Download PDF

Clinical Trial Results:
A Multi-center, Randomized, 52 Week Treatment, Double-blind, Triple-dummy, Parallel Group Study to Assess the Efficacy and Safety of QMF149 Compared to Mometasone Furoate in Patients With Asthma

Summary
EudraCT number	2015-002529-21
Trial protocol	GB EE LV DE LT HU CZ SK IE PL BG HR
Global end of trial date	28 Jun 2019

Results information
Results version number	v1(current)
This version publication date	05 Jan 2020
First version publication date	05 Jan 2020
Other versions

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

CQVM149B2301

ISRCTN number

US NCT number

NCT02554786

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Pharma AG

Sponsor organisation address

CH-4002, Basel, Switzerland,

Public contact

Clinical Disclosure Office, Novartis Pharmaceuticals AG, +44 613241111,

Scientific contact

Clinical Disclosure Office, Novartis Pharmaceuticals AG, +44 613241111,

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

Yes

EMA paediatric investigation plan number(s)

EMEA-000104-PIP20-16

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

28 Jun 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

28 Jun 2019

Was the trial ended prematurely?

Main objective of the trial

To demonstrate the superiority of either QMF149 150/160 μg delivered via Concept1 once daily (o.d.) (in the evening) to mometasone furoate (MF) 400 μg o.d (in the evening) delivered via Twisthaler® or QMF149 150/320 μg delivered via Concept1 o.d. (in the evening) to MF 800 μg delivered via Twisthaler® (delivered as 400 μg twice a day [b.i.d.]) in terms of trough forced expiratory volume in one second (trough FEV1) at 26 weeks in subjects with asthma.

Protection of trial subjects

This study was conducted in compliance with Good Clinical Practice (GCP), including the archiving of essential documents.

Background therapy

Fluticasone propionate received by all subjects during 2 weeks of Run-In Epoch until randomisation.

Evidence for comparator

Actual start date of recruitment

29 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

Russian Federation: 337

Country: Number of subjects enrolled

Serbia: 135

Country: Number of subjects enrolled

India: 203

Country: Number of subjects enrolled

Japan: 118

Country: Number of subjects enrolled

China: 127

Country: Number of subjects enrolled

Guatemala: 65

Country: Number of subjects enrolled

Mexico: 18

Country: Number of subjects enrolled

South Africa: 71

Country: Number of subjects enrolled

United States: 37

Country: Number of subjects enrolled

Egypt: 10

Country: Number of subjects enrolled

Korea, Republic of: 37

Country: Number of subjects enrolled

Poland: 111

Country: Number of subjects enrolled

Romania: 151

Country: Number of subjects enrolled

Slovakia: 101

Country: Number of subjects enrolled

United Kingdom: 13

Country: Number of subjects enrolled

Croatia: 11

Country: Number of subjects enrolled

Bulgaria: 157

Country: Number of subjects enrolled

Czech Republic: 82

Country: Number of subjects enrolled

Estonia: 14

Country: Number of subjects enrolled

Germany: 197

Country: Number of subjects enrolled

Hungary: 170

Country: Number of subjects enrolled

Ireland: 1

Country: Number of subjects enrolled

Latvia: 31

Country: Number of subjects enrolled

Lithuania: 19

Worldwide total number of subjects

2216

EEA total number of subjects

1058

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)

107

Adults (18-64 years)

1812

From 65 to 84 years

297

85 years and over

Subject disposition

Top of page

Recruitment details

Subjects took part in 316 investigative sites in 24 countries from 29 Dec 2015 to 28 Jun 2019.

Screening details

3890 subjects were screened of which 2216 were randomised to 1 of the 5 treatment groups with a randomisation 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, Carer

Are arms mutually exclusive

Yes

QMF149 150/320 μg

Arm description

QMF149 (Indacaterol acetate/Mometasone furoate) 150/320 μg was delivered o.d. via Concept1 inhaler in the evening.

Arm type

Experimental

Investigational medicinal product name

Indacaterol acetate/Mometasone furoate

Investigational medicinal product code

Other name

QMF149

Pharmaceutical forms

Inhalation powder, hard capsule

Routes of administration

Inhalation use

Dosage and administration details

150/320 μg, o.d. via Concept1 inhaler in the evening.

QMF149 150/160 μg

Arm description

QMF149 (Indacaterol acetate/Mometasone furoate) 150/160 μg was delivered o.d. via Concept1 inhaler in the evening.

Arm type

Experimental

Investigational medicinal product name

Indacaterol acetate/Mometasone furoate

Investigational medicinal product code

Other name

QMF149

Pharmaceutical forms

Inhalation powder, hard capsule

Routes of administration

Inhalation use

Dosage and administration details

150/160 μg, o.d. via Concept1 inhaler in the evening.

MF 800 μg

Arm description

MF 800 μg of total daily dose (400 μg twice daily, in the morning and in the evening) was delivered via Twisthaler®.

Arm type

Active comparator

Investigational medicinal product name

Mometasone furoate

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder

Routes of administration

Inhalation use

Dosage and administration details

400 μg twice daily, in the morning and in the evening via Twisthaler®.

MF 400 μg

Arm description

MF 400 μg was delivered o.d. via Twisthaler® in the evening.

Arm type

Active comparator

Investigational medicinal product name

Mometasone furoate

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder

Routes of administration

Inhalation use

Dosage and administration details

MF 400 μg, o.d. via Twisthaler® in the evening.

Salmeterol /fluticasone 50/500 μg

Arm description

Salmeterol xinafoate/fluticasone propionate 50/500 μg was delivered twice daily (in the morning and in the evening) via Accuhaler®.

Arm type

Active comparator

Investigational medicinal product name

Salmeterol/fluticasone

Investigational medicinal product code

Other name

Seretide

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

50/500 μg, twice daily in the morning and in the evening via Accuhaler®.

Number of subjects in period 1	QMF149 150/320 μg	QMF149 150/160 μg	MF 800 μg	MF 400 μg	Salmeterol /fluticasone 50/500 μg
Started	445	439	442	444	446
Completed	410	413	412	403	416
Not completed	35	26	30	41	30
Physician decision	-	1	4	1	1
Technical problems	1	1	-	2	2
Adverse event, non-fatal	-	-	-	-	2
Death	-	-	-	1	-
Non-compliance with study treatment	-	1	1	-	1
Pregnancy	-	-	-	1	-
Lost to follow-up	4	3	4	2	2
Subject/guardian decision	29	17	18	30	20
Protocol deviation	1	3	3	4	2

Baseline characteristics

Top of page

Reporting group title

QMF149 150/320 μg

Reporting group description

QMF149 (Indacaterol acetate/Mometasone furoate) 150/320 μg was delivered o.d. via Concept1 inhaler in the evening.

Reporting group title

QMF149 150/160 μg

Reporting group description

QMF149 (Indacaterol acetate/Mometasone furoate) 150/160 μg was delivered o.d. via Concept1 inhaler in the evening.

Reporting group title

MF 800 μg

Reporting group description

MF 800 μg of total daily dose (400 μg twice daily, in the morning and in the evening) was delivered via Twisthaler®.

Reporting group title

MF 400 μg

Reporting group description

MF 400 μg was delivered o.d. via Twisthaler® in the evening.

Reporting group title

Salmeterol /fluticasone 50/500 μg

Reporting group description

Salmeterol xinafoate/fluticasone propionate 50/500 μg was delivered twice daily (in the morning and in the evening) via Accuhaler®.

Reporting group values	QMF149 150/320 μg	QMF149 150/160 μg	MF 800 μg	MF 400 μg	Salmeterol /fluticasone 50/500 μg	Total
Number of subjects	445	439	442	444	446	2216
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)	22	20	21	22	22	107
Adults (18-64 years)	369	355	369	354	365	1812
From 65-84 years	54	64	52	68	59	297
85 years and over	0	0	0	0	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	47.1 ( 14.56 )	47.4 ( 14.76 )	47.5 ( 14.99 )	48.7 ( 14.98 )	48.9 ( 14.59 )	-
Gender categorical
Units: Subjects
Female	262	253	250	272	256	1293
Male	183	186	192	172	190	923

End points

Top of page

Reporting group title

QMF149 150/320 μg

Reporting group description

QMF149 (Indacaterol acetate/Mometasone furoate) 150/320 μg was delivered o.d. via Concept1 inhaler in the evening.

Reporting group title

QMF149 150/160 μg

Reporting group description

QMF149 (Indacaterol acetate/Mometasone furoate) 150/160 μg was delivered o.d. via Concept1 inhaler in the evening.

Reporting group title

MF 800 μg

Reporting group description

MF 800 μg of total daily dose (400 μg twice daily, in the morning and in the evening) was delivered via Twisthaler®.

Reporting group title

MF 400 μg

Reporting group description

MF 400 μg was delivered o.d. via Twisthaler® in the evening.

Reporting group title

Salmeterol /fluticasone 50/500 μg

Reporting group description

Salmeterol xinafoate/fluticasone propionate 50/500 μg was delivered twice daily (in the morning and in the evening) via Accuhaler®.

Primary: Trough Forced Expiratory Volume in One Second (Trough FEV1) at Week 26

Top of page

End point title

Trough Forced Expiratory Volume in One Second (Trough FEV1) at Week 26 ^[1]

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. Full Analysis Set (FAS) consisted of all subjects in the randomised (RAN) set who received at least one dose of study medication.

End point type

Primary

End point timeframe

Week 26 (Day 184)

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The arm groups QMF149 150/320 μg, QMF149 150/160 μg, MF 800 μg and MF 400 μg were planned to be reported for this endpoint.

End point values	QMF149 150/320 μg	QMF149 150/160 μg	MF 800 μg	MF 400 μg
Number of subjects analysed	395 ^[2]	389 ^[3]	372 ^[4]	376 ^[5]
Units: litre(s)
least squares mean (standard error)	2.383 ( 0.0159 )	2.387 ( 0.0160 )	2.250 ( 0.0162 )	2.176 ( 0.0162 )

Notes
[2] - Subjects analysed is number of subjects with data available for this endpoint point.
[3] - Subjects analysed is number of subjects with data available for this endpoint point.
[4] - Subjects analysed is number of subjects with data available for this endpoint point.
[5] - Subjects analysed is number of subjects with data available for this endpoint point.

QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

767

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

Least Squares mean (LS Mean)

Point estimate

0.132

Confidence interval

level

95%

sides

2-sided

lower limit

0.088

upper limit

0.176

Variability estimate

Standard error of the mean

Dispersion value

0.0223

QMF149 150/160 μg vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

765

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.211

Confidence interval

level

95%

sides

2-sided

lower limit

0.167

upper limit

0.255

Variability estimate

Standard error of the mean

Dispersion value

0.0224

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

Top of page

End point title

Asthma Control Questionnaire (ACQ-7) at Week 26 ^[6]

End point description

The ACQ-7 measured asthma symptom control and consisted 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. FAS consisted of all subjects in the RAN set who received at least one dose of study.

End point type

Secondary

End point timeframe

Week 26

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The arm groups QMF149 150/320 μg, QMF149 150/160 μg, MF 800 μg and MF 400 μg were planned to be reported for this endpoint.

End point values	QMF149 150/320 μg	QMF149 150/160 μg	MF 800 μg	MF 400 μg
Number of subjects analysed	407 ^[7]	407 ^[8]	405 ^[9]	393 ^[10]
Units: score on a scale
least squares mean (standard error)	1.267 ( 0.0350 )	1.261 ( 0.0350 )	1.439 ( 0.0352 )	1.509 ( 0.0354 )

Notes
[7] - Subjects analysed is number of subjects with data available for this endpoint point.
[8] - Subjects analysed is number of subjects with data available for this endpoint point.
[9] - Subjects analysed is number of subjects with data available for this endpoint point.
[10] - Subjects analysed is number of subjects with data available for this endpoint point.

QMF149 vs MF

Statistical analysis description

The comparison of QMF149 vs. MF was based on combined effects of QMF mid QMF high v Mf mid MF high.

Comparison groups

QMF149 150/160 μg v MF 400 μg v MF 800 μg v QMF149 150/320 μg

Number of subjects included in analysis

1612

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

-0.209

Confidence interval

level

95%

sides

2-sided

lower limit

-0.27

upper limit

-0.149

Variability estimate

Standard error of the mean

Dispersion value

0.031

Secondary: Trough FEV1 at Week 52

Top of page

End point title

Trough FEV1 at Week 52

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. FAS consisted of all subjects in the RAN set who received at least one dose of study medication.

End point type

Secondary

End point timeframe

Week 52

End point values	QMF149 150/320 μg	QMF149 150/160 μg	MF 800 μg	MF 400 μg	Salmeterol /fluticasone 50/500 μg
Number of subjects analysed	372 ^[11]	383 ^[12]	364 ^[13]	369 ^[14]	382 ^[15]
Units: litre(s)
least squares mean (standard error)	2.386 ( 0.0168 )	2.357 ( 0.0167 )	2.249 ( 0.0170 )	2.148 ( 0.0170 )	2.338 ( 0.0167 )

Notes
[11] - Subjects analysed is number of subjects with data available for this endpoint point.
[12] - Subjects analysed is number of subjects with data available for this endpoint point.
[13] - Subjects analysed is number of subjects with data available for this endpoint point.
[14] - Subjects analysed is number of subjects with data available for this endpoint point.
[15] - Subjects analysed is number of subjects with data available for this endpoint point.

QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

736

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.136

Confidence interval

level

95%

sides

2-sided

lower limit

0.09

upper limit

0.183

Variability estimate

Standard error of the mean

Dispersion value

0.0235

QMF149 150/160 μg vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

752

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.209

Confidence interval

level

95%

sides

2-sided

lower limit

0.163

upper limit

0.255

Variability estimate

Standard error of the mean

Dispersion value

0.0235

QMF149 150/320 μg vs S/F 50/500 μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

754

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.04

Method

MMRM

Parameter type

LS Mean

Point estimate

0.048

Confidence interval

level

95%

sides

2-sided

lower limit

0.002

upper limit

0.094

Variability estimate

Standard error of the mean

Dispersion value

0.0234

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 trough 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. FAS consisted of all subjects in the RAN set who received at least one dose of study medication.

End point type

Secondary

End point timeframe

Weeks 4 (Day 30) and 12 (Day 86)

End point values	QMF149 150/320 μg	QMF149 150/160 μg	MF 800 μg	MF 400 μg	Salmeterol /fluticasone 50/500 μg
Number of subjects analysed	430 ^[16]	427 ^[17]	430 ^[18]	427 ^[19]	439 ^[20]
Units: litre(s)
least squares mean (standard error)
Day 30 (n=430, 424, 421, 412, 435)	2.369 ( 0.0141 )	2.367 ( 0.0142 )	2.237 ( 0.0143 )	2.171 ( 0.0143 )	2.333 ( 0.0141 )
Day 86 (n=414, 414, 419, 398, 428)	2.368 ( 0.0148 )	2.361 ( 0.0148 )	2.245 ( 0.0148 )	2.177 ( 0.0149 )	2.330 ( 0.0146 )

Notes
[16] - n represents number of subjects analysed at the given time point.
[17] - n represents number of subjects analysed at the given time point.
[18] - n represents number of subjects analysed at the given time point.
[19] - n represents number of subjects analysed at the given time point.
[20] - n represents number of subjects analysed at the given time point.

Day 30: QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

860

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.132

Confidence interval

level

95%

sides

2-sided

lower limit

0.094

upper limit

0.17

Variability estimate

Standard error of the mean

Dispersion value

0.0193

Day 30: QMF149 150/160 μg vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

854

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.196

Confidence interval

level

95%

sides

2-sided

lower limit

0.158

upper limit

0.234

Variability estimate

Standard error of the mean

Dispersion value

0.0194

Day 30: QMF149 150/320 μg vs S/F 50/500 μg

Comparison groups

Salmeterol /fluticasone 50/500 μg v QMF149 150/320 μg

Number of subjects included in analysis

869

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.064

Method

MMRM

Parameter type

LS Mean

Point estimate

0.0192

Confidence interval

level

95%

sides

2-sided

lower limit

-0.002

upper limit

0.073

Variability estimate

Standard error of the mean

Dispersion value

0.0192

Day 86: QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

860

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.122

Confidence interval

level

95%

sides

2-sided

lower limit

0.083

upper limit

0.162

Variability estimate

Standard error of the mean

Dispersion value

0.0201

Day 86: QMF149 150/160 μg vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

854

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.184

Confidence interval

level

95%

sides

2-sided

lower limit

0.144

upper limit

0.224

Variability estimate

Standard error of the mean

Dispersion value

0.0202

Day 86: QMF149 150/320 μg vs S/F 50/500 μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

869

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.063

Method

MMRM

Parameter type

LS Mean

Point estimate

0.037

Confidence interval

level

95%

sides

2-sided

lower limit

-0.002

upper limit

0.076

Variability estimate

Standard error of the mean

Dispersion value

0.02

Secondary: Post Dose FEV1 (5 Minutes-1 Hour)

Top of page

End point title

Post Dose FEV1 (5 Minutes-1 Hour)

End point description

Post-dose FEV1 measurements were analyzed at 5 minutes, 15 minutes, 30 minutes and 1 hour. 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. FAS consisted of all subjects in the RAN set who received at least one dose of study medication.

