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Clinical Trial Results:
A multicenter, partially-blinded, randomized, 24-week, parallel-group, non-inferiority, open-label active controlled study to compare the efficacy and safety of QVM149 with a free triple combination of salmeterol/fluticasone + tiotropium in patients with uncontrolled asthma

Summary
EudraCT number	2017-000136-34
Trial protocol	CZ HU GR PL ES SK
Global end of trial date	19 Jul 2019

Results information
Results version number	v2(current)
This version publication date	13 Jun 2021
First version publication date	31 Jul 2020
Other versions	v1
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

CQVM149B2306

ISRCTN number

US NCT number

NCT03158311

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

19 Jul 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

19 Jul 2019

Was the trial ended prematurely?

Main objective of the trial

The main objective of this trial was to demonstrate non-inferiority of either QVM149 high-dose (150/50/160 μg) or QVM149 medium-dose (150/50/80 μg) to comparator salmeterol/fluticasone + tiotropium in terms of Asthma Quality of Life Questionnaire (AQLQ) after 24 weeks of treatment in uncontrolled moderate to severe asthmatics patients.

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 short acting β2-agonist (100 μg salbutamol MDI or equivalent albuterol MDI) which they were instructed to use throughout the study as rescue medication. Nebulized salbutamol was not allowed as rescue medication throughout the entire trial. No other rescue treatment was permitted.

Background therapy

Evidence for comparator

Actual start date of recruitment

05 Feb 2018

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Slovakia: 30

Country: Number of subjects enrolled

South Africa: 47

Country: Number of subjects enrolled

Spain: 13

Country: Number of subjects enrolled

Taiwan: 4

Country: Number of subjects enrolled

Turkey: 25

Country: Number of subjects enrolled

Vietnam: 16

Country: Number of subjects enrolled

Argentina: 412

Country: Number of subjects enrolled

Chile: 27

Country: Number of subjects enrolled

Colombia: 8

Country: Number of subjects enrolled

Czech Republic: 54

Country: Number of subjects enrolled

Germany: 213

Country: Number of subjects enrolled

Greece: 24

Country: Number of subjects enrolled

Hungary: 99

Country: Number of subjects enrolled

India: 73

Country: Number of subjects enrolled

Israel: 45

Country: Number of subjects enrolled

Mexico: 20

Country: Number of subjects enrolled

Peru: 27

Country: Number of subjects enrolled

Poland: 16

Country: Number of subjects enrolled

Russian Federation: 217

Country: Number of subjects enrolled

Serbia: 56

Worldwide total number of subjects

1426

EEA total number of subjects

449

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)

1137

From 65 to 84 years

289

85 years and over

Subject disposition

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Recruitment details

Participants took part in 166 investigative sites in 20 countries from 05 Feb 2018 to 19 Jul 2019.

Screening details

A total of 1917 participants were screened. A 2 week run-in phase preceded the randomized treatment phase of the study. 1821 participants entered the run-in phase. Those participants who met the inclusion criteria entered the randomized treatment phase. Participants were randomized with a randomization ratio of 1:1:1 to three treatment arms.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Single blind

Roles blinded

Assessor ^[1]

Are arms mutually exclusive

Yes

QVM149 150/50/80 μg

Arm description

QVM149 150/50/80 μg o.d. delivered via Concept1

Arm type

Experimental

Investigational medicinal product name

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

QVM149 150/50/80 μg once daily delivered via Concept1

QVM149 150/50/160 μg

Arm description

QVM149 150/50/160 μg o.d. delivered via Concept1

Arm type

Experimental

Investigational medicinal product name

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

QVM149 150/50/160 μg once daily delivered via Concept1

Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg

Arm description

Salmeterol/fluticasone 50/500 μg b.i.d. delivered via Accuhaler® plus tiotropium 5 μg o.d. delivered via Respimat®

Arm type

Active comparator

Investigational medicinal product name

Salmeterol/flucticasone plus tiotropium

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

Salmeterol/fluticasone 50/500 μg twice daily delivered via Accuhaler® plus tiotropium 5 μg once daily delivered via Respimat®.

Notes
[1] - The roles blinded appear inconsistent with a simple blinded trial.
Justification: The free triple combination of salmeterol/fluticasone + tiotropium was open label. Within the two QVM149 treatment arms patients, investigator staff, and persons performing the assessments, remained blind to the identity of the actual QVM149 treatment dose but had knowledge that the patient had been assigned QVM149 as study treatment. The data analysts and sponsor team were blinded

Number of subjects in period 1	QVM149 150/50/80 μg	QVM149 150/50/160 μg	Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg
Started	474	476	476
Full Analysis Set (FAS)	474	476	475
Safety Set (SAF)	474	476	475
Completed	452	460	448
Not completed	22	16	28
Physician decision	2	3	7
Techinical Problems	3	1	5
Adverse event, non-fatal	5	3	3
Randomized but not treated	-	-	1
Pregnancy	-	2	-
Subject/Guardian Decision	10	6	11
Study Terminated by Sponsor	1	-	-
Lost to follow-up	1	1	1

Baseline characteristics

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Reporting group title

QVM149 150/50/80 μg

Reporting group description

QVM149 150/50/80 μg o.d. delivered via Concept1

Reporting group title

QVM149 150/50/160 μg

Reporting group description

QVM149 150/50/160 μg o.d. delivered via Concept1

Reporting group title

Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg

Reporting group description

Salmeterol/fluticasone 50/500 μg b.i.d. delivered via Accuhaler® plus tiotropium 5 μg o.d. delivered via Respimat®

Reporting group values	QVM149 150/50/80 μg	QVM149 150/50/160 μg	Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg	Total
Number of subjects	474	476	476	1426
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
Adults (18-64 years)	381	375	381	1137
From 65-84 years	93	101	95	289
85 years and over	0	0	0	0
Age Continuous
Units: Years
arithmetic mean (standard deviation)	51.9 ( 13.58 )	52.7 ( 13.34 )	53.1 ( 13.08 )	-
Sex: Female, Male
Units: Participants
Female	306	289	307	902
Male	168	187	169	524
Race/Ethnicity, Customized
Units: Subjects
American Indian or Alaska Native	5	1	10	16
Asian	36	34	33	103
Black or African American	6	5	3	14
White	401	392	391	1184
Other	26	44	39	109

End points

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Reporting group title

QVM149 150/50/80 μg

Reporting group description

QVM149 150/50/80 μg o.d. delivered via Concept1

Reporting group title

QVM149 150/50/160 μg

Reporting group description

QVM149 150/50/160 μg o.d. delivered via Concept1

Reporting group title

Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg

Reporting group description

Salmeterol/fluticasone 50/500 μg b.i.d. delivered via Accuhaler® plus tiotropium 5 μg o.d. delivered via Respimat®

Primary: Change from Baseline in Asthma Quality of Life Questionnaire (AQLQ) Total Score

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End point title

Change from Baseline in Asthma Quality of Life Questionnaire (AQLQ) Total Score

End point description

The AQLQ is a 32-item asthma 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, where 1=totally limited/problems all the time and 7= not at all limited/no problems. It consists of 4 domains: symptoms, activity limitation, emotional funtion, and emotional stimuli. The overall score is calculated as the mean of 32 items. Higher AQLQ scores indicate better health-related quality of life.

