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Clinical Trial Results:
A Randomized, Double-Blind, Parallel Group, Multi-Center Study to Assess the Efficacy and Safety of PT009 Compared to PT005, PT008, and Open-label Symbicort® Turbuhaler®, as an Active Control, on Lung Function over a 24-Week Treatment Period in Subjects With Moderate to Very Severe COPD

Summary
EudraCT number	2016-000154-34
Trial protocol	CZ HU DE PL
Global end of trial date	30 Nov 2017

Results information
Results version number	v1(current)
This version publication date	21 Mar 2019
First version publication date	21 Mar 2019
Other versions

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

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Trial information

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Sponsor protocol code

PT009002

ISRCTN number

US NCT number

NCT02766608

WHO universal trial number (UTN)

Sponsor organisation name

Pearl Therapeutics, a Member of the AstraZeneca Group

Sponsor organisation address

200 Cardinal Way, Redwood City, United States, 94063

Public contact

Paul M. Dorinsky, MD, Pearl Therapeutics, a Member of the AstraZeneca Group, 1 6503052600, paul.dorinsky1@astrazeneca.com

Scientific contact

Paul M. Dorinsky, MD, Pearl Therapeutics, a Member of the AstraZeneca Group, 1 6503052600, paul.dorinsky1@astrazeneca.com

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

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

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

Analysis stage

Final

Date of interim/final analysis

30 Nov 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

30 Nov 2017

Global end of trial reached?

Yes

Global end of trial date

30 Nov 2017

Was the trial ended prematurely?

Main objective of the trial

The primary objective of this study is to assess the effects of BFF MDI relative to FF MDI and BD MDI on lung function

Protection of trial subjects

For subjects who were on ICS LABA, the ICS LABA was discontinued, however, then prescribed an ICS Monotherapy at an equivalent dosing regimen for the duration of the study. Subjects were also given sponsor provided Ventolin HFA as rescue medication.

Background therapy

Evidence for comparator

Actual start date of recruitment

31 May 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Canada: 107

Country: Number of subjects enrolled

Czech Republic: 208

Country: Number of subjects enrolled

Germany: 135

Country: Number of subjects enrolled

Hungary: 201

Country: Number of subjects enrolled

Poland: 310

Country: Number of subjects enrolled

Russian Federation: 384

Country: Number of subjects enrolled

United States: 1016

Worldwide total number of subjects

2361

EEA total number of subjects

854

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

1132

From 65 to 84 years

1229

85 years and over

Subject disposition

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Recruitment details

This study randomized subjects at 244 study centers in 7 countries, from June 2016 and November 2017. The study period was scheduled to take up to approximately 30 weeks for each individual subject from the time of screening through the follow-up period.

Screening details

Subjects were randomized in a 3:3:3:1:1 ratio to BFF 320/9.6, BFF 160/9.6, FF 9.6, BD 320, and Symbicort.

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, Monitor, Data analyst, Carer, Assessor

Blinding implementation details

Subjects assigned to blinded study drug will be instructed to dose while at home from the site-primed MDI only, unless all of the following replacement conditions are met: o Dose indicator is in the red zone (Refer to Appendix 1 for dose indicator reading instructions) o The dose indicator registers ≤ 10 puffs remaining, and o Their next scheduled study clinic visit is not the following day