End point type

Secondary

End point timeframe

Up to Week 52 (Day 364)

End point values	QMF149 150/320 μg	QMF149 150/160 μg	MF 800 μg	MF 400 μg	Salmeterol /fluticasone 50/500 μg
Number of subjects analysed	441 ^[21]	434 ^[22]	438 ^[23]	438 ^[24]	442 ^[25]
Units: litre(s)
least squares mean (standard error)
Day 1: 5 minutes (n=427,426,429,432,435)	2.279 ( 0.0084 )	2.270 ( 0.0085 )	2.138 ( 0.0085 )	2.118 ( 0.0084 )	2.224 ( 0.0084 )
Day 1: 15 minutes (n=434,425,433,433,441)	2.321 ( 0.0088 )	2.312 ( 0.0089 )	2.159 ( 0.0089 )	2.137 ( 0.0089 )	2.278 ( 0.0088 )
Day 1: 30 minutes (n=439,431,434,438,441)	2.338 ( 0.0095 )	2.326 ( 0.0096 )	2.162 ( 0.0096 )	2.141 ( 0.0095 )	2.310 ( 0.0095 )
Day 1: 1 hour (n=440,434,435,438,442)	2.343 ( 0.0100 )	2.347 ( 0.0101 )	2.166 ( 0.0101 )	2.142 ( 0.0100 )	2.337 ( 0.0100 )
Day 30: 5 minutes (n=428,420,419,411,435)	2.413 ( 0.0142 )	2.406 ( 0.0144 )	2.224 ( 0.0145 )	2.174 ( 0.0145 )	2.360 ( 0.0142 )
Day 30: 30 minutes(n=429,420,421,412,435)	2.432 ( 0.0143 )	2.426 ( 0.0145 )	2.238 ( 0.0146 )	2.174 ( 0.0146 )	2.389 ( 0.0143 )
Day 30: 1 hour (n=428,416,421,410,435)	2.448 ( 0.0145 )	2.440 ( 0.0146 )	2.257 ( 0.0147 )	2.183 ( 0.0148 )	2.411 ( 0.0144 )
Day 86:5 minutes (n=411,411,416,395,427)	2.411 ( 0.0150 )	2.409 ( 0.0150 )	2.248 ( 0.0150 )	2.178 ( 0.0153 )	2.356 ( 0.0148 )
Day 86: 30 minutes (n=412,411,417,395,426)	2.436 ( 0.0149 )	2.431 ( 0.0149 )	2.257 ( 0.0149 )	2.179 ( 0.0152 )	2.398 ( 0.0147 )
Day 86:1 hour (n=412,410,417,396,426)	2.456 ( 0.0151 )	2.436 ( 0.0151 )	2.269 ( 0.0151 )	2.188 ( 0.0154 )	2.413 ( 0.0149 )
Day 183: 5 minutes (n=404,399,400,385,409)	2.403 ( 0.0160 )	2.406 ( 0.0161 )	2.240 ( 0.0162 )	2.163 ( 0.0164 )	2.359 ( 0.0160 )
Day 183: 30 minutes (n=405,401,399,383,407)	2.426 ( 0.0163 )	2.427 ( 0.0164 )	2.250 ( 0.0165 )	2.168 ( 0.0167 )	2.386 ( 0.0163 )
Day 183: 1 hour (n=405,400,397,385,409)	2.432 ( 0.0161 )	2.423 ( 0.0162 )	2.253 ( 0.0163 )	2.165 ( 0.0165 )	2.393 ( 0.0161 )
Day 364: 5 minutes (n=375,389,380,374,403)	2.384 ( 0.0172 )	2.379 ( 0.0169 )	2.245 ( 0.0172 )	2.130 ( 0.0173 )	2.358 ( 0.0168 )
Day 364: 30 minutes (n=377,393,379,373,401)	2.408 ( 0.0171 )	2.399 ( 0.0169 )	2.253 ( 0.0172 )	2.135 ( 0.0172 )	2.377 ( 0.0167 )
Day 364:1 hour (n=378,393,379,375,402)	2.414 ( 0.0175 )	2.390 ( 0.0172 )	2.251 ( 0.0175 )	2.128 ( 0.0176 )	2.383 ( 0.0171 )

Notes
[21] - n represents number of subjects analysed at the given time point.
[22] - n represents number of subjects analysed at the given time point.
[23] - n represents number of subjects analysed at the given time point.
[24] - n represents number of subjects analysed at the given time point.
[25] - n represents number of subjects analysed at the given time point.

Day 1: 5 minutes QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

879

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.142

Confidence interval

level

95%

sides

2-sided

lower limit

0.119

upper limit

0.164

Variability estimate

Standard error of the mean

Dispersion value

0.0116

Day 1: 5 minutes QMF149 150/160 μg vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

872

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.152

Confidence interval

level

95%

sides

2-sided

lower limit

0.129

upper limit

0.175

Variability estimate

Standard error of the mean

Dispersion value

0.0116

Day 1:5 minutes QMF149 150/320 μg vs S/F 50/500 μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

883

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.055

Confidence interval

level

95%

sides

2-sided

lower limit

0.032

upper limit

0.078

Variability estimate

Standard error of the mean

Dispersion value

0.0116

Day 1: 15 minutes QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

879

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.162

Confidence interval

level

95%

sides

2-sided

lower limit

0.138

upper limit

0.186

Variability estimate

Standard error of the mean

Dispersion value

0.0122

Day 1: 15 minutes QMF149 150/160 μg vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

872

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.174

Confidence interval

level

95%

sides

2-sided

lower limit

0.15

upper limit

0.198

Variability estimate

Standard error of the mean

Dispersion value

0.0123

Day 1:15 minutes QMF149 150/320 μg vs S/F 50/500μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

883

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.044

Confidence interval

level

95%

sides

2-sided

lower limit

0.02

upper limit

0.068

Variability estimate

Standard error of the mean

Dispersion value

0.0122

Day 1: 30 minutes QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

879

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.175

Confidence interval

level

95%

sides

2-sided

lower limit

0.149

upper limit

0.201

Variability estimate

Standard error of the mean

Dispersion value

0.0132

Day 1: 30 minutes QMF149 150/160 μg vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

872

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.185

Confidence interval

level

95%

sides

2-sided

lower limit

0.159

upper limit

0.211

Variability estimate

Standard error of the mean

Dispersion value

0.0132

Day 1:30 minutes QMF149 150/320μg vs S/F 50/500μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

883

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.038

Method

MMRM

Parameter type

LS Mean

Point estimate

0.027

Confidence interval

level

95%

sides

2-sided

lower limit

0.001

upper limit

0.053

Variability estimate

Standard error of the mean

Dispersion value

0.0132

Day 1: 1 hour QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

879

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.178

Confidence interval

level

95%

sides

2-sided

lower limit

0.15

upper limit

0.205

Variability estimate

Standard error of the mean

Dispersion value

0.0139

Day 1: 1 hour QMF149 150/160 μg vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

872

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.205

Confidence interval

level

95%

sides

2-sided

lower limit

0.177

upper limit

0.232

Variability estimate

Standard error of the mean

Dispersion value

0.0139

Day 1: 1 hour QMF149 150/320 μg vs S/F 50/500 μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

883

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.632

Method

MMRM

Parameter type

LS Mean

Point estimate

0.007

Confidence interval

level

95%

sides

2-sided

lower limit

-0.021

upper limit

0.034

Variability estimate

Standard error of the mean

Dispersion value

0.0139

Day 30: 5 minutes QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

879

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.189

Confidence interval

level

95%

sides

2-sided

lower limit

0.151

upper limit

0.226

Variability estimate

Standard error of the mean

Dispersion value

0.0192

Day 30: 5 minutes QMF149 150/160 μg vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

872

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.232

Confidence interval

level

95%

sides

2-sided

lower limit

0.194

upper limit

0.27

Variability estimate

Standard error of the mean

Dispersion value

0.0194

Day 30:5 minutes QMF149 150/320 μg vs S/F 50/500μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

883

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.005

Method

MMRM

Parameter type

LS Mean

Point estimate

0.053

Confidence interval

level

95%

sides

2-sided

lower limit

0.016

upper limit

0.091

Variability estimate

Standard error of the mean

Dispersion value

0.0191

Day 30: 30 minutes QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

879

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

LS Mean

Point estimate

0.194

Confidence interval

level

95%

sides

2-sided

lower limit

0.156

upper limit

0.232

Variability estimate

Standard error of the mean

Dispersion value

0.0194

Day 30: 30 minutes QMF149 150/160 μg vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

872

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.253

Confidence interval

level

95%

sides

2-sided

lower limit

0.214

upper limit

0.291

Variability estimate

Standard error of the mean

Dispersion value

0.0196

Day 30:30 minutes QMF149 150/320μg vs S/F 50/500μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

883

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.026

Method

MMRM

Parameter type

LS Mean

Point estimate

0.043

Confidence interval

level

95%

sides

2-sided

lower limit

0.005

upper limit

0.08

Variability estimate

Standard error of the mean

Dispersion value

0.0192

Day 30: 1 hour QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

879

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.19

Confidence interval

level

95%

sides

2-sided

lower limit

0.152

upper limit

0.229

Variability estimate

Standard error of the mean

Dispersion value

0.0196

Day 30: 1 hour QMF149 150/160 μg vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

872

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.258

Confidence interval

level

95%

sides

2-sided

lower limit

0.219

upper limit

0.296

Variability estimate

Standard error of the mean

Dispersion value

0.0198

Day 30: 1 hour QMF149 150/320 μg vs S/F 50/500 μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

883

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.059

Method

MMRM

Parameter type

LS Mean

Point estimate

0.037

Confidence interval

level

95%

sides

2-sided

lower limit

-0.001

upper limit

0.075

Variability estimate

Standard error of the mean

Dispersion value

0.0194

Day 86: 5 minutes QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

879

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.163

Confidence interval

level

95%

sides

2-sided

lower limit

0.123

upper limit

0.203

Variability estimate

Standard error of the mean

Dispersion value

0.0204

Day 86: 5 minutes QMF149 150/160 μg vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

872

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.231

Confidence interval

level

95%

sides

2-sided

lower limit

0.191

upper limit

0.271

Variability estimate

Standard error of the mean

Dispersion value

0.0206

Day 86: 5 minutes QMF149 150/320μg vs S/F 50/500μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

883

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.007

Method

MMRM

Parameter type

LS Mean

Point estimate

0.055

Confidence interval

level

95%

sides

2-sided

lower limit

0.015

upper limit

0.095

Variability estimate

Standard error of the mean

Dispersion value

0.0203

Day 86: 30 minutes QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

879

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.18

Confidence interval

level

95%

sides

2-sided

lower limit

0.14

upper limit

0.219

Variability estimate

Standard error of the mean

Dispersion value

0.0203

Day 86: 30 minutes QMF149 150/160 μg vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

872

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.252

Confidence interval

level

95%

sides

2-sided

lower limit

0.211

upper limit

0.292

Variability estimate

Standard error of the mean

Dispersion value

0.0205

Day 86:30 minutes QMF149 150/320μg vs S/F 50/500μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

883

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.057

Method

MMRM

Parameter type

LS Mean

Point estimate

0.038

Confidence interval

level

95%

sides

2-sided

lower limit

-0.001

upper limit

0.078

Variability estimate

Standard error of the mean

Dispersion value

0.0202

Day 86: 1 hour QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

879

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.187

Confidence interval

level

95%

sides

2-sided

lower limit

0.147

upper limit

0.227

Variability estimate

Standard error of the mean

Dispersion value

0.0205

Day 86: 1 hour QMF149 150/160 μg vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

872

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.249

Confidence interval

level

95%

sides

2-sided

lower limit

0.208

upper limit

0.289

Variability estimate

Standard error of the mean

Dispersion value

0.0208

Day 86: 1 hour QMF149 150/320 μg vs S/F 50/500 μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

883

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.037

Method

MMRM

Parameter type

LS Mean

Point estimate

0.043

Confidence interval

level

95%

sides

2-sided

lower limit

0.003

upper limit

0.083

Variability estimate

Standard error of the mean

Dispersion value

0.0205

Day 183: 5 minutes QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

879

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.163

Confidence interval

level

95%

sides

2-sided

lower limit

0.121

upper limit

0.206

Variability estimate

Standard error of the mean

Dispersion value

0.0217

Day 183: 5 minutes QMF149 150/160 μg vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

872

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.243

Confidence interval

level

95%

sides

2-sided

lower limit

0.2

upper limit

0.286

Variability estimate

Standard error of the mean

Dispersion value

0.0219

Day 183:5 minutes QMF149 150/320μg vs S/F 50/500μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

883

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.041

Method

MMRM

Parameter type

LS Mean

Point estimate

0.044

Confidence interval

level

95%

sides

2-sided

lower limit

0.002

upper limit

0.087

Variability estimate

Standard error of the mean

Dispersion value

0.0216

Day 183: 30 minutes QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

879

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.176

Confidence interval

level

95%

sides

2-sided

lower limit

0.133

upper limit

0.22

Variability estimate

Standard error of the mean

Dispersion value

0.0222

Day 183: 30 minutes QMF149 150/160 μg vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

872

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.259

Confidence interval

level

95%

sides

2-sided

lower limit

0.215

upper limit

0.303

Variability estimate

Standard error of the mean

Dispersion value

0.0224

Day 183:30minutes QMF149 150/320μg vs S/F 50/500μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

883

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.071

Method

MMRM

Parameter type

LS Mean

Point estimate

0.04

Confidence interval

level

95%

sides

2-sided

lower limit

-0.003

upper limit

0.083

Variability estimate

Standard error of the mean

Dispersion value

0.0221

Day 183: 1 hour QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

879

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.18

Confidence interval

level

95%

sides

2-sided

lower limit

0.137

upper limit

0.223

Variability estimate

Standard error of the mean

Dispersion value

0.0219

Day 183: 1 hour QMF149 150/160 μg vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

872

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.259

Confidence interval

level

95%

sides

2-sided

lower limit

0.215

upper limit

0.302

Variability estimate

Standard error of the mean

Dispersion value

0.0222

Day 183: 1 hour QMF149 150/320μg vs S/F 50/500μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

883

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.071

Method

MMRM

Parameter type

LS Mean

Point estimate

0.039

Confidence interval

level

95%

sides

2-sided

lower limit

-0.003

upper limit

0.082

Variability estimate

Standard error of the mean

Dispersion value

0.0218

Day 364: 5 minutes QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

879

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

0.094

upper limit

0.184

Variability estimate

Standard error of the mean

Dispersion value

0.0229

Day 364: 5 minutes QMF149 150/160 μg vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

872

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.249

Confidence interval

level

95%

sides

2-sided

lower limit

0.205

upper limit

0.294

Variability estimate

Standard error of the mean

Dispersion value

0.0228

Day 364:5 minutes QMF149 150/320μg vs S/F 50/500μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

883

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.244

Method

MMRM

Parameter type

LS Mean

Point estimate

0.026

Confidence interval

level

95%

sides

2-sided

lower limit

-0.018

upper limit

0.071

Variability estimate

Standard error of the mean

Dispersion value

0.0227

Day 364: 30 minutes QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

879

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.155

Confidence interval

level

95%

sides

2-sided

lower limit

0.11

upper limit

0.2

Variability estimate

Standard error of the mean

Dispersion value

0.0228

Day 364: 30 minutes QMF149 150/160 μg vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

872

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.264

Confidence interval

level

95%

sides

2-sided

lower limit

0.219

upper limit

0.308

Variability estimate

Standard error of the mean

Dispersion value

0.0227

Day 364:30minutes QMF149 150/320μg vs S/F 50/500μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

883

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.162

Method

MMRM

Parameter type

LS Mean

Point estimate

0.032

Confidence interval

level

95%

sides

2-sided

lower limit

-0.013

upper limit

0.076

Variability estimate

Standard error of the mean

Dispersion value

0.0226

Day 364: 1 hour QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

879

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.163

Confidence interval

level

95%

sides

2-sided

lower limit

0.117

upper limit

0.209

Variability estimate

Standard error of the mean

Dispersion value

0.0234

Day 364: 1 hour QMF149 150/160 μg vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

872

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.262

Confidence interval

level

95%

sides

2-sided

lower limit

0.216

upper limit

0.308

Variability estimate

Standard error of the mean

Dispersion value

0.0232

Day 364: 1 hour QMF149 150/320 μg vs S/F 50/500 μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

883

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.182

Method

MMRM

Parameter type

LS Mean

Point estimate

0.031

Confidence interval

level

95%

sides

2-sided

lower limit

-0.014

upper limit

0.076

Variability estimate

Standard error of the mean

Dispersion value

0.0231

Secondary: Trough Forced Vital Capacity (FVC)

Top of page

End point title

Trough Forced Vital Capacity (FVC)

End point description

FVC is the total amount of air exhaled during the FEV test. Trough FVC is defined as average of the two FVC measurements taken 23 hr 15 min and 23 hr 45 min post-evening dose. It was assessed by performing spirometric assessment. FAS consisted of all subjects in the RAN set who received at least one dose of study medication.