End point type

Primary

End point timeframe

Baseline and Week 24

End point values	QVM149 150/50/80 μg	QVM149 150/50/160 μg	Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg
Number of subjects analysed	436	453	435
Units: Score on a scale
least squares mean (standard error)	0.715 ( 0.070 )	0.827 ( 0.069 )	0.753 ( 0.069 )

AQLQ: QVM149 150/50/80 μg vs Active comparator

Comparison groups

QVM149 150/50/80 μg v Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg

Number of subjects included in analysis

871

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[1]

P-value

< 0.001 ^[2]

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

Least Square mean (LS Mean)

Point estimate

-0.038

Confidence interval

level

97.5%

sides

1-sided

lower limit

-0.139

upper limit

Variability estimate

Standard error of the mean

Dispersion value

0.051

Notes
[1] - Non-inferiority margin: 0.25 points
[2] - P-Value is one-sided

AQLQ: QVM149 150/50/1600 μg vs Active Comparator

Comparison groups

QVM149 150/50/160 μg v Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg

Number of subjects included in analysis

888

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[3]

P-value

< 0.001 ^[4]

Method

MMRM

Parameter type

LS Mean

Point estimate

0.073

Confidence interval

level

97.5%

sides

1-sided

lower limit

-0.027

upper limit

Variability estimate

Standard error of the mean

Dispersion value

0.051

Notes
[3] - Non-inferiority margin: 0.25 points
[4] - P-Value is one-sided

Secondary: Change from Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1)

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End point title

Change from Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1)

End point description

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. Trough FEV1 is the mean of two FEV1 values measures taken 15 minutes (min) and 45 min prior to evening dose.

End point type

Secondary

End point timeframe

Baseline, Week 8, Week 16 and Week 24

End point values	QVM149 150/50/80 μg	QVM149 150/50/160 μg	Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg
Number of subjects analysed	420	438	425
Units: Litre (L)
least squares mean (standard error)
Week 8 (Number analyzed: 382/395/371)	0.246 ( 0.020 )	0.309 ( 0.020 )	0.243 ( 0.020 )
Week 16 (Number analyzed: 357/389/371)	0.251 ( 0.020 )	0.319 ( 0.020 )	0.253 ( 0.020 )
Week 24 (Number analyzed: 367/385/372)	0.248 ( 0.021 )	0.334 ( 0.021 )	0.238 ( 0.021 )

FEV1:QVM149 150/50/80μg vs Active Comparator

Statistical analysis description

Week 8

Comparison groups

QVM149 150/50/80 μg v Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg

Number of subjects included in analysis

845

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.892 ^[5]

Method

MMRM

Parameter type

LS Mean

Point estimate

0.003

Confidence interval

level

95%

sides

2-sided

lower limit

-0.046

upper limit

0.052

Variability estimate

Standard error of the mean

Dispersion value

0.025

Notes
[5] - P-value is two-sided

FEV1: QVM149 150/50/160 μg vs Active Comparator

Statistical analysis description

Week 8

Comparison groups

QVM149 150/50/160 μg v Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg

Number of subjects included in analysis

863

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.007 ^[6]

Method

MMRM

Parameter type

LS Mean

Point estimate

0.067

Confidence interval

level

95%

sides

2-sided

lower limit

0.018

upper limit

0.115

Variability estimate

Standard error of the mean

Dispersion value

0.025

Notes
[6] - P-value is two-sided

FEV1: QVM149 150/50/80 μg vs Active Comparator

Statistical analysis description

Week 16

Comparison groups

QVM149 150/50/80 μg v Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg

Number of subjects included in analysis

845

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.945 ^[7]

Method

MMRM

Parameter type

LS Mean

Point estimate

-0.002

Confidence interval

level

95%

sides

2-sided

lower limit

-0.05

upper limit

0.047

Variability estimate

Standard error of the mean

Dispersion value

0.025

Notes
[7] - P-value is two-sided

FEV1: QVM149 150/50/160 μg vs Active Comparator

Statistical analysis description

Week 16

Comparison groups

QVM149 150/50/160 μg v Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg

Number of subjects included in analysis

863

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.007 ^[8]

Method

MMRM

Parameter type

LS Mean

Point estimate

0.066

Confidence interval

level

95%

sides

2-sided

lower limit

0.018

upper limit

0.114

Variability estimate

Standard error of the mean

Dispersion value

0.025

Notes
[8] - P-value is two-sided

FEV1: QVM149 150/50/80 μg vs Active Comparator

Statistical analysis description

Week 24

Comparison groups

QVM149 150/50/80 μg v Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg

Number of subjects included in analysis

845

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.713 ^[9]

Method

MMRM

Parameter type

LS Mean

Point estimate

0.009

Confidence interval

level

95%

sides

2-sided

lower limit

-0.041

upper limit

0.06

Variability estimate

Standard error of the mean

Dispersion value

0.026

Notes
[9] - P-value is two-sided

FEV1: QVM149 150/50/160 μg vs Active Comparator

Statistical analysis description

Week 24

Comparison groups

QVM149 150/50/160 μg v Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg

Number of subjects included in analysis

863

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[10]

Method

MMRM

Parameter type

LS Mean

Point estimate

0.096

Confidence interval

level

95%

sides

2-sided

lower limit

0.046

upper limit

0.146

Variability estimate

Standard error of the mean

Dispersion value

0.026

Notes
[10] - P-value is two-sided

Secondary: Change from Baseline in Asthma Control Questionnaire (ACQ-7) Total Score

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End point title

Change from Baseline in Asthma Control Questionnaire (ACQ-7) Total Score

End point description

The ACQ-7 measured asthma symptom control and consists of 7 items: 5 on symptom assessment, 1 on rescue medication use and 1 on airway calibre (FEV1 % predicted). All seven items are scored on a 7-point Likert scale, with 0 indicating total control and 6 indicating poor control. The questions are equally weighted and the total score is the mean of the seven items. Higher score indicates worst symptoms. The first 6 questions of the ACQ-7 were completed by the participant while the last question was completed by the study investigator using data from the Master Scope spirometer. A negative change from baseline indicates improvement in lung function.