Are arms mutually exclusive

Yes

BFF MDI 320/9.6 μg

Arm description

Budesonide Formoterol Fumarate Metered Dose Inhalation 320/9.6 μg

Arm type

Experimental

Investigational medicinal product name

Budesonide Formoterol Fumarate

Investigational medicinal product code

Other name

BFF MDI

Pharmaceutical forms

Pressurised inhalation, suspension

Routes of administration

Inhalation use

Dosage and administration details

Taken as 2 inhalations BID

BFF MDI 160/9.6 μg

Arm description

Budesonide Formoterol Fumarate Metered Dose Inhalation 160/9.6 μg

Arm type

Experimental

Investigational medicinal product name

Budesonide Formoterol Fumarate MDI

Investigational medicinal product code

Other name

BFF MDI

Pharmaceutical forms

Pressurised inhalation, suspension

Routes of administration

Inhalation use

Dosage and administration details

Taken as 2 inhalations BID

FF MDI 9.6 μg

Arm description

Formoterol Fumarate Metered Dose Inhalation 9.6 μg

Arm type

Experimental

Investigational medicinal product name

Formoterol Fumarate MDI

Investigational medicinal product code

Other name

FF MDI

Pharmaceutical forms

Pressurised inhalation, suspension

Routes of administration

Inhalation use

Dosage and administration details

Taken as 2 inhalations BID

BD MDI 320 μg

Arm description

Budesonide Metered Dose Inhalation 320 μg

Arm type

Experimental

Investigational medicinal product name

Budesonide MDI

Investigational medicinal product code

Other name

BD MDI

Pharmaceutical forms

Pressurised inhalation, suspension

Routes of administration

Inhalation use

Dosage and administration details

Taken as 2 inhalations

Symbicort TBH 400/12 μg

Arm description

Symbicort Turbuhaler 400/12 μg

Arm type

Active control

Investigational medicinal product name

Symbicort Turbuhaler

Investigational medicinal product code

Other name

Symbicort

Pharmaceutical forms

Pressurised inhalation, suspension

Routes of administration

Inhalation use

Dosage and administration details

Taken as 2 inhalations BID

Number of subjects in period 1	BFF MDI 320/9.6 μg	BFF MDI 160/9.6 μg	FF MDI 9.6 μg	BD MDI 320 μg	Symbicort TBH 400/12 μg
Started	655	637	644	206	219
Completed	576	567	554	169	190
Not completed	79	70	90	37	29
Administrative Reasons	3	1	1	-	-
Consent withdrawn by subject	21	20	24	13	10
Physician decision	3	2	3	1	2
Adverse event, non-fatal	27	22	17	13	12
Protocol disc criteria	3	3	4	-	-
Lost to follow-up	6	3	5	2	2
Lack of efficacy	16	15	32	8	2
Protocol deviation	-	4	4	-	1

Baseline characteristics

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Reporting group title

BFF MDI 320/9.6 μg

Reporting group description

Budesonide Formoterol Fumarate Metered Dose Inhalation 320/9.6 μg

Reporting group title

BFF MDI 160/9.6 μg

Reporting group description

Budesonide Formoterol Fumarate Metered Dose Inhalation 160/9.6 μg

Reporting group title

FF MDI 9.6 μg

Reporting group description

Formoterol Fumarate Metered Dose Inhalation 9.6 μg

Reporting group title

BD MDI 320 μg

Reporting group description

Budesonide Metered Dose Inhalation 320 μg

Reporting group title

Symbicort TBH 400/12 μg

Reporting group description

Symbicort Turbuhaler 400/12 μg

Reporting group values	BFF MDI 320/9.6 μg	BFF MDI 160/9.6 μg	FF MDI 9.6 μg	BD MDI 320 μg	Symbicort TBH 400/12 μg	Total
Number of subjects	655	637	644	206	219	2361
Age categorical
mITT Population
Units: Subjects
Adults (18-64 years)	322	298	313	101	98	1132
From 65-84 years	333	339	331	105	121	1229
Age Continuous
mITT Population
Units: years
least squares mean (standard deviation)	64.2 ± 7.7	64.3 ± 7.6	64.1 ± 8.0	64.2 ± 7.4	65.3 ± 7.0	-
Sex: Female, Male
mITT Population
Units: Subjects
Female	253	260	261	81	78	933
Male	402	377	383	125	141	1428
Ethnicity (NIH/OMB)
mITT Population
Units: Subjects
Hispanic or Latino	16	18	21	8	6	69
Not Hispanic or Latino	637	616	623	198	212	2286
Unknown or Not Reported	2	3	0	0	1	6
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	2	2	2	0	0	6
Asian	1	1	0	0	1	3
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0
Black or African American	19	15	20	9	8	71
White	633	619	622	197	210	2281
More than one race	0	0	0	0	0	0
Unknown or Not Reported	0	0	0	0	0	0

Subject analysis set title

BFF MDI 320/9.6 μg

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Budesonide Formoterol Fumarate Metered Dose Inhalation 320/9.6 μg

Subject analysis set title

BFF MDI 160/9.6 μg

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Budesonide Formoterol Fumarate Metered Dose Inhalation 160/9.6 μg

