^[23]

Method

Mixed model repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.24

Confidence interval

level

95%

sides

2-sided

lower limit

-0.37

upper limit

-0.1

Variability estimate

Standard error of the mean

Dispersion value

0.069

Notes
[23] - E-RS Chest Symptoms Score

Statistical analysis 9

Statistical analysis description

LS Mean difference comparing UMEC versus salmeterol at Week 21 to Week 24

Comparison groups

UMEC 62.5 mcg + Placebo v Salmeterol 50 mcg+Placebo

Number of subjects included in analysis

1274

Analysis specification

Pre-specified

Analysis type

P-value

= 0.34 ^[24]

Method

Mixed model repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.07

Confidence interval

level

95%

sides

2-sided

lower limit

-0.2

upper limit

0.07

Variability estimate

Standard error of the mean

Dispersion value

0.07

Notes
[24] - E-RS Chest Symptoms Score

Secondary: Percentage of E-RS responders according to E-RS total score

Top of page

End point title

Percentage of E-RS responders according to E-RS total score

End point description

The E-RS is intended to capture information related to respiratory symptoms. A daily symptom score for E-RS is derived by summing 11 item-scores. The domains include: RS-BRL comprised of 5 items, score range (0-17); RS-CSP comprised of 3 items, score range (0-11); and RS-CSY comprised of 4 items, score range (0-12). Total score ranged between 0-40 and higher values indicates severe respiratory symptoms. The instrument was completed each night prior to going to bed. Response is defined as an E-RS total score of at least 2 or 3.35 below Baseline. Participants with a Baseline but all missing post-Baseline data are also considered a non-responder. Analysis was performed using a generalized linear mixed model with treatment as an explanatory variable and four-weekly period, Baseline score, stratum (no. of bronchodilators per day during run-in), geographical region, four-weekly period by baseline and four-weekly period by treatment interactions included as covariates.

End point type

Secondary

End point timeframe

Week 21 to Week 24

End point values	UMEC/VI 62.5/25 mcg+ Placebo	UMEC 62.5 mcg + Placebo	Salmeterol 50 mcg+Placebo
Number of subjects analysed	809 ^[25]	800 ^[26]	808 ^[27]
Units: Percentage of responders	36	27	27

Notes
[25] - ITT Population. Participants represents those with data available at the time point being presented
[26] - ITT Population. Participants represents those with data available at the time point being presented
[27] - ITT Population. Participants represents those with data available at the time point being presented

Statistical analysis 1

Statistical analysis description

Odds Ratio (responder vs. a non-responder) comparing UMEC/VI vs UMEC at Week 21 to Week 24

Comparison groups

UMEC/VI 62.5/25 mcg+ Placebo v UMEC 62.5 mcg + Placebo

Number of subjects included in analysis

1609

Analysis specification

Pre-specified

Analysis type

P-value

< 0.001

Method

generalized linear mixed model

Parameter type

Odds ratio (OR)

Point estimate

1.52

Confidence interval

level

95%

sides

2-sided

lower limit

1.22

upper limit

1.89

Statistical analysis 2

Statistical analysis description

Odds Ratio (responder vs. a non-responder) comparing UMEC/VI vs salmeterol at Week 21 to Week 24

Comparison groups

UMEC/VI 62.5/25 mcg+ Placebo v Salmeterol 50 mcg+Placebo

Number of subjects included in analysis

1617

Analysis specification

Pre-specified

Analysis type

P-value

< 0.001

Method

generalized linear mixed model

Parameter type

Odds ratio (OR)

Point estimate

1.53

Confidence interval

level

95%

sides

2-sided

lower limit

1.23

upper limit

1.9

Statistical analysis 3

Statistical analysis description

Odds Ratio (responder vs. a non-responder) comparing UMEC vs salmeterol at Week 21 to Week 24

Comparison groups

UMEC 62.5 mcg + Placebo v Salmeterol 50 mcg+Placebo

Number of subjects included in analysis

1608

Analysis specification

Pre-specified

Analysis type

P-value

= 0.969

Method

generalized linear mixed model

Parameter type

Odds ratio (OR)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

0.8

upper limit

1.26

Secondary: Change from Baseline in St George’s Respiratory Questionnaire (SGRQ) total score