End point type

Secondary

End point timeframe

Baseline, Week 16 and Week 24

End point values	QVM149 150/50/80 μg	QVM149 150/50/160 μg	Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg
Number of subjects analysed	447	454	447
Units: Score on a scale
least squares mean (standard error)
Week 16 (Number analyzed: 436/441/428)	-1.043 ( 0.045 )	-1.098 ( 0.045 )	-1.020 ( 0.045 )
Week 24 (Number analyzed: 437/452/436)	-1.080 ( 0.046 )	-1.172 ( 0.045 )	-1.048 ( 0.046 )

ACQ-7: QVM149 150/50/80 μg vs Active Comparator

Statistical analysis description

Week 16

Comparison groups

QVM149 150/50/80 μg v Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg

Number of subjects included in analysis

894

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.308 ^[11]

Method

MMRM

Parameter type

LS Mean

Point estimate

-0.023

Confidence interval

level

95%

sides

2-sided

lower limit

-0.113

upper limit

0.067

Variability estimate

Standard error of the mean

Dispersion value

0.046

Notes
[11] - P-value is one-sided

ACQ-7: QVM149 150/50/160 μg vs Active Comparator

Statistical analysis description

Week 16

Comparison groups

QVM149 150/50/160 μg v Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg

Number of subjects included in analysis

901

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.044 ^[12]

Method

MMRM

Parameter type

LS Mean

Point estimate

-0.079

Confidence interval

level

95%

sides

2-sided

lower limit

-0.169

upper limit

0.012

Variability estimate

Standard error of the mean

Dispersion value

0.046

Notes
[12] - P-value is one-sided

ACQ-7: QVM149 150/50/80 μg vs Active Comparator

Statistical analysis description

Week 24

Comparison groups

QVM149 150/50/80 μg v Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg

Number of subjects included in analysis

894

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.245 ^[13]

Method

MMRM

Parameter type

LS Mean

Point estimate

-0.032

Confidence interval

level

95%

sides

2-sided

lower limit

-0.125

upper limit

0.06

Variability estimate

Standard error of the mean

Dispersion value

0.047

Notes
[13] - P-value is one sided

ACQ-7: QVM149 150/50/160 μg vs Active Comparator

Statistical analysis description

Week 24

Comparison groups

QVM149 150/50/160 μg v Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg

Number of subjects included in analysis

901

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.004 ^[14]

Method

MMRM

Parameter type

LS Mean

Point estimate

-0.124

Confidence interval

level

95%

sides

2-sided

lower limit

-0.216

upper limit

-0.032

Variability estimate

Standard error of the mean

Dispersion value

0.047

Notes
[14] - P-value is one sided

Secondary: Change from Baseline in AQLQ Total Score

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End point title

Change from Baseline in AQLQ Total Score

End point description

The AQLQ is a 32-item asthma 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, where 1=totally limited/problems all the time and 7= not at all limited/no problems. It consists of 4 domains: symptoms, activity limitation, emotional function and environmental stimuli. The overall score is calculated as the mean of 32 items. Higher AQLQ scores indicate better health-related quality of life.

End point type

Secondary

End point timeframe

Baseline and Week 16

End point values	QVM149 150/50/80 μg	QVM149 150/50/160 μg	Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg
Number of subjects analysed	435	442	429
Units: Score on a scale
least squares mean (standard error)	0.690 ( 0.069 )	0.755 ( 0.068 )	0.673 ( 0.069 )

AQLQ: QVM149 150/50/80 μg vs Active Comparator

Comparison groups

QVM149 150/50/80 μg v Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg

Number of subjects included in analysis

864

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.719 ^[15]

Method

MMRM

Parameter type

LS Mean

Point estimate

0.018

Confidence interval

level

95%

sides

2-sided

lower limit

-0.079

upper limit

0.115

Variability estimate

Standard error of the mean

Dispersion value

0.049

Notes
[15] - P-value is two-sided

AQLQ: QVM149 150/50/160 μg vs Active Comparator

Comparison groups

QVM149 150/50/160 μg v Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg

Number of subjects included in analysis

871

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.097 ^[16]

Method

MMRM

Parameter type

LS Mean

Point estimate

0.082

Confidence interval

level

95%

sides

2-sided

lower limit

-0.015

upper limit

0.179

Variability estimate

Standard error of the mean

Dispersion value

0.049

Notes
[16] - P-value is two-sided

Secondary: Percentage of Patients Achieving the Minimally Clinically Important Difference (MCID) Decrease from Baseline ACQ-7 ≥ 0.5

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End point title

Percentage of Patients Achieving the Minimally Clinically Important Difference (MCID) Decrease from Baseline ACQ-7 ≥ 0.5

End point description

End point type

Secondary

End point timeframe

Baseline and Week 24

End point values	QVM149 150/50/80 μg	QVM149 150/50/160 μg	Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg
Number of subjects analysed	447	454	447
Units: Percentage of participants
number (not applicable)	87.9	85.2	83.9

MCID ACQ-7:QVM149 150/50/80μg vs Active Comparator

Comparison groups

QVM149 150/50/80 μg v Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg

Number of subjects included in analysis

894

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.061 ^[17]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.23

Confidence interval

level

95%

sides

2-sided

lower limit

0.94

upper limit

1.61

Notes
[17] - P-value is one sided

MCID ACQ-7:QVM149 150/50/160μg vsActive Comparator

Comparison groups

QVM149 150/50/160 μg v Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg

Number of subjects included in analysis

901

Analysis specification

Pre-specified

Analysis type

P-value

= 0.227 ^[18]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.11

Confidence interval

level

95%

sides

2-sided

lower limit

0.85

upper limit

1.46

Notes
[18] - P-value is one-sided

Secondary: Percentage of Patients Achieving the Minimally Clinically Important Difference (MCID) Change from baseline AQLQ ≥ 0.5

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End point title

Percentage of Patients Achieving the Minimally Clinically Important Difference (MCID) Change from baseline AQLQ ≥ 0.5

End point description

The AQLQ is a 32-item asthma 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, where 1=totally limited/problems all the time and 7= not at all limited/no problems. It consists of 4 domains: symptoms, activity limitation, emotional function and environmental stimuli. The overall score is calculated as the mean of 32 items. Higher AQLQ scores indicate better health-related quality of life. An improvement of 0.5 points in AQLQ score is considered to be the minimally clinically important difference in asthma.

End point type

Secondary

End point timeframe

Baseline and Week 24

End point values	QVM149 150/50/80 μg	QVM149 150/50/160 μg	Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg
Number of subjects analysed	444	454	441
Units: Percentage of participants
number (not applicable)	71.6	73.3	67.8

MCID AQLQ: QVM149 150/50/80μg vs Active Comparator

Comparison groups

QVM149 150/50/80 μg v Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg

Number of subjects included in analysis

885

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.108 ^[19]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.17

Confidence interval

level

95%

sides

2-sided

lower limit

0.91

upper limit

1.49

Notes
[19] - P-value is one sided

MCID AQLQ:QVM149 150/50/160μg vs Active Comparator

Comparison groups

QVM149 150/50/160 μg v Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg

Number of subjects included in analysis

895

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.013 ^[20]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.33

Confidence interval

level

95%

sides

2-sided

lower limit

1.03

upper limit

1.7

Notes
[20] - P-Value is one sided

Secondary: Change from Baseline in Forced Vital Capacity (FVC)

Top of page

End point title

Change from Baseline in Forced Vital Capacity (FVC)

End point description

FVC is the total volume of air exhaled during a expiratory maneuvre. It was assessed by performing a spirometry assessment.