Subject analysis set title

FF MDI 9.6 μg

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Formoterol Fumarate Metered Dose Inhalation 9.6 μg

Subject analysis set title

BD MDI 320 μg

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Budesonide Metered Dose Inhalation 320 μg

Subject analysis set title

Symbicort TBH 400/12 ug

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Symbicort Turbuhaler 400/12 ug

Subject analysis sets values	BFF MDI 320/9.6 μg	BFF MDI 160/9.6 μg	FF MDI 9.6 μg	BD MDI 320 μg	Symbicort TBH 400/12 ug
Number of subjects	664	649	648	209	219
Age categorical
mITT Population
Units: Subjects
Adults (18-64 years)	322	298	313	101	98
From 65-84 years	333	339	331	105	121
Age Continuous
mITT Population
Units: years
least squares mean (standard deviation)	64.2 ± 7.7	64.3 ± 7.6	64.1 ± 8.0	64.2 ± 7.4	65.3 ± 7.0
Sex: Female, Male
mITT Population
Units: Subjects
Female	253	260	261	81	78
Male	402	377	383	125	141
Ethnicity (NIH/OMB)
mITT Population
Units: Subjects
Hispanic or Latino	16	18	21	8	6
Not Hispanic or Latino	637	616	623	198	212
Unknown or Not Reported	2	3	0	0	1
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	2	2	2	0	0
Asian	1	1	0	0	1
Native Hawaiian or Other Pacific Islander	0	0	0	0	0
Black or African American	19	15	20	9	8
White	633	619	622	197	210
More than one race	0	0	0	0	0
Unknown or Not Reported	0	0	0	0	0

End points

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Reporting group title

BFF MDI 320/9.6 μg

Reporting group description

Budesonide Formoterol Fumarate Metered Dose Inhalation 320/9.6 μg

Reporting group title

BFF MDI 160/9.6 μg

Reporting group description

Budesonide Formoterol Fumarate Metered Dose Inhalation 160/9.6 μg

Reporting group title

FF MDI 9.6 μg

Reporting group description

Formoterol Fumarate Metered Dose Inhalation 9.6 μg

Reporting group title

BD MDI 320 μg

Reporting group description

Budesonide Metered Dose Inhalation 320 μg

Reporting group title

Symbicort TBH 400/12 μg

Reporting group description

Symbicort Turbuhaler 400/12 μg

Subject analysis set title

BFF MDI 320/9.6 μg

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Budesonide Formoterol Fumarate Metered Dose Inhalation 320/9.6 μg

Subject analysis set title

BFF MDI 160/9.6 μg

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Budesonide Formoterol Fumarate Metered Dose Inhalation 160/9.6 μg

Subject analysis set title

FF MDI 9.6 μg

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Formoterol Fumarate Metered Dose Inhalation 9.6 μg

Subject analysis set title

BD MDI 320 μg

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Budesonide Metered Dose Inhalation 320 μg

Subject analysis set title

Symbicort TBH 400/12 ug

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Symbicort Turbuhaler 400/12 ug

Primary: Change from baseline in morning pre-dose trough FEV1 over 24 weeks (BFF MDI versus FF MDI)

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End point title

Change from baseline in morning pre-dose trough FEV1 over 24 weeks (BFF MDI versus FF MDI)

End point description

Change from baseline in morning pre-dose trough FEV1 (Forced expiratory volume in 1 second) over 24 weeks (BFF MDI versus FF MDI)

End point type

Primary

End point timeframe

over 24 weeks

End point values	BFF MDI 320/9.6 μg	BFF MDI 160/9.6 μg	FF MDI 9.6 μg	BD MDI 320 μg	Symbicort TBH 400/12 μg
Number of subjects analysed	627	615	613	190	211
Units: Liter
least squares mean (confidence interval 95%)	0.058 (0.045 to 0.071)	0.033 (0.020 to 0.047)	0.027 (0.014 to 0.041)	-0.029 (-0.053 to -0.004)	0.067 (0.044 to 0.090)