Top of page

End point title

Change from Baseline in St George’s Respiratory Questionnaire (SGRQ) total score

End point description

SGRQ is a disease-specific questionnaire designed to measure impact of respiratory disease and its treatment on HRQoL of participants with COPD. It contains 14 questions with a total of 40 items grouped into domains (Symptoms, Activity and Impacts). SGRQ total score was calculated as 100 multiplied by summed weights from all positive items divided by sum of weights for all items in questionnaire. It ranges from 0 to 100, higher score indicates poor HRQoL. Baseline is last non-missing score recorded prior to dosing on Day 1. Change from Baseline was calculated by subtracting Baseline value from the value at Week 24. Analysis was performed using mixed model repeated measures (MMRM) with covariates of Baseline SGRQ total score, geographical region, stratum (no. of bronchodilators per day during run-in), visit, treatment, visit by Baseline and visit by treatment interactions.

End point type

Secondary

End point timeframe

Baseline (Pre-dose on Day 1) and Week 24

End point values	UMEC/VI 62.5/25 mcg+ Placebo	UMEC 62.5 mcg + Placebo	Salmeterol 50 mcg+Placebo
Number of subjects analysed	704 ^[28]	636 ^[29]	674 ^[30]
Units: Scores on a scale
least squares mean (standard error)	-4.98 ( 0.465 )	-5.23 ( 0.484 )	-3.29 ( 0.475 )

Notes
[28] - ITT Population. Participants represents those with data available at the time point being presented
[29] - ITT Population. Participants represents those with data available at the time point being presented
[30] - ITT Population. Participants represents those with data available at the time point being presented

Statistical analysis 1

Statistical analysis description

LS Mean difference comparing UMEC/VI versus UMEC at Week 24.

Comparison groups

UMEC/VI 62.5/25 mcg+ Placebo v UMEC 62.5 mcg + Placebo

Number of subjects included in analysis

1340

Analysis specification

Pre-specified

Analysis type

P-value

= 0.709

Method

mixed model repeated measure

Parameter type

Mean difference (net)

Point estimate

0.25

Confidence interval

level

95%

sides

2-sided

lower limit

-1.07

upper limit

1.57

Variability estimate

Standard error of the mean

Dispersion value

0.672

Statistical analysis 2

Statistical analysis description

LS Mean difference comparing UMEC/VI versus salmeterol at Week 24.

Comparison groups

UMEC/VI 62.5/25 mcg+ Placebo v Salmeterol 50 mcg+Placebo

Number of subjects included in analysis

1378

Analysis specification

Pre-specified

Analysis type

P-value

= 0.011

Method

mixed model repeated measure

Parameter type

Mean difference (net)

Point estimate

-1.69

Confidence interval

level

95%

sides

2-sided

lower limit

-2.99

upper limit

-0.39

Variability estimate

Standard error of the mean

Dispersion value

0.665

Statistical analysis 3

Statistical analysis description

LS Mean difference comparing UMEC versus salmeterol at Week 24.

Comparison groups

UMEC 62.5 mcg + Placebo v Salmeterol 50 mcg+Placebo

Number of subjects included in analysis

1310

Analysis specification

Pre-specified

Analysis type

P-value

= 0.004

Method

mixed model repeated measure

Parameter type

Mean difference (net)

Point estimate

-1.94

Confidence interval

level

95%

sides

2-sided

lower limit

-3.27

upper limit

-0.61

Variability estimate

Standard error of the mean

Dispersion value

0.678

Secondary: Change from Baseline in COPD assessment test (CAT)

Top of page

End point title

Change from Baseline in COPD assessment test (CAT)

End point description

The CAT is a participant-completed instrument designed to provide a simple and reliable measure of health status in COPD for the assessment and long-term follow-up of the individual participant. The CAT consists of eight items, each formatted on a differential scale. Participants rated their experience on a 6-point scale for each question, ranging from 0 (no impact) to 5 (high impact). A total CAT score was calculated by summing the non-missing scores on the eight items ranging from 0 to 40 with higher scores indicating greater disease impact. Baseline is defined as the last non-missing score recorded prior to dosing on Day 1. Change from Baseline was calculated by subtracting Baseline value from the value at Week 24. Analysis was performed using mixed model repeated measures (MMRM) with covariates of Baseline CAT score, geographical region, stratum (no. of bronchodilators per day during run-in), visit, treatment, visit by Baseline and visit by treatment interactions.