End point type

Secondary

End point timeframe

Up to Week 52 (Day 365)

End point values	QMF149 150/320 μg	QMF149 150/160 μg	MF 800 μg	MF 400 μg	Salmeterol /fluticasone 50/500 μg
Number of subjects analysed	439 ^[26]	433 ^[27]	436 ^[28]	441 ^[29]	441 ^[30]
Units: litre(s)
least squares mean (standard error)
Day 2 (n=432,430,410,435,419)	3.342 ( 0.0173 )	3.342 ( 0.0174 )	3.256 ( 0.0177 )	3.203 ( 0.0173 )	3.344 ( 0.0176 )
Day 184 (n=395,389,372,376,391)	3.372 ( 0.0179 )	3.387 ( 0.0180 )	3.322 ( 0.0183 )	3.246 ( 0.0182 )	3.355 ( 0.0180 )
Day 365 (n=372,383,365,369,382)	3.394 ( 0.0182 )	3.364 ( 0.0181 )	3.319 ( 0.0184 )	3.218 ( 0.0183 )	3.358 ( 0.0182 )

Notes
[26] - n represents number of subjects analysed at the given time point.
[27] - n represents number of subjects analysed at the given time point.
[28] - n represents number of subjects analysed at the given time point.
[29] - n represents number of subjects analysed at the given time point.
[30] - n represents number of subjects analysed at the given time point.

Day 2: QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

875

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

0.04

upper limit

0.133

Variability estimate

Standard error of the mean

Dispersion value

0.0237

Day 2: QMF149 150/160 μg vs MF 400 μg

Comparison groups

MF 400 μg v QMF149 150/160 μg

Number of subjects included in analysis

874

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

0.093

upper limit

0.185

Variability estimate

Standard error of the mean

Dispersion value

0.0235

Day 2: QMF149 150/320 μg vs S/F 50/500 μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

880

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.927

Method

MMRM

Parameter type

LS Mean

Point estimate

-0.002

Confidence interval

level

95%

sides

2-sided

lower limit

-0.049

upper limit

0.044

Variability estimate

Standard error of the mean

Dispersion value

0.0237

Day 184: QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

875

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.044

Method

MMRM

Parameter type

LS Mean

Point estimate

0.05

Confidence interval

level

95%

sides

2-sided

lower limit

0.001

upper limit

0.098

Variability estimate

Standard error of the mean

Dispersion value

0.0246

Day 184: QMF149 150/160 μg vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

874

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.141

Confidence interval

level

95%

sides

2-sided

lower limit

0.093

upper limit

0.19

Variability estimate

Standard error of the mean

Dispersion value

0.0246

Day 184: QMF149 150/320 μg vs S/F 50/500 μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

880

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.49

Method

MMRM

Parameter type

LS Mean

Point estimate

0.017

Confidence interval

level

95%

sides

2-sided

lower limit

-0.031

upper limit

0.065

Variability estimate

Standard error of the mean

Dispersion value

0.0244

Day 365: QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

875

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.002

Method

MMRM

Parameter type

LS Mean

Point estimate

0.076

Confidence interval

level

95%

sides

2-sided

lower limit

0.027

upper limit

0.125

Variability estimate

Standard error of the mean

Dispersion value

0.0249

Day 365: QMF149 150/160 μg vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

874

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.146

Confidence interval

level

95%

sides

2-sided

lower limit

0.098

upper limit

0.195

Variability estimate

Standard error of the mean

Dispersion value

0.0248

Day 365: QMF149 150/320μg vs S/F 50/500μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

880

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.143

Method

MMRM

Parameter type

LS Mean

Point estimate

0.036

Confidence interval

level

95%

sides

2-sided

lower limit

-0.012

upper limit

0.085

Variability estimate

Standard error of the mean

Dispersion value

0.0248

Secondary: Trough Forced Expiratory Flow (FEF)Between 25% and 75% of FVC (FEF25-75)

Top of page

End point title

Trough Forced Expiratory Flow (FEF)Between 25% and 75% of FVC (FEF25-75)

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. FAS consisted of all subjects in the RAN set who received at least one dose of study medication.

End point type

Secondary

End point timeframe

Up to Week 52 (Day 365)

End point values	QMF149 150/320 μg	QMF149 150/160 μg	MF 800 μg	MF 400 μg	Salmeterol /fluticasone 50/500 μg
Number of subjects analysed	439 ^[31]	433 ^[32]	436 ^[33]	441 ^[34]	441 ^[35]
Units: Liters/second(L/s)
least squares mean (standard error)
Day 2: (n=432,430,410,435,419)	1.644 ( 0.0186 )	1.617 ( 0.0187 )	1.455 ( 0.0191 )	1.406 ( 0.0186 )	1.662 ( 0.0189 )
Day 184: (n=395,389,372,376,391)	1.775 ( 0.0249 )	1.738 ( 0.0250 )	1.546 ( 0.0253 )	1.473 ( 0.0254 )	1.692 ( 0.0250 )
Day 365: (372,383,365,369,382)	1.745 ( 0.0259 )	1.686 ( 0.0257 )	1.530 ( 0.0261 )	1.440 ( 0.0261 )	1.692 ( 0.0258 )

Notes
[31] - n represents number of subjects analysed at the given time point.
[32] - n represents number of subjects analysed at the given time point.
[33] - n represents number of subjects analysed at the given time point.
[34] - n represents number of subjects analysed at the given time point.
[35] - n represents number of subjects analysed at the given time point.

Day 2: QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

875

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.189

Confidence interval

level

95%

sides

2-sided

lower limit

0.139

upper limit

0.238

Variability estimate

Standard error of the mean

Dispersion value

0.0253

Day 2: QMF149 150/160 μg vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

874

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.21

Confidence interval

level

95%

sides

2-sided

lower limit

0.161

upper limit

0.259

Variability estimate

Standard error of the mean

Dispersion value

0.025

Day 2: QMF149 150/320 μg vs S/F 50/500 μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

880

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.475

Method

MMRM

Parameter type

LS Mean

Point estimate

-0.018

Confidence interval

level

95%

sides

2-sided

lower limit

-0.067

upper limit

0.031

Variability estimate

Standard error of the mean

Dispersion value

0.0252

Day 184: QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

875

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.228

Confidence interval

level

95%

sides

2-sided

lower limit

0.161

upper limit

0.296

Variability estimate

Standard error of the mean

Dispersion value

0.0345

Day 184: QMF149 150/160 μg vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

874

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.265

Confidence interval

level

95%

sides

2-sided

lower limit

0.197

upper limit

0.333

Variability estimate

Standard error of the mean

Dispersion value

0.0346

Day 184: QMF149 150/320 μg vs S/F 50/500 μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

880

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.015

Method

MMRM

Parameter type

LS Mean

Point estimate

0.083

Confidence interval

level

95%

sides

2-sided

lower limit

0.016

upper limit

0.151

Variability estimate

Standard error of the mean

Dispersion value

0.0343

Day 365: QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

875

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.215

Confidence interval

level

95%

sides

2-sided

lower limit

0.145

upper limit

0.285

Variability estimate

Standard error of the mean

Dispersion value

0.0358

Day 365: QMF149 150/160 μg vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

874

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.246

Confidence interval

level

95%

sides

2-sided

lower limit

0.176

upper limit

0.316

Variability estimate

Standard error of the mean

Dispersion value

0.0357

Day 365: QMF149 150/320 μg vs S/F 50/500 μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

880

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.139

Method

MMRM

Parameter type

LS Mean

Point estimate

0.053

Confidence interval

level

95%

sides

2-sided

lower limit

-0.017

upper limit

0.122

Variability estimate

Standard error of the mean

Dispersion value

0.0356

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 subjects 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 each time point, the subject 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. FAS consisted of all subjects in the RAN set who received at least one dose of study medication.

End point type

Secondary

End point timeframe

Up to Weeks 26 and 52

End point values	QMF149 150/320 μg	QMF149 150/160 μg	MF 800 μg	MF 400 μg	Salmeterol /fluticasone 50/500 μg
Number of subjects analysed	443 ^[36]	437 ^[37]	440 ^[38]	443 ^[39]	444 ^[40]
Units: Liters/minute(L/min)
least squares mean (standard error)
Week 26: Mean morning PEF(n=418,419,430,422,426)	42.4 ( 2.15 )	38.1 ( 2.15 )	12.8 ( 2.13 )	5.9 ( 2.14 )	29.1 ( 2.14 )
Week 26:Mean evening PEF(n=417,420,425,419,423)	32.5 ( 2.05 )	30.4 ( 2.04 )	7.7 ( 2.04 )	0.0 ( 2.05 )	23.9 ( 2.04 )
Week 52:Mean morning PEF(n=415,420,427,422,424)	42.1 ( 2.24 )	36.9 ( 2.22 )	13.4 ( 2.21 )	6.7 ( 2.22 )	28.3 ( 2.22 )
Week 52:Mean evening PEF(n=416,420,424,418,422)	31.2 ( 2.14 )	28.7 ( 2.13 )	7.4 ( 2.13 )	-0.3 ( 2.14 )	22.1 ( 2.13 )

Notes
[36] - n represents number of subjects analysed at the given time point.
[37] - n represents number of subjects analysed at the given time point.
[38] - n represents number of subjects analysed at the given time point.
[39] - n represents number of subjects analysed at the given time point.
[40] - n represents number of subjects analysed at the given time point.

Wk 26: Mean morning QMF149 150/320 μg vs MF 800

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

883

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Linear Mixed Model (LMM)

Parameter type

LS Mean

Point estimate

29.6

Confidence interval

level

95%

sides

2-sided

lower limit

23.8

upper limit

35.4

Variability estimate

Standard error of the mean

Dispersion value

2.96

Wk 26: Mean morning QMF149 150/160 vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

880

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

LMM

Parameter type

LS Mean

Point estimate

32.2

Confidence interval

level

95%

sides

2-sided

lower limit

26.4

upper limit

38.1

Variability estimate

Standard error of the mean

Dispersion value

2.97

Wk 26:Mean morning QMF149 150/320μg v S/F 50/500μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

887

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

LMM

Parameter type

LS Mean

Point estimate

13.3

Confidence interval

level

95%

sides

2-sided

lower limit

7.5

upper limit

19.1

Variability estimate

Standard error of the mean

Dispersion value

2.97

Wk 26:Mean evening QMF149 150/320μg vs MF 800μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

883

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

LMM

Parameter type

LS Mean

Point estimate

24.8

Confidence interval

level

95%

sides

2-sided

lower limit

19.3

upper limit

30.3

Variability estimate

Standard error of the mean

Dispersion value

2.82

Wk 26:Mean evening QMF149 150/160μg vs MF 400μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

880

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

LMM

Parameter type

LS Mean

Point estimate

30.4

Confidence interval

level

95%

sides

2-sided

lower limit

24.8

upper limit

35.9

Variability estimate

Standard error of the mean

Dispersion value

2.83

Wk 26:Mean evening QMF149 150/320μg v S/F 50/500μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

887

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.002

Method

LMM

Parameter type

LS Mean

Point estimate

8.6

Confidence interval

level

95%

sides

2-sided

lower limit

3.1

upper limit

14.2

Variability estimate

Standard error of the mean

Dispersion value

2.83

Wk 52:Mean morning QMF149 150/320μg vs MF 800μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

883

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

LMM

Parameter type

LS Mean

Point estimate

28.7

Confidence interval

level

95%

sides

2-sided

lower limit

22.7

upper limit

34.8

Variability estimate

Standard error of the mean

Dispersion value

3.07

Wk 52:Mean morning QMF149 150/160μg vs MF 400μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

880

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

LMM

Parameter type

LS Mean

Point estimate

30.2

Confidence interval

level

95%

sides

2-sided

lower limit

24.2

upper limit

36.3

Variability estimate

Standard error of the mean

Dispersion value

3.07

Wk 52:Mean morning QMF149 150/320μg v S/F 50/500μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

887

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

LMM

Parameter type

LS Mean

Point estimate

13.8

Confidence interval

level

95%

sides

2-sided

lower limit

7.7

upper limit

19.8

Variability estimate

Standard error of the mean

Dispersion value

3.08

Wk 52:Mean evening QMF149 150/320μg vs MF 800μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

883

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

LMM

Parameter type

LS Mean

Point estimate

23.7

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

29.5

Variability estimate

Standard error of the mean

Dispersion value

2.94

Wk 52: Mean evening QMF149 150/160 vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

880

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

23.3

upper limit

34.8

Variability estimate

Standard error of the mean

Dispersion value

2.94

Wk 52:Mean evening QMF149 150/320μg v S/F 50/500μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

887

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.002

Method

LMM

Parameter type

LS Mean

Point estimate

9.1

Confidence interval

level

95%

sides

2-sided

lower limit

3.3

upper limit

14.9

Variability estimate

Standard error of the mean

Dispersion value

2.95

Secondary: ACQ-7 at Weeks 4, 12 and 52

Top of page

End point title

ACQ-7 at Weeks 4, 12 and 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 total score was calculated as the mean of all questions. FAS consisted of all subjects in the RAN set who received at least one dose of study medication.

End point type

Secondary

End point timeframe

Weeks 4, 12 and 52

End point values	QMF149 150/320 μg	QMF149 150/160 μg	MF 800 μg	MF 400 μg	Salmeterol /fluticasone 50/500 μg
Number of subjects analysed	429 ^[41]	427 ^[42]	431 ^[43]	428 ^[44]	439 ^[45]
Units: score on a scale
least squares mean (standard error)
Week 4 (n=426,422,429,425,437)	1.486 ( 0.0337 )	1.533 ( 0.0338 )	1.659 ( 0.0338 )	1.730 ( 0.0337 )	1.541 ( 0.0335 )
Week 12 (n=419,414,422,407,429)	1.394 ( 0.0347 )	1.377 ( 0.0348 )	1.523 ( 0.0348 )	1.625 ( 0.0350 )	1.445 ( 0.0345 )
Week 52 (n=385,397,387,377,405)	1.231 ( 0.0358 )	1.183 ( 0.0356 )	1.373 ( 0.0359 )	1.449 ( 0.0361 )	1.221 ( 0.0354 )

Notes
[41] - n represents number of subjects analysed at the given time point.
[42] - n represents number of subjects analysed at the given time point.
[43] - n represents number of subjects analysed at the given time point.
[44] - n represents number of subjects analysed at the given time point.
[45] - n represents number of subjects analysed at the given time point.