End point type

Secondary

End point timeframe

Baseline, Week 8, Week 16 and Week 24

End point values	QVM149 150/50/80 μg	QVM149 150/50/160 μg	Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg
Number of subjects analysed	420	438	425
Units: Litre (L)
least squares mean (standard error)
Week 8 (Number analyzed: 382/395/371)	0.216 ( 0.021 )	0.272 ( 0.021 )	0.219 ( 0.021 )
Week 16 (Number analyzed: 357/389/371)	0.221 ( 0.021 )	0.275 ( 0.021 )	0.217 ( 0.021 )
Week 24 (Number analyzed: 367/385/372)	0.214 ( 0.022 )	0.280 ( 0.022 )	0.186 ( 0.022 )

FVC: QVM149 150/50/80μg vs Active Comparator

Statistical analysis description

Week 8

Comparison groups

QVM149 150/50/80 μg v Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg

Number of subjects included in analysis

845

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.908 ^[21]

Method

MMRM

Parameter type

LS Mean

Point estimate

-0.003

Confidence interval

level

95%

sides

2-sided

lower limit

-0.055

upper limit

0.049

Variability estimate

Standard error of the mean

Dispersion value

0.027

Notes
[21] - P-Value is two-sided

FVC: QVM149 150/50/160μg vs Active Comparator

Statistical analysis description

Week 8

Comparison groups

QVM149 150/50/160 μg v Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg

Number of subjects included in analysis

863

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.046 ^[22]

Method

MMRM

Parameter type

LS Mean

Point estimate

0.053

Confidence interval

level

95%

sides

2-sided

lower limit

0.001

upper limit

0.104

Variability estimate

Standard error of the mean

Dispersion value

0.026

Notes
[22] - P-Value is two-sided

FVC: QVM149 150/50/80μg vs Active Comparator

Statistical analysis description

Week 16

Comparison groups

QVM149 150/50/80 μg v Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg

Number of subjects included in analysis

845

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.87 ^[23]

Method

MMRM

Parameter type

LS Mean

Point estimate

0.004

Confidence interval

level

95%

sides

2-sided

lower limit

-0.047

upper limit

0.056

Variability estimate

Standard error of the mean

Dispersion value

0.026

Notes
[23] - P-Value is two-sided

FVC: QVM149 150/50/160μg vs Active Comparator

Statistical analysis description

Week 16

Comparison groups

QVM149 150/50/160 μg v Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg

Number of subjects included in analysis

863

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.028 ^[24]

Method

MMRM

Parameter type

LS Mean

Point estimate

0.058

Confidence interval

level

95%

sides

2-sided

lower limit

0.006

upper limit

0.109

Variability estimate

Standard error of the mean

Dispersion value

0.026

Notes
[24] - P-Value is two-sided

FVC: QVM149 150/50/80μg vs Active Comparator

Statistical analysis description

Week 24

Comparison groups

QVM149 150/50/80 μg v Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg

Number of subjects included in analysis

845

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.303 ^[25]

Method

MMRM

Parameter type

LS Mean

Point estimate

0.028

Confidence interval

level

95%

sides

2-sided

lower limit

-0.026

upper limit

0.083

Variability estimate

Standard error of the mean

Dispersion value

0.028

Notes
[25] - P-Value is two-sided

FVC: QVM149 150/50/160μg vs Active Comparator

Statistical analysis description

Week 24

Comparison groups

QVM149 150/50/160 μg v Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg

Number of subjects included in analysis

863

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[26]

Method

MMRM

Parameter type

LS Mean

Point estimate

0.095

Confidence interval

level

95%

sides

2-sided

lower limit

0.041

upper limit

0.148

Variability estimate

Standard error of the mean

Dispersion value

0.027

Notes
[26] - P-Value is two-sided

Secondary: Change from Baseline in Forced Expiratory Flow between 25% and 75% of Forced Vital Capacity (FEF25-75)

Top of page

End point title

Change from Baseline in Forced Expiratory Flow between 25% and 75% of Forced Vital Capacity (FEF25-75)

End point description

Forced expiratory flow during the mid (25 - 75%) portion of the FVC. It was assessed by performing spirometric assessment.

End point type

Secondary

End point timeframe

Baseline, Week 8, Week 16 and Week 24

End point values	QVM149 150/50/80 μg	QVM149 150/50/160 μg	Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg
Number of subjects analysed	420	438	425
Units: Litres/second (L/s)
least squares mean (standard error)
Week 8 (Number analyzed: 382/395/371)	0.290 ( 0.027 )	0.332 ( 0.027 )	0.270 ( 0.027 )
Week 16 (Number analyzed: 357/389/371)	0.291 ( 0.028 )	0.355 ( 0.027 )	0.297 ( 0.027 )
Week 24 (Number analyzed: 367/385/372)	0.290 ( 0.028 )	0.375 ( 0.028 )	0.286 ( 0.028 )

FEF25-75:QVM149 150/50/80μg vs Active Comparator

Statistical analysis description

Week 8

Comparison groups

QVM149 150/50/80 μg v Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg

Number of subjects included in analysis

845

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.563 ^[27]

Method

MMRM

Parameter type

LS Mean

Point estimate

0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.048

upper limit

0.087

Variability estimate

Standard error of the mean

Dispersion value

0.034

Notes
[27] - P-value is two-sided

FEF25-75:QVM149 150/50/160μg vs Active Comparator

Statistical analysis description

Week 8

Comparison groups

QVM149 150/50/160 μg v Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg

Number of subjects included in analysis

863

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.068 ^[28]

Method

MMRM

Parameter type

LS Mean

Point estimate

0.062

Confidence interval

level

95%

sides

2-sided

lower limit

-0.005

upper limit

0.129

Variability estimate

Standard error of the mean

Dispersion value

0.034

Notes
[28] - P-Value is two-sided

FEF25-75:QVM149 150/50/80μg vs Active Comparator

Statistical analysis description

Week 16

Comparison groups

QVM149 150/50/80 μg v Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg

Number of subjects included in analysis

845

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.844 ^[29]

Method

MMRM

Parameter type

LS Mean

Point estimate

-0.007

Confidence interval

level

95%

sides

2-sided

lower limit

-0.076

upper limit

0.062

Variability estimate

Standard error of the mean

Dispersion value

0.035

Notes
[29] - P-Value is two-sided

FEF25-75:QVM149 150/50/160μg vs Active Comparator

Statistical analysis description

Week 16

Comparison groups

QVM149 150/50/160 μg v Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg

Number of subjects included in analysis

863

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.097 ^[30]

Method

MMRM

Parameter type

LS Mean

Point estimate

0.058

Confidence interval

level

95%

sides

2-sided

lower limit

-0.01

upper limit

0.125

Variability estimate

Standard error of the mean

Dispersion value

0.035

Notes
[30] - P-Value is two-sided

FEF25-75:QVM149 150/50/80μg vs Active Comparator

Statistical analysis description

Week 24

Comparison groups

QVM149 150/50/80 μg v Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg

Number of subjects included in analysis

845

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.927 ^[31]

Method

MMRM

Parameter type

LS Mean

Point estimate

0.003

Confidence interval

level

95%

sides

2-sided

lower limit

-0.067

upper limit

0.074

Variability estimate

Standard error of the mean

Dispersion value

0.036

Notes
[31] - P-Value is two-sided

FEF25-75:QVM149 150/50/160μg vs Active Comparator

Statistical analysis description

Week 24

Comparison groups

QVM149 150/50/160 μg v Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg

Number of subjects included in analysis

863

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.013 ^[32]

Method

MMRM

Parameter type

LS Mean

Point estimate

0.089

Confidence interval

level

95%

sides

2-sided

lower limit

0.019

upper limit

0.159

Variability estimate

Standard error of the mean

Dispersion value

0.036

Notes
[32] - P-Value is two-sided

Adverse events

Top of page

Timeframe for reporting adverse events

Adverse events were collected starting on or after the time of first administration of study drug but not later than 7 days (30 days in case of a Serious Adverse Events) after the last administration.