End point type

Secondary

End point timeframe

Baseline (Pre-dose on Day 1) and Week 24

End point values	UMEC/VI 62.5/25 mcg+ Placebo	UMEC 62.5 mcg + Placebo	Salmeterol 50 mcg+Placebo
Number of subjects analysed	703 ^[31]	633 ^[32]	669 ^[33]
Units: Scores on a scale
least squares mean (standard error)	-3.5 ( 0.21 )	-3.4 ( 0.22 )	-2.9 ( 0.21 )

Notes
[31] - ITT Population. Participants represents those with data available at the time point being presented
[32] - ITT Population. Participants represents those with data available at the time point being presented
[33] - ITT Population. Participants represents those with data available at the time point being presented

Statistical analysis 1

Statistical analysis description

LS Mean difference comparing UMEC/VI versus UMEC at Week 24.

Comparison groups

UMEC/VI 62.5/25 mcg+ Placebo v UMEC 62.5 mcg + Placebo

Number of subjects included in analysis

1336

Analysis specification

Pre-specified

Analysis type

P-value

= 0.891

Method

mixed model repeated measures

Parameter type

Mean difference (net)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.6

upper limit

0.6

Variability estimate

Standard error of the mean

Dispersion value

0.3

Statistical analysis 2

Statistical analysis description

LS Mean difference comparing UMEC/VI versus salmeterol at Week 24.

Comparison groups

UMEC/VI 62.5/25 mcg+ Placebo v Salmeterol 50 mcg+Placebo

Number of subjects included in analysis

1372

Analysis specification

Pre-specified

Analysis type

P-value

= 0.074

Method

mixed model repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.5

Confidence interval

level

95%

sides

2-sided

lower limit

-1.1

upper limit

0.1

Variability estimate

Standard error of the mean

Dispersion value

0.3

Statistical analysis 3

Statistical analysis description

LS Mean difference comparing UMEC versus salmeterol at Week 24.

Comparison groups

UMEC 62.5 mcg + Placebo v Salmeterol 50 mcg+Placebo

Number of subjects included in analysis

1302

Analysis specification

Pre-specified

Analysis type

P-value

= 0.107

Method

mixed model repeated measures

Parameter type

Odds ratio (OR)

Point estimate

-0.5

Confidence interval

level

95%

sides

2-sided

lower limit

-1.1

upper limit

0.1

Variability estimate

Standard error of the mean

Dispersion value

0.31

Secondary: Percentage of responders according to CAT

Top of page

End point title

Percentage of responders according to CAT

End point description

The CAT is a participant-completed instrument designed to provide a simple and reliable measure of health status in COPD for the assessment and long-term follow-up of the individual participant. The CAT consists of eight items. Participants rated their experience on a 6-point scale for each question, ranging from 0 (no impact) to 5 (high impact). A total CAT score was calculated by summing the non-missing scores on the eight items ranging from 0 to 40 with higher scores indicating greater disease impact. Response was defined as an CAT score of >=2 below Baseline. Non response was defined as CAT score <2 units below Baseline or a missing CAT score with no subsequent on treatment scores. Analysis was performed using a generalized linear mixed model with treatment as an explanatory variable and visit, baseline CAT score, stratum (no. of bronchodilators per day during run-in), geographical region, visit by baseline and visit by treatment interactions included as covariates.

End point type

Secondary

End point timeframe

Week 24

End point values	UMEC/VI 62.5/25 mcg+ Placebo	UMEC 62.5 mcg + Placebo	Salmeterol 50 mcg+Placebo
Number of subjects analysed	812 ^[34]	804 ^[35]	809 ^[36]
Units: Percentage of responders	55	48	50

Notes
[34] - ITT Population.
[35] - ITT Population.
[36] - ITT Population.

Statistical analysis 1

Statistical analysis description

Odds Ratio (responder vs. a non-responder) comparing UMEC/VI versus UMEC at Week 24.

Comparison groups

UMEC/VI 62.5/25 mcg+ Placebo v UMEC 62.5 mcg + Placebo

Number of subjects included in analysis

1616

Analysis specification

Pre-specified

Analysis type

P-value

= 0.003

Method

generalized linear mixed model

Parameter type

Odds ratio (OR)

Point estimate

1.35

Confidence interval

level

95%

sides

2-sided

lower limit

1.11

upper limit

1.65

Statistical analysis 2

Statistical analysis description

Odds Ratio (responder vs. a non-responder) comparing UMEC/VI versus salmeterol at Week 24.

