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Clinical Trial Results:
A multicenter, randomized, 52-week, double-blind, parallel-group, active controlled study to compare the efficacy and safety of QVM149 with QMF149 in patients with asthma

Summary
EudraCT number	2015-002899-25
Trial protocol	EE LT DE SK PT AT HU NL FI BE ES DK LV GR FR BG IE HR SI IT
Global end of trial date	14 Jun 2019

Results information
Results version number	v3(current)
This version publication date	21 May 2021
First version publication date	28 Jun 2020
Other versions	v1 , v2
Version creation reason	Correction of full data set Additional text added in the field Adverse Events reporting additional description.

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

CQVM149B2302

ISRCTN number

US NCT number

NCT02571777

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Pharma AG

Sponsor organisation address

CH-4002, Basel, Switzerland,

Public contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com

Scientific contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.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

14 Jun 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

14 Jun 2019

Was the trial ended prematurely?

Main objective of the trial

The primary objective was to demonstrate superiority of either QVM149 150/50/80 μg o.d. to QMF149 150/160 μg o.d. or QVM149 150/50/160 μg o.d. to QMF149 150/320 μg o.d., all delivered via Concept1 in terms of trough Forced Expiratory Volume in 1 second (FEV1) after 26 weeks of treatment in patients with asthma.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial. At Visit 1, all patients were provided with a SABA (100 μg salbutamol/90 μg albuterol) via metered-dose inhaler (MDI) which they were instructed to use throughout the study as rescue medication.

Background therapy

Evidence for comparator

Actual start date of recruitment

08 Dec 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Slovakia: 76

Country: Number of subjects enrolled

South Africa: 46

Country: Number of subjects enrolled

Spain: 49

Country: Number of subjects enrolled

Sweden: 12

Country: Number of subjects enrolled

Switzerland: 14

Country: Number of subjects enrolled

Thailand: 31

Country: Number of subjects enrolled

United Kingdom: 9

Country: Number of subjects enrolled

Vietnam: 28

Country: Number of subjects enrolled

Jordan: 7

Country: Number of subjects enrolled

Argentina: 424

Country: Number of subjects enrolled

Austria: 19

Country: Number of subjects enrolled

Belgium: 42

Country: Number of subjects enrolled

Bulgaria: 59

Country: Number of subjects enrolled

Canada: 37

Country: Number of subjects enrolled

Chile: 58

Country: Number of subjects enrolled

China: 66

Country: Number of subjects enrolled

Colombia: 16

Country: Number of subjects enrolled

Croatia: 11

Country: Number of subjects enrolled

Denmark: 2

Country: Number of subjects enrolled

Estonia: 29

Country: Number of subjects enrolled

Finland: 1

Country: Number of subjects enrolled

France: 3

Country: Number of subjects enrolled

Germany: 208

Country: Number of subjects enrolled

Greece: 57

Country: Number of subjects enrolled

Hungary: 142

Country: Number of subjects enrolled

India: 392

Country: Number of subjects enrolled

Ireland: 7

Country: Number of subjects enrolled

Israel: 97

Country: Number of subjects enrolled

Italy: 31

Country: Number of subjects enrolled

Japan: 78

Country: Number of subjects enrolled

Latvia: 60

Country: Number of subjects enrolled

Lebanon: 7

Country: Number of subjects enrolled

Lithuania: 75

Country: Number of subjects enrolled

Mexico: 47

Country: Number of subjects enrolled

Netherlands: 33

Country: Number of subjects enrolled

Peru: 26

Country: Number of subjects enrolled

Philippines: 55

Country: Number of subjects enrolled

Poland: 161

Country: Number of subjects enrolled

Portugal: 10

Country: Number of subjects enrolled

Romania: 132

Country: Number of subjects enrolled

Russian Federation: 435

Worldwide total number of subjects

3092

EEA total number of subjects

1228

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)

2523

From 65 to 84 years

569

85 years and over

Subject disposition

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Recruitment details

Participants took part in 415 investigative sites in 41 countries.

Screening details

4851 participants were screened of which 3092 participants were randomized to 1 of the 5 treatment groups with a randomization ratio of 1:1:1:1:1.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Data analyst, Assessor

Are arms mutually exclusive

Yes

QVM149 150/50/160 µg o.d.

Arm description

QVM149 150/50/160 μg (indacaterol acetate/glycopyrronium/mometasone furoate) once daily (o.d.) delivered via Concept1 device

Arm type

Experimental

Investigational medicinal product name

QVM149 150/50/160 μg (indacaterol acetate/glycopyrronium bromide/mometasone furoate)

Investigational medicinal product code

QVM149

Other name

Pharmaceutical forms

Inhalation powder, hard capsule

Routes of administration

Inhalation use

Dosage and administration details

Once daily (o.d.) delivered via Concept1 device

QVM149 150/50/80 µg o.d.

Arm description

QVM149 150/50/80 μg (indacaterol acetate/glycopyrronium/mometasone furoate) once daily (o.d.) delivered via Concept1 device

Arm type

Experimental

Investigational medicinal product name

QVM149 150/50/80 μg (indacaterol acetate/glycopyrronium bromide/mometasone furoate)

Investigational medicinal product code

QVM149

Other name

Pharmaceutical forms

Inhalation powder, hard capsule

Routes of administration

Inhalation use

Dosage and administration details

Once daily (o.d.) delivered via Concept1 device

QMF149 150/320 µg o.d.

Arm description

QMF149 150/320 μg (indacaterol acetate/mometasone furoate) once daily (o.d.) delivered via Concept1 device

Arm type

Active comparator

Investigational medicinal product name

QMF149 150/320 μg (indacaterol acetate/mometasone furoate)

Investigational medicinal product code

QMF149

Other name

Pharmaceutical forms

Inhalation powder, hard capsule

Routes of administration

Inhalation use

Dosage and administration details

Once daily (o.d.) delivered via Concept1 device

QMF149 150/160 µg o.d.

Arm description

QMF149 150/160 μg (indacaterol acetate/mometasone furoate) once daily (o.d.) delivered via Concept1 device

Arm type

Active comparator

Investigational medicinal product name

QMF149 150/160 μg (indacaterol acetate/mometasone furoate)

Investigational medicinal product code

QMF149

Other name

Pharmaceutical forms

Inhalation powder, hard capsule

Routes of administration

Inhalation use

Dosage and administration details

Once daily (o.d.) delivered via Concept1 device

Salmeterol/fluticasone 50/500 μg b.i.d.

Arm description

Salmeterol xinafoate /fluticasone propionate 50/500 μg twice daily (b.i.d.) delivered via Accuhaler®

Arm type

Active comparator

Investigational medicinal product name

QVM149 150/50/160 μg (indacaterol acetate/glycopyrronium/mometasone furoate)

Investigational medicinal product code

QVM149

Other name

Pharmaceutical forms

Inhalation powder

Routes of administration

Inhalation use

Dosage and administration details

Twice daily (b.i.d.) delivered via Accuhaler®

Number of subjects in period 1	QVM149 150/50/160 µg o.d.	QVM149 150/50/80 µg o.d.	QMF149 150/320 µg o.d.	QMF149 150/160 µg o.d.	Salmeterol/fluticasone 50/500 μg b.i.d.
Started	619	620	618	617	618
Full Analysis Set (FAS)	615	616	611	607	612
Safety Set (SAF)	616	617	613	608	618
Completed	580	582	577	580	582
Not completed	39	38	41	37	36
Adverse event, serious fatal	1	1	4	-	-
Physician decision	1	7	5	2	4
Protocol Deviation	2	3	4	8	4
Pregnancy	-	-	-	2	-
Lost to follow-up	1	1	2	-	1
Subject/guardian decision	34	26	26	25	27

Baseline characteristics

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Reporting group title

QVM149 150/50/160 µg o.d.

Reporting group description

QVM149 150/50/160 μg (indacaterol acetate/glycopyrronium/mometasone furoate) once daily (o.d.) delivered via Concept1 device

Reporting group title

QVM149 150/50/80 µg o.d.

Reporting group description

QVM149 150/50/80 μg (indacaterol acetate/glycopyrronium/mometasone furoate) once daily (o.d.) delivered via Concept1 device

Reporting group title

QMF149 150/320 µg o.d.

Reporting group description

QMF149 150/320 μg (indacaterol acetate/mometasone furoate) once daily (o.d.) delivered via Concept1 device

Reporting group title

QMF149 150/160 µg o.d.

Reporting group description

QMF149 150/160 μg (indacaterol acetate/mometasone furoate) once daily (o.d.) delivered via Concept1 device

Reporting group title

Salmeterol/fluticasone 50/500 μg b.i.d.

Reporting group description

Salmeterol xinafoate /fluticasone propionate 50/500 μg twice daily (b.i.d.) delivered via Accuhaler®

Reporting group values	QVM149 150/50/160 µg o.d.	QVM149 150/50/80 µg o.d.	QMF149 150/320 µg o.d.	QMF149 150/160 µg o.d.	Salmeterol/fluticasone 50/500 μg b.i.d.	Total
Number of subjects	619	620	618	617	618	3092
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0
Adults (18-64 years)	507	504	514	502	496	2523
From 65-84 years	112	116	104	115	122	569
85 years and over	0	0	0	0	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	52.1 ± 12.91	52.4 ± 12.71	52.0 ± 12.81	51.8 ± 12.86	52.9 ± 12.23	-
Sex: Female, Male
Units: Participants
Female	381	362	380	378	417	1918
Male	238	258	238	239	201	1174
Race/Ethnicity, Customized
Units: Subjects
Caucasian	456	458	453	452	468	2287
Black	4	5	3	4	1	17
Asian	139	133	133	135	131	671
Native American	7	8	8	4	5	32
Unknown	0	0	0	1	0	1
Other	13	16	21	21	13	84

End points

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Reporting group title

QVM149 150/50/160 µg o.d.

Reporting group description

QVM149 150/50/160 μg (indacaterol acetate/glycopyrronium/mometasone furoate) once daily (o.d.) delivered via Concept1 device

Reporting group title

QVM149 150/50/80 µg o.d.

Reporting group description

QVM149 150/50/80 μg (indacaterol acetate/glycopyrronium/mometasone furoate) once daily (o.d.) delivered via Concept1 device

Reporting group title

QMF149 150/320 µg o.d.

Reporting group description

QMF149 150/320 μg (indacaterol acetate/mometasone furoate) once daily (o.d.) delivered via Concept1 device

Reporting group title

QMF149 150/160 µg o.d.

Reporting group description

QMF149 150/160 μg (indacaterol acetate/mometasone furoate) once daily (o.d.) delivered via Concept1 device

Reporting group title

Salmeterol/fluticasone 50/500 μg b.i.d.

Reporting group description

Salmeterol xinafoate /fluticasone propionate 50/500 μg twice daily (b.i.d.) delivered via Accuhaler®

Primary: Trough Forced Expiratory Volume in 1 Second (Trough FEV1) of QVM149 versus QMF149 at week 26

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End point title

Trough Forced Expiratory Volume in 1 Second (Trough FEV1) of QVM149 versus QMF149 at week 26

End point description

Trough FEV1 was assessed by performing spirometric assessment. It is defined as average of the two FEV1 measurements taken 23 hr 15 min and 23 hr 45 min post-evening dose. FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation, measured through spirometry testing. The primary endpoint considered the following 2 comparison groups: - QVM149 150/50/80 μg o.d. compared with QMF149 150/160 μg o.d. both delivered via Concept1 - QVM149 150/50/160 μg o.d. compared with QMF149 150/320 μg o.d. both delivered via Concept1.

End point type

Primary

End point timeframe

26 weeks

End point values	QVM149 150/50/160 µg o.d.	QVM149 150/50/80 µg o.d.	QMF149 150/320 µg o.d.	QMF149 150/160 µg o.d.	Salmeterol/fluticasone 50/500 μg b.i.d.
Number of subjects analysed	614	614	606	602	607
Units: litre (L)
least squares mean (standard error)	2.050 ± 0.0128	2.029 ± 0.0129	1.984 ± 0.0129	1.953 ± 0.0130	1.930 ± 0.0131

QVM149 150/50/160 µg vs QMF149 150/320 µg

Comparison groups

QMF149 150/320 µg o.d. v QVM149 150/50/160 µg o.d.

Number of subjects included in analysis

1220

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

LS Mean

Point estimate

0.065

Confidence interval

level

95%

sides

2-sided

lower limit

0.031

upper limit

0.099

Variability estimate

Standard error of the mean

Dispersion value

0.0176

QVM149 150/50/80 µg vs QMF149 150/160 µg

Comparison groups

QVM149 150/50/80 µg o.d. v QMF149 150/160 µg o.d.

Number of subjects included in analysis

1216

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.076

Confidence interval

level

95%

sides

2-sided

lower limit

0.041

upper limit

0.111

Variability estimate

Standard error of the mean

Dispersion value

0.0176

Secondary: Asthma Control Questionnaire (ACQ-7) at Week 26 and Week 52

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End point title

Asthma Control Questionnaire (ACQ-7) at Week 26 and Week 52

End point description

The ACQ-7 measured asthma symptom control and consists of 7 items: 5 on symptom assessment, 1 on rescue bronchodilator use and 1 on airway calibre (FEV1 % predicted). All 7 questions of the ACQ-7 were equally weighted. Items 1-5 were scored along a 7-point response scale, where 0 = totally controlled and 6 = severely uncontrolled. Item 6 is scored between 0 = no rescue medication and 6 = More than 16 puffs/inhalations most days. The 7th item was scored by the investigator based on the FEV1 % predicted from the masterscope at the site (i.e., Score = 0 means > 95% of predicted FEV1, 1 = 90 - 95%, 2 = 80 - 89%, 3 = 70 - 79%, 4 = 60 - 69%, 5 = 50 - 59%, and Score = 6 means < 50% of predicted FEV1). The ACQ-7 total score reported below was calculated as the mean of scores of all 7 items and ranged between 0 and 6, with higher scores indicating worse asthma symptom control.

End point type

Secondary

End point timeframe

26 weeks, 52 weeks

End point values	QVM149 150/50/160 µg o.d.	QVM149 150/50/80 µg o.d.	QMF149 150/320 µg o.d.	QMF149 150/160 µg o.d.	Salmeterol/fluticasone 50/500 μg b.i.d.
Number of subjects analysed	607	595	596	598	599
Units: Score on a scale
least squares mean (standard error)
Week 26	1.542 ± 0.0329	1.543 ± 0.0330	1.528 ± 0.0329	1.614 ± 0.0331	1.628 ± 0.0329
Week 52	1.406 ± 0.0334	1.535 ± 0.0337	1.465 ± 0.0335	1.545 ± 0.0338	1.527 ± 0.0335

QVM149 150/50/160 µg vs QMF149 150/320 µg

Statistical analysis description

Week 26

Comparison groups

QVM149 150/50/160 µg o.d. v QMF149 150/320 µg o.d.