Baseline morning pre-dose FEV1 over 24 wks

Statistical analysis description

Primary endpoint analysis - BFF MDI versus FF MDI

Comparison groups

BFF MDI 320/9.6 μg v BFF MDI 160/9.6 μg v FF MDI 9.6 μg v BD MDI 320 μg

Number of subjects included in analysis

2045

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.05

Method

repeated measures linear mixed model

Confidence interval

Baseline morning pre-dose FEV1 over 24wks

Statistical analysis description

Primary endpoint BFF 320/9.6 vs Symbicort TBH 400/12 ug

Comparison groups

BFF MDI 320/9.6 μg v Symbicort TBH 400/12 μg

Number of subjects included in analysis

838

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

repeated measures linear mixed model

Parameter type

LS Mean Difference

Point estimate

-0.009

Confidence interval

level

95%

sides

2-sided

lower limit

-0.036

upper limit

0.018

Baseline morning pre-dose FEV1 over 24wks

Statistical analysis description

Primary endpoint BFF 160/9.6 vs Symbicort 400/12 ug

Comparison groups

BFF MDI 160/9.6 μg v Symbicort TBH 400/12 μg

Number of subjects included in analysis

826

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

repeated measures linear mixed model

Parameter type

LS Mean Difference

Point estimate

-0.034

Confidence interval

level

95%

sides

2-sided

lower limit

-0.061

upper limit

-0.007

Primary: Change from baseline in FEV1 AUC0-4 (BFF MDI vs BD MDI)

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End point title

Change from baseline in FEV1 AUC0-4 (BFF MDI vs BD MDI)

End point description

Change from baseline in FEV1 (Forced Expiratory Volume) AUC0-4 (Area under the curve from 0 to 4 hours) (BFF MDI vs BD MDI)

End point type

Primary

End point timeframe

over 24 weeks

End point values	BFF MDI 320/9.6 μg	BFF MDI 160/9.6 μg	FF MDI 9.6 μg	BD MDI 320 μg	Symbicort TBH 400/12 μg
Number of subjects analysed	654	636	643	206	218
Units: Liter
least squares mean (confidence interval 95%)	0.211 (0.198 to 0.223)	0.195 (0.183 to 0.208)	0.188 (0.176 to 0.201)	0.030 (0.008 to 0.052)	0.202 (0.181 to 0.224)

FEV1 AUC0-4

Statistical analysis description

Primary endpoint analysis Change from baseline in FEV1 AUC0-4: BFF vs BD

Comparison groups

BFF MDI 320/9.6 μg v BFF MDI 160/9.6 μg v FF MDI 9.6 μg v BD MDI 320 μg

Number of subjects included in analysis

2139

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.05

Method

repeated measures linear mixed model

Confidence interval

FEV1 AUC0-4

Statistical analysis description

Primary endpoint analysis -Change from baseline in FEV1 AUC0-4: BFF 320/9.6 ug vs Symbicort TBH 400/12 ug

Comparison groups

BFF MDI 320/9.6 μg v Symbicort TBH 400/12 μg

Number of subjects included in analysis

872

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

mixed model for repeated measures

Parameter type

LS Mean Difference

Point estimate

0.008

Confidence interval

level

95%

sides

2-sided

lower limit

-0.017

upper limit

0.033

FEV1 AUC0-4

Statistical analysis description

Primary endpoint analysis Change from baseline in FEV1 AUC0-4: BFF 160/9.6 ug vs Symbicort TBH 400/12 ug

Comparison groups

BFF MDI 160/9.6 μg v Symbicort TBH 400/12 μg

Number of subjects included in analysis

854

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Parameter type

LS Mean (SE)

Point estimate

-0.007

Confidence interval

level

95%

sides

2-sided

lower limit

-0.032

upper limit

0.018

Variability estimate

Standard error of the mean

Dispersion value

0.5769

Secondary: Time to first moderate or severe COPD exacerbation (BFF MDI vs FF MDI).

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End point title

Time to first moderate or severe COPD exacerbation (BFF MDI vs FF MDI).

End point description

Time to first moderate or severe COPD (Chronic Obstructive Pulmonary Disease) exacerbation (BFF MDI vs FF MDI).