Comparison groups

UMEC/VI 62.5/25 mcg+ Placebo v Salmeterol 50 mcg+Placebo

Number of subjects included in analysis

1621

Analysis specification

Pre-specified

Analysis type

P-value

= 0.037

Method

generalized linear mixed model

Parameter type

Odds ratio (OR)

Point estimate

1.23

Confidence interval

level

95%

sides

2-sided

lower limit

1.01

upper limit

1.5

Statistical analysis 3

Statistical analysis description

Odds Ratio (responder vs. a non-responder) comparing UMEC versus salmeterol at Week 24.

Comparison groups

UMEC 62.5 mcg + Placebo v Salmeterol 50 mcg+Placebo

Number of subjects included in analysis

1613

Analysis specification

Pre-specified

Analysis type

P-value

= 0.363

Method

generalized linear mixed model

Parameter type

Odds ratio (OR)

Point estimate

0.91

Confidence interval

level

95%

sides

2-sided

lower limit

0.75

upper limit

1.11

Secondary: Number of participants with on treatment adverse events (AE) and serious adverse events (SAE)

Top of page

End point title

Number of participants with on treatment adverse events (AE) and serious adverse events (SAE)

End point description

An AE is 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. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment or all events associated with liver injury and impaired liver function based on pre-defined criteria were categorized as SAE.

End point type

Secondary

End point timeframe

Up to Week 24

End point values	UMEC/VI 62.5/25 mcg+ Placebo	UMEC 62.5 mcg + Placebo	Salmeterol 50 mcg+Placebo
Number of subjects analysed	812 ^[37]	804 ^[38]	809 ^[39]
Units: Participants
Any AE	315	316	314
Any SAE	49	35	38

Notes
[37] - ITT Population.
[38] - ITT Population.
[39] - ITT Population.

No statistical analyses for this end point

Secondary: Percentage of responders based on the Saint (St) George Respiratory Questionnaire COPD specific (SGRQ-C) Total Score

Top of page

End point title

Percentage of responders based on the Saint (St) George Respiratory Questionnaire COPD specific (SGRQ-C) Total Score

End point description

SGRQ-C is a disease-specific questionnaire designed to measure impact of respiratory disease and its treatment on HRQoL of participants with COPD. It contains 14 questions with a total of 40 items grouped into domains (Symptoms, Activity and Impacts). SGRQ-C total score was calculated as 100 multiplied by summed weights from all positive items divided by sum of weights for all items in questionnaire. It ranges from 0 to 100, higher score indicates poor HRQoL. SGRQ-C total score was converted to SGRQ total score by multiplying (SGRQ-Cx0.90) + 3.10 units. Analysis was performed using a generalized linear mixed model with treatment as an explanatory variable and visit, Baseline SGRQ score, stratum (no. of bronchodilators per day during run-in), geographical region, visit by Baseline and visit by treatment interactions included as covariates. Response was defined as an SGRQ total score of 4 or more units below Baseline.

End point type

Secondary

End point timeframe

Week 24

End point values	UMEC/VI 62.5/25 mcg+ Placebo	UMEC 62.5 mcg + Placebo	Salmeterol 50 mcg+Placebo
Number of subjects analysed	811 ^[40]	802 ^[41]	809 ^[42]
Units: Percentage of responders	45	41	36

Notes
[40] - ITT Population. Participants represents those with data available at the time point being presented
[41] - ITT Population. Participants represents those with data available at the time point being presented
[42] - ITT Population. Participants represents those with data available at the time point being presented

Statistical analysis 1

Statistical analysis description

Odds Ratio (responder vs. a non-responder) comparing UMEC/VI versus UMEC at Week 24.

Comparison groups

UMEC/VI 62.5/25 mcg+ Placebo v UMEC 62.5 mcg + Placebo

Number of subjects included in analysis

1613

Analysis specification

Pre-specified

Analysis type

P-value

= 0.063

Method

generalized linear mixed model

Parameter type

Odds ratio (OR)

Point estimate

1.21

Confidence interval

level

95%

sides

2-sided

lower limit

0.99

upper limit

1.48

Statistical analysis 2

Statistical analysis description

Odds Ratio (responder vs. a non-responder) comparing UMEC/VI versus salmeterol at Week 24.