Week 4: QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

860

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

-0.172

Confidence interval

level

95%

sides

2-sided

lower limit

-0.254

upper limit

-0.091

Variability estimate

Standard error of the mean

Dispersion value

0.0415

Week 4: QMF149 150/160 μg vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

855

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

-0.196

Confidence interval

level

95%

sides

2-sided

lower limit

-0.278

upper limit

-0.115

Variability estimate

Standard error of the mean

Dispersion value

0.0416

Week 4: QMF149 150/320 μg vs S/F 50/500 μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

868

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.186

Method

MMRM

Parameter type

LS Mean

Point estimate

-0.055

Confidence interval

level

95%

sides

2-sided

lower limit

-0.136

upper limit

0.026

Variability estimate

Standard error of the mean

Dispersion value

0.0414

Week 12: QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

860

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.003

Method

MMRM

Parameter type

LS Mean

Point estimate

-0.129

Confidence interval

level

95%

sides

2-sided

lower limit

-0.214

upper limit

-0.044

Variability estimate

Standard error of the mean

Dispersion value

0.0431

Week 12: QMF149 150/160 μg vs MF 400 μg

Comparison groups

MF 400 μg v QMF149 150/160 μg

Number of subjects included in analysis

855

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

-0.248

Confidence interval

level

95%

sides

2-sided

lower limit

-0.333

upper limit

-0.162

Variability estimate

Standard error of the mean

Dispersion value

0.0435

Week 12: QMF149 150/320 μg vs S/F 50/500 μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

868

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.232

Method

MMRM

Parameter type

LS Mean

Point estimate

-0.052

Confidence interval

level

95%

sides

2-sided

lower limit

-0.136

upper limit

0.033

Variability estimate

Standard error of the mean

Dispersion value

0.0431

Week 52: QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

860

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.002

Method

MMRM

Parameter type

LS Mean

Point estimate

-0.141

Confidence interval

level

95%

sides

2-sided

lower limit

-0.229

upper limit

-0.053

Variability estimate

Standard error of the mean

Dispersion value

0.0449

Week 52: QMF149 150/160 μg vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

855

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

-0.266

Confidence interval

level

95%

sides

2-sided

lower limit

-0.354

upper limit

-0.177

Variability estimate

Standard error of the mean

Dispersion value

0.045

Week 52: QMF149 150/320 μg vs S/F 50/500 μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

868

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.824

Method

MMRM

Parameter type

LS Mean

Point estimate

0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.078

upper limit

0.098

Variability estimate

Standard error of the mean

Dispersion value

0.0447

Secondary: Percentage of Subjects Achieving the Minimal Important Difference (MID) ACQ ≥ 0.5 at Weeks 26 and 52

Top of page

End point title

Percentage of Subjects Achieving the Minimal Important Difference (MID) ACQ ≥ 0.5 at Weeks 26 and 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. FAS consisted of all subjects in the RAN set who received at least one dose of study.

End point type

Secondary

End point timeframe

Weeks 26 (Day 183) and 52 (Day 364)

End point values	QMF149 150/320 μg	QMF149 150/160 μg	MF 800 μg	MF 400 μg	Salmeterol /fluticasone 50/500 μg
Number of subjects analysed	443 ^[46]	437 ^[47]	440 ^[48]	443 ^[49]	444 ^[50]
Units: percentage of subjects
number (not applicable)
Day 183 (n=407,407,405,393,410)	76.4	76.2	72.3	66.9	75.9
Day 364 (n=385,397,387,377,405)	77.7	82.1	73.6	69.2	77.3

Notes
[46] - n represents number of subjects analysed at the given time point.
[47] - n represents number of subjects analysed at the given time point.
[48] - n represents number of subjects analysed at the given time point.
[49] - n represents number of subjects analysed at the given time point.
[50] - n represents number of subjects analysed at the given time point.

Day 183: QMF149 150/320 μg vs MF 800 μg

Comparison groups

MF 800 μg v QMF149 150/320 μg

Number of subjects included in analysis

883

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.094

Method

Logistic regression model

Parameter type

Odds ratio (OR)

Point estimate

1.31

Confidence interval

level

95%

sides

2-sided

lower limit

0.95

upper limit

1.81

Day 183: QMF149 150/160 μg v MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

880

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Logistic regression model

Parameter type

Odds ratio (OR)

Point estimate

1.73

Confidence interval

level

95%

sides

2-sided

lower limit

1.26

upper limit

2.37

Day 183: QMF149 150/320 μg vs S/F 50/500 μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

887

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.746

Method

Logistic regression model

Parameter type

Odds ratio (OR)

Point estimate

1.06

Confidence interval

level

95%

sides

2-sided

lower limit

0.76

upper limit

1.46

Day 364: QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

883

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.088

Method

Logistic regression model

Parameter type

Odds ratio (OR)

Point estimate

1.34

Confidence interval

level

95%

sides

2-sided

lower limit

0.96

upper limit

1.87

Day 364: QMF149 150/160 μg vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

880

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Logistic regression model

Parameter type

Odds ratio (OR)

Point estimate

2.24

Confidence interval

level

95%

sides

2-sided

lower limit

1.58

upper limit

3.17

Day 364: QMF149 150/320 μg vs S/F 50/500 μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

887

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.771

Method

Logistic regression model

Parameter type

Odds ratio (OR)

Point estimate

1.05

Confidence interval

level

95%

sides

2-sided

lower limit

0.75

upper limit

1.49

Secondary: Change From Baseline in Percentage of Asthma Symptoms Free Days

Top of page

End point title

Change From Baseline in Percentage of Asthma Symptoms Free Days

End point description

All subjects 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 subjects with respect to shortness of breath, wheeze, cough, chest tightness, and impact on usual daily activities due to symptoms. FAS consisted of all subjects in the RAN set who received at least one dose of study medication.

End point type

Secondary

End point timeframe

Up to Week 52

End point values	QMF149 150/320 μg	QMF149 150/160 μg	MF 800 μg	MF 400 μg	Salmeterol /fluticasone 50/500 μg
Number of subjects analysed	401 ^[51]	402 ^[52]	408 ^[53]	404 ^[54]	405 ^[55]
Units: percentage of days
least squares mean (standard error)	28.3 ( 1.72 )	28.4 ( 1.72 )	22.5 ( 1.72 )	19.3 ( 1.72 )	24.9 ( 1.72 )

Notes
[51] - Subjects analysed is number of subjects with data available for this endpoint point.
[52] - Subjects analysed is number of subjects with data available for this endpoint point.
[53] - Subjects analysed is number of subjects with data available for this endpoint point.
[54] - Subjects analysed is number of subjects with data available for this endpoint point.
[55] - Subjects analysed is number of subjects with data available for this endpoint point.

QMF149 150/320 μg v MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

809

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.012

Method

Linear Mixed Model (LMM)

Parameter type

LS Mean

Point estimate

5.8

Confidence interval

level

95%

sides

2-sided

lower limit

1.3

upper limit

10.2

Variability estimate

Standard error of the mean

Dispersion value

2.29

QMF149 150/160 μg v MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

806

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

LMM

Parameter type

LS Mean

Point estimate

9.1

Confidence interval

level

95%

sides

2-sided

lower limit

4.6

upper limit

13.6

Variability estimate

Standard error of the mean

Dispersion value

2.29

QMF149 150/320 μg vs S/F 50/500 μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

806

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.135

Method

LMM

Parameter type

LS Mean

Point estimate

3.4

Confidence interval

level

95%

sides

2-sided

lower limit

-1.1

upper limit

7.9

Variability estimate

Standard error of the mean

Dispersion value

2.29

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 subjects 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). FAS consisted of all subjects in the RAN set who received at least one dose of study medication.

End point type

Secondary

End point timeframe

Up to Week 52

End point values	QMF149 150/320 μg	QMF149 150/160 μg	MF 800 μg	MF 400 μg	Salmeterol /fluticasone 50/500 μg
Number of subjects analysed	416 ^[56]	420 ^[57]	425 ^[58]	419 ^[59]	423 ^[60]
Units: percentage of days
least squares mean (standard error)	28.0 ( 1.69 )	28.0 ( 1.69 )	23.0 ( 1.68 )	20.0 ( 1.69 )	24.8 ( 1.68 )

Notes
[56] - Subjects analysed is number of subjects with data available for this endpoint point.
[57] - Subjects analysed is number of subjects with data available for this endpoint point.
[58] - Subjects analysed is number of subjects with data available for this endpoint point.
[59] - Subjects analysed is number of subjects with data available for this endpoint point.
[60] - Subjects analysed is number of subjects with data available for this endpoint point.

QMF149 150/320 μg v MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

841

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.026

Method

LMM

Parameter type

LS Mean

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

0.6

upper limit

9.4

Variability estimate

Standard error of the mean

Dispersion value

2.25

QMF149 150/160 μg v MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

839

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

LMM

Parameter type

LS Mean

Point estimate

8.1

Confidence interval

level

95%

sides

2-sided

lower limit

3.7

upper limit

12.5

Variability estimate

Standard error of the mean

Dispersion value

2.25

QMF149 150/320 μg vs S/F 50/500 μg

Comparison groups

Salmeterol /fluticasone 50/500 μg v QMF149 150/320 μg

Number of subjects included in analysis

839

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.151

Method

LMM

Parameter type

LS Mean

Point estimate

3.2

Confidence interval

level

95%

sides

2-sided

lower limit

-1.2

upper limit

7.7

Variability estimate

Standard error of the mean

Dispersion value

2.25

Secondary: Change From Baseline in Percentage of Nights With no Night-time Awakenings

Top of page

End point title

Change From Baseline in Percentage of Nights With no Night-time Awakenings

End point description

All subjects 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). FAS consisted of all subjects in the RAN set who received at least one dose of study medication.

End point type

Secondary

End point timeframe

Up to Week 52

End point values	QMF149 150/320 μg	QMF149 150/160 μg	MF 800 μg	MF 400 μg	Salmeterol /fluticasone 50/500 μg
Number of subjects analysed	415 ^[61]	420 ^[62]	428 ^[63]	422 ^[64]	424 ^[65]
Units: percentage of nights
least squares mean (standard error)	17.0 ( 1.28 )	16.4 ( 1.27 )	14.2 ( 1.27 )	12.5 ( 1.27 )	16.1 ( 1.27 )

Notes
[61] - Subjects analysed is number of subjects with data available for this endpoint point.
[62] - Subjects analysed is number of subjects with data available for this endpoint point.
[63] - Subjects analysed is number of subjects with data available for this endpoint point.
[64] - Subjects analysed is number of subjects with data available for this endpoint point.
[65] - Subjects analysed is number of subjects with data available for this endpoint point.

QMF149 150/320 μg v MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

843

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.104

Method

LMM

Parameter type

LS Mean

Point estimate

2.8

Confidence interval

level

95%

sides

2-sided

lower limit

-0.6

upper limit

6.2

Variability estimate

Standard error of the mean

Dispersion value

1.72

QMF149 150/160 μg v MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

842

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.024

Method

LMM

Parameter type

LS Mean

Point estimate

3.9

Confidence interval

level

95%

sides

2-sided

lower limit

0.5

upper limit

7.3

Variability estimate

Standard error of the mean

Dispersion value

1.72

QMF149 150/320 μg vs S/F 50/500 μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

839

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.588

Method

LMM

Parameter type

LS Mean

Point estimate

0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-2.5

upper limit

4.3

Variability estimate

Standard error of the mean

Dispersion value

1.73

Secondary: Change From Baseline in Percentage of Mornings With no Symptoms on Awakening

Top of page

End point title

Change From Baseline in Percentage of Mornings With no Symptoms on Awakening

End point description

All subjects 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 mornings with no symptoms on awakening was “Did you have asthma symptoms upon awakening in the morning?” to be answered with “None” with scores from 0 (no problem)-4 (very severe problems). FAS consisted of all subjects in the RAN set who received at least one dose of study medication.

End point type

Secondary

End point timeframe

Up to Week 52

End point values	QMF149 150/320 μg	QMF149 150/160 μg	MF 800 μg	MF 400 μg	Salmeterol /fluticasone 50/500 μg
Number of subjects analysed	415 ^[66]	420 ^[67]	428 ^[68]	422 ^[69]	424 ^[70]
Units: percentage of mornings
least squares mean (standard error)	25.5 ( 1.66 )	22.9 ( 1.65 )	19.1 ( 1.65 )	14.1 ( 1.65 )	20.7 ( 1.65 )

Notes
[66] - Subjects analysed is number of subjects with data available for this endpoint point.
[67] - Subjects analysed is number of subjects with data available for this endpoint point.
[68] - Subjects analysed is number of subjects with data available for this endpoint point.
[69] - Subjects analysed is number of subjects with data available for this endpoint point.
[70] - Subjects analysed is number of subjects with data available for this endpoint point.

QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

843

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.003

Method

LMM

Parameter type

LS Mean

Point estimate

6.4

Confidence interval

level

95%

sides

2-sided

lower limit

2.1

upper limit

10.7

Variability estimate

Standard error of the mean

Dispersion value

2.19

QMF149 150/160 μg vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

842

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

LMM

Parameter type

LS Mean

Point estimate

8.9

Confidence interval

level

95%

sides

2-sided

lower limit

4.6

upper limit

13.2

Variability estimate

Standard error of the mean

Dispersion value

2.19

QMF149 150/320 μg vs S/F 50/500 μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

839

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.029

Method

LMM

Parameter type

LS Mean

Point estimate

4.8

Confidence interval

level

95%

sides

2-sided

lower limit

0.5

upper limit

9.1

Variability estimate

Standard error of the mean

Dispersion value

2.2

Secondary: Rescue Medication Usage

Top of page

End point title

Rescue Medication Usage

End point description

All subjectswere given salbutamol/albuterol to use as rescue medication throughout the study along with e-Diary to record rescue medication use. The number of puffs of rescue medication during the past 12 hours is recorded twice (morning/evening) by the subjects prior to taking study medication. The mean daily number of puffs of rescue medication use will be calculated for each subjects, done separately for morning (night-time), evening (daytime), and daily (night-time plus daytime) rescue medication use. FAS consisted of all subjects in the RAN set who received at least one dose of study medication. no. represents number. NT represents night time. dly represents daily DT represents day time

End point type

Secondary

End point timeframe

Up to Weeks 26 and 52

End point values	QMF149 150/320 μg	QMF149 150/160 μg	MF 800 μg	MF 400 μg	Salmeterol /fluticasone 50/500 μg
Number of subjects analysed	443 ^[71]	437 ^[72]	440 ^[73]	443 ^[74]	444 ^[75]
Units: number of puffs
least squares mean (standard error)
Week1-26 Mean NT no. of puff n=418,419,430,422,426	-0.38 ( 0.028 )	-0.27 ( 0.028 )	-0.26 ( 0.028 )	-0.19 ( 0.028 )	-0.34 ( 0.028 )
Week1-26 Mean DT no. of puff n=417,420,427,419,424	-0.57 ( 0.035 )	-0.46 ( 0.035 )	-0.38 ( 0.035 )	-0.34 ( 0.035 )	-0.53 ( 0.035 )
Week1-26Mean dly no. of puff n=426,428,433,428,432	-0.96 ( 0.059 )	-0.73 ( 0.059 )	-0.65 ( 0.059 )	-0.53 ( 0.059 )	-0.87 ( 0.059 )
Week1-52Mean NT no. of puff n=415,420,428,422,424	-0.40 ( 0.029 )	-0.30 ( 0.029 )	-0.29 ( 0.028 )	-0.20 ( 0.029 )	-0.35 ( 0.029 )
Week1-52 Mean DT no. of puff n=416,420,425,419,423	-0.60 ( 0.035 )	-0.51 ( 0.035 )	-0.43 ( 0.035 )	-0.36 ( 0.035 )	-0.55 ( 0.035 )
Week1-52Mean dly no. of puff n=426,428,433,428,432	-1.00 ( 0.060 )	-0.80 ( 0.060 )	-0.72 ( 0.060 )	-0.56 ( 0.060 )	-0.91 ( 0.060 )

Notes
[71] - n represents number of subjects analysed at the given time point.
[72] - n represents number of subjects analysed at the given time point.
[73] - n represents number of subjects analysed at the given time point.
[74] - n represents number of subjects analysed at the given time point.
[75] - n represents number of subjects analysed at the given time point.