End point type

Secondary

End point timeframe

over 24 Weeks

End point values	BFF MDI 320/9.6 μg	BFF MDI 160/9.6 μg	FF MDI 9.6 μg	BD MDI 320 μg	Symbicort TBH 400/12 μg
Number of subjects analysed	111	127	150	206	219
Units: Participants	17	20	23	19	15

No statistical analyses for this end point

Secondary: Percentage of subjects achieving an MCID (Minimal clinically important difference) of 4 units or more in SGRQ over 24 weeks

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End point title

Percentage of subjects achieving an MCID (Minimal clinically important difference) of 4 units or more in SGRQ over 24 weeks

End point description

The SGRQ (St. George’s Respiratory Questionnaire) is a disease-specific questionnaire, self-completed by participants, used to evaluate the effect of BFF MDI, FF MDI, BD MDI, & Symbicort TBH on health-related quality of life as compared to placebo in subjects with COPD. The scores range from 0 (minimum, best possible health status) to 100 (maximum, worst possible health status). The SGRQ contains 76 items grouped into three domains (symptoms, activity and impacts). Change from Baseline at a particular visit was calculated as the SGRQ total score at that visit minus Baseline. A decrease from baseline in SGRQ total score of 4 units or more is considered a clinically meaningful improvement in quality of life.

End point type

Secondary

End point timeframe

over 24 weeks

End point values	BFF MDI 320/9.6 μg	BFF MDI 160/9.6 μg	FF MDI 9.6 μg	BD MDI 320 μg	Symbicort TBH 400/12 μg
Number of subjects analysed	649 ^[1]	635 ^[2]	640 ^[3]	204 ^[4]	217 ^[5]
Units: Percentage of Subjects
Percent observed	47	47	44	42	48

Notes
[1] - Observed % (n/N) for Treatment 302 /649
[2] - Observed % (n/N) for Treatment 299/635
[3] - Observed % (n/N) for Treatment 279/640
[4] - Observed % (n/N) for Treatment 86/204
[5] - Observed % (n/N) for Treatment 105/217

No statistical analyses for this end point

Secondary: Change from baseline in morning pre-dose trough FEV1 over 24 weeks (BFF MDI vs BD MDI)

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End point title

Change from baseline in morning pre-dose trough FEV1 over 24 weeks (BFF MDI vs BD MDI)

End point description

Change from baseline in morning pre-dose trough FEV1(Forced Expiratory Volume in 1 second) over 24 weeks (BFF MDI vs BD MDI)

End point type

Secondary

End point timeframe

over 24 weeks

End point values	BFF MDI 320/9.6 μg	BFF MDI 160/9.6 μg	FF MDI 9.6 μg	BD MDI 320 μg	Symbicort TBH 400/12 μg
Number of subjects analysed	627	615	613	190	211
Units: Liter
least squares mean (confidence interval 95%)	0.058 (0.045 to 0.071)	0.033 (0.020 to 0.047)	0.027 (0.014 to 0.041)	-0.029 (-0.053 to -0.004)	0.067 (0.044 to 0.090)

No statistical analyses for this end point

Secondary: Peak change from baseline in FEV1 over 24 weeks (BFF MDI vs BD MDI)

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End point title

Peak change from baseline in FEV1 over 24 weeks (BFF MDI vs BD MDI)

End point description

Peak change from baseline in FEV1 (Forced Expiratory Volume in 1 second) over 24 weeks (BFF MDI vs BD MDI)

End point type

Secondary

End point timeframe

over 24 weeks

End point values	BFF MDI 320/9.6 μg	BFF MDI 160/9.6 μg	FF MDI 9.6 μg	BD MDI 320 μg	Symbicort TBH 400/12 μg
Number of subjects analysed	654	636	643	206	218
Units: Liter
least squares mean (confidence interval 95%)	0.289 (0.276 to 0.302)	0.274 (0.261 to 0.287)	0.269 (0.256 to 0.282)	0.120 (0.097 to 0.143)	0.281 (0.259 to 0.304)

No statistical analyses for this end point

Secondary: Change from baseline in average daily rescue Ventolin HFA use over 24 weeks (BFF MDI vs BD MDI)

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End point title

Change from baseline in average daily rescue Ventolin HFA use over 24 weeks (BFF MDI vs BD MDI)

End point description

Change from baseline in average daily rescue Ventolin HFA use over 24 weeks (BFF MDI vs BD MDI)