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 150/50/80µg

Reporting group description

QVM149 150/50/80 µg o.d. delivered via Concept1

Reporting group title

QVM149 150/50/160µg

Reporting group description

QVM149 150/50/160 μg o.d. delivered via Concept1

Reporting group title

Salmeterol/fluticasone 50/500µg plus tiotropium 5µg

Reporting group description

Salmeterol/fluticasone 50/500 μg b.i.d. delivered via Accuhaler® plus tiotropium 5 μg o.d. delivered via Respimat®

Serious adverse events	QVM149 150/50/80µg	QVM149 150/50/160µg	Salmeterol/fluticasone 50/500µg plus tiotropium 5µg
Total subjects affected by serious adverse events
subjects affected / exposed	14 / 474 (2.95%)	18 / 476 (3.78%)	19 / 475 (4.00%)
number of deaths (all causes)	0	0	1
number of deaths resulting from adverse events	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign neoplasm
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fibroadenoma of breast
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Large intestine benign neoplasm
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory tract neoplasm
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thrombophlebitis superficial
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Hyperpyrexia
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Asthma
subjects affected / exposed	4 / 474 (0.84%)	3 / 476 (0.63%)	2 / 475 (0.42%)
occurrences causally related to treatment / all	0 / 4	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchiectasis
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Hepatic enzyme increased
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intentional product misuse
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	2 / 475 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Meniscus injury
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Wrist fracture
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Atrioventricular block second degree
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Carotid artery stenosis
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Guillain-Barre syndrome
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemorrhagic stroke
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Polyneuropathy
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Lymphadenopathy
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal hernia
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Large intestine polyp
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endocrine disorders
Goitre
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Atypical pneumonia
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchiolitis
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
H1N1 influenza
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatitis viral
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung infection
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pilonidal cyst
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 474 (0.00%)	5 / 476 (1.05%)	0 / 475 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Postoperative abscess
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rectal abscess
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Viral upper respiratory tract infection
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	QVM149 150/50/80µg	QVM149 150/50/160µg	Salmeterol/fluticasone 50/500µg plus tiotropium 5µg
Total subjects affected by non serious adverse events
subjects affected / exposed	245 / 474 (51.69%)	246 / 476 (51.68%)	241 / 475 (50.74%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Infected neoplasm
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Prostatic adenoma
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Respiratory tract neoplasm
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Uterine leiomyoma
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Vascular disorders
Hot flush
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Hypertension
subjects affected / exposed	7 / 474 (1.48%)	5 / 476 (1.05%)	5 / 475 (1.05%)
occurrences all number	8	5	5
Malignant hypertension
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	1	0	0
Peripheral venous disease
subjects affected / exposed	1 / 474 (0.21%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	1	1	0
Phlebitis
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Varicophlebitis
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	1	0	0
Varicose vein
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	1	0	0
Surgical and medical procedures
Tooth extraction
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Chest discomfort
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Chest pain
subjects affected / exposed	1 / 474 (0.21%)	1 / 476 (0.21%)	1 / 475 (0.21%)
occurrences all number	1	1	1
Chills
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	1	0	0
Discomfort
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Fatigue
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Hyperpyrexia
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	1	0	0
Impaired healing
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	2	0
Inflammation
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Non-cardiac chest pain
subjects affected / exposed	0 / 474 (0.00%)	2 / 476 (0.42%)	1 / 475 (0.21%)
occurrences all number	0	2	1
Oedema peripheral
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	1 / 475 (0.21%)
occurrences all number	0	1	1
Pain
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Procedural failure
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Pyrexia
subjects affected / exposed	2 / 474 (0.42%)	3 / 476 (0.63%)	2 / 475 (0.42%)
occurrences all number	2	3	2
Immune system disorders
Allergy to arthropod bite
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Atopy
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Food allergy
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Hypersensitivity
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	1	0	1
Perennial allergy
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Reproductive system and breast disorders
Breast cyst
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Breast disorder
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Breast mass
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	1	0	0
Menorrhagia
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Menstruation irregular
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Metrorrhagia
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Prostatitis
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Respiratory, thoracic and mediastinal disorders
Allergic sinusitis
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	1	0	0
Asthma
subjects affected / exposed	125 / 474 (26.37%)	114 / 476 (23.95%)	125 / 475 (26.32%)
occurrences all number	189	163	200
Catarrh
subjects affected / exposed	2 / 474 (0.42%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	2	1	0
Cough
subjects affected / exposed	8 / 474 (1.69%)	7 / 476 (1.47%)	9 / 475 (1.89%)
occurrences all number	9	9	10
Dysphonia
subjects affected / exposed	4 / 474 (0.84%)	8 / 476 (1.68%)	7 / 475 (1.47%)
occurrences all number	4	8	7
Dyspnoea
subjects affected / exposed	1 / 474 (0.21%)	1 / 476 (0.21%)	2 / 475 (0.42%)
occurrences all number	1	1	2
Epistaxis
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Haemoptysis
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	1 / 475 (0.21%)
occurrences all number	0	1	1
Larynx irritation
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Nasal congestion
subjects affected / exposed	2 / 474 (0.42%)	1 / 476 (0.21%)	1 / 475 (0.21%)
occurrences all number	3	1	1
Nasal obstruction
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	1	0	0
Nasal polyps
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Nasal septum deviation
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Oropharyngeal discomfort
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	1	0	0
Oropharyngeal pain
subjects affected / exposed	5 / 474 (1.05%)	8 / 476 (1.68%)	2 / 475 (0.42%)
occurrences all number	5	8	2
Pleurisy
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Productive cough
subjects affected / exposed	2 / 474 (0.42%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	2	1	0
Respiratory tract congestion
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	1	0	0
Rhinitis allergic
subjects affected / exposed	8 / 474 (1.69%)	3 / 476 (0.63%)	6 / 475 (1.26%)
occurrences all number	8	3	6
Rhinorrhoea
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	1	0	0
Sleep apnoea syndrome
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Throat irritation
subjects affected / exposed	0 / 474 (0.00%)	5 / 476 (1.05%)	1 / 475 (0.21%)
occurrences all number	0	5	1
Tonsillar hypertrophy
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	2
Vasomotor rhinitis
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	1	0	0
Vocal cord inflammation
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Depression
subjects affected / exposed	0 / 474 (0.00%)	3 / 476 (0.63%)	0 / 475 (0.00%)
occurrences all number	0	3	0
Insomnia
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Restlessness
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	1	0	1
Aspartate aminotransferase increased
subjects affected / exposed	2 / 474 (0.42%)	1 / 476 (0.21%)	1 / 475 (0.21%)
occurrences all number	2	1	1
Blood alkaline phosphatase increased
subjects affected / exposed	2 / 474 (0.42%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	2	0	1
Blood glucose increased