Comparison groups

UMEC/VI 62.5/25 mcg+ Placebo v Salmeterol 50 mcg+Placebo

Number of subjects included in analysis

1620

Analysis specification

Pre-specified

Analysis type

P-value

< 0.001

Method

generalized linear mixed model

Parameter type

Odds ratio (OR)

Point estimate

1.49

Confidence interval

level

95%

sides

2-sided

lower limit

1.22

upper limit

1.83

Statistical analysis 3

Statistical analysis description

Odds Ratio (responder vs. a non-responder) comparing UMEC versus salmeterol at Week 24.

Comparison groups

UMEC 62.5 mcg + Placebo v Salmeterol 50 mcg+Placebo

Number of subjects included in analysis

1611

Analysis specification

Pre-specified

Analysis type

P-value

= 0.045

Method

generalized linear mixed model

Parameter type

Odds ratio (OR)

Point estimate

1.23

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

1.51

Adverse events

Top of page

Timeframe for reporting adverse events

On-Treatment serious adverse events (SAEs) and non-serious AEs (nSAEs) were collected from start of study treatment until Week 24.

Adverse event reporting additional description

On-Treatment SAEs and nSAEs were reported for ITT Population.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

21.0

Reporting group title

UMEC/VI 62.5/25 mcg+ Placebo

Reporting group description

Participants with COPD received UMEC/VI 62.5/25 mcg once daily via the ELLIPTA DPI along with placebo BID via the DISKUS DPI for 24 weeks. In addition albuterol/salbutamol was provided to participants to use on an as-needed basis for relief of COPD symptoms throughout the study. Participants were followed up 7 days after the last dose of study medication.