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.729

Method

MMRM

Parameter type

LS Mean

Point estimate

0.014

Confidence interval

level

95%

sides

2-sided

lower limit

-0.066

upper limit

0.094

Variability estimate

Standard error of the mean

Dispersion value

0.0406

QVM149 150/50/160 µg vs S/F 50/500 µg

Statistical analysis description

Week 26

Comparison groups

QVM149 150/50/160 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1206

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.034

Method

MMRM

Parameter type

LS Mean

Point estimate

-0.086

Confidence interval

level

95%

sides

2-sided

lower limit

-0.165

upper limit

-0.006

Variability estimate

Standard error of the mean

Dispersion value

0.0404

QVM149 150/50/80 µg vs QMF149 150/160 µg

Statistical analysis description

Week 26

Comparison groups

QVM149 150/50/80 µg o.d. v QMF149 150/160 µg o.d.

Number of subjects included in analysis

1193

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.085

Method

MMRM

Parameter type

LS Mean

Point estimate

-0.071

Confidence interval

level

95%

sides

2-sided

lower limit

-0.151

upper limit

0.01

Variability estimate

Standard error of the mean

Dispersion value

0.0409

QVM149 150/50/80 µg vs S/F 50/500 µg

Statistical analysis description

Week 26

Comparison groups

QVM149 150/50/80 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1194

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.038

Method

MMRM

Parameter type

LS Mean

Point estimate

-0.084

Confidence interval

level

95%

sides

2-sided

lower limit

-0.164

upper limit

-0.005

Variability estimate

Standard error of the mean

Dispersion value

0.0406

QVM149 150/50/160 µg vs QMF149 150/320 µg

Statistical analysis description

Week 52

Comparison groups

QVM149 150/50/160 µg o.d. v QMF149 150/320 µg o.d.

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.157

Method

MMRM

Parameter type

LS Mean

Point estimate

-0.059

Confidence interval

level

95%

sides

2-sided

lower limit

-0.14

upper limit

0.023

Variability estimate

Standard error of the mean

Dispersion value

0.0415

QVM149 150/50/160 µg vs S/F 50/500 µg

Statistical analysis description

Week 52

Comparison groups

QVM149 150/50/160 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1206

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.003

Method

MMRM

Parameter type

LS Mean

Point estimate

-0.121

Confidence interval

level

95%

sides

2-sided

lower limit

-0.202

upper limit

-0.04

Variability estimate

Standard error of the mean

Dispersion value

0.0414

QVM149 150/50/80 µg vs QMF149 150/160 µg

Statistical analysis description

Week 52

Comparison groups

QVM149 150/50/80 µg o.d. v QMF149 150/160 µg o.d.

Number of subjects included in analysis

1193

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.814

Method

MMRM

Parameter type

LS Mean

Point estimate

-0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.092

upper limit

0.072

Variability estimate

Standard error of the mean

Dispersion value

0.042

QVM149 150/50/80 µg vs S/F 50/500 µg

Statistical analysis description

Week 52

Comparison groups

QVM149 150/50/80 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1194

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.845

Method

MMRM

Parameter type

LS Mean

Point estimate

0.008

Confidence interval

level

95%

sides

2-sided

lower limit

-0.073

upper limit

0.09

Variability estimate

Standard error of the mean

Dispersion value

0.0416

Secondary: Trough Forced Expiratory Volume in 1 Second (Trough FEV1) of QVM149 versus salmeterol/fluticasone at week 26

Top of page

End point title

Trough Forced Expiratory Volume in 1 Second (Trough FEV1) of QVM149 versus salmeterol/fluticasone at week 26

End point description

Trough FEV1 was assessed by performing spirometric assessment. It is defined as average of the two FEV1 measurements taken 23 hr 15 min and 23 hr 45 min post-evening dose. FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation, measured through spirometry testing. This secondary endpoint considered the following 2 comparison groups: - QVM149 150/50/80 μg o.d. via Concept1 compared with salmeterol/fluticasone 50/500 μg b.i.d. via Accuhaler® - QVM149 150/50/160 μg o.d. via Concept 1 compared with salmeterol/fluticasone 50/500 μg b.i.d. via Accuhaler®

End point type

Secondary

End point timeframe

26 weeks

End point values	QVM149 150/50/160 µg o.d.	QVM149 150/50/80 µg o.d.	QMF149 150/320 µg o.d.	QMF149 150/160 µg o.d.	Salmeterol/fluticasone 50/500 μg b.i.d.
Number of subjects analysed	614	614	606	602	607
Units: litre (L)
least squares mean (standard error)	2.050 ± 0.0128	2.029 ± 0.0129	1.984 ± 0.0129	1.953 ± 0.0130	1.930 ± 0.0131

QVM149 150/50/160 µg vs S/F 50/500 µg

Comparison groups

QVM149 150/50/160 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1221

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.119

Confidence interval

level

95%

sides

2-sided

lower limit

0.085

upper limit

0.154

Variability estimate

Standard error of the mean

Dispersion value

0.0177

QVM149 150/50/80 µg vs S/F 50/500 µg

Comparison groups

QVM149 150/50/80 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1221

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.099

Confidence interval

level

95%

sides

2-sided

lower limit

0.064

upper limit

0.133

Variability estimate

Standard error of the mean

Dispersion value

0.0177

Secondary: Trough FEV1 at week 52

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End point title

Trough FEV1 at week 52

End point description

End point type

Secondary

End point timeframe

52 weeks

End point values	QVM149 150/50/160 µg o.d.	QVM149 150/50/80 µg o.d.	QMF149 150/320 µg o.d.	QMF149 150/160 µg o.d.	Salmeterol/fluticasone 50/500 μg b.i.d.
Number of subjects analysed	614	614	606	602	607
Units: litre (L)
least squares mean (standard error)	2.050 ± 0.0129	1.992 ± 0.0130	1.965 ± 0.0130	1.930 ± 0.0130	1.905 ± 0.0132

QVM149 150/50/160 µg vs QMF149 150/320 µg

Comparison groups

QVM149 150/50/160 µg o.d. v QMF149 150/320 µg o.d.

Number of subjects included in analysis

1220

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.086

Confidence interval

level

95%

sides

2-sided

lower limit

0.051

upper limit

0.12

Variability estimate

Standard error of the mean

Dispersion value

0.0176

QVM149 150/50/160 µg vs S/F 50/500 µg

Comparison groups

QVM149 150/50/160 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1221

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.145

Confidence interval

level

95%

sides

2-sided

lower limit

0.111

upper limit

0.18

Variability estimate

Standard error of the mean

Dispersion value

0.0178

QVM149 150/50/80 µg vs QMF149 150/160 µg

Comparison groups

QVM149 150/50/80 µg o.d. v QMF149 150/160 µg o.d.

Number of subjects included in analysis

1216

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.062

Confidence interval

level

95%

sides

2-sided

lower limit

0.027

upper limit

0.096

Variability estimate

Standard error of the mean

Dispersion value

0.0178

QVM149 150/50/80 µg vs S/F 50/500 µg

Comparison groups

QVM149 150/50/80 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1221

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.087

Confidence interval

level

95%

sides

2-sided

lower limit

0.052

upper limit

0.122

Variability estimate

Standard error of the mean

Dispersion value

0.0179

Secondary: Pre-dose Forced Vital Capacity (FVC) at week 4 and week 12

Top of page

End point title

Pre-dose Forced Vital Capacity (FVC) at week 4 and week 12

End point description

Pre-dose FVC is defined as average of the two FVC measurements taken 45 min and 15 min pre evening dose. It was assessed by performing spirometric assessment. FVC is the total amount of air exhaled during the FEV test.

End point type

Secondary

End point timeframe

4 weeks, 12 weeks

End point values	QVM149 150/50/160 µg o.d.	QVM149 150/50/80 µg o.d.	QMF149 150/320 µg o.d.	QMF149 150/160 µg o.d.	Salmeterol/fluticasone 50/500 μg b.i.d.
Number of subjects analysed	606	594	592	596	598
Units: litre (L)
least squares mean (standard error)
Week 4	3.091 ± 0.0161	3.059 ± 0.0163	3.018 ± 0.0163	3.020 ± 0.0163	2.952 ± 0.0163
Week 12	3.067 ± 0.0162	3.065 ± 0.0164	3.011 ± 0.0163	3.014 ± 0.0164	2.965 ± 0.0163

QVM149 150/50/160 µg vs QMF149 150/320 µg

Statistical analysis description

Week 4

Comparison groups

QVM149 150/50/160 µg o.d. v QMF149 150/320 µg o.d.

Number of subjects included in analysis

1198

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.073

Confidence interval

level

95%

sides

2-sided

lower limit

0.03

upper limit

0.116

Variability estimate

Standard error of the mean

Dispersion value

0.0218

QVM149 150/50/160 µg vs S/F 50/500 µg

Statistical analysis description

Week 4

Comparison groups

QVM149 150/50/160 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1204

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.139

Confidence interval

level

95%

sides

2-sided

lower limit

0.096

upper limit

0.181

Variability estimate

Standard error of the mean

Dispersion value

0.0217

QVM149 150/50/80 µg vs QMF149 150/160 µg

Statistical analysis description

Week 4

Comparison groups

QVM149 150/50/80 µg o.d. v QMF149 150/160 µg o.d.

Number of subjects included in analysis

1190

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.074

Method

MMRM

Parameter type

LS Mean

Point estimate

0.039

Confidence interval

level

95%

sides

2-sided

lower limit

-0.004

upper limit

0.082

Variability estimate

Standard error of the mean

Dispersion value

0.022

QVM149 150/50/80 µg vs S/F 50/500 µg

Statistical analysis description

Week 4

Comparison groups

QVM149 150/50/80 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1192

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.108

Confidence interval

level

95%

sides

2-sided

lower limit

0.065

upper limit

0.15

Variability estimate

Standard error of the mean

Dispersion value

0.0219

QVM149 150/50/160 µg vs QMF149 150/320 µg

Statistical analysis description

Week 12

Comparison groups

QVM149 150/50/160 µg o.d. v QMF149 150/320 µg o.d.

Number of subjects included in analysis

1198

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.01

Method

MMRM

Parameter type

LS Mean

Point estimate

0.056

Confidence interval

level

95%

sides

2-sided

lower limit

0.014

upper limit

0.099

Variability estimate

Standard error of the mean

Dispersion value

0.0219

QVM149 150/50/160 µg vs S/F 50/500 µg

Statistical analysis description

Week 12

Comparison groups

QVM149 150/50/160 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1204

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.102

Confidence interval

level

95%

sides

2-sided

lower limit

0.059

upper limit

0.145

Variability estimate

Standard error of the mean

Dispersion value

0.0218

QVM149 150/50/80 µg vs QMF149 150/160 µg

Statistical analysis description

Week 12

Comparison groups

QVM149 150/50/80 µg o.d. v QMF149 150/160 µg o.d.

Number of subjects included in analysis

1190

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.022

Method

MMRM

Parameter type

LS Mean

Point estimate

0.05

Confidence interval

level

95%

sides

2-sided

lower limit

0.007

upper limit

0.094

Variability estimate

Standard error of the mean

Dispersion value

0.0221

QVM149 150/50/80 µg vs S/F 50/500 µg

Statistical analysis description

Week 12

Comparison groups

QVM149 150/50/80 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1192

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.099

Confidence interval

level

95%

sides

2-sided

lower limit

0.056

upper limit

0.142

Variability estimate

Standard error of the mean

Dispersion value

0.022

Secondary: Trough Forced Expiratory Flow (FEF) between 25% and 75% of FVC (FEF25-75) at 52 weeks

Top of page

End point title

Trough Forced Expiratory Flow (FEF) between 25% and 75% of FVC (FEF25-75) at 52 weeks

End point description

FEF is the flow (or speed) of air coming out of the lung during the middle portion of a forced expiration. Trough FEF25-75% is defined as average of the two FEF25-75% measurements taken 23 hr 15 min and 23 hr 45 min post-evening dose. It was assessed by performing spirometric assessment.

End point type

Secondary

End point timeframe

Up to Week 52

End point values	QVM149 150/50/160 µg o.d.	QVM149 150/50/80 µg o.d.	QMF149 150/320 µg o.d.	QMF149 150/160 µg o.d.	Salmeterol/fluticasone 50/500 μg b.i.d.
Number of subjects analysed	614	614	606	602	607
Units: L/s
least squares mean (standard error)	1.354 ± 0.0190	1.263 ± 0.0192	1.260 ± 0.0191	1.214 ± 0.0192	1.207 ± 0.0194

QVM149 150/50/160 µg vs QMF149 150/320 µg

Comparison groups

QVM149 150/50/160 µg o.d. v QMF149 150/320 µg o.d.

Number of subjects included in analysis

1220

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.095

Confidence interval

level

95%

sides

2-sided

lower limit

0.045

upper limit

0.145

Variability estimate

Standard error of the mean

Dispersion value

0.0254

QVM149 150/50/160 µg vs S/F 50/500 µg

Comparison groups

QVM149 150/50/160 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1221

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.147

Confidence interval

level

95%

sides

2-sided

lower limit

0.097

upper limit

0.198

Variability estimate

Standard error of the mean

Dispersion value

0.0256

QVM149 150/50/80 µg vs QMF149 150/160 µg

Comparison groups

QVM149 150/50/80 µg o.d. v QMF149 150/160 µg o.d.

Number of subjects included in analysis

1216

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.057

Method

MMRM

Parameter type

LS Mean

Point estimate

0.049

Confidence interval

level

95%

sides

2-sided

lower limit

-0.001

upper limit

0.099

Variability estimate

Standard error of the mean

Dispersion value

0.0256

QVM149 150/50/80 µg vs S/F 50/500 µg

Comparison groups

QVM149 150/50/80 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1221

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.029

Method

MMRM

Parameter type

LS Mean

Point estimate

0.056

Confidence interval

level

95%

sides

2-sided

lower limit

0.006

upper limit

0.107

Variability estimate

Standard error of the mean

Dispersion value

0.0258

Secondary: Change from baseline in morning and evening Peak Expiratory Flow Rate (PEF) over 26 and 52 weeks of treatment

Top of page

End point title

Change from baseline in morning and evening Peak Expiratory Flow Rate (PEF) over 26 and 52 weeks of treatment

End point description

PEF is a person's maximum speed of expiration. All the participants were instructed to record PEF twice daily using a mini Peak Flow Meter device, once in the morning (before taking the morning dose) and once approximately 12 h later in the evening (before taking the evening dose) at home. At each timepoint, the participant was instructed to perform 3 consecutive manoeuvres within 10 minutes. These PEF values were captured in the e-PEF/diary. The best of 3 values were used.