End point type

Secondary

End point timeframe

over 24 Weeks

End point values	BFF MDI 320/9.6 μg	BFF MDI 160/9.6 μg	FF MDI 9.6 μg	BD MDI 320 μg	Symbicort TBH 400/12 μg
Number of subjects analysed	654	636	641	206	218
Units: Puffs per day
least squares mean (confidence interval 95%)	-1.3 (-1.5 to -1.1)	-1.3 (-1.4 to -1.1)	-1.1 (-1.2 to -0.9)	-0.6 (-0.9 to -0.3)	-1.2 (-1.5 to -0.9)

No statistical analyses for this end point

Secondary: Time to onset of action on Day 1 - 5 Minutes (BFF MDI vs BD MDI)

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End point title

Time to onset of action on Day 1 - 5 Minutes (BFF MDI vs BD MDI)

End point description

Time to onset of action on Day 1 (BFF MDI vs BD MDI). Change from baseline at 5 Minutes.

End point type

Secondary

End point timeframe

Day 1 - 5 Minutes

End point values	BFF MDI 320/9.6 μg	BFF MDI 160/9.6 μg	FF MDI 9.6 μg	BD MDI 320 μg	Symbicort TBH 400/12 μg
Number of subjects analysed	535	536	534	171	173
Units: Liter
least squares mean (confidence interval 95%)	0.157 (0.148 to 0.166)	0.151 (0.142 to 0.161)	0.160 (0.150 to 0.169)	0.025 (0.009 to 0.041)	0.131 (0.115 to 0.148)

No statistical analyses for this end point

Secondary: Time to onset of action on Day 1 - 15 Minutes (BFF MDI vs BD MDI)

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End point title

Time to onset of action on Day 1 - 15 Minutes (BFF MDI vs BD MDI)

End point description

Time to onset of action on Day 1- 15 Minutes (BFF MDI vs BD MDI). Change from baseline at 15 Minutes.

End point type

Secondary

End point timeframe

Day 1 - 15 Minutes

End point values	BFF MDI 320/9.6 μg	BFF MDI 160/9.6 μg	FF MDI 9.6 μg	BD MDI 320 μg	Symbicort TBH 400/12 μg
Number of subjects analysed	624	615	612	203	211
Units: Liter
least squares mean (confidence interval 95%)	0.190 (0.180 to 0.200)	0.186 (0.176 to 0.196)	0.201 (0.191 to 0.211)	0.040 (0.022 to 0.058)	0.167 (0.149 to 0.184)

No statistical analyses for this end point

Secondary: Time to onset of action on Day 1 - 30 Minutes (BFF MDI vs BD MDI)

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End point title

Time to onset of action on Day 1 - 30 Minutes (BFF MDI vs BD MDI)

End point description

Time to onset of action on Day 1 (BFF MDI vs BD MDI). Change from baseline at 30 Minutes.

End point type

Secondary

End point timeframe

Day 1 - 30 Minutes

End point values	BFF MDI 320/9.6 μg	BFF MDI 160/9.6 μg	FF MDI 9.6 μg	BD MDI 320 μg	Symbicort TBH 400/12 μg
Number of subjects analysed	648	627	638	203	214
Units: Liter
least squares mean (confidence interval 95%)	0.207 (0.196 to 0.217)	0.207 (0.196 to 0.218)	0.215 (0.205 to 0.226)	0.047 (0.028 to 0.066)	0.190 (0.172 to 0.209)

No statistical analyses for this end point

Secondary: Time to onset of action on Day 1 - 1 Hour (BFF MDI vs BD MDI)

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End point title

Time to onset of action on Day 1 - 1 Hour (BFF MDI vs BD MDI)

End point description

Time to onset of action on Day 1 (BFF MDI vs BD MDI). Change from baseline at 1 hour.