Reporting group title

Salmeterol 50 mcg+Placebo

Reporting group description

Reporting group title

UMEC 62.5 mcg + Placebo

Reporting group description

Serious adverse events	UMEC/VI 62.5/25 mcg+ Placebo	Salmeterol 50 mcg+Placebo	UMEC 62.5 mcg + Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	49 / 812 (6.03%)	38 / 809 (4.70%)	35 / 804 (4.35%)
number of deaths (all causes)	4	0	4
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder neoplasm
subjects affected / exposed	1 / 812 (0.12%)	1 / 809 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Small cell lung cancer
subjects affected / exposed	0 / 812 (0.00%)	1 / 809 (0.12%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma of lung
subjects affected / exposed	1 / 812 (0.12%)	1 / 809 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Adenocarcinoma of colon
subjects affected / exposed	0 / 812 (0.00%)	0 / 809 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Adenosquamous cell lung cancer
subjects affected / exposed	1 / 812 (0.12%)	0 / 809 (0.00%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Benign lung neoplasm
subjects affected / exposed	1 / 812 (0.12%)	0 / 809 (0.00%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung neoplasm malignant
subjects affected / exposed	1 / 812 (0.12%)	0 / 809 (0.00%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Malignant melanoma
subjects affected / exposed	1 / 812 (0.12%)	0 / 809 (0.00%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Meningioma
subjects affected / exposed	1 / 812 (0.12%)	0 / 809 (0.00%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Non-small cell lung cancer metastatic
subjects affected / exposed	0 / 812 (0.00%)	1 / 809 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Papillary cystadenoma lymphomatosum
subjects affected / exposed	0 / 812 (0.00%)	0 / 809 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	0 / 812 (0.00%)	1 / 809 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Peripheral arterial occlusive disease
subjects affected / exposed	1 / 812 (0.12%)	1 / 809 (0.12%)	2 / 804 (0.25%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haematoma
subjects affected / exposed	2 / 812 (0.25%)	0 / 809 (0.00%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Aortic stenosis
subjects affected / exposed	0 / 812 (0.00%)	0 / 809 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypertensive emergency
subjects affected / exposed	1 / 812 (0.12%)	0 / 809 (0.00%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	0 / 812 (0.00%)	1 / 809 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subclavian artery stenosis
subjects affected / exposed	1 / 812 (0.12%)	0 / 809 (0.00%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Varicose vein
subjects affected / exposed	0 / 812 (0.00%)	1 / 809 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Non-cardiac chest pain
subjects affected / exposed	0 / 812 (0.00%)	1 / 809 (0.12%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Asthenia
subjects affected / exposed	0 / 812 (0.00%)	0 / 809 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	0 / 812 (0.00%)	0 / 809 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	7 / 812 (0.86%)	9 / 809 (1.11%)	7 / 804 (0.87%)
occurrences causally related to treatment / all	0 / 7	0 / 9	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 2
Pneumothorax
subjects affected / exposed	0 / 812 (0.00%)	1 / 809 (0.12%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Acute respiratory failure
subjects affected / exposed	0 / 812 (0.00%)	0 / 809 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Hypoxia
subjects affected / exposed	0 / 812 (0.00%)	0 / 809 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung infiltration
subjects affected / exposed	1 / 812 (0.12%)	0 / 809 (0.00%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	1 / 812 (0.12%)	0 / 809 (0.00%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Depression
subjects affected / exposed	0 / 812 (0.00%)	1 / 809 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Rib fracture
subjects affected / exposed	1 / 812 (0.12%)	1 / 809 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Concussion
subjects affected / exposed	1 / 812 (0.12%)	0 / 809 (0.00%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Craniocerebral injury
subjects affected / exposed	1 / 812 (0.12%)	0 / 809 (0.00%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fibula fracture
subjects affected / exposed	0 / 812 (0.00%)	0 / 809 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	0 / 812 (0.00%)	1 / 809 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Post-thoracotomy pain syndrome
subjects affected / exposed	1 / 812 (0.12%)	0 / 809 (0.00%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed	1 / 812 (0.12%)	0 / 809 (0.00%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tendon rupture
subjects affected / exposed	0 / 812 (0.00%)	1 / 809 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular pseudoaneurysm
subjects affected / exposed	0 / 812 (0.00%)	1 / 809 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	2 / 812 (0.25%)	2 / 809 (0.25%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	1 / 812 (0.12%)	0 / 809 (0.00%)	2 / 804 (0.25%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	1 / 812 (0.12%)	0 / 809 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1
Cardio-respiratory arrest
subjects affected / exposed	1 / 812 (0.12%)	0 / 809 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1
Acute coronary syndrome
subjects affected / exposed	1 / 812 (0.12%)	0 / 809 (0.00%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	0 / 812 (0.00%)	1 / 809 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Angina unstable
subjects affected / exposed	1 / 812 (0.12%)	0 / 809 (0.00%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrioventricular block complete
subjects affected / exposed	0 / 812 (0.00%)	0 / 809 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	1 / 812 (0.12%)	0 / 809 (0.00%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	0 / 812 (0.00%)	0 / 809 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	1 / 812 (0.12%)	0 / 809 (0.00%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ventricular fibrillation
subjects affected / exposed	0 / 812 (0.00%)	1 / 809 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Transient ischaemic attack
subjects affected / exposed	1 / 812 (0.12%)	0 / 809 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Basilar artery stenosis
subjects affected / exposed	0 / 812 (0.00%)	0 / 809 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Brain stem stroke
subjects affected / exposed	0 / 812 (0.00%)	0 / 809 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebellar infarction
subjects affected / exposed	1 / 812 (0.12%)	0 / 809 (0.00%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	0 / 812 (0.00%)	1 / 809 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	0 / 812 (0.00%)	0 / 809 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Presyncope
subjects affected / exposed	0 / 812 (0.00%)	1 / 809 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Status epilepticus
subjects affected / exposed	0 / 812 (0.00%)	0 / 809 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tethered cord syndrome
subjects affected / exposed	0 / 812 (0.00%)	0 / 809 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 812 (0.00%)	1 / 809 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Microcytic anaemia
subjects affected / exposed	0 / 812 (0.00%)	0 / 809 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Splenic infarction
subjects affected / exposed	1 / 812 (0.12%)	0 / 809 (0.00%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	1 / 812 (0.12%)	0 / 809 (0.00%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Small intestinal obstruction
subjects affected / exposed	2 / 812 (0.25%)	0 / 809 (0.00%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	1 / 812 (0.12%)	0 / 809 (0.00%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Duodenal ulcer
subjects affected / exposed	0 / 812 (0.00%)	0 / 809 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Enteritis
subjects affected / exposed	0 / 812 (0.00%)	1 / 809 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Enterocolitis haemorrhagic
subjects affected / exposed	0 / 812 (0.00%)	0 / 809 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Femoral hernia strangulated
subjects affected / exposed	1 / 812 (0.12%)	0 / 809 (0.00%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastric polyps
subjects affected / exposed	1 / 812 (0.12%)	0 / 809 (0.00%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastric ulcer
subjects affected / exposed	0 / 812 (0.00%)	0 / 809 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	1 / 812 (0.12%)	0 / 809 (0.00%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 812 (0.12%)	0 / 809 (0.00%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 812 (0.00%)	0 / 809 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Large intestine polyp
subjects affected / exposed	1 / 812 (0.12%)	0 / 809 (0.00%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	1 / 812 (0.12%)	0 / 809 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 812 (0.00%)	0 / 809 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Rotator cuff syndrome
subjects affected / exposed	2 / 812 (0.25%)	0 / 809 (0.00%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	0 / 812 (0.00%)	1 / 809 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal pain
subjects affected / exposed	0 / 812 (0.00%)	1 / 809 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Synovial cyst
subjects affected / exposed	0 / 812 (0.00%)	1 / 809 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	4 / 812 (0.49%)	5 / 809 (0.62%)	4 / 804 (0.50%)
occurrences causally related to treatment / all	0 / 4	0 / 5	0 / 4
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Sepsis
subjects affected / exposed	2 / 812 (0.25%)	0 / 809 (0.00%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Appendicitis perforated
subjects affected / exposed	0 / 812 (0.00%)	0 / 809 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bacterial colitis
subjects affected / exposed	0 / 812 (0.00%)	1 / 809 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Encephalitis
subjects affected / exposed	0 / 812 (0.00%)	0 / 809 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infective exacerbation of chronic obstructive airways disease
subjects affected / exposed	0 / 812 (0.00%)	1 / 809 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Muscle abscess
subjects affected / exposed	1 / 812 (0.12%)	0 / 809 (0.00%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	1 / 812 (0.12%)	0 / 809 (0.00%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	1 / 812 (0.12%)	0 / 809 (0.00%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 812 (0.00%)	0 / 809 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 812 (0.00%)	1 / 809 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolic acidosis
subjects affected / exposed	1 / 812 (0.12%)	0 / 809 (0.00%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	UMEC/VI 62.5/25 mcg+ Placebo	Salmeterol 50 mcg+Placebo	UMEC 62.5 mcg + Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	68 / 812 (8.37%)	84 / 809 (10.38%)	87 / 804 (10.82%)
Infections and infestations
Nasopharyngitis
subjects affected / exposed	68 / 812 (8.37%)	84 / 809 (10.38%)	87 / 804 (10.82%)
occurrences all number	81	94	103