End point type

Secondary

End point timeframe

Baseline, 26 weeks, 52 weeks

End point values	QVM149 150/50/160 µg o.d.	QVM149 150/50/80 µg o.d.	QMF149 150/320 µg o.d.	QMF149 150/160 µg o.d.	Salmeterol/fluticasone 50/500 μg b.i.d.
Number of subjects analysed	596	584	581	584	586
Units: L/min
least squares mean (standard error)
Week 26 - Mean morning PEF	47.7 ± 1.93	40.5 ± 1.95	29.5 ± 1.95	25.6 ± 1.95	12.5 ± 1.95
Week 26 - Mean evening PEF	39.6 ± 1.87	34.7 ± 1.88	22.8 ± 1.88	20.6 ± 1.89	10.4 ± 1.89
Week 52 - Mean morning PEF	47.5 ± 2.03	41.2 ± 2.05	28.8 ± 2.05	25.6 ± 2.06	12.7 ± 2.05
Week 52 - Mean evening PEF	38.7 ± 1.97	35.0 ± 1.99	21.2 ± 1.99	20.1 ± 2.00	9.2 ± 1.99

QVM149 150/50/160 µg vs QMF149 150/320 µg

Statistical analysis description

Week 26 - Mean morning PEF

Comparison groups

QVM149 150/50/160 µg o.d. v QMF149 150/320 µg o.d.

Number of subjects included in analysis

1177

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Linear Mixed Model (LMM)

Parameter type

LS Mean

Point estimate

18.2

Confidence interval

level

95%

sides

2-sided

lower limit

13.2

upper limit

23.3

Variability estimate

Standard error of the mean

Dispersion value

2.59

QVM149 150/50/160 µg vs S/F 50/500 µg

Statistical analysis description

Week 26 - Mean morning PEF

Comparison groups

QVM149 150/50/160 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1182

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

LMM

Parameter type

LS Mean

Point estimate

35.3

Confidence interval

level

95%

sides

2-sided

lower limit

30.2

upper limit

40.3

Variability estimate

Standard error of the mean

Dispersion value

2.58

QVM149 150/50/80 µg vs QMF149 150/160 µg

Statistical analysis description

Week 26 - Mean morning PEF

Comparison groups

QVM149 150/50/80 µg o.d. v QMF149 150/160 µg o.d.

Number of subjects included in analysis

1168

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

LMM

Parameter type

LS Mean

Point estimate

14.9

Confidence interval

level

95%

sides

2-sided

lower limit

9.8

upper limit

Variability estimate

Standard error of the mean

Dispersion value

2.61

QVM149 150/50/80 µg vs S/F 50/500 µg

Statistical analysis description

Week 26 - Mean morning PEF

Comparison groups

QVM149 150/50/80 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1170

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

LMM

Parameter type

LS Mean

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

22.9

upper limit

33.1

Variability estimate

Standard error of the mean

Dispersion value

2.6

QVM149 150/50/160 µg vs QMF149 150/320 µg

Statistical analysis description

Week 26 - Mean evening PEF

Comparison groups

QVM149 150/50/160 µg o.d. v QMF149 150/320 µg o.d.

Number of subjects included in analysis

1177

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

LMM

Parameter type

LS Mean

Point estimate

16.8

Confidence interval

level

95%

sides

2-sided

lower limit

11.8

upper limit

21.7

Variability estimate

Standard error of the mean

Dispersion value

2.53

QVM149 150/50/160 µg vs S/F 50/500 µg

Statistical analysis description

Week 26 - Mean evening PEF

Comparison groups

QVM149 150/50/160 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1182

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

LMM

Parameter type

LS Mean

Point estimate

29.1

Confidence interval

level

95%

sides

2-sided

lower limit

24.2

upper limit

34.1

Variability estimate

Standard error of the mean

Dispersion value

2.53

QVM149 150/50/80 µg vs QMF149 150/160 µg

Statistical analysis description

Week 26 - Mean evening PEF

Comparison groups

QVM149 150/50/80 µg o.d. v QMF149 150/160 µg o.d.

Number of subjects included in analysis

1168

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

LMM

Parameter type

LS Mean

Point estimate

14.1

Confidence interval

level

95%

sides

2-sided

lower limit

9.1

upper limit

19.1

Variability estimate

Standard error of the mean

Dispersion value

2.55

QVM149 150/50/80 µg vs S/F 50/500 µg

Statistical analysis description

Week 26 - Mean evening PEF

Comparison groups

QVM149 150/50/80 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1170

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

LMM

Parameter type

LS Mean

Point estimate

24.3

Confidence interval

level

95%

sides

2-sided

lower limit

19.3

upper limit

29.3

Variability estimate

Standard error of the mean

Dispersion value

2.54

QVM149 150/50/160 µg vs QMF149 150/320 µg

Statistical analysis description

Week 52 - Mean morning PEF

Comparison groups

QVM149 150/50/160 µg o.d. v QMF149 150/320 µg o.d.

Number of subjects included in analysis

1177

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

LMM

Parameter type

LS Mean

Point estimate

18.7

Confidence interval

level

95%

sides

2-sided

lower limit

13.4

upper limit

24.1

Variability estimate

Standard error of the mean

Dispersion value

2.72

QVM149 150/50/160 µg vs S/F 50/500 µg

Statistical analysis description

Week 52 - Mean morning PEF

Comparison groups

QVM149 150/50/160 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1182

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

LMM

Parameter type

LS Mean

Point estimate

34.8

Confidence interval

level

95%

sides

2-sided

lower limit

29.5

upper limit

40.1

Variability estimate

Standard error of the mean

Dispersion value

2.7

QVM149 150/50/80 µg vs QMF149 150/160 µg

Statistical analysis description

Week 52 - Mean morning PEF

Comparison groups

QVM149 150/50/80 µg o.d. v QMF149 150/160 µg o.d.

Number of subjects included in analysis

1168

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

LMM

Parameter type

LS Mean

Point estimate

15.6

Confidence interval

level

95%

sides

2-sided

lower limit

10.2

upper limit

20.9

Variability estimate

Standard error of the mean

Dispersion value

2.74

QVM149 150/50/80 µg vs S/F 50/500 µg

Statistical analysis description

Week 52 - Mean morning PEF

Comparison groups

QVM149 150/50/80 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1170

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

LMM

Parameter type

LS Mean

Point estimate

28.5

Confidence interval

level

95%

sides

2-sided

lower limit

23.2

upper limit

33.8

Variability estimate

Standard error of the mean

Dispersion value

2.72

QVM149 150/50/160 µg vs QMF149 150/320 µg

Statistical analysis description

Week 52 - Mean evening PEF

Comparison groups

QVM149 150/50/160 µg o.d. v QMF149 150/320 µg o.d.

Number of subjects included in analysis

1177

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

LMM

Parameter type

LS Mean

Point estimate

17.5

Confidence interval

level

95%

sides

2-sided

lower limit

12.3

upper limit

22.8

Variability estimate

Standard error of the mean

Dispersion value

2.66

QVM149 150/50/160 µg vs S/F 50/500 µg

Statistical analysis description

Week 52 - Mean evening PEF

Comparison groups

QVM149 150/50/160 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1182

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

LMM

Parameter type

LS Mean

Point estimate

29.5

Confidence interval

level

95%

sides

2-sided

lower limit

24.2

upper limit

34.7

Variability estimate

Standard error of the mean

Dispersion value

2.66

QVM149 150/50/80 µg vs QMF149 150/160 µg

Statistical analysis description

Week 52 - Mean evening PEF

Comparison groups

QVM149 150/50/80 µg o.d. v QMF149 150/160 µg o.d.

Number of subjects included in analysis

1168

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

LMM

Parameter type

LS Mean

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

9.7

upper limit

20.2

Variability estimate

Standard error of the mean

Dispersion value

2.69

QVM149 150/50/80 µg vs S/F 50/500 µg

Statistical analysis description

Week 52 - Mean evening PEF

Comparison groups

QVM149 150/50/80 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1170

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

LMM

Parameter type

LS Mean

Point estimate

25.8

Confidence interval

level

95%

sides

2-sided

lower limit

20.5

upper limit

Variability estimate

Standard error of the mean

Dispersion value

2.68

Secondary: Change from baseline in percentage of asthma symptom-free days over 52 weeks

Top of page

End point title

Change from baseline in percentage of asthma symptom-free days over 52 weeks

End point description

All participants were provided with an electronic diary (e-Diary) to record clinical symptoms. They were instructed to routinely complete the e-Diary twice daily at the same time each morning and again approximately 12 hours later in the evening. The e-Diary was reviewed at each visit until study completion. Asthma symptoms free days are days with no daytime symptoms, no night-time awakenings and no symptoms on awakening. The daytime asthma symptom score was based on the daily e-diary recordings by participants with respect to shortness of breath, wheeze, cough, chest tightness, and impact on usual daily activities due to symptoms.

End point type

Secondary

End point timeframe

Baseline, 52 weeks

End point values	QVM149 150/50/160 µg o.d.	QVM149 150/50/80 µg o.d.	QMF149 150/320 µg o.d.	QMF149 150/160 µg o.d.	Salmeterol/fluticasone 50/500 μg b.i.d.
Number of subjects analysed	566	552	559	554	558
Units: Percentage of days
least squares mean (standard error)	22.4 ± 1.35	18.0 ± 1.36	22.2 ± 1.36	18.0 ± 1.37	18.9 ± 1.36

QVM149 150/50/160 µg vs QMF149 150/320 µg

Comparison groups

QVM149 150/50/160 µg o.d. v QMF149 150/320 µg o.d.

Number of subjects included in analysis

1125

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.907

Method

LMM

Parameter type

LS Mean

Point estimate

0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-3.3

upper limit

3.8

Variability estimate

Standard error of the mean

Dispersion value

1.81

QVM149 150/50/160 µg vs S/F 50/500 µg

Comparison groups

QVM149 150/50/160 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1124

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.055

Method

LMM

Parameter type

LS Mean

Point estimate

3.5

Confidence interval

level

95%

sides

2-sided

lower limit

-0.1

upper limit

Variability estimate

Standard error of the mean

Dispersion value

1.81

QVM149 150/50/80 µg vs QMF149 150/160 µg

Comparison groups

QVM149 150/50/80 µg o.d. v QMF149 150/160 µg o.d.

Number of subjects included in analysis

1106

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.997

Method

LMM

Parameter type

LS Mean

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-3.6

upper limit

3.6

Variability estimate

Standard error of the mean

Dispersion value

1.83

QVM149 150/50/80 µg vs S/F 50/500 µg

Comparison groups

QVM149 150/50/80 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1110

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.606

Method

LMM

Parameter type

LS Mean

Point estimate

-0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-4.5

upper limit

2.6

Variability estimate

Standard error of the mean

Dispersion value

1.82

Secondary: Change from baseline in percentage of days with no daytime symptoms

Top of page

End point title

Change from baseline in percentage of days with no daytime symptoms

End point description

All participants were provided with an electronic diary (e-Diary) to record clinical symptoms. They were instructed to routinely complete the e-Diary twice daily at the same time each morning and again approximately 12 hours later in the evening. The e-Diary was reviewed at each visit until study completion. For days with no daytime symptoms, all 5 evening questions must have a score = 0 with respect to shortness of breath, wheeze, cough, chest tightness and impact on usual daily activities due to symptoms, each with scores from 0 (no problems) to 4 (very severe problems).

End point type

Secondary

End point timeframe

Baseline, 52 weeks

End point values	QVM149 150/50/160 µg o.d.	QVM149 150/50/80 µg o.d.	QMF149 150/320 µg o.d.	QMF149 150/160 µg o.d.	Salmeterol/fluticasone 50/500 μg b.i.d.
Number of subjects analysed	594	577	579	579	578
Units: Percentage of days
least squares mean (standard error)	22.5 ± 1.32	17.9 ± 1.34	21.8 ± 1.33	18.0 ± 1.34	18.8 ± 1.34

QVM149 150/50/160 µg vs QMF149 150/320 µg

Comparison groups

QVM149 150/50/160 µg o.d. v QMF149 150/320 µg o.d.

Number of subjects included in analysis

1173

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.712

Method

LMM

Parameter type

LS Mean

Point estimate

0.7

Confidence interval

level

95%

sides

2-sided

lower limit

-2.8

upper limit

4.2

Variability estimate

Standard error of the mean

Dispersion value

1.78

QVM149 150/50/160 µg vs S/F 50/500 µg

Comparison groups

QVM149 150/50/160 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1172

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.038

Method

LMM

Parameter type

LS Mean

Point estimate

3.7

Confidence interval

level

95%

sides

2-sided

lower limit

0.2

upper limit

7.2

Variability estimate

Standard error of the mean

Dispersion value

1.78

QVM149 150/50/80 µg vs QMF149 150/160 µg

Comparison groups

QVM149 150/50/80 µg o.d. v QMF149 150/160 µg o.d.

Number of subjects included in analysis

1156

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.943

Method

LMM

Parameter type

LS Mean

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-3.7

upper limit

3.4

Variability estimate

Standard error of the mean

Dispersion value

1.8

QVM149 150/50/80 µg vs S/F 50/500 µg

Comparison groups

QVM149 150/50/80 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1155

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.612

Method

LMM

Parameter type

LS Mean

Point estimate

-0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-4.4

upper limit

2.6

Variability estimate

Standard error of the mean

Dispersion value

1.79

Secondary: Change from baseline in percentage of nights with no night-time awakenings over 52 weeks

Top of page

End point title

Change from baseline in percentage of nights with no night-time awakenings over 52 weeks

End point description

All participants were provided with an electronic diary (e-Diary) to record clinical symptoms. They were instructed to routinely complete the e-Diary twice daily at the same time each morning and again approximately 12 hours later in the evening. The e-Diary was reviewed at each visit until study completion. The question asked for nights with no night-time awakenings was "How did you sleep last night?" had to be answered with "I did not wake up because of any breathing problems" with scores from 0 (no problem)-4 (very severe problems).

End point type

Secondary

End point timeframe

Baseline, 52 weeks

End point values	QVM149 150/50/160 µg o.d.	QVM149 150/50/80 µg o.d.	QMF149 150/320 µg o.d.	QMF149 150/160 µg o.d.	Salmeterol/fluticasone 50/500 μg b.i.d.
Number of subjects analysed	599	584	582	584	586
Units: Percentage of days
least squares mean (standard error)	18.0 ± 1.11	17.6 ± 1.12	18.4 ± 1.13	16.1 ± 1.13	16.9 ± 1.12

QVM149 150/50/160 µg vs QMF149 150/320 µg

Comparison groups

QVM149 150/50/160 µg o.d. v QMF149 150/320 µg o.d.

Number of subjects included in analysis

1181

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.809

Method

LMM

Parameter type

LS Mean

Point estimate

-0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-3.3

upper limit

2.6

Variability estimate

Standard error of the mean

Dispersion value

1.51

QVM149 150/50/160 µg vs S/F 50/500 µg

Comparison groups

QVM149 150/50/160 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1185

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.467

Method

LMM

Parameter type

LS Mean

Point estimate

1.1

Confidence interval

level

95%

sides

2-sided

lower limit

-1.9

upper limit

Variability estimate

Standard error of the mean

Dispersion value

1.5

QVM149 150/50/80 µg vs QMF149 150/160 µg

Comparison groups

QVM149 150/50/80 µg o.d. v QMF149 150/160 µg o.d.