Week1-26 Mean NT QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

883

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.001

Method

LMM

Parameter type

LS Mean

Point estimate

-0.13

Confidence interval

level

95%

sides

2-sided

lower limit

-0.2

upper limit

-0.05

Variability estimate

Standard error of the mean

Dispersion value

0.039

Week1-26 Mean NT QMF149 150/160 μg vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

880

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.035

Method

LMM

Parameter type

LS Mean

Point estimate

-0.08

Confidence interval

level

95%

sides

2-sided

lower limit

-0.16

upper limit

-0.01

Variability estimate

Standard error of the mean

Dispersion value

0.039

Week1-26 Mean NT QMF149 150/320 μg vs S/F 50/500μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

887

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.261

Method

LMM

Parameter type

LS Mean

Point estimate

-0.04

Confidence interval

level

95%

sides

2-sided

lower limit

-0.12

upper limit

0.03

Variability estimate

Standard error of the mean

Dispersion value

0.039

Week1-26 Mean DT QMF149 150/320 μg vs MF 800μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

883

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

LMM

Parameter type

LS Mean

Point estimate

-0.19

Confidence interval

level

95%

sides

2-sided

lower limit

-0.28

upper limit

-0.09

Variability estimate

Standard error of the mean

Dispersion value

0.047

Week1-26 Mean DT QMF149 150/160 μg vs MF 400μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

880

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.011

Method

LMM

Parameter type

LS Mean

Point estimate

-0.12

Confidence interval

level

95%

sides

2-sided

lower limit

-0.21

upper limit

-0.03

Variability estimate

Standard error of the mean

Dispersion value

0.047

Week1-26 Mean DT QMF149 150/320 μg vs S/F 50/500μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

887

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.425

Method

LMM

Parameter type

LS Mean

Point estimate

-0.04

Confidence interval

level

95%

sides

2-sided

lower limit

-0.13

upper limit

0.06

Variability estimate

Standard error of the mean

Dispersion value

0.047

Week1-26 Mean dly QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

883

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

LMM

Parameter type

LS Mean

Point estimate

-0.31

Confidence interval

level

95%

sides

2-sided

lower limit

-0.46

upper limit

-0.15

Variability estimate

Standard error of the mean

Dispersion value

0.081

Week1-26 Mean dly QMF149 150/160 μg vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

880

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.017

Method

LMM

Parameter type

LS Mean

Point estimate

-0.19

Confidence interval

level

95%

sides

2-sided

lower limit

-0.35

upper limit

-0.03

Variability estimate

Standard error of the mean

Dispersion value

0.081

Week1-26 Mean dly QMF149 150/320μg v S/F 50/500μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

887

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.29

Method

LMM

Parameter type

LS Mean

Point estimate

-0.09

Confidence interval

level

95%

sides

2-sided

lower limit

-0.24

upper limit

-0.07

Variability estimate

Standard error of the mean

Dispersion value

0.081

Week1-52 Mean NT QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

883

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.004

Method

LMM

Parameter type

LS Mean

Point estimate

-0.11

Confidence interval

level

95%

sides

2-sided

lower limit

-0.19

upper limit

-0.04

Variability estimate

Standard error of the mean

Dispersion value

0.039

Week1-52 Mean NT QMF149 150/160 μg vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

880

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.019

Method

LMM

Parameter type

LS Mean

Point estimate

-0.09

Confidence interval

level

95%

sides

2-sided

lower limit

-0.17

upper limit

-0.02

Variability estimate

Standard error of the mean

Dispersion value

0.039

Week1-52 Mean NT QMF149 150/320 μg vs S/F 50/500μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

887

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.226

Method

LMM

Parameter type

LS Mean

Point estimate

-0.05

Confidence interval

level

95%

sides

2-sided

lower limit

-0.12

upper limit

0.03

Variability estimate

Standard error of the mean

Dispersion value

0.039

Week1-52 Mean DT QMF149 150/320 μg vs MF 800μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

883

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

LMM

Parameter type

LS Mean

Point estimate

-0.17

Confidence interval

level

95%

sides

2-sided

lower limit

-0.26

upper limit

-0.07

Variability estimate

Standard error of the mean

Dispersion value

0.048

Week1-52 Mean DT QMF149 150/160 μg vs MF 400μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

880

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.002

Method

LMM

Parameter type

LS Mean

Point estimate

-0.15

Confidence interval

level

95%

sides

2-sided

lower limit

-0.24

upper limit

-0.05

Variability estimate

Standard error of the mean

Dispersion value

0.048

Week1-52 Mean DT QMF149 150/320 μg vs S/F 50/500μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

887

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.384

Method

LMM

Parameter type

LS Mean

Point estimate

-0.04

Confidence interval

level

95%

sides

2-sided

lower limit

-0.14

upper limit

0.05

Variability estimate

Standard error of the mean

Dispersion value

0.048

Week1-52 Mean dly QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

883

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

LMM

Parameter type

LS Mean

Point estimate

-0.28

Confidence interval

level

95%

sides

2-sided

lower limit

-0.44

upper limit

-0.12

Variability estimate

Standard error of the mean

Dispersion value

0.081

Week1-52 Mean dly QMF149 150/160 μg vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

880

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.004

Method

LMM

Parameter type

LS Mean

Point estimate

-0.23

Confidence interval

level

95%

sides

2-sided

lower limit

-0.39

upper limit

-0.07

Variability estimate

Standard error of the mean

Dispersion value

0.081

Week1-52 Mean dly QMF149 150/320μg v S/F 50/500μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

887

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.245

Method

LMM

Parameter type

LS Mean

Point estimate

-0.09

Confidence interval

level

95%

sides

2-sided

lower limit

-0.25

upper limit

0.06

Variability estimate

Standard error of the mean

Dispersion value

0.081

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

The exacerbation categories were: All (mild, moderate and severe) and combination of moderate or severe and severe. FAS consisted of all subjects in the RAN set who received at least one dose of study medication. Mod represents moderate, sev represents severe, asth represents asthma and exa represents exacerbation.

End point type

Secondary

End point timeframe

Up to Week 52

End point values	QMF149 150/320 μg	QMF149 150/160 μg	MF 800 μg	MF 400 μg	Salmeterol /fluticasone 50/500 μg
Number of subjects analysed	443 ^[76]	437 ^[77]	440 ^[78]	443 ^[79]	444 ^[80]
Units: days
median (full range (min-max))
Moderate or severe asthma exacerbation	366.0 (2 to 389)	366.0 (1 to 429)	366.0 (2 to 390)	364.0 (2 to 402)	366.0 (2 to 395)
Severe asthma exacerbation	367.0 (2 to 389)	366.0 (1 to 429)	366.0 (2 to 390)	366.0 (2 to 402)	366.0 (3 to 395)
All (mild, moderate or severe) asthma exacerbation	366.0 (2 to 389)	366.0 (1 to 429)	364.5 (2 to 390)	306.0 (2 to 402)	365.0 (2 to 394)

Notes
[76] - Subjects analysed is number of subjects with data available for this endpoint point.
[77] - Subjects analysed is number of subjects with data available for this endpoint point.
[78] - Subjects analysed is number of subjects with data available for this endpoint point.
[79] - Subjects analysed is number of subjects with data available for this endpoint point.
[80] - Subjects analysed is number of subjects with data available for this endpoint point.

Mod or sev asth exa:QMF149 150/320 μg v MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

883

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.53

Confidence interval

level

95%

sides

2-sided

lower limit

0.39

upper limit

0.72

Mod or sev asth exa:QMF149 150/160 μg v MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

880

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.45

Confidence interval

level

95%

sides

2-sided

lower limit

0.34

upper limit

0.6

Mod or sev asth exa:QMF149 150/160μg vS/F 50/500μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

887

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.209

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.81

Confidence interval

level

95%

sides

2-sided

lower limit

0.59

upper limit

1.12

Sev asth exa:QMF149 150/320 μg v MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

883

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.003

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.54

Confidence interval

level

95%

sides

2-sided

lower limit

0.36

upper limit

0.81

Sev asth exa:QMF149 150/160 μg v MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

880

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.44

Confidence interval

level

95%

sides

2-sided

lower limit

0.3

upper limit

0.63

Sev asth exa:QMF149 150/320 μg v S/F 50/500 μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

887

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.115

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.71

Confidence interval

level

95%

sides

2-sided

lower limit

0.47

upper limit

1.09

All asth exa :QMF149 150/320 μg v MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

883

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.65

Confidence interval

level

95%

sides

2-sided

lower limit

0.51

upper limit

0.82

All asth exa :QMF149 150/160 μg v MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

880

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.48

Confidence interval

level

95%

sides

2-sided

lower limit

0.38

upper limit

0.6

All asth exa:QMF149 150/320 μg v S/F 50/500 μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

887

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.185

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.84

Confidence interval

level

95%

sides

2-sided

lower limit

0.66

upper limit

1.08

Secondary: Time to First Hospitalization for Asthma Exacerbation

Top of page

End point title

Time to First Hospitalization for Asthma Exacerbation

End point description

End point type

Secondary

End point timeframe

Up to Week 52

End point values	QMF149 150/320 μg	QMF149 150/160 μg	MF 800 μg	MF 400 μg	Salmeterol /fluticasone 50/500 μg
Number of subjects analysed	443 ^[81]	437 ^[82]	440 ^[83]	443 ^[84]	444 ^[85]
Units: days
median (full range (min-max))	367 (2 to 389)	367 (1 to 429)	367 (2 to 390)	366 (2 to 402)	367 (3 to 395)

Notes
[81] - Subjects analysed is number of subjects with data available for this endpoint point.
[82] - Subjects analysed is number of subjects with data available for this endpoint point.
[83] - Subjects analysed is number of subjects with data available for this endpoint point.
[84] - Subjects analysed is number of subjects with data available for this endpoint point.
[85] - Subjects analysed is number of subjects with data available for this endpoint point.

QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

883

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.337

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.51

Confidence interval

level

95%

sides

2-sided

lower limit

0.13

upper limit

2.03

QMF149 150/160 μg vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

880

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.063

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.14

Confidence interval

level

95%

sides

2-sided

lower limit

0.02

upper limit

1.11

QMF149 150/320 μg vs S/F 50/500 μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

887

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.599

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.62

Confidence interval

level

95%

sides

2-sided

lower limit

0.27

upper limit

9.7

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

End point type

Secondary

End point timeframe

Up to Week 52

End point values	QMF149 150/320 μg	QMF149 150/160 μg	MF 800 μg	MF 400 μg	Salmeterol /fluticasone 50/500 μg
Number of subjects analysed	443 ^[86]	437 ^[87]	440 ^[88]	443 ^[89]	444 ^[90]
Units: rate of exacerbations per year
number (confidence interval 95%)
Moderate or severe asthma exacerbation	0.25 (0.20 to 0.32)	0.27 (0.21 to 0.34)	0.39 (0.32 to 0.48)	0.56 (0.46 to 0.68)	0.27 (0.22 to 0.34)
Severe asthma exacerbation	0.13 (0.09 to 0.17)	0.13 (0.10 to 0.18)	0.18 (0.13 to 0.23)	0.29 (0.23 to 0.38)	0.14 (0.10 to 0.19)
All (mild, moderate,severe) asthma exacerbation	0.49 (0.41 to 0.60)	0.48 (0.40 to 0.59)	0.74 (0.62 to 0.88)	1.05 (0.89 to 1.24)	0.52 (0.43 to 0.63)

Notes
[86] - Subjects analysed is number of subjects with data available for this endpoint point.
[87] - Subjects analysed is number of subjects with data available for this endpoint point.
[88] - Subjects analysed is number of subjects with data available for this endpoint point.
[89] - Subjects analysed is number of subjects with data available for this endpoint point.
[90] - Subjects analysed is number of subjects with data available for this endpoint point.

Mod or sev asth exa:QMF149 150/320 μg v MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

883

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.008

Method

Generalized linear model

Parameter type

Rate ratio

Point estimate

0.65

Confidence interval

level

95%

sides

2-sided

lower limit

0.48

upper limit

0.89

Mod or sev asth exa:QMF149 150/160 μg v MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

880

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Generalized linear model

Parameter type

Rate ratio

Point estimate

0.47

Confidence interval

level

95%

sides

2-sided

lower limit

0.35

upper limit

0.64

Mod or sev asth exa:QMF149 150/320μg vS/F 50/500μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

887

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.669

Method

Generalized linear model

Parameter type

Rate ratio

Point estimate

0.93

Confidence interval

level

95%

sides

2-sided

lower limit

0.67

upper limit

1.29

Sev asth exa:QMF149 150/320 μg v MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

883

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.108

Method

Generalized linear model

Parameter type

Rate ratio

Point estimate

0.71

Confidence interval

level

95%

sides

2-sided

lower limit

0.47

upper limit

1.08

Sev asth exa:QMF149 150/160 μg v MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

880

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Generalized linear model

Parameter type

Rate ratio

Point estimate

0.46

Confidence interval

level

95%

sides

2-sided

lower limit

0.31

upper limit

0.67

Sev asth exa:QMF149 150/320 μg v S/F 50/500 μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

887

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.597

Method

Generalized linear model

Parameter type

Rate ratio

Point estimate

0.89

Confidence interval

level

95%

sides

2-sided

lower limit

0.58

upper limit

1.37

All asth exa :QMF149 150/320 μg v MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

883

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.002

Method

Generalized linear model

Parameter type

Rate ratio

Point estimate

0.67

Confidence interval

level

95%

sides

2-sided

lower limit

0.52

upper limit

0.87

All asth exa :QMF149 150/160 μg v MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

880

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Generalized linear model

Parameter type

Rate ratio

Point estimate

0.46

Confidence interval

level

95%

sides

2-sided

lower limit

0.36

upper limit

0.59

All asth exa:QMF149 150/320 μg v S/F 50/500 μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

887

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.681

Method

Generalized linear model

Parameter type

Rate ratio

Point estimate

0.95

Confidence interval

level

95%

sides

2-sided

lower limit

0.72

upper limit

1.23

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

End point type

Secondary

End point timeframe

Up to Week 52

End point values	QMF149 150/320 μg	QMF149 150/160 μg	MF 800 μg	MF 400 μg	Salmeterol /fluticasone 50/500 μg
Number of subjects analysed	443 ^[91]	437 ^[92]	440 ^[93]	443 ^[94]	444 ^[95]
Units: days
arithmetic mean (standard deviation)
Moderate or severe asthma exacerbation	2.6 ( 10.60 )	3.0 ( 12.53 )	3.7 ( 11.40 )	5.8 ( 13.98 )	3.1 ( 9.68 )
Severe asthma exacerbation	1.3 ( 6.02 )	1.7 ( 8.48 )	1.7 ( 6.07 )	3.2 ( 9.16 )	1.9 ( 7.76 )
All (mild, moderate, severe) asthma exacerbation	5.4 ( 18.81 )	5.0 ( 17.55 )	6.9 ( 22.96 )	10.1 ( 25.15 )	5.1 ( 14.48 )

Notes
[91] - Subjects analysed is number of subjects with data available for this endpoint point.
[92] - Subjects analysed is number of subjects with data available for this endpoint point.
[93] - Subjects analysed is number of subjects with data available for this endpoint point.
[94] - Subjects analysed is number of subjects with data available for this endpoint point.
[95] - Subjects analysed is number of subjects with data available for this endpoint point.

Mod or sev asth exa:QMF149 150/320 μg v MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

883

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Van Elteren Test

Confidence interval

Mod or sev asth exa:QMF149 150/160 μg v MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

880

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Van Elteren Test

Confidence interval

Mod or sev asth exa:QMF149 150/160μg vS/F 50/500μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

887

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.059

Method

Van Elteren Test

Confidence interval

Sev asth exa:QMF149 150/320 μg v MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

883

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.004

Method

van Elteren test

Confidence interval

Sev asth exa:QMF149 150/160 μg v MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

880

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

van Elteren test

Confidence interval

Sev asth exa:QMF149 150/320 μg v S/F 50/500 μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

887

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.025

Method

van Elteren test

Confidence interval

All asth exa :QMF149 150/320 μg v MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

883

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.002

Method

van Elteren test

Confidence interval

All asth exa :QMF149 150/160 μg v MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

880

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

van Elteren test

Confidence interval

All asth exa:QMF149 150/320 μg v S/F 50/500 μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

887

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.074

Method

van Elteren test

Confidence interval

Secondary: Percentage of Subjects With at Least One Asthma Exacerbation by Exacerbation Category

Top of page

End point title

Percentage of Subjects With at Least One Asthma Exacerbation by Exacerbation Category

End point description

End point type

Secondary

End point timeframe

Up to Week 52

End point values	QMF149 150/320 μg	QMF149 150/160 μg	MF 800 μg	MF 400 μg	Salmeterol /fluticasone 50/500 μg
Number of subjects analysed	443	437	440	443	444
Units: percentage of subjects
number (not applicable)
Moderate or severe asthma exacerbation	14.9	16.9	26.1	32.5	19.1
Severe asthma exacerbation	8.1	9.8	14.5	20.1	11.9
Moderate asthma exacerbation	7.7	8.2	14.3	16.5	9.2
Mild asthma exacerbation	13.3	12.1	17.5	19.6	15.1
All (mild, moderate, severe) asthma exacerbation	25.5	25.6	36.1	44.5	30.6

No statistical analyses for this end point

Secondary: Time in Days to Permanent Discontinuation of Study Medication Due to Asthma Exacerbations

Top of page

End point title

Time in Days to Permanent Discontinuation of Study Medication Due to Asthma Exacerbations

End point description

End point type

Secondary

End point timeframe

Up to Week 52

End point values	QMF149 150/320 μg	QMF149 150/160 μg	MF 800 μg	MF 400 μg	Salmeterol /fluticasone 50/500 μg
Number of subjects analysed	443 ^[96]	437 ^[97]	440 ^[98]	443 ^[99]	444 ^[100]
Units: days
median (full range (min-max))	367 (2 to 389)	367 (1 to 429)	367 (2 to 390)	366 (2 to 402)	367 (3 to 395)

Notes
[96] - Subjects analysed is number of subjects with data available for this endpoint point.
[97] - Subjects analysed is number of subjects with data available for this endpoint point.
[98] - Subjects analysed is number of subjects with data available for this endpoint point.
[99] - Subjects analysed is number of subjects with data available for this endpoint point.
[100] - Subjects analysed is number of subjects with data available for this endpoint point.

QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

883

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.222

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.26

Confidence interval

level

95%

sides

2-sided

lower limit

0.03

upper limit

2.29

QMF149 150/160 μg vs MF 400 μg

Statistical analysis description

99999 indicates upper limit of CI and it was not estimable.

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

880

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.992

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

99999

QMF149 150/320 μg vs S/F 50/500 μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

887

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.618

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.54

Confidence interval

level

95%

sides

2-sided

lower limit

0.05

upper limit

6.01

Secondary: Percentage of Subjects Who Permanently Discontinued Study Medication Due to Asthma Exacerbations

Top of page

End point title

Percentage of Subjects Who Permanently Discontinued Study Medication Due to Asthma Exacerbations

End point description

FAS consisted of all subjects in the RAN set who received at least one dose of study medication.

End point type

Secondary

End point timeframe

Up to Week 52

End point values	QMF149 150/320 μg	QMF149 150/160 μg	MF 800 μg	MF 400 μg	Salmeterol /fluticasone 50/500 μg
Number of subjects analysed	443 ^[101]	437 ^[102]	440 ^[103]	443 ^[104]	444 ^[105]
Units: percentage of subjects
number (not applicable)	0.2	0	0.9	1.6	0.5

Notes
[101] - Subjects analysed is number of subjects with data available for this endpoint point.
[102] - Subjects analysed is number of subjects with data available for this endpoint point.
[103] - Subjects analysed is number of subjects with data available for this endpoint point.
[104] - Subjects analysed is number of subjects with data available for this endpoint point.
[105] - Subjects analysed is number of subjects with data available for this endpoint point.

No statistical analyses for this end point

Secondary: Total Amounts of Systemic Corticosteroids (in Doses) Used to Treat Asthma Exacerbations

Top of page

End point title

Total Amounts of Systemic Corticosteroids (in Doses) Used 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 subject could return to the study after successfully completing a taper of approximately 7-10 days. FAS consisted of all subjects in the RAN set who received at least one dose of study medication.

End point type

Secondary

End point timeframe

Up to Week 52

End point values	QMF149 150/320 μg	QMF149 150/160 μg	MF 800 μg	MF 400 μg	Salmeterol /fluticasone 50/500 μg
Number of subjects analysed	443 ^[106]	437 ^[107]	440 ^[108]	443 ^[109]	444 ^[110]
Units: milligram(s)
arithmetic mean (standard deviation)	26 ( 136.92 )	29.9 ( 124.98 )	28 ( 95.18 )	47.8 ( 139.98 )	26.9 ( 114.36 )

Notes
[106] - Subjects analysed is number of subjects with data available for this endpoint point.
[107] - Subjects analysed is number of subjects with data available for this endpoint point.
[108] - Subjects analysed is number of subjects with data available for this endpoint point.
[109] - Subjects analysed is number of subjects with data available for this endpoint point.
[110] - Subjects analysed is number of subjects with data available for this endpoint point.

No statistical analyses for this end point

Secondary: Change From Baseline in Percentage of Rescue Medication Free Days

Top of page

End point title

Change From Baseline in Percentage of Rescue Medication Free Days

End point description

All subjects 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 subject did not use any puffs of rescue medication during daytime and night-time. FAS consisted of all subjects in the RAN set who received at least one dose of study medication.

End point type

Secondary

End point timeframe

Up to Weeks 26 and 52

End point values	QMF149 150/320 μg	QMF149 150/160 μg	MF 800 μg	MF 400 μg	Salmeterol /fluticasone 50/500 μg
Number of subjects analysed	443 ^[111]	437 ^[112]	440 ^[113]	443 ^[114]	444 ^[115]
Units: percentage of days
least squares mean (standard error)
Weeks 1-26 (n=412, 416, 424, 414, 421)	31.5 ( 1.53 )	27.4 ( 1.53 )	21.4 ( 1.52 )	19.1 ( 1.53 )	27.4 ( 1.52 )
Weeks 1-52 (n=408, 416, 420, 414, 416)	33.1 ( 1.55 )	29.4 ( 1.54 )	23.5 ( 1.54 )	20.8 ( 1.54 )	28.8 ( 1.54 )

Notes
[111] - n= Number of subjects analysed at the given time point.
[112] - n= Number of subjects analysed at the given time point.
[113] - n= Number of subjects analysed at the given time point.
[114] - n= Number of subjects analysed at the given time point.
[115] - n= Number of subjects analysed at the given time point.

Weeks 1-26: QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

883

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Linear Mixed Model (LMM)

Parameter type

LS Mean

Point estimate

10.1

Confidence interval

level

95%

sides

2-sided

lower limit

6.2

upper limit

14.1

Variability estimate

Standard error of the mean

Dispersion value

2.02

Weeks 1-26: QMF149 150/160 μg vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

880

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

LMM

Parameter type

LS Mean

Point estimate

8.3

Confidence interval

level

95%

sides

2-sided

lower limit

4.3

upper limit

12.3

Variability estimate

Standard error of the mean

Dispersion value

2.02

Weeks 1-26: QMF149 150/320 μg vs S/F 50/500 μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

887

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.045

Method

LMM

Parameter type

LS Mean

Point estimate

4.1

Confidence interval

level

95%

sides

2-sided

lower limit

0.1

upper limit

Variability estimate

Standard error of the mean

Dispersion value

2.02

Weeks 1-52: QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

883

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

LMM

Parameter type

LS Mean

Point estimate

9.6

Confidence interval

level

95%

sides

2-sided

lower limit

5.7

upper limit

13.6

Variability estimate

Standard error of the mean

Dispersion value

2.03

Weeks 1-52: QMF149 150/160 μg vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

880

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

LMM

Parameter type

LS Mean

Point estimate

8.6

Confidence interval

level

95%

sides

2-sided

lower limit

4.7

upper limit

12.6

Variability estimate

Standard error of the mean

Dispersion value

2.03

Weeks 1-52: QMF149 150/320 μg vs S/F 50/500 μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

887

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.034

Method

LMM

Parameter type

LS Mean

Point estimate

4.3

Confidence interval

level

95%

sides

2-sided

lower limit

0.3

upper limit

8.3

Variability estimate

Standard error of the mean

Dispersion value

2.04

Secondary: Asthma Quality of Life Questionnaire (AQLQ)

Top of page

End point title

Asthma Quality of Life Questionnaire (AQLQ)

End point description

AQLQ is a 32-item disease specific questionnaire designed to measure functional impairments that are most important to subjects 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) FAS consisted of all subjects in the RAN set who received at least one dose of study medication.

End point type

Secondary

End point timeframe

Up to Week 52 (Day 364)

End point values	QMF149 150/320 μg	QMF149 150/160 μg	MF 800 μg	MF 400 μg	Salmeterol /fluticasone 50/500 μg
Number of subjects analysed	428 ^[116]	426 ^[117]	431 ^[118]	428 ^[119]	438 ^[120]
Units: score on a scale
least squares mean (standard error)
Day 30 (n=427, 423, 430, 425, 436)	5.560 ( 0.0327 )	5.498 ( 0.0328 )	5.413 ( 0.0326 )	5.374 ( 0.0327 )	5.515 ( 0.0324 )
Day 86 (n=419, 416, 422, 406, 428)	5.618 ( 0.0356 )	5.629 ( 0.0357 )	5.564 ( 0.0355 )	5.510 ( 0.0359 )	5.592 ( 0.0352 )
Day 183 (n=406, 407, 405, 393, 410)	5.724 ( 0.0372 )	5.738 ( 0.0372 )	5.598 ( 0.0372 )	5.581 ( 0.0376 )	5.639 ( 0.0369 )
Day 254 (n=392, 395, 388, 385, 405)	5.761 ( 0.0383 )	5.781 ( 0.0382 )	5.689 ( 0.0383 )	5.614 ( 0.0386 )	5.700 ( 0.0378 )
Day 364 (n=384, 397, 389, 378, 405)	5.783 ( 0.0391 )	5.832 ( 0.0388 )	5.705 ( 0.0389 )	5.641 ( 0.0394 )	5.742 ( 0.0384 )

Notes
[116] - n= Number of subjects analysed at the given time point.
[117] - n= Number of subjects analysed at the given time point.
[118] - n= Number of subjects analysed at the given time point.
[119] - n= Number of subjects analysed at the given time point.
[120] - n= Number of subjects analysed at the given time point.

Day 30: QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

859

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.002

Method

MMRM

Parameter type

LS Mean

Point estimate

0.147

Confidence interval

level

95%

sides

2-sided

lower limit

0.056

upper limit

0.237

Variability estimate

Standard error of the mean

Dispersion value

0.0462

Day 30: QMF149 150/160 μg vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

854

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.008

Method

MMRM

Parameter type

LS Mean

Point estimate

0.123

Confidence interval

level

95%

sides

2-sided

lower limit

0.032

upper limit

0.214

Variability estimate

Standard error of the mean

Dispersion value

0.0464

Day 30: QMF149 150/320 μg vs S/F 50/500 μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

866

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.33

Method

MMRM

Parameter type

LS Mean

Point estimate

0.045

Confidence interval

level

95%

sides

2-sided

lower limit

-0.045

upper limit

0.135

Variability estimate

Standard error of the mean

Dispersion value

0.046

Day 86: QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

859

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.28

Method

MMRM

Parameter type

LS Mean

Point estimate

0.054

Confidence interval

level

95%

sides

2-sided

lower limit

-0.044

upper limit

0.153

Variability estimate

Standard error of the mean

Dispersion value

0.0503

Day 86: QMF149 150/160 μg vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

854

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.02

Method

MMRM

Parameter type

LS Mean

Point estimate

0.118

Confidence interval

level

95%

sides

2-sided

lower limit

0.019

upper limit

0.217

Variability estimate

Standard error of the mean

Dispersion value

0.0507

Day 86: QMF149 150/320 μg vs S/F 50/500 μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

866

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.598

Method

MMRM

Parameter type

LS Mean

Point estimate

0.026

Confidence interval

level

95%

sides

2-sided

lower limit

-0.072

upper limit

0.125

Variability estimate

Standard error of the mean

Dispersion value

0.0501

Day 183: QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

859

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.016

Method

MMRM

Parameter type

LS Mean

Point estimate

0.127

Confidence interval

level

95%

sides

2-sided

lower limit

0.023

upper limit

0.23

Variability estimate

Standard error of the mean

Dispersion value

0.0526

Day 183: QMF149 150/160 μg vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

854

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.003

Method

MMRM

Parameter type

LS Mean

Point estimate

0.156

Confidence interval

level

95%

sides

2-sided

lower limit

0.053

upper limit

0.26

Variability estimate

Standard error of the mean

Dispersion value

0.0529

Day 183: QMF149 150/320 μg vs S/F 50/500 μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

866

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.103

Method

MMRM

Parameter type

LS Mean

Point estimate

0.085

Confidence interval

level

95%

sides

2-sided

lower limit

-0.017

upper limit

0.188

Variability estimate

Standard error of the mean

Dispersion value

0.0525

Day 254: QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

859

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.188

Method

MMRM

Parameter type

LS Mean

Point estimate

0.071

Confidence interval

level

95%

sides

2-sided

lower limit

-0.035

upper limit

0.178

Variability estimate

Standard error of the mean

Dispersion value

0.0542

Day 254: QMF149 150/160 μg vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

854

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.002

Method

MMRM

Parameter type

LS Mean

Point estimate

0.168

Confidence interval

level

95%

sides

2-sided

lower limit

0.061

upper limit

0.274

Variability estimate

Standard error of the mean

Dispersion value

0.0543

Day 254: QMF149 150/320 μg vs S/F 50/500 μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

866

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.258

Method

MMRM

Parameter type

LS Mean

Point estimate

0.061

Confidence interval

level

95%

sides

2-sided

lower limit

-0.045

upper limit

0.166

Variability estimate

Standard error of the mean

Dispersion value

0.0538

Day 364: QMF149 150/320 μg vs MF 800 μg

Comparison groups

QMF149 150/320 μg v MF 800 μg

Number of subjects included in analysis

859

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.154

Method

MMRM

Parameter type

LS Mean

Point estimate

0.079

Confidence interval

level

95%

sides

2-sided

lower limit

-0.03

upper limit

0.187

Variability estimate

Standard error of the mean

Dispersion value

0.0552

Day 364: QMF149 150/160 μg vs MF 400 μg

Comparison groups

QMF149 150/160 μg v MF 400 μg

Number of subjects included in analysis

854

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

MMRM

Parameter type

LS Mean

Point estimate

0.191

Confidence interval

level

95%

sides

2-sided

lower limit

0.082

upper limit

0.299

Variability estimate

Standard error of the mean

Dispersion value

0.0553

Day 364: QMF149 150/320 μg vs S/F 50/500 μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

866

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.455

Method

MMRM

Parameter type

LS Mean

Point estimate

0.041

Confidence interval

level

95%

sides

2-sided

lower limit

-0.067

upper limit

0.148

Variability estimate

Standard error of the mean

Dispersion value

0.0548

Secondary: Trough FEV1 Measured After 26 Weeks of Treatment

Top of page

End point title

Trough FEV1 Measured After 26 Weeks of Treatment ^[121]

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. FAS consisted of all subjects in the RAN set who received at least one dose of study medication.

End point type

Secondary

End point timeframe

Week 26

Notes
[121] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The arm groups QMF149 150/320 μg and Salmeterol/fluticasone 50/500 μg were planned to be reported for this endpoint.

End point values	QMF149 150/320 μg	Salmeterol /fluticasone 50/500 μg
Number of subjects analysed	395 ^[122]	391 ^[123]
Units: litre(s)
least squares mean (standard error)	2.383 ( 0.0159 )	2.346 ( 0.0160 )

Notes
[122] - Subjects analysed is number of subjects with data available for this endpoint point.
[123] - Subjects analysed is number of subjects with data available for this endpoint point.

QMF149 150/320 μg vs S/F 50/500 μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

786

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.101

Method

MMRM

Parameter type

LS Mean

Point estimate

0.036

Confidence interval

level

95%

sides

2-sided

lower limit

-0.007

upper limit

0.08

Variability estimate

Standard error of the mean

Dispersion value

0.0222

Secondary: Asthma Control as Assessed by the ACQ-7 After 26 Weeks Treatment

Top of page

End point title

Asthma Control as Assessed by the ACQ-7 After 26 Weeks Treatment ^[124]

End point description

End point type

Secondary

End point timeframe

Week 26

Notes
[124] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The arm groups QMF149 150/320 μg and Salmeterol/fluticasone 50/500 μg were planned to be reported for this endpoint.

End point values	QMF149 150/320 μg	Salmeterol /fluticasone 50/500 μg
Number of subjects analysed	407 ^[125]	410 ^[126]
Units: score on a scale
least squares mean (standard error)	1.267 ( 0.0350 )	1.322 ( 0.0349 )

Notes
[125] - Subjects analysed is number of subjects with data available for this endpoint point.
[126] - Subjects analysed is number of subjects with data available for this endpoint point.

QMF149 150/320 μg vs S/F 50/500 μg

Comparison groups

QMF149 150/320 μg v Salmeterol /fluticasone 50/500 μg

Number of subjects included in analysis

817

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.214

Method

MMRM

Parameter type

LS Mean

Point estimate

-0.054

Confidence interval

level

95%

sides

2-sided

lower limit

-0.14

upper limit

0.031

Variability estimate

Standard error of the mean

Dispersion value

0.0437

Secondary: Percentage of Subjects With Composite Endpoint of Serious Asthma Outcomes

Top of page

End point title

Percentage of Subjects With Composite Endpoint of Serious Asthma Outcomes

End point description

A composite endpoint of serious asthma outcomes is defined as asthma-related hospitalisation, asthma-related intubation, or asthma-related death and was reviewed by the Adjudication Committee. Safety Set consisted of all subjects who received at least one dose of study medication.