More information

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Were there any global substantial amendments to the protocol? Yes

07 Feb 2017

Amendment 1:: Regulatory Agency Identifying Number(s): A typographical error in the EudraCT no. corrected. IND no. added. Section 4.1and Section 4.4: Typographical errors and inconsistencies corrected. Inconsistencies between Section 4.4, Section 7.3.1.5 and Section 7.1 revised. Section 7.1 Time and Events table: Un-intentional deletion of the (“x”) were added to confirm that concomitant medications should be reviewed at every clinic visit was corrected. Increased the visit window. Typographical error and inconsistencies corrected as described in Appendix 9, Section 12.9. Section 7.2.2 Critical procedures performed at Screening (Visit 1): To clarify that height and weight are collected at Visit 1 “Height and weight” added. Section 7.3.2 Spirometry: “At Screening, before the morning dose of usual COPD. medication(s)” added. Section 7.3.7: Physical activity monitor (study subset). Inconsistency between Section 1, Section 4.1 and Section 7.3.7 revised.

21 Feb 2017

Amendment 2 : This protocol amendment was created to comply with Health Canada guidelines. They require pharmaceutical manufacturers to expeditiously report domestic cases of unusual failure in efficacy (UFIE) for new drugs to the Marketed Health Products Directorate (MHPD) within 15 days of first notification. Changes were made to Section 7.4.1 and Appendix 4.