Number of subjects included in analysis

1168

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.318

Method

LMM

Parameter type

LS Mean

Point estimate

1.5

Confidence interval

level

95%

sides

2-sided

lower limit

-1.5

upper limit

4.5

Variability estimate

Standard error of the mean

Dispersion value

1.52

QVM149 150/50/80 µg vs S/F 50/500 µg

Comparison groups

QVM149 150/50/80 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1170

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.64

Method

LMM

Parameter type

LS Mean

Point estimate

0.7

Confidence interval

level

95%

sides

2-sided

lower limit

-2.3

upper limit

3.7

Variability estimate

Standard error of the mean

Dispersion value

1.51

Secondary: Change from baseline in percentage of mornings with no symptoms on rising over 52 weeks

Top of page

End point title

Change from baseline in percentage of mornings with no symptoms on rising over 52 weeks

End point description

All participants were provided with an electronic diary (e-Diary) to record clinical symptoms. They were instructed to routinely complete the e-Diary twice daily at the same time each morning and again approximately 12 hours later in the evening. The e-Diary was reviewed at each visit until study completion. The question asked for nights with no night-time awakenings was "How did you sleep last night?" had to be answered with "I did not wake up because of any breathing problems" with scores from 0 (no problem)-4 (very severe problems).

End point type

Secondary

End point timeframe

Baseline, 52 weeks

End point values	QVM149 150/50/160 µg o.d.	QVM149 150/50/80 µg o.d.	QMF149 150/320 µg o.d.	QMF149 150/160 µg o.d.	Salmeterol/fluticasone 50/500 μg b.i.d.
Number of subjects analysed	599	584	582	584	586
Units: Percentage of days
least squares mean (standard error)	19.5 ± 1.33	18.5 ± 1.35	19.9 ± 1.35	15.5 ± 1.35	15.6 ± 1.34

QVM149 150/50/160 µg vs QMF149 150/320 µg

Comparison groups

QVM149 150/50/160 µg o.d. v QMF149 150/320 µg o.d.

Number of subjects included in analysis

1181

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.814

Method

LMM

Parameter type

LS Mean

Point estimate

-0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-4

upper limit

3.2

Variability estimate

Standard error of the mean

Dispersion value

1.83

QVM149 150/50/160 µg vs S/F 50/500 µg

Comparison groups

QVM149 150/50/160 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1185

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.036

Method

LMM

Parameter type

LS Mean

Point estimate

3.8

Confidence interval

level

95%

sides

2-sided

lower limit

0.2

upper limit

7.4

Variability estimate

Standard error of the mean

Dispersion value

1.83

QVM149 150/50/80 µg vs QMF149 150/160 µg

Comparison groups

QVM149 150/50/80 µg o.d. v QMF149 150/160 µg o.d.

Number of subjects included in analysis

1168

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.098

Method

LMM

Parameter type

LS Mean

Point estimate

3.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.6

upper limit

6.7

Variability estimate

Standard error of the mean

Dispersion value

1.84

QVM149 150/50/80 µg vs S/F 50/500 µg

Comparison groups

QVM149 150/50/80 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1170

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.118

Method

LMM

Parameter type

LS Mean

Point estimate

2.9

Confidence interval

level

95%

sides

2-sided

lower limit

-0.7

upper limit

6.5

Variability estimate

Standard error of the mean

Dispersion value

1.84

Secondary: Change from baseline in percentage of days without rescue medication use over 26 and 52 weeks

Top of page

End point title

Change from baseline in percentage of days without rescue medication use over 26 and 52 weeks

End point description

Percentage of days without rescue medication usage (100 μg salbutamol/90 μg albuterol via metered-dose inhaler) as recorded by e-diary over 26 and 52 weeks of treatment.

End point type

Secondary

End point timeframe

Baseline, 26 weeks, 52 weeks

End point values	QVM149 150/50/160 µg o.d.	QVM149 150/50/80 µg o.d.	QMF149 150/320 µg o.d.	QMF149 150/160 µg o.d.	Salmeterol/fluticasone 50/500 μg b.i.d.
Number of subjects analysed	590	577	578	580	579
Units: Percentage of days
least squares mean (standard error)
Week 26	22.5 ± 1.32	19.5 ± 1.33	23.3 ± 1.33	18.2 ± 1.33	19.6 ± 1.33
Week 52	25.0 ± 1.36	21.9 ± 1.36	24.9 ± 1.36	20.8 ± 1.37	21.8 ± 1.36

QVM149 150/50/160 µg vs QMF149 150/320 µg

Statistical analysis description

Week 26

Comparison groups

QVM149 150/50/160 µg o.d. v QMF149 150/320 µg o.d.

Number of subjects included in analysis

1168

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.645

Method

LMM

Parameter type

LS Mean

Point estimate

-0.8

Confidence interval

level

95%

sides

2-sided

lower limit

-4.2

upper limit

2.6

Variability estimate

Standard error of the mean

Dispersion value

1.74

QVM149 150/50/160 µg vs S/F 50/500 µg

Statistical analysis description

Week 26

Comparison groups

QVM149 150/50/160 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1169

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.095

Method

LMM

Parameter type

LS Mean

Point estimate

2.9

Confidence interval

level

95%

sides

2-sided

lower limit

-0.5

upper limit

6.3

Variability estimate

Standard error of the mean

Dispersion value

1.73

QVM149 150/50/80 µg vs QMF149 150/160 µg

Statistical analysis description

Week 26

Comparison groups

QVM149 150/50/80 µg o.d. v QMF149 150/160 µg o.d.

Number of subjects included in analysis

1157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.46

Method

LMM

Parameter type

LS Mean

Point estimate

1.3

Confidence interval

level

95%

sides

2-sided

lower limit

-2.1

upper limit

4.7

Variability estimate

Standard error of the mean

Dispersion value

1.75

QVM149 150/50/80 µg vs S/F 50/500 µg

Statistical analysis description

Week 26

Comparison groups

QVM149 150/50/80 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1156

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.971

Method

LMM

Parameter type

LS Mean

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-3.5

upper limit

3.4

Variability estimate

Standard error of the mean

Dispersion value

1.75

QVM149 150/50/160 µg vs QMF149 150/320 µg

Statistical analysis description

Week 52

Comparison groups

QVM149 150/50/160 µg o.d. v QMF149 150/320 µg o.d.

Number of subjects included in analysis

1168

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.963

Method

LMM

Parameter type

LS Mean

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-3.4

upper limit

3.6

Variability estimate

Standard error of the mean

Dispersion value

1.78

QVM149 150/50/160 µg vs S/F 50/500 µg

Statistical analysis description

Week 52

Comparison groups

QVM149 150/50/160 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1169

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.075

Method

LMM

Parameter type

LS Mean

Point estimate

3.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.3

upper limit

6.6

Variability estimate

Standard error of the mean

Dispersion value

1.77

QVM149 150/50/80 µg vs QMF149 150/160 µg

Statistical analysis description

Week 52

Comparison groups

QVM149 150/50/80 µg o.d. v QMF149 150/160 µg o.d.

Number of subjects included in analysis

1157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.517

Method

LMM

Parameter type

LS Mean

Point estimate

1.2

Confidence interval

level

95%

sides

2-sided

lower limit

-2.3

upper limit

4.7

Variability estimate

Standard error of the mean

Dispersion value

1.79

QVM149 150/50/80 µg vs S/F 50/500 µg

Statistical analysis description

Week 52

Comparison groups

QVM149 150/50/80 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1156

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.956

Method

LMM

Parameter type

LS Mean

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-3.4

upper limit

3.6

Variability estimate

Standard error of the mean

Dispersion value

1.78

Secondary: Percentage of patients achieving the minimal clinically important difference (MCID) ACQ ≥ 0.5 at Week 26 and Week 52

Top of page

End point title

Percentage of patients achieving the minimal clinically important difference (MCID) ACQ ≥ 0.5 at Week 26 and Week 52

End point description

Change from baseline in ACQ-7 scores of ≤ 0.5 was defined as minimal clinically important difference and were considered clinically meaningful. The ACQ-7 measured asthma symptom control and consists of 7 items: 5 on symptom assessment, 1 on rescue bronchodilator use and 1 on airway calibre (FEV1 % predicted). All 7 questions of the ACQ-7 were equally weighted. Items 1-5 were scored along a 7-point response scale, where 0 = totally controlled and 6 = severely uncontrolled. Item 6 is scored between 0 = no rescue medication and 6 = More than 16 puffs/inhalations most days. The 7th item was scored by the investigator based on the FEV1 % predicted from the masterscope at the site (i.e., Score = 0 means > 95% of predicted FEV1, 1 = 90 - 95%, 2 = 80 - 89%, 3 = 70 - 79%, 4 = 60 - 69%, 5 = 50 - 59%, and Score = 6 means < 50% of predicted FEV1). The total score was calculated as the mean of all questions.

End point type

Secondary

End point timeframe

26 weeks, 52 weeks

End point values	QVM149 150/50/160 µg o.d.	QVM149 150/50/80 µg o.d.	QMF149 150/320 µg o.d.	QMF149 150/160 µg o.d.	Salmeterol/fluticasone 50/500 μg b.i.d.
Number of subjects analysed	615	616	611	607	612
Units: Percentage of participants
number (not applicable)
Week 26	71.2	71.7	74.2	70.7	67.4
Week 52	78.8	72.8	77.9	73.1	72.8

QVM149 150/50/160 µg vs QMF149 150/320 µg

Statistical analysis description

Week 26

Comparison groups

QVM149 150/50/160 µg o.d. v QMF149 150/320 µg o.d.

Number of subjects included in analysis

1226

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.535

Method

Logistic regression model

Parameter type

Odds ratio (OR)

Point estimate

0.92

Confidence interval

level

95%

sides

2-sided

lower limit

0.7

upper limit

1.2

QVM149 150/50/160 µg vs S/F 50/500 µg

Statistical analysis description

Week 26

Comparison groups

QVM149 150/50/160 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1227

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.151

Method

Logistic regression model

Parameter type

Odds ratio (OR)

Point estimate

1.21

Confidence interval

level

95%

sides

2-sided

lower limit

0.93

upper limit

1.57

QVM149 150/50/80 µg vs QMF149 150/160 µg

Statistical analysis description

Week 26

Comparison groups

QVM149 150/50/80 µg o.d. v QMF149 150/160 µg o.d.

Number of subjects included in analysis

1223

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.38

Method

Logistic regression model

Parameter type

Odds ratio (OR)

Point estimate

1.13

Confidence interval

level

95%

sides

2-sided

lower limit

0.86

upper limit

1.48

QVM149 150/50/80 µg vs S/F 50/500 µg

Statistical analysis description

Week 26

Comparison groups

QVM149 150/50/80 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1228

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.172

Method

Logistic regression model

Parameter type

Odds ratio (OR)

Point estimate

1.2

Confidence interval

level

95%

sides

2-sided

lower limit

0.92

upper limit

1.57

QVM149 150/50/160 µg vs QMF149 150/320 µg

Statistical analysis description

Week 52

Comparison groups

QVM149 150/50/160 µg o.d. v QMF149 150/320 µg o.d.

Number of subjects included in analysis

1226

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.51

Method

Logistic regression model

Parameter type

Odds ratio (OR)

Point estimate

1.1

Confidence interval

level

95%

sides

2-sided

lower limit

0.83

upper limit

1.47

QVM149 150/50/160 µg vs S/F 50/500 µg

Statistical analysis description

Week 52

Comparison groups

QVM149 150/50/160 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1227

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.017

Method

Logistic regression model

Parameter type

Odds ratio (OR)

Point estimate

1.41

Confidence interval

level

95%

sides

2-sided

lower limit

1.06

upper limit

1.86

QVM149 150/50/80 µg vs QMF149 150/160 µg

Statistical analysis description

Week 52

Comparison groups

QVM149 150/50/80 µg o.d. v QMF149 150/160 µg o.d.

Number of subjects included in analysis

1223

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.744

Method

Logistic regression model

Parameter type

Odds ratio (OR)

Point estimate

1.05

Confidence interval

level

95%

sides

2-sided

lower limit

0.79

upper limit

1.38

QVM149 150/50/80 µg vs S/F 50/500 µg

Statistical analysis description

Week 52

Comparison groups

QVM149 150/50/80 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1228

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.922

Method

Logistic regression model

Parameter type

Odds ratio (OR)

Point estimate

0.99

Confidence interval

level

95%

sides

2-sided

lower limit

0.75

upper limit

1.29

Secondary: Time to first hospitalization for asthma exacerbation

Top of page

End point title

Time to first hospitalization for asthma exacerbation

End point description

Time from start of treatment until the first event (hospitalization for asthma exacerbation) or censoring. Patients without the event were considered as censored at the date of last treatment + 1 day. For patients having the event, the start date of the hospitalization was considered to calculate the time to event (i.e., the number of days from start of treatment up to the event start date).

End point type

Secondary

End point timeframe

52 weeks on average, up to 416 days

End point values	QVM149 150/50/160 µg o.d.	QVM149 150/50/80 µg o.d.	QMF149 150/320 µg o.d.	QMF149 150/160 µg o.d.	Salmeterol/fluticasone 50/500 μg b.i.d.
Number of subjects analysed	615	616	611	607	612
Units: days
median (full range (min-max))	367.0 (2 to 416)	367.0 (2 to 396)	367.0 (1 to 411)	367.0 (1 to 408)	367.0 (1 to 416)

QVM149 150/50/160 µg vs QMF149 150/320 µg

Comparison groups

QVM149 150/50/160 µg o.d. v QMF149 150/320 µg o.d.

Number of subjects included in analysis

1226

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.371

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.66

Confidence interval

level

95%

sides

2-sided

lower limit

0.27

upper limit

1.63

QVM149 150/50/160 µg vs S/F 50/500 µg

Comparison groups

QVM149 150/50/160 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1227

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.996

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

0.37

upper limit

2.66

QVM149 150/50/80 µg vs QMF149 150/160 µg

Comparison groups

QVM149 150/50/80 µg o.d. v QMF149 150/160 µg o.d.

Number of subjects included in analysis

1223

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.145

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.89

Confidence interval

level

95%

sides

2-sided

lower limit

0.8

upper limit

4.47

QVM149 150/50/80 µg vs S/F 50/500 µg

Comparison groups

QVM149 150/50/80 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1228

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.15

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.88

Confidence interval

level

95%

sides

2-sided

lower limit

0.8

upper limit

4.43

Secondary: Time to first asthma exacerbation by exacerbation category

Top of page

End point title

Time to first asthma exacerbation by exacerbation category

End point description

Time from start of treatment until the first event (asthma exacerbation) or censoring. Patients without the event were considered as censored at the date of last treatment + 1 day. For patients having the event, the start date of the exacerbation was considered to calculate the time to event (i.e., the number of days from start of treatment up to the event start date). The exacerbation categories were: All (mild, moderate and severe), combination of moderate or severe and severe.