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Blood uric acid increased
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Breath sounds abnormal
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Crystal urine
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Haemoglobin increased
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Hepatic enzyme increased
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Liver function test increased
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	1	0	0
Red blood cells urine
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Weight decreased
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Injury, poisoning and procedural complications
Animal bite
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	1	0	0
Bronchial injury
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Chest injury
subjects affected / exposed	1 / 474 (0.21%)	1 / 476 (0.21%)	1 / 475 (0.21%)
occurrences all number	1	1	1
Contusion
subjects affected / exposed	4 / 474 (0.84%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	4	0	1
Epicondylitis
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Exposure to allergen
subjects affected / exposed	9 / 474 (1.90%)	3 / 476 (0.63%)	2 / 475 (0.42%)
occurrences all number	9	3	2
Fall
subjects affected / exposed	0 / 474 (0.00%)	2 / 476 (0.42%)	1 / 475 (0.21%)
occurrences all number	0	2	1
Fibula fracture
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Hand fracture
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Joint dislocation
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	1	0	0
Joint injury
subjects affected / exposed	0 / 474 (0.00%)	3 / 476 (0.63%)	0 / 475 (0.00%)
occurrences all number	0	3	0
Ligament sprain
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	1	0	1
Lip injury
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Medication error
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	2 / 475 (0.42%)
occurrences all number	0	0	2
Muscle strain
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Radius fracture
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Rib fracture
subjects affected / exposed	0 / 474 (0.00%)	2 / 476 (0.42%)	0 / 475 (0.00%)
occurrences all number	0	2	0
Skin abrasion
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	2	0	0
Spinal column injury
subjects affected / exposed	2 / 474 (0.42%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	2	0	0
Thermal burn
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Upper limb fracture
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	1	0	0
Cardiac disorders
Angina pectoris
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Atrioventricular block first degree
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Bundle branch block left
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Cardiac failure
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Cardiac failure chronic
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Coronary artery disease
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	1 / 475 (0.21%)
occurrences all number	0	1	2
Palpitations
subjects affected / exposed	0 / 474 (0.00%)	2 / 476 (0.42%)	0 / 475 (0.00%)
occurrences all number	0	2	0
Sinus tachycardia
subjects affected / exposed	1 / 474 (0.21%)	2 / 476 (0.42%)	2 / 475 (0.42%)
occurrences all number	1	2	2
Supraventricular tachycardia
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Nervous system disorders
Burning sensation
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	1 / 475 (0.21%)
occurrences all number	0	1	1
Convulsions local
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Dizziness
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	2 / 475 (0.42%)
occurrences all number	1	0	2
Headache
subjects affected / exposed	10 / 474 (2.11%)	15 / 476 (3.15%)	9 / 475 (1.89%)
occurrences all number	10	16	10
Hemianopia
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Hypersomnia
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Hypoaesthesia
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Intercostal neuralgia
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Migraine
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	4 / 475 (0.84%)
occurrences all number	0	1	4
Muscle contractions involuntary
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Neuritis
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	1	0	0
Paraesthesia
subjects affected / exposed	0 / 474 (0.00%)	2 / 476 (0.42%)	0 / 475 (0.00%)
occurrences all number	0	2	0
Phantom limb syndrome
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	1	0	0
Polyneuropathy
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Presyncope
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Sciatica
subjects affected / exposed	2 / 474 (0.42%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	2	0	1
Syncope
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Tension headache
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	1	0	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 474 (0.00%)	2 / 476 (0.42%)	0 / 475 (0.00%)
occurrences all number	0	2	0
Haemolysis
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Lymphadenitis
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Ear and labyrinth disorders
Deafness
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Tinnitus
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Eye disorders
Blepharitis
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Cataract
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	1	0	1
Conjunctivitis allergic
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	2 / 475 (0.42%)
occurrences all number	1	0	2
Eye disorder
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	1	0	0
Eye pruritus
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	1	0	0
Maculopathy
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Panophthalmitis
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Vision blurred
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	1 / 474 (0.21%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	1	1	0
Abdominal distension
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Abdominal hernia
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Abdominal pain
subjects affected / exposed	3 / 474 (0.63%)	2 / 476 (0.42%)	0 / 475 (0.00%)
occurrences all number	4	2	0
Abdominal pain upper
subjects affected / exposed	2 / 474 (0.42%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	2	1	0
Aphthous ulcer
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	1 / 475 (0.21%)
occurrences all number	0	1	1
Chronic gastritis
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Colitis
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Constipation
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Diarrhoea
subjects affected / exposed	2 / 474 (0.42%)	5 / 476 (1.05%)	4 / 475 (0.84%)
occurrences all number	2	5	4
Dry mouth
subjects affected / exposed	3 / 474 (0.63%)	1 / 476 (0.21%)	5 / 475 (1.05%)
occurrences all number	3	1	5
Duodenitis
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Dyspepsia
subjects affected / exposed	2 / 474 (0.42%)	3 / 476 (0.63%)	1 / 475 (0.21%)
occurrences all number	2	3	1
Enteritis
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	1	0	1
Gastritis
subjects affected / exposed	4 / 474 (0.84%)	4 / 476 (0.84%)	1 / 475 (0.21%)
occurrences all number	4	4	1
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 474 (0.21%)	2 / 476 (0.42%)	2 / 475 (0.42%)
occurrences all number	1	3	2
Haemorrhoids
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	1	0	0
Hiatus hernia
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Inguinal hernia
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Hyperchlorhydria
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Large intestine polyp
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Lip dry
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Nausea
subjects affected / exposed	3 / 474 (0.63%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	3	1	0
Pancreatitis
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	1	0	0
Oesophagitis
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Pancreatitis chronic
subjects affected / exposed	1 / 474 (0.21%)	2 / 476 (0.42%)	0 / 475 (0.00%)
occurrences all number	1	2	0
Salivary gland calculus
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	1	0	0
Umbilical hernia
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Toothache
subjects affected / exposed	7 / 474 (1.48%)	3 / 476 (0.63%)	4 / 475 (0.84%)
occurrences all number	7	3	4
Vomiting
subjects affected / exposed	1 / 474 (0.21%)	1 / 476 (0.21%)	1 / 475 (0.21%)
occurrences all number	1	1	1
Hepatobiliary disorders
Cholecystitis chronic
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Hepatic steatosis
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Liver disorder
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	1	0	0
Dermatitis allergic
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Dermatitis atopic
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Dermatitis contact
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Dry skin
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Eczema
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	1 / 475 (0.21%)
occurrences all number	0	1	1
Pruritus
subjects affected / exposed	2 / 474 (0.42%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	2	0	0
Psoriasis
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Skin burning sensation
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	1	0	0