End point type

Secondary

End point timeframe

Up to Week 52

End point values	QMF149 150/320 μg	QMF149 150/160 μg	MF 800 μg	MF 400 μg	Salmeterol /fluticasone 50/500 μg
Number of subjects analysed	443 ^[127]	437 ^[128]	440 ^[129]	443 ^[130]	444 ^[131]
Units: percentage of subjects
number (not applicable)	0.7	0.5	1.6	1.8	0.5

Notes
[127] - Subjects analysed is number of subjects with data available for this endpoint point.
[128] - Subjects analysed is number of subjects with data available for this endpoint point.
[129] - Subjects analysed is number of subjects with data available for this endpoint point.
[130] - Subjects analysed is number of subjects with data available for this endpoint point.
[131] - Subjects analysed is number of subjects with data available for this endpoint point.

No statistical analyses for this end point

Secondary: Percentage of Subjects With Adverse Events (AE) and Serious Adverse Events (SAE)

Top of page

End point title

Percentage of Subjects With Adverse Events (AE) and Serious Adverse Events (SAE)

End point description

An AE is any untoward medical occurrence (i.e., any unfavorable and unintended sign including abnormal laboratory findings, symptom or disease) in a subject or clinical investigation subject after providing written informed consent for participation in the study. An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) undesirable sign(s), symptom(s) or medical conditions(s) which meets any one of the following criteria: is fatal or life-threatening, results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect, requires in subjects hospitalization or prolongation of existing hospitalization or is medically significant, i.e. defined as an event that jeopardizes the subjects or may require medical or surgical intervention. The Safety Set consisted of all subjects who received at least one dose of study medication.

End point type

Secondary

End point timeframe

Approximately up to 56 weeks

End point values	QMF149 150/320 μg	QMF149 150/160 μg	MF 800 μg	MF 400 μg	Salmeterol /fluticasone 50/500 μg
Number of subjects analysed	443 ^[132]	437 ^[133]	440 ^[134]	443 ^[135]	444 ^[136]
Units: percentage of subjects
number (not applicable)
Adverse Events(AEs)	64.6	66.8	70.0	72.2	65.3
Serious Adverse Events(SAEs)	4.7	4.6	4.8	7.0	4.7

Notes
[132] - Subjects analysed is number of subjects with data available for this endpoint point.
[133] - Subjects analysed is number of subjects with data available for this endpoint point.
[134] - Subjects analysed is number of subjects with data available for this endpoint point.
[135] - Subjects analysed is number of subjects with data available for this endpoint point.
[136] - Subjects analysed is number of subjects with data available for this endpoint point.

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Serious adverse events: From first dose up to 30 days post last dose (approximately 56 weeks) Other adverse events: From first dose up to 7 days post last dose (approximately 53 weeks)

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

21.1

Reporting group title

QMF 150/320

Reporting group description

QMF 150/320

Reporting group title

QMF 150/160

Reporting group description

QMF 150/160

Reporting group title

MF 800

Reporting group description

MF 800

Reporting group title

MF 400

Reporting group description

MF 400

Reporting group title

S/F 50/500

Reporting group description

S/F 50/500

Serious adverse events	QMF 150/320	QMF 150/160	MF 800	MF 400	S/F 50/500
Total subjects affected by serious adverse events
subjects affected / exposed	21 / 443 (4.74%)	20 / 437 (4.58%)	21 / 440 (4.77%)	31 / 443 (7.00%)	21 / 444 (4.73%)
number of deaths (all causes)	0	0	0	1	0
number of deaths resulting from adverse events	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasm
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	1 / 443 (0.23%)	0 / 444 (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
Papillary thyroid cancer
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	0 / 443 (0.00%)	1 / 444 (0.23%)
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
Renal neoplasm
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	1 / 443 (0.23%)	0 / 444 (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
Uterine cancer
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	0 / 443 (0.00%)	1 / 444 (0.23%)
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
Uterine leiomyoma
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	1 / 443 (0.23%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Aortic dissection
subjects affected / exposed	0 / 443 (0.00%)	1 / 437 (0.23%)	0 / 440 (0.00%)	0 / 443 (0.00%)	0 / 444 (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
Hypertensive crisis
subjects affected / exposed	1 / 443 (0.23%)	0 / 437 (0.00%)	0 / 440 (0.00%)	1 / 443 (0.23%)	0 / 444 (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
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	1 / 443 (0.23%)	0 / 444 (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
Cervical dysplasia
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	1 / 443 (0.23%)	0 / 444 (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
Cervix enlargement
subjects affected / exposed	0 / 443 (0.00%)	1 / 437 (0.23%)	0 / 440 (0.00%)	0 / 443 (0.00%)	0 / 444 (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
Endometrial hyperplasia
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	1 / 443 (0.23%)	0 / 444 (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
Endometriosis
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	0 / 443 (0.00%)	1 / 444 (0.23%)
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
Metrorrhagia
subjects affected / exposed	0 / 443 (0.00%)	1 / 437 (0.23%)	0 / 440 (0.00%)	0 / 443 (0.00%)	0 / 444 (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
Vaginal prolapse
subjects affected / exposed	0 / 443 (0.00%)	1 / 437 (0.23%)	0 / 440 (0.00%)	0 / 443 (0.00%)	0 / 444 (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
Respiratory, thoracic and mediastinal disorders
Asphyxia
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	1 / 443 (0.23%)	0 / 444 (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 / 1	0 / 0
Asthma
subjects affected / exposed	3 / 443 (0.68%)	2 / 437 (0.46%)	6 / 440 (1.36%)	8 / 443 (1.81%)	2 / 444 (0.45%)
occurrences causally related to treatment / all	1 / 4	0 / 2	0 / 6	0 / 8	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Atelectasis
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	1 / 443 (0.23%)	0 / 444 (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
Chronic rhinosinusitis with nasal polyps
subjects affected / exposed	0 / 443 (0.00%)	1 / 437 (0.23%)	1 / 440 (0.23%)	0 / 443 (0.00%)	0 / 444 (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
Haemothorax
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	1 / 443 (0.23%)	0 / 444 (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
Hydrothorax
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	1 / 443 (0.23%)	0 / 444 (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 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	0 / 443 (0.00%)	1 / 444 (0.23%)
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
Nasal septum deviation
subjects affected / exposed	0 / 443 (0.00%)	1 / 437 (0.23%)	0 / 440 (0.00%)	0 / 443 (0.00%)	0 / 444 (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
Pleurisy
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	1 / 440 (0.23%)	0 / 443 (0.00%)	0 / 444 (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
Pulmonary mass
subjects affected / exposed	0 / 443 (0.00%)	1 / 437 (0.23%)	0 / 440 (0.00%)	0 / 443 (0.00%)	0 / 444 (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
Psychiatric disorders
Depression
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	0 / 443 (0.00%)	1 / 444 (0.23%)
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
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	1 / 440 (0.23%)	1 / 443 (0.23%)	0 / 444 (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
Aspartate aminotransferase increased
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	1 / 443 (0.23%)	0 / 444 (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
Blood bilirubin increased
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	0 / 443 (0.00%)	1 / 444 (0.23%)
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
Injury, poisoning and procedural complications
Accidental device ingestion
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	1 / 443 (0.23%)	0 / 444 (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
Ankle fracture
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	1 / 443 (0.23%)	0 / 444 (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
Clavicle fracture
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	1 / 443 (0.23%)	0 / 444 (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
Concussion
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	0 / 443 (0.00%)	1 / 444 (0.23%)
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
Eye injury
subjects affected / exposed	0 / 443 (0.00%)	1 / 437 (0.23%)	0 / 440 (0.00%)	0 / 443 (0.00%)	0 / 444 (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
Forearm fracture
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	0 / 443 (0.00%)	1 / 444 (0.23%)
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
Hand fracture
subjects affected / exposed	1 / 443 (0.23%)	0 / 437 (0.00%)	0 / 440 (0.00%)	0 / 443 (0.00%)	0 / 444 (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
Head injury
subjects affected / exposed	1 / 443 (0.23%)	0 / 437 (0.00%)	0 / 440 (0.00%)	0 / 443 (0.00%)	0 / 444 (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
Humerus fracture
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	1 / 443 (0.23%)	0 / 444 (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
Ligament sprain
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	1 / 440 (0.23%)	0 / 443 (0.00%)	0 / 444 (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
Meniscus injury
subjects affected / exposed	1 / 443 (0.23%)	0 / 437 (0.00%)	0 / 440 (0.00%)	0 / 443 (0.00%)	0 / 444 (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
Postoperative wound complication
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	0 / 443 (0.00%)	1 / 444 (0.23%)
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
Radius fracture
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	1 / 440 (0.23%)	1 / 443 (0.23%)	0 / 444 (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
Rib fracture
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	2 / 443 (0.45%)	0 / 444 (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
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	2 / 443 (0.45%)	0 / 437 (0.00%)	0 / 440 (0.00%)	0 / 443 (0.00%)	1 / 444 (0.23%)
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
Atrial fibrillation
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	1 / 440 (0.23%)	0 / 443 (0.00%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	1 / 443 (0.23%)	0 / 437 (0.00%)	0 / 440 (0.00%)	1 / 443 (0.23%)	0 / 444 (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
Nervous system disorders
Cerebellar haematoma
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	1 / 440 (0.23%)	0 / 443 (0.00%)	0 / 444 (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
Cerebral infarction
subjects affected / exposed	1 / 443 (0.23%)	0 / 437 (0.00%)	1 / 440 (0.23%)	0 / 443 (0.00%)	0 / 444 (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
Headache
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	1 / 443 (0.23%)	0 / 444 (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
Hydrocephalus
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	1 / 440 (0.23%)	0 / 443 (0.00%)	0 / 444 (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
Intracranial aneurysm
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	0 / 443 (0.00%)	1 / 444 (0.23%)
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
Migraine with aura
subjects affected / exposed	0 / 443 (0.00%)	1 / 437 (0.23%)	0 / 440 (0.00%)	0 / 443 (0.00%)	0 / 444 (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
Sciatica
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	1 / 440 (0.23%)	0 / 443 (0.00%)	0 / 444 (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
Subarachnoid haemorrhage
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	0 / 443 (0.00%)	1 / 444 (0.23%)
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
Vertebral artery aneurysm
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	0 / 443 (0.00%)	1 / 444 (0.23%)
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
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	1 / 443 (0.23%)	0 / 444 (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
Corneal deposits
subjects affected / exposed	0 / 443 (0.00%)	1 / 437 (0.23%)	0 / 440 (0.00%)	0 / 443 (0.00%)	0 / 444 (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
Optic ischaemic neuropathy
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	1 / 443 (0.23%)	0 / 444 (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
Retinal detachment
subjects affected / exposed	1 / 443 (0.23%)	0 / 437 (0.00%)	0 / 440 (0.00%)	0 / 443 (0.00%)	0 / 444 (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 disorders
Abdominal hernia
subjects affected / exposed	1 / 443 (0.23%)	0 / 437 (0.00%)	0 / 440 (0.00%)	0 / 443 (0.00%)	0 / 444 (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
Abdominal pain upper
subjects affected / exposed	0 / 443 (0.00%)	1 / 437 (0.23%)	0 / 440 (0.00%)	0 / 443 (0.00%)	0 / 444 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulum intestinal
subjects affected / exposed	1 / 443 (0.23%)	0 / 437 (0.00%)	0 / 440 (0.00%)	0 / 443 (0.00%)	0 / 444 (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
Diverticulum intestinal haemorrhagic
subjects affected / exposed	0 / 443 (0.00%)	1 / 437 (0.23%)	0 / 440 (0.00%)	0 / 443 (0.00%)	0 / 444 (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
Gastric polyps
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	0 / 443 (0.00%)	1 / 444 (0.23%)
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
Gastric ulcer haemorrhage
subjects affected / exposed	0 / 443 (0.00%)	1 / 437 (0.23%)	0 / 440 (0.00%)	0 / 443 (0.00%)	0 / 444 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	1 / 440 (0.23%)	0 / 443 (0.00%)	0 / 444 (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
Inguinal hernia
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	0 / 443 (0.00%)	1 / 444 (0.23%)
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
Irritable bowel syndrome
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	1 / 443 (0.23%)	0 / 444 (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
Large intestine polyp
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	0 / 443 (0.00%)	1 / 444 (0.23%)
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
Pancreatitis acute
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	1 / 443 (0.23%)	0 / 444 (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
Peptic ulcer
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	1 / 440 (0.23%)	0 / 443 (0.00%)	0 / 444 (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
Hepatobiliary disorders
Cholecystitis acute
subjects affected / exposed	1 / 443 (0.23%)	0 / 437 (0.00%)	0 / 440 (0.00%)	0 / 443 (0.00%)	0 / 444 (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
Cholelithiasis
subjects affected / exposed	1 / 443 (0.23%)	1 / 437 (0.23%)	0 / 440 (0.00%)	0 / 443 (0.00%)	0 / 444 (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
Skin and subcutaneous tissue disorders
Angioedema
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	1 / 443 (0.23%)	0 / 444 (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
Dermatitis atopic
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	1 / 443 (0.23%)	0 / 444 (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
Renal and urinary disorders
Calculus urethral
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	1 / 440 (0.23%)	0 / 443 (0.00%)	0 / 444 (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
Hydronephrosis
subjects affected / exposed	1 / 443 (0.23%)	0 / 437 (0.00%)	0 / 440 (0.00%)	0 / 443 (0.00%)	0 / 444 (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
Hydroureter
subjects affected / exposed	1 / 443 (0.23%)	0 / 437 (0.00%)	0 / 440 (0.00%)	0 / 443 (0.00%)	0 / 444 (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
Ureteric stenosis
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	1 / 443 (0.23%)	0 / 444 (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
Ureterolithiasis
subjects affected / exposed	1 / 443 (0.23%)	0 / 437 (0.00%)	0 / 440 (0.00%)	0 / 443 (0.00%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urethral stenosis
subjects affected / exposed	0 / 443 (0.00%)	1 / 437 (0.23%)	0 / 440 (0.00%)	0 / 443 (0.00%)	0 / 444 (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
Endocrine disorders
Goitre
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	0 / 443 (0.00%)	1 / 444 (0.23%)
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
Musculoskeletal and connective tissue disorders
Arthropathy
subjects affected / exposed	1 / 443 (0.23%)	0 / 437 (0.00%)	0 / 440 (0.00%)	0 / 443 (0.00%)	0 / 444 (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
Back pain
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	1 / 443 (0.23%)	0 / 444 (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
Bursitis
subjects affected / exposed	0 / 443 (0.00%)	1 / 437 (0.23%)	0 / 440 (0.00%)	0 / 443 (0.00%)	0 / 444 (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
Foot deformity
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	1 / 443 (0.23%)	0 / 444 (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
Intervertebral disc protrusion
subjects affected / exposed	1 / 443 (0.23%)	0 / 437 (0.00%)	1 / 440 (0.23%)	0 / 443 (0.00%)	0 / 444 (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
Joint effusion
subjects affected / exposed	1 / 443 (0.23%)	0 / 437 (0.00%)	0 / 440 (0.00%)	0 / 443 (0.00%)	0 / 444 (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
Osteochondrosis
subjects affected / exposed	0 / 443 (0.00%)	1 / 437 (0.23%)	0 / 440 (0.00%)	0 / 443 (0.00%)	0 / 444 (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
Osteoporosis
subjects affected / exposed	1 / 443 (0.23%)	0 / 437 (0.00%)	0 / 440 (0.00%)	0 / 443 (0.00%)	0 / 444 (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	1 / 443 (0.23%)	0 / 437 (0.00%)	0 / 440 (0.00%)	0 / 443 (0.00%)	0 / 444 (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
Infections and infestations
Appendicitis
subjects affected / exposed	1 / 443 (0.23%)	1 / 437 (0.23%)	0 / 440 (0.00%)	0 / 443 (0.00%)	0 / 444 (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
Complicated appendicitis
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	0 / 443 (0.00%)	1 / 444 (0.23%)
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
Dengue fever
subjects affected / exposed	1 / 443 (0.23%)	0 / 437 (0.00%)	0 / 440 (0.00%)	0 / 443 (0.00%)	0 / 444 (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
Diverticulitis
subjects affected / exposed	1 / 443 (0.23%)	0 / 437 (0.00%)	0 / 440 (0.00%)	0 / 443 (0.00%)	0 / 444 (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
Gastroenteritis salmonella
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	1 / 440 (0.23%)	0 / 443 (0.00%)	0 / 444 (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
Lower respiratory tract infection
subjects affected / exposed	0 / 443 (0.00%)	1 / 437 (0.23%)	1 / 440 (0.23%)	0 / 443 (0.00%)	0 / 444 (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
Otitis media
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	1 / 440 (0.23%)	0 / 443 (0.00%)	0 / 444 (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
Peritonitis
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	1 / 440 (0.23%)	0 / 443 (0.00%)	3 / 444 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 443 (0.23%)	3 / 437 (0.69%)	5 / 440 (1.14%)	2 / 443 (0.45%)	0 / 444 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 5	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia viral
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	0 / 443 (0.00%)	1 / 444 (0.23%)
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
Pulmonary tuberculosis
subjects affected / exposed	1 / 443 (0.23%)	0 / 437 (0.00%)	0 / 440 (0.00%)	0 / 443 (0.00%)	0 / 444 (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
Respiratory tract infection bacterial
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	0 / 443 (0.00%)	1 / 444 (0.23%)
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
Sepsis
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	1 / 440 (0.23%)	0 / 443 (0.00%)	0 / 444 (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
Sialoadenitis
subjects affected / exposed	0 / 443 (0.00%)	1 / 437 (0.23%)	0 / 440 (0.00%)	0 / 443 (0.00%)	0 / 444 (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 / 443 (0.00%)	0 / 437 (0.00%)	1 / 440 (0.23%)	0 / 443 (0.00%)	0 / 444 (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	0 / 443 (0.00%)	1 / 437 (0.23%)	0 / 440 (0.00%)	0 / 443 (0.00%)	0 / 444 (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
Metabolism and nutrition disorders
Diabetes mellitus inadequate control
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	1 / 440 (0.23%)	0 / 443 (0.00%)	0 / 444 (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
Electrolyte imbalance
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	1 / 443 (0.23%)	0 / 444 (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
Type 2 diabetes mellitus
subjects affected / exposed	0 / 443 (0.00%)	0 / 437 (0.00%)	0 / 440 (0.00%)	0 / 443 (0.00%)	1 / 444 (0.23%)
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	QMF 150/320	QMF 150/160	MF 800	MF 400	S/F 50/500
Total subjects affected by non serious adverse events
subjects affected / exposed	228 / 443 (51.47%)	233 / 437 (53.32%)	263 / 440 (59.77%)	290 / 443 (65.46%)	239 / 444 (53.83%)
Vascular disorders
Hypertension
subjects affected / exposed	10 / 443 (2.26%)	14 / 437 (3.20%)	13 / 440 (2.95%)	11 / 443 (2.48%)	6 / 444 (1.35%)
occurrences all number	12	17	14	12	7
Nervous system disorders
Headache
subjects affected / exposed	26 / 443 (5.87%)	21 / 437 (4.81%)	24 / 440 (5.45%)	23 / 443 (5.19%)	22 / 444 (4.95%)
occurrences all number	39	24	37	32	28
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	3 / 443 (0.68%)	9 / 437 (2.06%)	5 / 440 (1.14%)	4 / 443 (0.90%)	9 / 444 (2.03%)
occurrences all number	4	9	5	4	9
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	112 / 443 (25.28%)	113 / 437 (25.86%)	157 / 440 (35.68%)	194 / 443 (43.79%)	137 / 444 (30.86%)
occurrences all number	211	202	308	418	233
Cough
subjects affected / exposed	8 / 443 (1.81%)	9 / 437 (2.06%)	12 / 440 (2.73%)	15 / 443 (3.39%)	8 / 444 (1.80%)
occurrences all number	9	9	13	16	9
Oropharyngeal pain
subjects affected / exposed	11 / 443 (2.48%)	6 / 437 (1.37%)	8 / 440 (1.82%)	9 / 443 (2.03%)	8 / 444 (1.80%)
occurrences all number	12	7	8	11	8
Rhinitis allergic
subjects affected / exposed	5 / 443 (1.13%)	11 / 437 (2.52%)	7 / 440 (1.59%)	11 / 443 (2.48%)	7 / 444 (1.58%)
occurrences all number	5	11	7	12	8
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	9 / 443 (2.03%)	17 / 437 (3.89%)	9 / 440 (2.05%)	5 / 443 (1.13%)	8 / 444 (1.80%)
occurrences all number	9	21	13	5	12
Infections and infestations
Bronchitis
subjects affected / exposed	20 / 443 (4.51%)	22 / 437 (5.03%)	22 / 440 (5.00%)	21 / 443 (4.74%)	17 / 444 (3.83%)
occurrences all number	22	25	27	25	18
Gastroenteritis
subjects affected / exposed	4 / 443 (0.90%)	9 / 437 (2.06%)	4 / 440 (0.91%)	6 / 443 (1.35%)	8 / 444 (1.80%)
occurrences all number	4	9	4	6	9
Influenza
subjects affected / exposed	12 / 443 (2.71%)	13 / 437 (2.97%)	19 / 440 (4.32%)	10 / 443 (2.26%)	15 / 444 (3.38%)
occurrences all number	13	13	22	11	17
Nasopharyngitis
subjects affected / exposed	50 / 443 (11.29%)	58 / 437 (13.27%)	78 / 440 (17.73%)	82 / 443 (18.51%)	47 / 444 (10.59%)
occurrences all number	66	87	96	108	70
Pharyngitis
subjects affected / exposed	10 / 443 (2.26%)	11 / 437 (2.52%)	12 / 440 (2.73%)	12 / 443 (2.71%)	14 / 444 (3.15%)
occurrences all number	10	12	13	18	15
Respiratory tract infection viral
subjects affected / exposed	10 / 443 (2.26%)	16 / 437 (3.66%)	14 / 440 (3.18%)	12 / 443 (2.71%)	13 / 444 (2.93%)
occurrences all number	11	21	23	18	18
Rhinitis
subjects affected / exposed	10 / 443 (2.26%)	10 / 437 (2.29%)	9 / 440 (2.05%)	5 / 443 (1.13%)	8 / 444 (1.80%)
occurrences all number	10	12	9	6	8
Upper respiratory tract infection
subjects affected / exposed	22 / 443 (4.97%)	27 / 437 (6.18%)	40 / 440 (9.09%)	37 / 443 (8.35%)	38 / 444 (8.56%)
occurrences all number	29	33	54	55	57
Upper respiratory tract infection bacterial
subjects affected / exposed	5 / 443 (1.13%)	7 / 437 (1.60%)	6 / 440 (1.36%)	14 / 443 (3.16%)	8 / 444 (1.80%)
occurrences all number	6	10	7	14	8
Viral infection
subjects affected / exposed	7 / 443 (1.58%)	8 / 437 (1.83%)	11 / 440 (2.50%)	7 / 443 (1.58%)	6 / 444 (1.35%)
occurrences all number	9	8	12	8	7
Viral upper respiratory tract infection
subjects affected / exposed	7 / 443 (1.58%)	11 / 437 (2.52%)	21 / 440 (4.77%)	20 / 443 (4.51%)	21 / 444 (4.73%)
occurrences all number	9	15	31	31	26