End point type

Secondary

End point timeframe

52 weeks on average, up to 416 days

End point values	QVM149 150/50/160 µg o.d.	QVM149 150/50/80 µg o.d.	QMF149 150/320 µg o.d.	QMF149 150/160 µg o.d.	Salmeterol/fluticasone 50/500 μg b.i.d.
Number of subjects analysed	615	616	611	607	612
Units: days
median (full range (min-max))
Moderate or severe asthma exacerbation	366.0 (2 to 416)	366.0 (2 to 396)	366.0 (1 to 411)	365.0 (1 to 387)	365.0 (1 to 416)
Severe asthma exacerbation	366.0 (2 to 416)	366.0 (2 to 396)	366.0 (1 to 411)	366.0 (1 to 389)	366.0 (1 to 416)
All (mild, moderate or severe) asthma exacerbation	363.0 (2 to 416)	364.0 (2 to 396)	361.0 (1 to 411)	360.0 (1 to 384)	278.0 (1 to 416)

QVM149 150/50/160 µg vs QMF149 150/320 µg

Statistical analysis description

Moderate or severe asthma exacerbation

Comparison groups

QVM149 150/50/160 µg o.d. v QMF149 150/320 µg o.d.

Number of subjects included in analysis

1226

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.523

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.94

Confidence interval

level

95%

sides

2-sided

lower limit

0.77

upper limit

1.15

QVM149 150/50/160 µg vs S/F 50/500 µg

Statistical analysis description

Moderate or severe asthma exacerbation

Comparison groups

QVM149 150/50/160 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1227

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.7

Confidence interval

level

95%

sides

2-sided

lower limit

0.58

upper limit

0.84

QVM149 150/50/80 µg vs QMF149 150/160 µg

Statistical analysis description

Moderate or severe asthma exacerbation

Comparison groups

QVM149 150/50/80 µg o.d. v QMF149 150/160 µg o.d.

Number of subjects included in analysis

1223

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.164

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.87

Confidence interval

level

95%

sides

2-sided

lower limit

0.72

upper limit

1.06

QVM149 150/50/80 µg vs S/F 50/500 µg

Statistical analysis description

Moderate or severe asthma exacerbation

Comparison groups

QVM149 150/50/80 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1228

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.005

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.76

Confidence interval

level

95%

sides

2-sided

lower limit

0.63

upper limit

0.92

QVM149 150/50/160 µg vs QMF149 150/320 µg

Statistical analysis description

Severe asthma exacerbation

Comparison groups

QVM149 150/50/160 µg o.d. v QMF149 150/320 µg o.d.

Number of subjects included in analysis

1226

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.476

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.92

Confidence interval

level

95%

sides

2-sided

lower limit

0.72

upper limit

1.16

QVM149 150/50/160 µg vs S/F 50/500 µg

Statistical analysis description

Severe asthma exacerbation

Comparison groups

QVM149 150/50/160 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1227

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.68

Confidence interval

level

95%

sides

2-sided

lower limit

0.54

upper limit

0.85

QVM149 150/50/80 µg vs QMF149 150/160 µg

Statistical analysis description

Severe asthma exacerbation

Comparison groups

QVM149 150/50/80 µg o.d. v QMF149 150/160 µg o.d.

Number of subjects included in analysis

1223

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.243

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.88

Confidence interval

level

95%

sides

2-sided

lower limit

0.7

upper limit

1.09

QVM149 150/50/80 µg vs S/F 50/500 µg

Statistical analysis description

Severe asthma exacerbation

Comparison groups

QVM149 150/50/80 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1228

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.027

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.78

Confidence interval

level

95%

sides

2-sided

lower limit

0.63

upper limit

0.97

QVM149 150/50/160 µg vs QMF149 150/320 µg

Statistical analysis description

All (mild, moderate, severe) asthma exacerbation

Comparison groups

QVM149 150/50/160 µg o.d. v QMF149 150/320 µg o.d.

Number of subjects included in analysis

1226

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.497

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.94

Confidence interval

level

95%

sides

2-sided

lower limit

0.79

upper limit

1.12

QVM149 150/50/160 µg vs S/F 50/500 µg

Statistical analysis description

All (mild, moderate, severe) asthma exacerbation

Comparison groups

QVM149 150/50/160 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1227

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.71

Confidence interval

level

95%

sides

2-sided

lower limit

0.6

upper limit

0.84

QVM149 150/50/80 µg vs QMF149 150/160 µg

Statistical analysis description

All (mild, moderate, severe) asthma exacerbation

Comparison groups

QVM149 150/50/80 µg o.d. v QMF149 150/160 µg o.d.

Number of subjects included in analysis

1223

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.126

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.87

Confidence interval

level

95%

sides

2-sided

lower limit

0.73

upper limit

1.04

QVM149 150/50/80 µg vs S/F 50/500 µg

Statistical analysis description

All (mild, moderate, severe) asthma exacerbation

Comparison groups

QVM149 150/50/80 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1228

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.72

Confidence interval

level

95%

sides

2-sided

lower limit

0.61

upper limit

0.85

Secondary: Annual rate of asthma exacerbations by exacerbation category

Top of page

End point title

Annual rate of asthma exacerbations by exacerbation category

End point description

The exacerbation categories were: All (mild, moderate and severe) and combination of moderate or severe and severe.

End point type

Secondary

End point timeframe

52 weeks

End point values	QVM149 150/50/160 µg o.d.	QVM149 150/50/80 µg o.d.	QMF149 150/320 µg o.d.	QMF149 150/160 µg o.d.	Salmeterol/fluticasone 50/500 μg b.i.d.
Number of subjects analysed	615	616	611	607	612
Units: Exacerbations per year
arithmetic mean (confidence interval 95%)
Moderate or severe asthma exacerbation	0.46 (0.39 to 0.54)	0.58 (0.50 to 0.67)	0.54 (0.47 to 0.63)	0.67 (0.58 to 0.77)	0.72 (0.63 to 0.82)
Severe asthma exacerbation	0.26 (0.22 to 0.31)	0.38 (0.32 to 0.45)	0.33 (0.28 to 0.39)	0.41 (0.35 to 0.48)	0.45 (0.39 to 0.53)
All (mild, moderate, severe) asthma exacerbation	0.74 (0.64 to 0.85)	0.86 (0.75 to 0.98)	0.93 (0.82 to 1.06)	0.98 (0.86 to 1.11)	1.23 (1.08 to 1.39)

QVM149 150/50/160 µg vs QMF149 150/320 µg

Statistical analysis description

Moderate or severe asthma exacerbation

Comparison groups

QVM149 150/50/160 µg o.d. v QMF149 150/320 µg o.d.

Number of subjects included in analysis

1226

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.12

Method

Generalized linear model

Parameter type

Rate ratio

Point estimate

0.85

Confidence interval

level

95%

sides

2-sided

lower limit

0.68

upper limit

1.04

QVM149 150/50/160 µg vs S/F 50/500 µg

Statistical analysis description

Moderate or severe asthma exacerbation

Comparison groups

QVM149 150/50/160 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1227

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Generalized linear model

Parameter type

Rate ratio

Point estimate

0.64

Confidence interval

level

95%

sides

2-sided

lower limit

0.52

upper limit

0.78

QVM149 150/50/80 µg vs QMF149 150/160 µg

Statistical analysis description

Moderate or severe asthma exacerbation

Comparison groups

QVM149 150/50/80 µg o.d. v QMF149 150/160 µg o.d.

Number of subjects included in analysis

1223

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.17

Method

Generalized linear modeñ

Parameter type

Rate ratio

Point estimate

0.87

Confidence interval

level

95%

sides

2-sided

lower limit

0.71

upper limit

1.06

QVM149 150/50/80 µg vs S/F 50/500 µg

Statistical analysis description

Moderate or severe asthma exacerbation

Comparison groups

QVM149 150/50/80 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1228

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.041

Method

Generalized linear model

Parameter type

Rate ratio

Point estimate

0.81

Confidence interval

level

95%

sides

2-sided

lower limit

0.66

upper limit

0.99

QVM149 150/50/160 µg vs QMF149 150/320 µg

Statistical analysis description

Severe asthma exacerbation

Comparison groups

QVM149 150/50/160 µg o.d. v QMF149 150/320 µg o.d.

Number of subjects included in analysis

1226

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.05

Method

Generalized linear model

Parameter type

Rate ratio

Point estimate

0.78

Confidence interval

level

95%

sides

2-sided

lower limit

0.61

upper limit

QVM149 150/50/160 µg vs S/F 50/500 µg

Statistical analysis description

Severe asthma exacerbation

Comparison groups

QVM149 150/50/160 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1227

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Generalized linear model

Parameter type

Rate ratio

Point estimate

0.58

Confidence interval

level

95%

sides

2-sided

lower limit

0.45

upper limit

0.73

QVM149 150/50/80 µg vs QMF149 150/160 µg

Statistical analysis description

Severe asthma exacerbation

Comparison groups

QVM149 150/50/80 µg o.d. v QMF149 150/160 µg o.d.

Number of subjects included in analysis

1223

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.531

Method

Generalized linear model

Parameter type

Rate ratio

Point estimate

0.93

Confidence interval

level

95%

sides

2-sided

lower limit

0.74

upper limit

1.17

QVM149 150/50/80 µg vs S/F 50/500 µg

Statistical analysis description

Severe asthma exacerbation

Comparison groups

QVM149 150/50/80 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1228

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.117

Method

Linear generalized model

Parameter type

Rate ratio

Point estimate

0.84

Confidence interval

level

95%

sides

2-sided

lower limit

0.67

upper limit

1.05

QVM149 150/50/160 µg vs QMF149 150/320 µg

Statistical analysis description

All (mild, moderate, severe) asthma exacerbation

Comparison groups

QVM149 150/50/160 µg o.d. v QMF149 150/320 µg o.d.

Number of subjects included in analysis

1226

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.016

Method

Generalized linear model

Parameter type

Rate ratio

Point estimate

0.79

Confidence interval

level

95%

sides

2-sided

lower limit

0.66

upper limit

0.96

QVM149 150/50/160 µg vs S/F 50/500 µg

Statistical analysis description

All (mild, moderate, severe) asthma exacerbation

Comparison groups

QVM149 150/50/160 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1227

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Generalized linear model

Parameter type

Rate ratio

Point estimate

0.6

Confidence interval

level

95%

sides

2-sided

lower limit

0.5

upper limit

0.72

QVM149 150/50/80 µg vs QMF149 150/160 µg

Statistical analysis description

All (mild, moderate, severe) asthma exacerbation

Comparison groups

QVM149 150/50/80 µg o.d. v QMF149 150/160 µg o.d.

Number of subjects included in analysis

1223

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.161

Method

Generalized linear model

Parameter type

Rate ratio

Point estimate

0.87

Confidence interval

level

95%

sides

2-sided

lower limit

0.72

upper limit

1.06

QVM149 150/50/80 µg vs S/F 50/500 µg

Statistical analysis description

All (mild, moderate, severe) asthma exacerbation

Comparison groups

QVM149 150/50/80 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1228

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Generalized linear model

Parameter type

Rate ratio

Point estimate

0.7

Confidence interval

level

95%

sides

2-sided

lower limit

0.58

upper limit

0.84

Secondary: Duration in days of asthma exacerbations by exacerbation category

Top of page

End point title

Duration in days of asthma exacerbations by exacerbation category

End point description

The exacerbation categories were: All (mild, moderate and severe) and combination of moderate or severe and severe.

End point type

Secondary

End point timeframe

Up to Week 52

End point values	QVM149 150/50/160 µg o.d.	QVM149 150/50/80 µg o.d.	QMF149 150/320 µg o.d.	QMF149 150/160 µg o.d.	Salmeterol/fluticasone 50/500 μg b.i.d.
Number of subjects analysed	615	616	611	607	612
Units: days
arithmetic mean (standard deviation)
Moderate or severe asthma exacerbation	4.5 ± 10.73	5.6 ± 12.87	6.7 ± 20.52	7.1 ± 17.17	8.1 ± 20.63
Severe asthma exacerbation	2.8 ± 7.31	4.1 ± 11.18	4.9 ± 19.07	4.5 ± 10.54	5.8 ± 18.24
All (mild, moderate, severe) asthma exacerbation	7.0 ± 16.02	8.1 ± 20.51	10.7 ± 28.70	9.6 ± 21.76	12.8 ± 29.21

QVM149 150/50/160 µg vs QMF149 150/320 µg

Statistical analysis description

Moderate or severe asthma exacerbation

Comparison groups

QVM149 150/50/160 µg o.d. v QMF149 150/320 µg o.d.

Number of subjects included in analysis

1226

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.183

Method

van Elteren test

Confidence interval

QVM149 150/50/160 µg vs S/F 50/500 µg

Statistical analysis description

Moderate or severe asthma exacerbation

Comparison groups

QVM149 150/50/160 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1227

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

van Elteren test

Confidence interval

QVM149 150/50/80 µg vs QMF149 150/160 µg

Statistical analysis description

Moderate or severe asthma exacerbation

Comparison groups

QVM149 150/50/80 µg o.d. v QMF149 150/160 µg o.d.

Number of subjects included in analysis

1223

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.155

Method

van Elteren test

Confidence interval

QVM149 150/50/80 µg vs S/F 50/500 µg

Statistical analysis description

Moderate or severe asthma exacerbation

Comparison groups

QVM149 150/50/80 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1228

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.007

Method

van Elteren test

Confidence interval

QVM149 150/50/160 µg vs QMF149 150/320 µg

Statistical analysis description

Severe asthma exacerbation

Comparison groups

QVM149 150/50/160 µg o.d. v QMF149 150/320 µg o.d.

Number of subjects included in analysis

1226

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.172

Method

van Elteren test

Confidence interval

QVM149 150/50/160 µg vs S/F 50/500 µg

Statistical analysis description

Severe asthma exacerbation

Comparison groups

QVM149 150/50/160 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1227

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

van Elteren test

Confidence interval

QVM149 150/50/80 µg vs QMF149 150/160 µg

Statistical analysis description

Severe asthma exacerbation

Comparison groups

QVM149 150/50/80 µg o.d. v QMF149 150/160 µg o.d.

Number of subjects included in analysis

1223

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.241

Method

van Elteren test

Confidence interval

QVM149 150/50/80 µg vs S/F 50/500 µg

Statistical analysis description

Severe asthma exacerbation

Comparison groups

QVM149 150/50/80 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1228

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.033

Method

van Elteren test

Confidence interval

QVM149 150/50/160 µg vs QMF149 150/320 µg

Statistical analysis description

All (mild, moderate, severe) asthma exacerbation

Comparison groups

QVM149 150/50/160 µg o.d. v QMF149 150/320 µg o.d.