Urticaria
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	1	0	1
Renal and urinary disorders
Chronic kidney disease
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Leukocyturia
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Nephrolithiasis
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Nocturia
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Pyelocaliectasis
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Renal colic
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Urinary incontinence
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Endocrine disorders
Hypothyroidism
subjects affected / exposed	1 / 474 (0.21%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	1	1	0
Thyroid cyst
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	4 / 474 (0.84%)	5 / 476 (1.05%)	2 / 475 (0.42%)
occurrences all number	4	5	3
Arthritis
subjects affected / exposed	1 / 474 (0.21%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	1	1	0
Back pain
subjects affected / exposed	5 / 474 (1.05%)	3 / 476 (0.63%)	2 / 475 (0.42%)
occurrences all number	5	3	2
Bone pain
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	1	0	0
Costochondritis
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Fibromyalgia
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Haemarthrosis
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Intervertebral disc protrusion
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Joint effusion
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	1 / 475 (0.21%)
occurrences all number	0	1	1
Muscle spasms
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	1	0	1
Musculoskeletal pain
subjects affected / exposed	1 / 474 (0.21%)	2 / 476 (0.42%)	1 / 475 (0.21%)
occurrences all number	1	2	1
Neck pain
subjects affected / exposed	1 / 474 (0.21%)	1 / 476 (0.21%)	1 / 475 (0.21%)
occurrences all number	1	1	1
Osteoarthritis
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	1	0	1
Osteochondrosis
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Osteoporosis postmenopausal
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Pain in extremity
subjects affected / exposed	1 / 474 (0.21%)	3 / 476 (0.63%)	1 / 475 (0.21%)
occurrences all number	1	3	1
Polyarthritis
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Rotator cuff syndrome
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	1	0	0
Spinal pain
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Synovial cyst
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	1	0	0
Tendonitis
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	1	0	0
Infections and infestations
Abscess limb
subjects affected / exposed	2 / 474 (0.42%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	2	0	0
Acute sinusitis
subjects affected / exposed	0 / 474 (0.00%)	2 / 476 (0.42%)	3 / 475 (0.63%)
occurrences all number	0	2	4
Bacterial infection
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Bacterial vaginosis
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Bronchitis
subjects affected / exposed	21 / 474 (4.43%)	22 / 476 (4.62%)	19 / 475 (4.00%)
occurrences all number	21	23	24
Candida infection
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	2
Cellulitis
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Chronic hepatitis C
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Conjunctivitis
subjects affected / exposed	2 / 474 (0.42%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	2	0	0
Cystitis
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	1	0	0
Ear infection
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Ear infection fungal
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Erysipelas
subjects affected / exposed	2 / 474 (0.42%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	2	0	0
Eye infection
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Folliculitis
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	1	0	0
Gastroenteritis
subjects affected / exposed	1 / 474 (0.21%)	5 / 476 (1.05%)	3 / 475 (0.63%)
occurrences all number	1	5	3
Gingivitis
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Helicobacter infection
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	1	0	0
Hordeolum
subjects affected / exposed	1 / 474 (0.21%)	1 / 476 (0.21%)	1 / 475 (0.21%)
occurrences all number	1	1	1
Infection
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Influenza
subjects affected / exposed	9 / 474 (1.90%)	5 / 476 (1.05%)	4 / 475 (0.84%)
occurrences all number	9	5	4
Laryngitis
subjects affected / exposed	3 / 474 (0.63%)	3 / 476 (0.63%)	2 / 475 (0.42%)
occurrences all number	3	3	2
Laryngitis viral
subjects affected / exposed	1 / 474 (0.21%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	2	1	0
Localised infection
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	1	0	0
Lower respiratory tract infection
subjects affected / exposed	6 / 474 (1.27%)	6 / 476 (1.26%)	7 / 475 (1.47%)
occurrences all number	8	7	7
Nasopharyngitis
subjects affected / exposed	34 / 474 (7.17%)	34 / 476 (7.14%)	43 / 475 (9.05%)
occurrences all number	36	38	53
Oral candidiasis
subjects affected / exposed	1 / 474 (0.21%)	2 / 476 (0.42%)	4 / 475 (0.84%)
occurrences all number	1	3	4
Oral herpes
subjects affected / exposed	2 / 474 (0.42%)	2 / 476 (0.42%)	1 / 475 (0.21%)
occurrences all number	2	2	1
Oropharyngeal candidiasis
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Otitis media
subjects affected / exposed	2 / 474 (0.42%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	2	0	0
Perichondritis
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Pharyngitis
subjects affected / exposed	18 / 474 (3.80%)	17 / 476 (3.57%)	10 / 475 (2.11%)
occurrences all number	19	17	10
Pharyngitis bacterial
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	1	0	1
Pharyngotonsillitis
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	1	0	0
Pilonidal cyst
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Pneumonia
subjects affected / exposed	2 / 474 (0.42%)	3 / 476 (0.63%)	2 / 475 (0.42%)
occurrences all number	2	3	2
Post procedural infection
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Pulpitis dental
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Respiratory tract infection
subjects affected / exposed	6 / 474 (1.27%)	2 / 476 (0.42%)	3 / 475 (0.63%)
occurrences all number	6	2	3
Respiratory tract infection viral
subjects affected / exposed	10 / 474 (2.11%)	9 / 476 (1.89%)	6 / 475 (1.26%)
occurrences all number	13	10	6
Rhinitis
subjects affected / exposed	7 / 474 (1.48%)	5 / 476 (1.05%)	4 / 475 (0.84%)
occurrences all number	7	5	4
Sinobronchitis
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	1	0	0
Sinusitis
subjects affected / exposed	4 / 474 (0.84%)	8 / 476 (1.68%)	9 / 475 (1.89%)
occurrences all number	4	9	9
Skin infection
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Tinea versicolour
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Tonsillitis
subjects affected / exposed	0 / 474 (0.00%)	3 / 476 (0.63%)	3 / 475 (0.63%)
occurrences all number	0	3	3
Tonsillitis bacterial
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	1	0	0
Tooth infection
subjects affected / exposed	1 / 474 (0.21%)	1 / 476 (0.21%)	1 / 475 (0.21%)
occurrences all number	1	1	1
Tracheitis
subjects affected / exposed	4 / 474 (0.84%)	1 / 476 (0.21%)	6 / 475 (1.26%)
occurrences all number	4	1	6
Tracheobronchitis
subjects affected / exposed	0 / 474 (0.00%)	2 / 476 (0.42%)	0 / 475 (0.00%)
occurrences all number	0	2	0
Upper respiratory tract infection
subjects affected / exposed	13 / 474 (2.74%)	10 / 476 (2.10%)	9 / 475 (1.89%)
occurrences all number	14	11	9
Upper respiratory tract infection bacterial
subjects affected / exposed	5 / 474 (1.05%)	9 / 476 (1.89%)	9 / 475 (1.89%)
occurrences all number	5	11	11
Urinary tract infection
subjects affected / exposed	6 / 474 (1.27%)	5 / 476 (1.05%)	4 / 475 (0.84%)
occurrences all number	6	5	4
Viral infection
subjects affected / exposed	1 / 474 (0.21%)	1 / 476 (0.21%)	1 / 475 (0.21%)
occurrences all number	1	1	1
Viral pharyngitis
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Viral rhinitis
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Viral tracheitis
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Viral upper respiratory tract infection
subjects affected / exposed	8 / 474 (1.69%)	11 / 476 (2.31%)	10 / 475 (2.11%)
occurrences all number	9	11	10
Vulvovaginal candidiasis
subjects affected / exposed	1 / 474 (0.21%)	1 / 476 (0.21%)	1 / 475 (0.21%)
occurrences all number	1	1	1
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	0 / 475 (0.00%)
occurrences all number	1	0	0
Dehydration
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Diabetes mellitus
subjects affected / exposed	1 / 474 (0.21%)	0 / 476 (0.00%)	2 / 475 (0.42%)
occurrences all number	1	0	2
Dyslipidaemia
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	1 / 475 (0.21%)
occurrences all number	0	1	1
Gout
subjects affected / exposed	1 / 474 (0.21%)	1 / 476 (0.21%)	1 / 475 (0.21%)
occurrences all number	1	2	1
Hyperglycaemia
subjects affected / exposed	2 / 474 (0.42%)	1 / 476 (0.21%)	1 / 475 (0.21%)
occurrences all number	2	1	1
Hyperuricaemia
subjects affected / exposed	0 / 474 (0.00%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	0	1	0
Hypoglycaemia
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Mineral metabolism disorder
subjects affected / exposed	0 / 474 (0.00%)	0 / 476 (0.00%)	1 / 475 (0.21%)
occurrences all number	0	0	1
Type 2 diabetes mellitus
subjects affected / exposed	1 / 474 (0.21%)	1 / 476 (0.21%)	0 / 475 (0.00%)
occurrences all number	1	1	0