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

30 Jul 2015

This amendment was made in order to comply with the Health Authorities requirements received after finalisation of the protocol version 00 regarding the paediatric population before finalisation of the Paediatric Investigational Plan. As this protocol includes adolescent patients, the following changes were made: 1.Modify the Section Discontinuation of study treatment in order to permanently discontinue study drug for any adolescent patients after one asthma exacerbation requiring hospitalisation 2.Modify inclusion criteria number 4 and 5 in Section Inclusion criteria and in the protocol summary to change the requirement of previous treatment of “any” dose of long-acting β2-adrenergic agonist/inhaled corticosteroids (LABA/ICS) to “low” dose of LABA/ICS.Also patients should qualify for treatment with medium or high dose LABA/ICS (GINA 2015 step≥ 3). The Section Supportive analyses was modified accordingly for the subgroup analysis Following changes and revisions were also made: 1.Change ACQ-5 to be given to the patients and site to ACQ-7 on Table of Assessment for Patients who Discontinue Study Treatment prematurely,Table of assessment,Section Health Status (Patient Reported Outcomes) and Section ACQ-7 at Weeks 4,12 and 52. Derivation of rescue medication from e-diary (6th item on ACQ) and FEV1 (7th item on ACQ) was not performed 2.Specification in Section Treatment exposure and compliance that the patient had entered on the e-diary the compliance of study drug once a week 3.Update on Section Electronic Diary in order to be aligned with Section Treatment exposure and compliance 4.Update on Section Peak Expiratory Flow (PEF) in order to clarify the PEF measurement start and update Table of assessment accordingly 5.Clarify in Section Euro QoL 5 Dimension (EQ-5D-5L) that it was validated in adults and adolescent 6.Update of the questions of Appendix 8:Patient Asthma Control e-Diary for the Patient Asthma diary in order to align to the exacerbations definition

01 Oct 2015

The purpose of this amendment was to modify the ACQ score inclusion criteria from ACQ≥2 to ACQ≥1.5 based on the 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. However, expert advisory board members suggested that a threshold of 1.5 is a more clinically meaningful for the patient population. Additionally, there was precedent for this threshold in recent asthma studies. The Protocol Summary, Section Study Design, Section Rationale for dosing, Section Risk and Benefits, Section Inclusion criteria, Section Supportive analysis were updated accordingly.

08 Sep 2016

The rationale for this amendment was changing the E-Diary Alert handling during run-in epoch due to asthma worsening. If an asthma worsening alert was observed during the run-in epoch, the patients were discontinued regardless of clinical context and the investigator’s judgment. This amendment allowed investigator’s discretion in determining the clinical significance of asthma worsening e-diary alerts during the run-in epoch and allowed the investigator to make the most appropriate decision as to whether patients continued in the study or were discontinued. If asthma worsening was confirmed as clinically significant by investigator, patients were discontinued. A combination of e-diary alerts and investigator’s judgment helped ensure that the most appropriate patients were enrolled in the study, while maintaining rigorous monitoring and assessment of patient safety.

14 Feb 2017

1.Modification of inclusion criteria for baseline ICS and ICS/LABA requirements and upper limit of FEV1 threshold. This was based on investigator feedback of real world asthma populations and intended to address variability in baseline FEV1 as well as evolving treatment patterns, whereby patient medications are more rapidly up-titrated in response to symptoms. This helped identify previously ineligible patients who potentially benefited from treatment with medium to high fixed dose combination of ICS/LABA. 2.The sample size was revised based on the re-estimation of drop-out rate at Week 26 at which time the primary and key secondary objectives were evaluated (Section Population and Section Safety Monitoring Analyses).

17 Jan 2018

1.Conduct primary analysis after all patients have completed at least 26 weeks treatment (V207): The primary and key secondary endpoints of this study were trough FEV1 and ACQ-7, respectively after 26 weeks of treatment, while the entire study treatment period was 52 weeks. Novartis had decided to perform primary analysis once all patients had completed 26 weeks of treatment (Visit 207) or prematurely withdrawn from the study. Two separate CSRs were written: CSR I was completed for the primary analyses once all patients had completed the assessments after 26 weeks of treatment or prematurely withdrawn from the study. It consisted of primary and key secondary objectives as well as other pre-specified objectives up to and including Week 26. CSR II was completed once all patients had completed 52 weeks of treatment plus 30 day follow up or prematurely withdrawn from the study. CSR II consisted of primary and secondary objectives analysed in CSR I in addition to all other objectives evaluated after 26 weeks and up to 52 weeks (plus follow up). 2.Modification of analysis of key secondary endpoint, ACQ-7: The key secondary objective was modified to demonstrate the benefit of indacaterol (QAB149) 150 μg monotherapy on ACQ-7. This was achieved by demonstrating superiority of combined medium and high QMF149 doses to combined medium and high MF doses, respectively in terms of ACQ-7 after 26 weeks of treatment. The analysis was performed only if the individual treatment comparisons were significant for the primary endpoint, trough FEV1 at week 26 (i.e., there was an evidence of efficacy of both doses of QMF149 over respective MF doses in terms of trough FEV1).

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

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

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 Multi-center, Randomized, 52 Week Treatment, Double-blind, Triple-dummy, Parallel Group Study to Assess the Efficacy and Safety of QMF149 Compared to Mometasone Furoate 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 One Second (Trough FEV1) at Week 26

Primary: Trough Forced Expiratory Volume in One Second (Trough FEV1) at Week 26

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

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

Secondary: Trough FEV1 at Week 52

Secondary: Trough FEV1 at Week 52

Secondary: Pre-dose FEV1 at Weeks 4 and 12

Secondary: Pre-dose FEV1 at Weeks 4 and 12

Secondary: Post Dose FEV1 (5 Minutes-1 Hour)

Secondary: Post Dose FEV1 (5 Minutes-1 Hour)

Secondary: Trough Forced Vital Capacity (FVC)

Secondary: Trough Forced Vital Capacity (FVC)

Secondary: Trough Forced Expiratory Flow (FEF)Between 25% and 75% of FVC (FEF25-75)

Secondary: Trough Forced Expiratory Flow (FEF)Between 25% and 75% of FVC (FEF25-75)

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: ACQ-7 at Weeks 4, 12 and 52

Secondary: ACQ-7 at Weeks 4, 12 and 52

Secondary: Percentage of Subjects Achieving the Minimal Important Difference (MID) ACQ ≥ 0.5 at Weeks 26 and 52

Secondary: Percentage of Subjects Achieving the Minimal Important Difference (MID) ACQ ≥ 0.5 at Weeks 26 and 52

Secondary: Change From Baseline in Percentage of Asthma Symptoms Free Days

Secondary: Change From Baseline in Percentage of Asthma Symptoms Free Days

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

Secondary: Change From Baseline in Percentage of Nights With no Night-time Awakenings

Secondary: Change From Baseline in Percentage of Mornings With no Symptoms on Awakening

Secondary: Change From Baseline in Percentage of Mornings With no Symptoms on Awakening

Secondary: Rescue Medication Usage

Secondary: Rescue Medication Usage

Secondary: Time to First Asthma Exacerbation by Exacerbation Category

Secondary: Time to First Asthma Exacerbation by Exacerbation Category

Secondary: Time to First Hospitalization for Asthma Exacerbation

Secondary: Time to First Hospitalization for Asthma Exacerbation

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 Subjects With at Least One Asthma Exacerbation by Exacerbation Category

Secondary: Percentage of Subjects With at Least One Asthma Exacerbation by Exacerbation Category

Secondary: Time in Days to Permanent Discontinuation of Study Medication Due to Asthma Exacerbations

Secondary: Time in Days to Permanent Discontinuation of Study Medication Due to Asthma Exacerbations

Secondary: Percentage of Subjects Who Permanently Discontinued Study Medication Due to Asthma Exacerbations

Secondary: Percentage of Subjects Who Permanently Discontinued Study Medication Due to Asthma Exacerbations

Secondary: Total Amounts of Systemic Corticosteroids (in Doses) Used to Treat Asthma Exacerbations

Secondary: Total Amounts of Systemic Corticosteroids (in Doses) Used to Treat Asthma Exacerbations

Secondary: Change From Baseline in Percentage of Rescue Medication Free Days

Secondary: Change From Baseline in Percentage of Rescue Medication Free Days

Secondary: Asthma Quality of Life Questionnaire (AQLQ)

Secondary: Asthma Quality of Life Questionnaire (AQLQ)

Secondary: Trough FEV1 Measured After 26 Weeks of Treatment

Secondary: Trough FEV1 Measured After 26 Weeks of Treatment

Secondary: Asthma Control as Assessed by the ACQ-7 After 26 Weeks Treatment

Secondary: Asthma Control as Assessed by the ACQ-7 After 26 Weeks Treatment

Secondary: Percentage of Subjects With Composite Endpoint of Serious Asthma Outcomes

Secondary: Percentage of Subjects With Composite Endpoint of Serious Asthma Outcomes

Secondary: Percentage of Subjects With Adverse Events (AE) and Serious Adverse Events (SAE)

Secondary: Percentage of Subjects With Adverse Events (AE) and Serious Adverse Events (SAE)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Multi-center, Randomized, 52 Week Treatment, Double-blind, Triple-dummy, Parallel Group Study to Assess the Efficacy and Safety of QMF149 Compared to Mometasone Furoate in Patients With Asthma