Number of subjects included in analysis

1226

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.095

Method

van Elteren test

Confidence interval

QVM149 150/50/160 µg vs S/F 50/500 µg

Statistical analysis description

All (mild, moderate, severe) asthma exacerbation

Comparison groups

QVM149 150/50/160 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1227

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

van Elteren test

Confidence interval

QVM149 150/50/80 µg vs QMF149 150/160 µg

Statistical analysis description

All (mild, moderate, severe) asthma exacerbation

Comparison groups

QVM149 150/50/80 µg o.d. v QMF149 150/160 µg o.d.

Number of subjects included in analysis

1223

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.09

Method

van Elteren test

Confidence interval

QVM149 150/50/80 µg vs S/F 50/500 µg

Statistical analysis description

All (mild, moderate, severe) asthma exacerbation

Comparison groups

QVM149 150/50/80 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1228

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

van Elteren test

Confidence interval

Secondary: Percentage of participants with at least one asthma exacerbation by exacerbation category

Top of page

End point title

Percentage of participants with at least one asthma exacerbation by exacerbation category

End point description

The exacerbation categories were: All (mild, moderate and severe) and combination of moderate or severe and severe.

End point type

Secondary

End point timeframe

Up to Week 52

End point values	QVM149 150/50/160 µg o.d.	QVM149 150/50/80 µg o.d.	QMF149 150/320 µg o.d.	QMF149 150/160 µg o.d.	Salmeterol/fluticasone 50/500 μg b.i.d.
Number of subjects analysed	615	616	611	607	612
Units: percentage of participants
number (not applicable)
Moderate or severe asthma exacerbation	30.2	32.5	31.8	35.9	39.7
Severe asthma exacerbation	21.8	24.6	23.2	27.3	29.7
All (mild, moderate, severe) asthma exacerbation	40.2	40.2	41.9	44.0	50.5

No statistical analyses for this end point

Secondary: Time in days to permanent discontinuation of study medication due to asthma exacerbation

Top of page

End point title

Time in days to permanent discontinuation of study medication due to asthma exacerbation

End point description

Time from start of treatment until the first event (permanent discontinuation of study medication due to asthma exacerbation) or censoring. Patients without the event were considered as censored at the date of last treatment + 1 day. For patients having the event, the date of the discontinuation of study medication was considered to calculate the time to event.

End point type

Secondary

End point timeframe

52 weeks on average, up to 416 days

End point values	QVM149 150/50/160 µg o.d.	QVM149 150/50/80 µg o.d.	QMF149 150/320 µg o.d.	QMF149 150/160 µg o.d.	Salmeterol/fluticasone 50/500 μg b.i.d.
Number of subjects analysed	615	616	611	607	612
Units: days
median (full range (min-max))	367.0 (11 to 416)	367.0 (2 to 399)	367.0 (3 to 411)	367.0 (2 to 408)	367.0 (2 to 416)

QVM149 150/50/160 µg vs QMF149 150/320 µg

Comparison groups

QVM149 150/50/160 µg o.d. v QMF149 150/320 µg o.d.

Number of subjects included in analysis

1226

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.314

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.49

Confidence interval

level

95%

sides

2-sided

lower limit

0.12

upper limit

1.96

QVM149 150/50/160 µg vs S/F 50/500 µg

Comparison groups

QVM149 150/50/160 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1227

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.055

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.28

Confidence interval

level

95%

sides

2-sided

lower limit

0.08

upper limit

1.03

QVM149 150/50/80 µg vs QMF149 150/160 µg

Comparison groups

QVM149 150/50/80 µg o.d. v QMF149 150/160 µg o.d.

Number of subjects included in analysis

1223

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.306

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.62

Confidence interval

level

95%

sides

2-sided

lower limit

0.25

upper limit

1.54

QVM149 150/50/80 µg vs S/F 50/500 µg

Comparison groups

QVM149 150/50/80 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1228

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.566

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.76

Confidence interval

level

95%

sides

2-sided

lower limit

0.3

upper limit

1.94

Secondary: Total amount of oral corticosteroid used (in prednisone-equivalent mg doses) to treat asthma exacerbations

Top of page

End point title

Total amount of oral corticosteroid used (in prednisone-equivalent mg doses) to treat asthma exacerbations

End point description

The treatment of asthma exacerbations including the initiation of systemic corticosteroids were done according to investigator's or treating physician's medical judgement and in line with national and international recommendations. If systemic corticosteroids were required, a participant could return to the study after successfully completing a taper of approximately 7-10 days.

End point type

Secondary

End point timeframe

Up to Week 52

End point values	QVM149 150/50/160 µg o.d.	QVM149 150/50/80 µg o.d.	QMF149 150/320 µg o.d.	QMF149 150/160 µg o.d.	Salmeterol/fluticasone 50/500 μg b.i.d.
Number of subjects analysed	615	616	611	607	612
Units: prednisone-equivalent milligram
arithmetic mean (standard deviation)	53.4 ± 169.76	72.0 ± 211.41	73.2 ± 235.90	82.5 ± 208.36	86.0 ± 199.79

No statistical analyses for this end point

Secondary: Change from baseline in percentage of rescue medication free days over 26 and 52 weeks

Top of page

End point title

Change from baseline in percentage of rescue medication free days over 26 and 52 weeks

End point description

All participants were given salbutamol/albuterol to use as rescue medication throughout the study along with e-Diary to record rescue medication use. Rescue medication free days is defined as any day where the participant did not use any puffs of rescue medication during daytime and night-time.

End point type

Secondary

End point timeframe

Baseline, 26 weeks, 52 weeks

End point values	QVM149 150/50/160 µg o.d.	QVM149 150/50/80 µg o.d.	QMF149 150/320 µg o.d.	QMF149 150/160 µg o.d.	Salmeterol/fluticasone 50/500 μg b.i.d.
Number of subjects analysed	590	577	578	580	579
Units: Percentage of days
least squares mean (standard error)
Week 26	22.5 ± 1.32	19.5 ± 1.33	23.3 ± 1.33	18.2 ± 1.33	19.6 ± 1.33
Week 52	25.0 ± 1.36	21.9 ± 1.36	24.9 ± 1.36	20.8 ± 1.37	21.8 ± 1.36

QVM149 150/50/160 µg vs QMF149 150/320 µg

Statistical analysis description

Week 26

Comparison groups

QVM149 150/50/160 µg o.d. v QMF149 150/320 µg o.d.

Number of subjects included in analysis

1168

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.645

Method

LMM

Parameter type

LS Mean

Point estimate

-0.8

Confidence interval

level

95%

sides

2-sided

lower limit

-4.2

upper limit

2.6

Variability estimate

Standard error of the mean

Dispersion value

1.74

QVM149 150/50/160 µg vs S/F 50/500 µg

Statistical analysis description

Week 26

Comparison groups

QVM149 150/50/160 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1169

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.095

Method

LMM

Parameter type

LS Mean

Point estimate

2.9

Confidence interval

level

95%

sides

2-sided

lower limit

-0.5

upper limit

6.3

Variability estimate

Standard error of the mean

Dispersion value

1.73

QVM149 150/50/80 µg vs QMF149 150/160 µg

Statistical analysis description

Week 26

Comparison groups

QVM149 150/50/80 µg o.d. v QMF149 150/160 µg o.d.

Number of subjects included in analysis

1157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.46

Method

LMM

Parameter type

LMM

Point estimate

1.3

Confidence interval

level

95%

sides

2-sided

lower limit

-2.1

upper limit

4.7

Variability estimate

Standard error of the mean

Dispersion value

1.75

QVM149 150/50/80 µg vs S/F 50/500 µg

Statistical analysis description

Week 26

Comparison groups

QVM149 150/50/80 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1156

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.971

Method

LMM

Parameter type

LS Mean

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-3.5

upper limit

3.4

Variability estimate

Standard error of the mean

Dispersion value

1.75

QVM149 150/50/160 µg vs QMF149 150/320 µg

Statistical analysis description

Week 52

Comparison groups

QVM149 150/50/160 µg o.d. v QMF149 150/320 µg o.d.

Number of subjects included in analysis

1168

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.963

Method

LMM

Parameter type

LMM

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-3.4

upper limit

3.6

Variability estimate

Standard error of the mean

Dispersion value

1.78

QVM149 150/50/160 µg vs S/F 50/500 µg

Statistical analysis description

Week 52

Comparison groups

QVM149 150/50/160 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1169

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.075

Method

LMM

Parameter type

LS Mean

Point estimate

3.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.3

upper limit

6.6

Variability estimate

Standard error of the mean

Dispersion value

1.77

QVM149 150/50/80 µg vs QMF149 150/160 µg

Statistical analysis description

Week 52

Comparison groups

QVM149 150/50/80 µg o.d. v QMF149 150/160 µg o.d.

Number of subjects included in analysis

1157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.517

Method

LMM

Parameter type

LS Mean

Point estimate

1.2

Confidence interval

level

95%

sides

2-sided

lower limit

-2.3

upper limit

4.7

Variability estimate

Standard error of the mean

Dispersion value

1.79

QVM149 150/50/80 µg vs S/F 50/500 µg

Statistical analysis description

Week 52

Comparison groups

QVM149 150/50/80 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1156

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.956

Method

LMM

Parameter type

LS Mean

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-3.4

upper limit

3.6

Variability estimate

Standard error of the mean

Dispersion value

1.78

Secondary: Asthma Quality of Life Questionnaire (AQLQ) at Week 52

Top of page

End point title

Asthma Quality of Life Questionnaire (AQLQ) at Week 52

End point description

AQLQ is a 32-item disease specific questionnaire designed to measure functional impairments that are most important to patients with asthma, with a recall time of two weeks and each question to be answered on a 7-point scale (1-totally limited/problems all the time, 7-not at all limited/no problems). It consists of 4 domains: - Symptoms = Mean of Items 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 29, 30 (12 items) - Activity limitation = Mean of Items 1, 2, 3, 4, 5, 11, 19, 25, 28, 31, 32 (11 items) - Emotional function = Mean of Items 7, 13, 15, 21, 27 (5 items) - Environmental stimuli = Mean of Items 9, 17, 23, 26 (4 items) - Overall Score = Mean of Items 1 to 32 (32 items) The overall AQLQ score reported below is the mean of all 32 responses and ranges from 1 to 7, where higher scores indicate better quality of life.

End point type

Secondary

End point timeframe

52 weeks

End point values	QVM149 150/50/160 µg o.d.	QVM149 150/50/80 µg o.d.	QMF149 150/320 µg o.d.	QMF149 150/160 µg o.d.	Salmeterol/fluticasone 50/500 μg b.i.d.
Number of subjects analysed	606	593	595	599	594
Units: Score on a scale
least squares mean (standard error)	5.555 ± 0.0354	5.445 ± 0.0358	5.535 ± 0.0356	5.499 ± 0.0358	5.495 ± 0.0357

QVM149 150/50/160 µg vs QMF149 150/320 µg

Comparison groups

QVM149 150/50/160 µg o.d. v QMF149 150/320 µg o.d.

Number of subjects included in analysis

1201

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.69

Method

MMRM

Parameter type

LS Mean

Point estimate

0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.078

upper limit

0.118

Variability estimate

Standard error of the mean

Dispersion value

0.0502

QVM149 150/50/160 µg vs S/F 50/500 µg

Comparison groups

QVM149 150/50/160 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1200

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.232

Method

MMRM

Parameter type

LS Mean

Point estimate

0.06

Confidence interval

level

95%

sides

2-sided

lower limit

-0.038

upper limit

0.159

Variability estimate

Standard error of the mean

Dispersion value

0.0502

QVM149 150/50/80 µg vs QMF149 150/160 µg

Comparison groups

QVM149 150/50/80 µg o.d. v QMF149 150/160 µg o.d.

Number of subjects included in analysis

1192

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.285

Method

MMRM

Parameter type

LS Mean

Point estimate

-0.054

Confidence interval

level

95%

sides

2-sided

lower limit

-0.153

upper limit

0.045

Variability estimate

Standard error of the mean

Dispersion value

0.0506

QVM149 150/50/80 µg vs S/F 50/500 µg

Comparison groups

QVM149 150/50/80 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1187

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.319

Method

MMRM

Parameter type

LS Mean

Point estimate

-0.05

Confidence interval

level

95%

sides

2-sided

lower limit

-0.15

upper limit

0.049

Variability estimate

Standard error of the mean

Dispersion value

0.0505

Secondary: Pre-dose FEV1 at weeks 4 and 12

Top of page

End point title

Pre-dose FEV1 at weeks 4 and 12

End point description

Pre-dose FEV1 is defined as average of the two FEV1 measurements taken 45 min and 15 min pre evening dose. It was assessed by performing spirometric assessment. FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation, measured through spirometry testing.

End point type

Secondary

End point timeframe

4 weeks, 12 weeks

End point values	QVM149 150/50/160 µg o.d.	QVM149 150/50/80 µg o.d.	QMF149 150/320 µg o.d.	QMF149 150/160 µg o.d.	Salmeterol/fluticasone 50/500 μg b.i.d.
Number of subjects analysed	606	594	592	596	598
Units: litres
least squares mean (standard deviation)
Week 4	2.032 ± 0.0122	1.983 ± 0.0123	1.963 ± 0.0124	1.950 ± 0.0123	1.887 ± 0.0123
Week 12	2.024 ± 0.0134	1.994 ± 0.0135	1.966 ± 0.0135	1.944 ± 0.0136	1.907 ± 0.0135

QVM149 150/50/160 µg vs QMF149 150/320 µg

Statistical analysis description

Week 4

Comparison groups

QVM149 150/50/160 µg o.d. v QMF149 150/320 µg o.d.

Number of subjects included in analysis

1198

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.068

Confidence interval

level

95%

sides

2-sided

lower limit

0.036

upper limit

0.101

Variability estimate

Standard error of the mean

Dispersion value

0.0166

QVM149 150/50/160 µg vs S/F 50/500 µg

Statistical analysis description

Week 4

Comparison groups

QVM149 150/50/160 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1204

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.145

Confidence interval

level

95%

sides

2-sided

lower limit

0.113

upper limit

0.177

Variability estimate

Standard error of the mean

Dispersion value

0.0165

QVM149 150/50/80 µg vs QMF149 150/160 µg

Statistical analysis description

Week 4

Comparison groups

QVM149 150/50/80 µg o.d. v QMF149 150/160 µg o.d.