More information

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Were there any global substantial amendments to the protocol? Yes

01 Aug 2017

The primary reasons for this amendment were to ensure consistency across sections of the protocol and to update drug supply sourcing strategies and operational details/processes. Protocol sections were harmonized with respect to the escalation and de-escalation of controller or maintenance therapy allowed during the treatment period. The drug supply sourcing strategy was updated as local sourcing for the comparative treatment arm (salmeterol/fluticasone and tiotropium) and the run-in medication (salmeterol/fluticasone) could occur, in addition to global sourcing.

16 Nov 2017

At the time of randomization, the Investigator needed to make an informed decision about the most appropriate treatment for each individual patient. If the most appropriate treatment was not a LABA+LAMA+ICS, the patient should be screenfailed and be treated according to his/her individual needs. The purpose of this amendment was to support this informed decision-making by adding relevant assessments at the run-in visit, (i.e., measurement of blood total IgE and antigen-specific IgE (ImmunoCAP) for common perennial aeroallergens). Furthermore, this amendment included a change in the hypotheses testing strategy. The key secondary objective (To evaluate efficacy of QVM149 high ICS dose and QVM149 medium ICS dose compared to salmeterol/fluticasone + tiotropium in terms of Trough FEV1 after 24 weeks of treatment) was treated as a regular secondary objective. In addition, the amendment addressed comments received from the Ethics Committee and Health Authority in Germany to clarify some procedures and data protection measures.

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, partially-blinded, randomized, 24-week, parallel-group, non-inferiority, open-label active controlled study to compare the efficacy and safety of QVM149 with a free triple combination of salmeterol/fluticasone + tiotropium in patients with uncontrolled asthma

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from Baseline in Asthma Quality of Life Questionnaire (AQLQ) Total Score

Primary: Change from Baseline in Asthma Quality of Life Questionnaire (AQLQ) Total Score

Secondary: Change from Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1)

Secondary: Change from Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1)

Secondary: Change from Baseline in Asthma Control Questionnaire (ACQ-7) Total Score

Secondary: Change from Baseline in Asthma Control Questionnaire (ACQ-7) Total Score

Secondary: Change from Baseline in AQLQ Total Score

Secondary: Change from Baseline in AQLQ Total Score

Secondary: Percentage of Patients Achieving the Minimally Clinically Important Difference (MCID) Decrease from Baseline ACQ-7 ≥ 0.5

Secondary: Percentage of Patients Achieving the Minimally Clinically Important Difference (MCID) Decrease from Baseline ACQ-7 ≥ 0.5

Secondary: Percentage of Patients Achieving the Minimally Clinically Important Difference (MCID) Change from baseline AQLQ ≥ 0.5

Secondary: Percentage of Patients Achieving the Minimally Clinically Important Difference (MCID) Change from baseline AQLQ ≥ 0.5

Secondary: Change from Baseline in Forced Vital Capacity (FVC)

Secondary: Change from Baseline in Forced Vital Capacity (FVC)

Secondary: Change from Baseline in Forced Expiratory Flow between 25% and 75% of Forced Vital Capacity (FEF25-75)

Secondary: Change from Baseline in Forced Expiratory Flow between 25% and 75% of Forced Vital Capacity (FEF25-75)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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

Clinical trials

Clinical Trial Results: A multicenter, partially-blinded, randomized, 24-week, parallel-group, non-inferiority, open-label active controlled study to compare the efficacy and safety of QVM149 with a free triple combination of salmeterol/fluticasone + tiotropium in patients with uncontrolled asthma

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from Baseline in Asthma Quality of Life Questionnaire (AQLQ) Total Score

Primary: Change from Baseline in Asthma Quality of Life Questionnaire (AQLQ) Total Score

Secondary: Change from Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1)

Secondary: Change from Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1)

Secondary: Change from Baseline in Asthma Control Questionnaire (ACQ-7) Total Score

Secondary: Change from Baseline in Asthma Control Questionnaire (ACQ-7) Total Score

Secondary: Change from Baseline in AQLQ Total Score

Secondary: Change from Baseline in AQLQ Total Score

Secondary: Percentage of Patients Achieving the Minimally Clinically Important Difference (MCID) Decrease from Baseline ACQ-7 ≥ 0.5

Secondary: Percentage of Patients Achieving the Minimally Clinically Important Difference (MCID) Decrease from Baseline ACQ-7 ≥ 0.5

Secondary: Percentage of Patients Achieving the Minimally Clinically Important Difference (MCID) Change from baseline AQLQ ≥ 0.5

Secondary: Percentage of Patients Achieving the Minimally Clinically Important Difference (MCID) Change from baseline AQLQ ≥ 0.5

Secondary: Change from Baseline in Forced Vital Capacity (FVC)

Secondary: Change from Baseline in Forced Vital Capacity (FVC)

Secondary: Change from Baseline in Forced Expiratory Flow between 25% and 75% of Forced Vital Capacity (FEF25-75)

Secondary: Change from Baseline in Forced Expiratory Flow between 25% and 75% of Forced Vital Capacity (FEF25-75)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A multicenter, partially-blinded, randomized, 24-week, parallel-group, non-inferiority, open-label active controlled study to compare the efficacy and safety of QVM149 with a free triple combination of salmeterol/fluticasone + tiotropium in patients with uncontrolled asthma