18 Apr 2017

Amendment 3: Clarifications concerning study design, stratification, permitted and prohibited COPD medications, stopping criteria, visit windows, chest x-rays performed in the context of the protocol and site professional expertise. Rate of COPD exacerbations from tertiary endpoints to exploratory endpoints. Addition of an inclusion criterion specific to France. Integration of Canadian Amendment 2, Correction of typographical errors and inconsistencies.

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

Clinical Trial Results:
A 24-week treatment, multi-center, randomized, double-blind, double-dummy, parallel group study to compare Umeclidinium/Vilanterol, Umeclidinium, and Salmeterol in subjects with chronic obstructive pulmonary disease (COPD)

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

Secondary: Self administered computerized (SAC) transient dyspnea index (TDI) Focal score at Week 24

Secondary: Self administered computerized (SAC) transient dyspnea index (TDI) Focal score at Week 24

Secondary: Percentage of TDI responders according to SAC TDI Focal score

Secondary: Percentage of TDI responders according to SAC TDI Focal score

Secondary: Mean change from Baseline in Evaluating Respiratory Symptoms (E-RS) total score

Secondary: Mean change from Baseline in Evaluating Respiratory Symptoms (E-RS) total score

Secondary: Mean change from Baseline in E-RS Subscale Score

Secondary: Mean change from Baseline in E-RS Subscale Score

Secondary: Percentage of E-RS responders according to E-RS total score

Secondary: Percentage of E-RS responders according to E-RS total score

Secondary: Change from Baseline in St George’s Respiratory Questionnaire (SGRQ) total score

Secondary: Change from Baseline in St George’s Respiratory Questionnaire (SGRQ) total score

Secondary: Change from Baseline in COPD assessment test (CAT)

Secondary: Change from Baseline in COPD assessment test (CAT)

Secondary: Percentage of responders according to CAT

Secondary: Percentage of responders according to CAT

Secondary: Number of participants with on treatment adverse events (AE) and serious adverse events (SAE)

Secondary: Number of participants with on treatment adverse events (AE) and serious adverse events (SAE)

Secondary: Percentage of responders based on the Saint (St) George Respiratory Questionnaire COPD specific (SGRQ-C) Total Score

Secondary: Percentage of responders based on the Saint (St) George Respiratory Questionnaire COPD specific (SGRQ-C) Total Score

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: A 24-week treatment, multi-center, randomized, double-blind, double-dummy, parallel group study to compare Umeclidinium/Vilanterol, Umeclidinium, and Salmeterol in subjects with chronic obstructive pulmonary disease (COPD)

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

Secondary: Self administered computerized (SAC) transient dyspnea index (TDI) Focal score at Week 24

Secondary: Self administered computerized (SAC) transient dyspnea index (TDI) Focal score at Week 24

Secondary: Percentage of TDI responders according to SAC TDI Focal score

Secondary: Percentage of TDI responders according to SAC TDI Focal score

Secondary: Mean change from Baseline in Evaluating Respiratory Symptoms (E-RS) total score

Secondary: Mean change from Baseline in Evaluating Respiratory Symptoms (E-RS) total score

Secondary: Mean change from Baseline in E-RS Subscale Score

Secondary: Mean change from Baseline in E-RS Subscale Score

Secondary: Percentage of E-RS responders according to E-RS total score

Secondary: Percentage of E-RS responders according to E-RS total score

Secondary: Change from Baseline in St George’s Respiratory Questionnaire (SGRQ) total score

Secondary: Change from Baseline in St George’s Respiratory Questionnaire (SGRQ) total score

Secondary: Change from Baseline in COPD assessment test (CAT)

Secondary: Change from Baseline in COPD assessment test (CAT)

Secondary: Percentage of responders according to CAT

Secondary: Percentage of responders according to CAT

Secondary: Number of participants with on treatment adverse events (AE) and serious adverse events (SAE)

Secondary: Number of participants with on treatment adverse events (AE) and serious adverse events (SAE)

Secondary: Percentage of responders based on the Saint (St) George Respiratory Questionnaire COPD specific (SGRQ-C) Total Score

Secondary: Percentage of responders based on the Saint (St) George Respiratory Questionnaire COPD specific (SGRQ-C) Total Score

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A 24-week treatment, multi-center, randomized, double-blind, double-dummy, parallel group study to compare Umeclidinium/Vilanterol, Umeclidinium, and Salmeterol in subjects with chronic obstructive pulmonary disease (COPD)