Number of subjects included in analysis

1190

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.049

Method

MMRM

Parameter type

LS Mean

Point estimate

0.033

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

0.066

Variability estimate

Standard error of the mean

Dispersion value

0.0167

QVM149 150/50/80 µg vs S/F 50/500 µg

Statistical analysis description

Week 4

Comparison groups

QVM149 150/50/80 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1192

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.096

Confidence interval

level

95%

sides

2-sided

lower limit

0.064

upper limit

0.129

Variability estimate

Standard error of the mean

Dispersion value

0.0166

QVM149 150/50/160 µg vs QMF149 150/320 µg

Statistical analysis description

Week 12

Comparison groups

QVM149 150/50/160 µg o.d. v QMF149 150/320 µg o.d.

Number of subjects included in analysis

1198

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.002

Method

MMRM

Parameter type

LS Mean

Point estimate

0.058

Confidence interval

level

95%

sides

2-sided

lower limit

0.022

upper limit

0.094

Variability estimate

Standard error of the mean

Dispersion value

0.0184

QVM149 150/50/160 µg vs S/F 50/500 µg

Statistical analysis description

Week 12

Comparison groups

QVM149 150/50/160 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1204

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.117

Confidence interval

level

95%

sides

2-sided

lower limit

0.081

upper limit

0.153

Variability estimate

Standard error of the mean

Dispersion value

0.0183

QVM149 150/50/80 µg vs QMF149 150/160 µg

Statistical analysis description

Week 12

Comparison groups

QVM149 150/50/80 µg o.d. v QMF149 150/160 µg o.d.

Number of subjects included in analysis

1190

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.007

Method

MMRM

Parameter type

LS Mean

Point estimate

0.05

Confidence interval

level

95%

sides

2-sided

lower limit

0.013

upper limit

0.086

Variability estimate

Standard error of the mean

Dispersion value

0.0185

QVM149 150/50/80 µg vs S/F 50/500 µg

Statistical analysis description

Week 12

Comparison groups

QVM149 150/50/80 µg o.d. v Salmeterol/fluticasone 50/500 μg b.i.d.

Number of subjects included in analysis

1192

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

MMRM

Point estimate

0.087

Confidence interval

level

95%

sides

2-sided

lower limit

0.051

upper limit

0.123

Variability estimate

Standard error of the mean

Dispersion value

0.0184

Secondary: Percentage of participants with composite endpoint of serious asthma outcomes

Top of page

End point title

Percentage of participants with composite endpoint of serious asthma outcomes

End point description

A composite endpoint of serious asthma outcomes is defined as asthma-related hospitalization, asthma-related intubation, or asthma-related death and was reviewed by the Adjudication Committee.

End point type

Secondary

End point timeframe

Up to Week 52

End point values	QVM149 150/50/160 µg o.d.	QVM149 150/50/80 µg o.d.	QMF149 150/320 µg o.d.	QMF149 150/160 µg o.d.	Salmeterol/fluticasone 50/500 μg b.i.d.
Number of subjects analysed	616	617	613	608	618
Units: Percentage of participants
number (not applicable)	1.4	2.5	1.9	1.6	1.2

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days (52 weeks on average, up to 416 days).

Adverse event reporting additional description

Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

22.0

Reporting group title

QVM149 150/50/160 μg o.d.

Reporting group description

QVM149 150/50/160 μg (indacaterol acetate/glycopyrronium/mometasone furoate) once daily (o.d.) delivered via Concept1 device

Reporting group title

QVM149 150/50/80 μg o.d.

Reporting group description

QVM149 150/50/80 μg (indacaterol acetate/glycopyrronium/mometasone furoate) once daily (o.d.) delivered via Concept1 device

Reporting group title

QMF149 150/320 μg o.d.

Reporting group description

QMF149 150/320 μg (indacaterol acetate/mometasone furoate) once daily (o.d.) delivered via Concept1 device

Reporting group title

QMF149 150/160 μg o.d.

Reporting group description

QMF149 150/160 μg (indacaterol acetate/mometasone furoate) once daily (o.d.) delivered via Concept1 device

Reporting group title

Salmeterol/fluticasone 50/500 μg b.i.d.

Reporting group description

Salmeterol xinafoate /fluticasone propionate 50/500 μg twice daily (b.i.d.) delivered via Accuhaler®

Serious adverse events	QVM149 150/50/160 μg o.d.	QVM149 150/50/80 μg o.d.	QMF149 150/320 μg o.d.	QMF149 150/160 μg o.d.	Salmeterol/fluticasone 50/500 μg b.i.d.
Total subjects affected by serious adverse events
subjects affected / exposed	46 / 616 (7.47%)	49 / 617 (7.94%)	52 / 613 (8.48%)	38 / 608 (6.25%)	39 / 618 (6.31%)
number of deaths (all causes)	2	1	4	0	0
number of deaths resulting from adverse events	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute leukaemia
subjects affected / exposed	0 / 616 (0.00%)	1 / 617 (0.16%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Adenocarcinoma of colon
subjects affected / exposed	0 / 616 (0.00%)	1 / 617 (0.16%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	1 / 613 (0.16%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Breast cancer
subjects affected / exposed	0 / 616 (0.00%)	1 / 617 (0.16%)	1 / 613 (0.16%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Central nervous system lymphoma
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	1 / 613 (0.16%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Chronic lymphocytic leukaemia
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	1 / 613 (0.16%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colon cancer
subjects affected / exposed	1 / 616 (0.16%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endometrial cancer
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	1 / 613 (0.16%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Liposarcoma
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	1 / 613 (0.16%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung neoplasm malignant
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	1 / 613 (0.16%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian adenoma
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	1 / 608 (0.16%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	1 / 608 (0.16%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Salivary gland adenoma
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	1 / 613 (0.16%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Soft tissue sarcoma
subjects affected / exposed	1 / 616 (0.16%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma
subjects affected / exposed	0 / 616 (0.00%)	1 / 617 (0.16%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Uterine cancer
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	1 / 613 (0.16%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Uterine leiomyoma
subjects affected / exposed	0 / 616 (0.00%)	1 / 617 (0.16%)	0 / 613 (0.00%)	1 / 608 (0.16%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Angiopathy
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	1 / 613 (0.16%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aortic dissection
subjects affected / exposed	1 / 616 (0.16%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Aortic dissection rupture
subjects affected / exposed	0 / 616 (0.00%)	1 / 617 (0.16%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	2 / 616 (0.32%)	0 / 617 (0.00%)	0 / 613 (0.00%)	1 / 608 (0.16%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhagic vasculitis
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	1 / 618 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	0 / 616 (0.00%)	2 / 617 (0.32%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypertensive crisis
subjects affected / exposed	1 / 616 (0.16%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombophlebitis
subjects affected / exposed	1 / 616 (0.16%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Varicose vein
subjects affected / exposed	2 / 616 (0.32%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	1 / 618 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	1 / 616 (0.16%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	2 / 616 (0.32%)	1 / 617 (0.16%)	0 / 613 (0.00%)	1 / 608 (0.16%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 616 (0.00%)	1 / 617 (0.16%)	1 / 613 (0.16%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sudden cardiac death
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	1 / 613 (0.16%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	1 / 616 (0.16%)	0 / 617 (0.00%)	1 / 613 (0.16%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sarcoidosis
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	1 / 618 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Cystocele
subjects affected / exposed	0 / 616 (0.00%)	1 / 617 (0.16%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endometriosis
subjects affected / exposed	1 / 616 (0.16%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian cyst
subjects affected / exposed	1 / 616 (0.16%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Postmenopausal haemorrhage
subjects affected / exposed	0 / 616 (0.00%)	1 / 617 (0.16%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Uterine polyp
subjects affected / exposed	1 / 616 (0.16%)	1 / 617 (0.16%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	9 / 616 (1.46%)	15 / 617 (2.43%)	12 / 613 (1.96%)	8 / 608 (1.32%)	9 / 618 (1.46%)
occurrences causally related to treatment / all	0 / 9	0 / 20	1 / 14	0 / 8	0 / 9
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis chronic
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	1 / 618 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cough
subjects affected / exposed	0 / 616 (0.00%)	2 / 617 (0.32%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 616 (0.00%)	1 / 617 (0.16%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemothorax
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	1 / 608 (0.16%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nasal polyps
subjects affected / exposed	0 / 616 (0.00%)	1 / 617 (0.16%)	0 / 613 (0.00%)	0 / 608 (0.00%)	1 / 618 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nasal septum deviation
subjects affected / exposed	1 / 616 (0.16%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 616 (0.00%)	1 / 617 (0.16%)	0 / 613 (0.00%)	0 / 608 (0.00%)	1 / 618 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	1 / 616 (0.16%)	0 / 617 (0.00%)	3 / 613 (0.49%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Sinus polyp
subjects affected / exposed	0 / 616 (0.00%)	1 / 617 (0.16%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sleep apnoea syndrome
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	1 / 608 (0.16%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Depression
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	1 / 608 (0.16%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Suicide attempt
subjects affected / exposed	1 / 616 (0.16%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Hepatic enzyme increased
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	2 / 613 (0.33%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Transaminases increased
subjects affected / exposed	1 / 616 (0.16%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Concussion
subjects affected / exposed	0 / 616 (0.00%)	2 / 617 (0.32%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Facial bones fracture
subjects affected / exposed	0 / 616 (0.00%)	1 / 617 (0.16%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	1 / 608 (0.16%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Foot fracture
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	1 / 613 (0.16%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fracture
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	1 / 613 (0.16%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hand fracture
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	2 / 608 (0.33%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Head injury
subjects affected / exposed	0 / 616 (0.00%)	1 / 617 (0.16%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	1 / 618 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	0 / 616 (0.00%)	1 / 617 (0.16%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	1 / 613 (0.16%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Limb injury
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	1 / 608 (0.16%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower limb fracture
subjects affected / exposed	0 / 616 (0.00%)	1 / 617 (0.16%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lumbar vertebral fracture
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	1 / 613 (0.16%)	0 / 608 (0.00%)	1 / 618 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Meniscus injury
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	1 / 613 (0.16%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Multiple fractures
subjects affected / exposed	0 / 616 (0.00%)	1 / 617 (0.16%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural discomfort
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	1 / 618 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	1 / 608 (0.16%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin abrasion
subjects affected / exposed	0 / 616 (0.00%)	1 / 617 (0.16%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin laceration
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	1 / 608 (0.16%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper limb fracture
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	1 / 608 (0.16%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute cardiac event
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	1 / 613 (0.16%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Acute coronary syndrome
subjects affected / exposed	0 / 616 (0.00%)	1 / 617 (0.16%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	1 / 613 (0.16%)	0 / 608 (0.00%)	1 / 618 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arrhythmia
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	1 / 608 (0.16%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 616 (0.00%)	1 / 617 (0.16%)	1 / 613 (0.16%)	1 / 608 (0.16%)	1 / 618 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrioventricular block complete
subjects affected / exposed	1 / 616 (0.16%)	0 / 617 (0.00%)	0 / 613 (0.00%)	1 / 608 (0.16%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	1 / 608 (0.16%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	1 / 608 (0.16%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac tamponade
subjects affected / exposed	1 / 616 (0.16%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Extrasystoles
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	1 / 618 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	1 / 616 (0.16%)	0 / 617 (0.00%)	1 / 613 (0.16%)	2 / 608 (0.33%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	1 / 608 (0.16%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Palpitations
subjects affected / exposed	1 / 616 (0.16%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	1 / 613 (0.16%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ventricular extrasystoles
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	1 / 613 (0.16%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Alcoholic seizure
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	1 / 613 (0.16%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Carpal tunnel syndrome
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	1 / 608 (0.16%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral infarction
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	1 / 613 (0.16%)	1 / 608 (0.16%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	0 / 616 (0.00%)	1 / 617 (0.16%)	0 / 613 (0.00%)	1 / 608 (0.16%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular disorder
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	1 / 613 (0.16%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cervicobrachial syndrome
subjects affected / exposed	0 / 616 (0.00%)	1 / 617 (0.16%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	1 / 613 (0.16%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypertensive encephalopathy
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	1 / 613 (0.16%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic neuropathy
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	1 / 613 (0.16%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	1 / 608 (0.16%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Loss of consciousness
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	1 / 618 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lumbar radiculopathy
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	1 / 618 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	0 / 616 (0.00%)	1 / 617 (0.16%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	1 / 613 (0.16%)	1 / 608 (0.16%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Transient global amnesia
subjects affected / exposed	0 / 616 (0.00%)	1 / 617 (0.16%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	2 / 616 (0.32%)	1 / 617 (0.16%)	1 / 613 (0.16%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 616 (0.16%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune thrombocytopenic purpura
subjects affected / exposed	0 / 616 (0.00%)	1 / 617 (0.16%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Middle ear effusion
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	1 / 608 (0.16%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Otorrhoea
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	1 / 608 (0.16%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Cataract
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	2 / 613 (0.33%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Optic ischaemic neuropathy
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	1 / 618 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal hernia
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	1 / 608 (0.16%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	1 / 616 (0.16%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Enteritis
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	2 / 613 (0.33%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal angiodysplasia
subjects affected / exposed	1 / 616 (0.16%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	1 / 616 (0.16%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intra-abdominal fluid collection
subjects affected / exposed	1 / 616 (0.16%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Large intestine perforation
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	1 / 613 (0.16%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	1 / 616 (0.16%)	1 / 617 (0.16%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peritoneal adhesions
subjects affected / exposed	1 / 616 (0.16%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Proctitis
subjects affected / exposed	1 / 616 (0.16%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	1 / 616 (0.16%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rectal polyp
subjects affected / exposed	1 / 616 (0.16%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Umbilical hernia
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	2 / 608 (0.33%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Bile duct stone
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	1 / 613 (0.16%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	0 / 616 (0.00%)	1 / 617 (0.16%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	3 / 616 (0.49%)	0 / 617 (0.00%)	0 / 613 (0.00%)	1 / 608 (0.16%)	1 / 618 (0.16%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic cirrhosis
subjects affected / exposed	0 / 616 (0.00%)	1 / 617 (0.16%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Liver injury
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	1 / 613 (0.16%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Primary biliary cholangitis
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	1 / 608 (0.16%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Steatohepatitis
subjects affected / exposed	1 / 616 (0.16%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Angioedema
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	1 / 613 (0.16%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urticaria
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	2 / 618 (0.32%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Calculus urethral
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	1 / 618 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nephritis
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	1 / 618 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	1 / 618 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal colic
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	1 / 613 (0.16%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	1 / 608 (0.16%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 616 (0.16%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	1 / 618 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Jaw disorder
subjects affected / exposed	1 / 616 (0.16%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myalgia
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	1 / 618 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	2 / 608 (0.33%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pathological fracture
subjects affected / exposed	1 / 616 (0.16%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rotator cuff syndrome
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	1 / 618 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal deformity
subjects affected / exposed	0 / 616 (0.00%)	1 / 617 (0.16%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	1 / 616 (0.16%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	2 / 618 (0.32%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bursitis infective
subjects affected / exposed	0 / 616 (0.00%)	1 / 617 (0.16%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	1 / 613 (0.16%)	0 / 608 (0.00%)	2 / 618 (0.32%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis infective
subjects affected / exposed	0 / 616 (0.00%)	1 / 617 (0.16%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic sinusitis
subjects affected / exposed	1 / 616 (0.16%)	0 / 617 (0.00%)	0 / 613 (0.00%)	2 / 608 (0.33%)	1 / 618 (0.16%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dengue fever
subjects affected / exposed	0 / 616 (0.00%)	1 / 617 (0.16%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	0 / 616 (0.00%)	1 / 617 (0.16%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	1 / 613 (0.16%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HIV infection
subjects affected / exposed	0 / 616 (0.00%)	1 / 617 (0.16%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatitis C
subjects affected / exposed	0 / 616 (0.00%)	1 / 617 (0.16%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	1 / 608 (0.16%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infectious pleural effusion
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	1 / 613 (0.16%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	1 / 608 (0.16%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	1 / 616 (0.16%)	1 / 617 (0.16%)	3 / 613 (0.49%)	1 / 608 (0.16%)	2 / 618 (0.32%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 3	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mastoiditis
subjects affected / exposed	1 / 616 (0.16%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nasopharyngitis
subjects affected / exposed	0 / 616 (0.00%)	1 / 617 (0.16%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Otitis media chronic
subjects affected / exposed	1 / 616 (0.16%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	0 / 616 (0.00%)	1 / 617 (0.16%)	1 / 613 (0.16%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	3 / 616 (0.49%)	2 / 617 (0.32%)	1 / 613 (0.16%)	3 / 608 (0.49%)	5 / 618 (0.81%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 1	0 / 3	1 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Postoperative wound infection
subjects affected / exposed	0 / 616 (0.00%)	1 / 617 (0.16%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary tuberculosis
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	1 / 618 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	1 / 608 (0.16%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	0 / 616 (0.00%)	1 / 617 (0.16%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rhinitis
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	1 / 618 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Salpingitis
subjects affected / exposed	0 / 616 (0.00%)	1 / 617 (0.16%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sinusitis
subjects affected / exposed	0 / 616 (0.00%)	1 / 617 (0.16%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection bacterial
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	1 / 613 (0.16%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	2 / 616 (0.32%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	1 / 618 (0.16%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	1 / 616 (0.16%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Viral upper respiratory tract infection
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	1 / 608 (0.16%)	0 / 618 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Type 2 diabetes mellitus
subjects affected / exposed	0 / 616 (0.00%)	0 / 617 (0.00%)	0 / 613 (0.00%)	0 / 608 (0.00%)	1 / 618 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 2%

Non-serious adverse events	QVM149 150/50/160 μg o.d.	QVM149 150/50/80 μg o.d.	QMF149 150/320 μg o.d.	QMF149 150/160 μg o.d.	Salmeterol/fluticasone 50/500 μg b.i.d.
Total subjects affected by non serious adverse events
subjects affected / exposed	367 / 616 (59.58%)	387 / 617 (62.72%)	377 / 613 (61.50%)	392 / 608 (64.47%)	419 / 618 (67.80%)
Vascular disorders
Hypertension
subjects affected / exposed	16 / 616 (2.60%)	19 / 617 (3.08%)	14 / 613 (2.28%)	17 / 608 (2.80%)	23 / 618 (3.72%)
occurrences all number	20	20	17	19	27
Nervous system disorders
Headache
subjects affected / exposed	23 / 616 (3.73%)	30 / 617 (4.86%)	24 / 613 (3.92%)	34 / 608 (5.59%)	25 / 618 (4.05%)
occurrences all number	32	32	27	44	35
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	17 / 616 (2.76%)	11 / 617 (1.78%)	10 / 613 (1.63%)	10 / 608 (1.64%)	15 / 618 (2.43%)
occurrences all number	23	11	11	12	20
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	243 / 616 (39.45%)	242 / 617 (39.22%)	249 / 613 (40.62%)	265 / 608 (43.59%)	306 / 618 (49.51%)
occurrences all number	436	476	539	574	710
Cough
subjects affected / exposed	24 / 616 (3.90%)	18 / 617 (2.92%)	11 / 613 (1.79%)	14 / 608 (2.30%)	15 / 618 (2.43%)
occurrences all number	28	21	11	16	19
Dysphonia
subjects affected / exposed	24 / 616 (3.90%)	13 / 617 (2.11%)	10 / 613 (1.63%)	9 / 608 (1.48%)	12 / 618 (1.94%)
occurrences all number	26	13	12	9	12
Rhinitis allergic
subjects affected / exposed	19 / 616 (3.08%)	17 / 617 (2.76%)	9 / 613 (1.47%)	15 / 608 (2.47%)	20 / 618 (3.24%)
occurrences all number	22	19	11	19	26
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	2 / 616 (0.32%)	14 / 617 (2.27%)	5 / 613 (0.82%)	12 / 608 (1.97%)	10 / 618 (1.62%)
occurrences all number	2	15	5	12	10
Back pain
subjects affected / exposed	12 / 616 (1.95%)	18 / 617 (2.92%)	18 / 613 (2.94%)	16 / 608 (2.63%)	14 / 618 (2.27%)
occurrences all number	13	20	20	19	14
Infections and infestations
Bronchitis
subjects affected / exposed	49 / 616 (7.95%)	48 / 617 (7.78%)	46 / 613 (7.50%)	44 / 608 (7.24%)	55 / 618 (8.90%)
occurrences all number	68	65	51	58	70
Influenza
subjects affected / exposed	19 / 616 (3.08%)	21 / 617 (3.40%)	23 / 613 (3.75%)	26 / 608 (4.28%)	25 / 618 (4.05%)
occurrences all number	24	26	25	30	30
Lower respiratory tract infection
subjects affected / exposed	13 / 616 (2.11%)	12 / 617 (1.94%)	12 / 613 (1.96%)	17 / 608 (2.80%)	22 / 618 (3.56%)
occurrences all number	18	13	14	22	27
Nasopharyngitis
subjects affected / exposed	64 / 616 (10.39%)	76 / 617 (12.32%)	73 / 613 (11.91%)	64 / 608 (10.53%)	83 / 618 (13.43%)
occurrences all number	82	101	93	90	117
Pharyngitis
subjects affected / exposed	22 / 616 (3.57%)	21 / 617 (3.40%)	20 / 613 (3.26%)	19 / 608 (3.13%)	20 / 618 (3.24%)
occurrences all number	26	21	22	19	23
Respiratory tract infection viral
subjects affected / exposed	18 / 616 (2.92%)	17 / 617 (2.76%)	11 / 613 (1.79%)	29 / 608 (4.77%)	22 / 618 (3.56%)
occurrences all number	23	24	16	38	29
Rhinitis
subjects affected / exposed	12 / 616 (1.95%)	20 / 617 (3.24%)	17 / 613 (2.77%)	20 / 608 (3.29%)	11 / 618 (1.78%)
occurrences all number	16	23	19	20	13
Sinusitis
subjects affected / exposed	14 / 616 (2.27%)	18 / 617 (2.92%)	9 / 613 (1.47%)	17 / 608 (2.80%)	14 / 618 (2.27%)
occurrences all number	15	20	10	22	14
Upper respiratory tract infection
subjects affected / exposed	33 / 616 (5.36%)	45 / 617 (7.29%)	52 / 613 (8.48%)	48 / 608 (7.89%)	52 / 618 (8.41%)
occurrences all number	46	60	66	65	66
Upper respiratory tract infection bacterial
subjects affected / exposed	17 / 616 (2.76%)	22 / 617 (3.57%)	27 / 613 (4.40%)	28 / 608 (4.61%)	29 / 618 (4.69%)
occurrences all number	18	26	32	31	33
Urinary tract infection
subjects affected / exposed	8 / 616 (1.30%)	5 / 617 (0.81%)	10 / 613 (1.63%)	9 / 608 (1.48%)	13 / 618 (2.10%)
occurrences all number	9	5	10	10	16
Viral upper respiratory tract infection
subjects affected / exposed	21 / 616 (3.41%)	31 / 617 (5.02%)	38 / 613 (6.20%)	26 / 608 (4.28%)	47 / 618 (7.61%)
occurrences all number	21	37	49	30	61

More information

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Were there any global substantial amendments to the protocol? Yes

03 Aug 2015

Amendment 1 added the validated method for collecting data for the ACQ-7 instrument. The changes were: Questions 1-6 of the ACQ-7 to be completed by patients based on one week recall. Item 7 to be completed by the Investigator using the MasterScope spirometer at the study site. Derivation of rescue medication from the e-diary (6th item on ACQ-7) was not to be performed.

31 Aug 2015

Appendix 1 and 5 were replaced. Appendix 1: Instruction for use of Concept1 (picture 3 and 5 were missing and a black field was covering the text describing Concept1 picture). Appendix 5 - AQLQ-S (questions 26-31 of the questionnaire were missing and the page was blank and a black field was covering part of the question 32) which were incomplete due to a technical issue during protocol publication. Updated: additional pregnancy testing requirements, and spirometry assessment method not to include reversibility test.

08 Oct 2015

Modified the ACQ score inclusion criteria from ACQ ≥ 2 to ACQ ≥1.5 based on recent feedback from an external expert advisory board in September 2015. Initial threshold of ≥2 was defined based on internal modelling and simulation data as well as published literature (Barnes et al 2014). However, expert advisory board members suggested that a threshold of 1.5 is more clinically meaningful for this patient population. Asthma worsening criteria was updated and relevant sections such as protocol summary rationale for dosing and supportive analysis.

08 Sep 2016

After approval of tiotropium Respimat 5 μg o.d. for asthma in September 2014, changes to GINA guidelines in 2015 were expected to result in a progressive increase in use of tiotropium (LAMA) as add on to ICS/LABA therapy in GINA ≥Step 4 patients. The Amendment reduced the exclusion period for LAMA use from 12 months to 3 months prior to Visit 1. This broadened the pool of eligible patients and help better reflect rapidly evolving medical practice in GINA Step ≥4 asthma patients eDiary alert handling during the Run-In Epoch due to asthma worsening was updated.

08 Feb 2017

A modification was made of the inclusion criteria for the duration of baseline LABA/ICS requirements from 1 year to 3 months. Revision of the sample size based on the re-estimation of the drop-out rate at Week 26 when the primary and key secondary objectives are evaluated.

18 Dec 2017

Primary analysis to be conducted after all patients have completed at least 26 weeks treatment (Visit 207).

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 multicenter, randomized, 52-week, double-blind, parallel-group, active controlled study to compare the efficacy and safety of QVM149 with QMF149 in patients with asthma

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Trough Forced Expiratory Volume in 1 Second (Trough FEV1) of QVM149 versus QMF149 at week 26

Primary: Trough Forced Expiratory Volume in 1 Second (Trough FEV1) of QVM149 versus QMF149 at week 26

Secondary: Asthma Control Questionnaire (ACQ-7) at Week 26 and Week 52

Secondary: Asthma Control Questionnaire (ACQ-7) at Week 26 and Week 52

Secondary: Trough Forced Expiratory Volume in 1 Second (Trough FEV1) of QVM149 versus salmeterol/fluticasone at week 26

Secondary: Trough Forced Expiratory Volume in 1 Second (Trough FEV1) of QVM149 versus salmeterol/fluticasone at week 26

Secondary: Trough FEV1 at week 52

Secondary: Trough FEV1 at week 52

Secondary: Pre-dose Forced Vital Capacity (FVC) at week 4 and week 12

Secondary: Pre-dose Forced Vital Capacity (FVC) at week 4 and week 12

Secondary: Trough Forced Expiratory Flow (FEF) between 25% and 75% of FVC (FEF25-75) at 52 weeks

Secondary: Trough Forced Expiratory Flow (FEF) between 25% and 75% of FVC (FEF25-75) at 52 weeks

Secondary: Change from baseline in morning and evening Peak Expiratory Flow Rate (PEF) over 26 and 52 weeks of treatment

Secondary: Change from baseline in morning and evening Peak Expiratory Flow Rate (PEF) over 26 and 52 weeks of treatment

Secondary: Change from baseline in percentage of asthma symptom-free days over 52 weeks

Secondary: Change from baseline in percentage of asthma symptom-free days over 52 weeks

Secondary: Change from baseline in percentage of days with no daytime symptoms

Secondary: Change from baseline in percentage of days with no daytime symptoms

Secondary: Change from baseline in percentage of nights with no night-time awakenings over 52 weeks

Secondary: Change from baseline in percentage of nights with no night-time awakenings over 52 weeks

Secondary: Change from baseline in percentage of mornings with no symptoms on rising over 52 weeks

Secondary: Change from baseline in percentage of mornings with no symptoms on rising over 52 weeks

Secondary: Change from baseline in percentage of days without rescue medication use over 26 and 52 weeks

Secondary: Change from baseline in percentage of days without rescue medication use over 26 and 52 weeks

Secondary: Percentage of patients achieving the minimal clinically important difference (MCID) ACQ ≥ 0.5 at Week 26 and Week 52

Secondary: Percentage of patients achieving the minimal clinically important difference (MCID) ACQ ≥ 0.5 at Week 26 and Week 52

Secondary: Time to first hospitalization for asthma exacerbation

Secondary: Time to first hospitalization for asthma exacerbation

Secondary: Time to first asthma exacerbation by exacerbation category

Secondary: Time to first asthma exacerbation by exacerbation category

Secondary: Annual rate of asthma exacerbations by exacerbation category

Secondary: Annual rate of asthma exacerbations by exacerbation category

Secondary: Duration in days of asthma exacerbations by exacerbation category

Secondary: Duration in days of asthma exacerbations by exacerbation category

Secondary: Percentage of participants with at least one asthma exacerbation by exacerbation category

Secondary: Percentage of participants with at least one asthma exacerbation by exacerbation category

Secondary: Time in days to permanent discontinuation of study medication due to asthma exacerbation

Secondary: Time in days to permanent discontinuation of study medication due to asthma exacerbation

Secondary: Total amount of oral corticosteroid used (in prednisone-equivalent mg doses) to treat asthma exacerbations

Secondary: Total amount of oral corticosteroid used (in prednisone-equivalent mg doses) to treat asthma exacerbations

Secondary: Change from baseline in percentage of rescue medication free days over 26 and 52 weeks

Secondary: Change from baseline in percentage of rescue medication free days over 26 and 52 weeks

Secondary: Asthma Quality of Life Questionnaire (AQLQ) at Week 52

Secondary: Asthma Quality of Life Questionnaire (AQLQ) at Week 52

Secondary: Pre-dose FEV1 at weeks 4 and 12

Secondary: Pre-dose FEV1 at weeks 4 and 12

Secondary: Percentage of participants with composite endpoint of serious asthma outcomes

Secondary: Percentage of participants with composite endpoint of serious asthma outcomes

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A multicenter, randomized, 52-week, double-blind, parallel-group, active controlled study to compare the efficacy and safety of QVM149 with QMF149 in patients with asthma