End point type

Secondary

End point timeframe

Day 1 - 1 Hour

End point values	BFF MDI 320/9.6 μg	BFF MDI 160/9.6 μg	FF MDI 9.6 μg	BD MDI 320 μg	Symbicort TBH 400/12 μg
Number of subjects analysed	649	628	640	204	215
Units: Liter
least squares mean (confidence interval 95%)	0.225 (0.213 to 0.236)	0.221 (0.210 to 0.233)	0.236 (0.225 to 0.248)	0.053 (0.033 to 0.073)	0.211 (0.191 to 0.231)

No statistical analyses for this end point

Secondary: Time to onset of action on Day 1 - 2 Hours (BFF MDI vs BD MDI)

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End point title

Time to onset of action on Day 1 - 2 Hours (BFF MDI vs BD MDI)

End point description

Time to onset of action on Day 1 (BFF MDI vs BD MDI). Change from baseline at 2 hours.

End point type

Secondary

End point timeframe

Day 1 - 2 Hours

End point values	BFF MDI 320/9.6 μg	BFF MDI 160/9.6 μg	FF MDI 9.6 μg	BD MDI 320 μg	Symbicort TBH 400/12 μg
Number of subjects analysed	649	629	636	205	217
Units: Liter
least squares mean (confidence interval 95%)	0.253 (0.241 to 0.265)	0.234 (0.222 to 0.247)	0.244 (0.231 to 0.256)	0.063 (0.042 to 0.085)	0.221 (0.200 to 0.243)

No statistical analyses for this end point

Secondary: Time to onset of action on Day 1 - 4 Hours (BFF MDI vs BD MDI)

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End point title

Time to onset of action on Day 1 - 4 Hours (BFF MDI vs BD MDI)

End point description

Time to onset of action on Day 1 (BFF MDI vs BD MDI). Change from baseline at 4 hours.

End point type

Secondary

End point timeframe

Day 1 - 4 Hours

End point values	BFF MDI 320/9.6 μg	BFF MDI 160/9.6 μg	FF MDI 9.6 μg	BD MDI 320 μg	Symbicort TBH 400/12 μg
Number of subjects analysed	651	630	634	201	217
Units: Time Point
least squares mean (confidence interval 95%)	0.230 (0.216 to 0.243)	0.215 (0.202 to 0.229)	0.212 (0.199 to 0.226)	0.073 (0.049 to 0.097)	0.209 (0.186 to 0.232)

No statistical analyses for this end point

Secondary: Time to CID (BFF MDI vs FF MDI)

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End point title

Time to CID (BFF MDI vs FF MDI)

End point description

Time to Clinically Important deterioration (BFF MDI vs FF MDI).

End point type

Secondary

End point timeframe

over 24 weeks

End point values	BFF MDI 320/9.6 μg	BFF MDI 160/9.6 μg	FF MDI 9.6 μg	BD MDI 320 μg	Symbicort TBH 400/12 μg
Number of subjects analysed	111 ^[6]	127 ^[7]	150 ^[8]	39 ^[9]	32 ^[10]
Units: Participants
number (not applicable)	17	20	23	19	15

Notes
[6] - % of subjects that had at least one COPD Exacerbation
[7] - % of subjects that had at least one COPD Exacerbation
[8] - % of subjects that had at least one COPD Exacerbation
[9] - % of subjects that had at least one COPD Exacerbation
[10] - % of subjects that had at least one COPD Exacerbation

No statistical analyses for this end point

Secondary: TDI focal score over 24 weeks

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End point title

TDI focal score over 24 weeks

End point description

TDI focal score over 24 weeks (BFF MDI vs FF MDI; BFF MDI vs BD MDI; BFF MDI 320/9.6 μg vs Symbicort TBH, non-inferiority).

End point type

Secondary

End point timeframe

over 24 weeks

End point values	BFF MDI 320/9.6 μg	BFF MDI 160/9.6 μg	FF MDI 9.6 μg	BD MDI 320 μg	Symbicort TBH 400/12 μg
Number of subjects analysed	618	607	605	185	206
Units: Scores on a scale
least squares mean (confidence interval 95%)	1.12 (0.98 to 1.27)	1.20 (1.06 to 1.35)	0.98 (0.83 to 1.12)	0.59 (0.33 to 0.86)	1.07 (0.81 to 1.32)

No statistical analyses for this end point

Secondary: Change from baseline in the E-RS-Total Score over 24 weeks

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End point title

Change from baseline in the E-RS-Total Score over 24 weeks

End point description

Change from baseline in the E-RS Total Score over 24 weeks (BFF MDI vs FF MDI; BFF MDI vs BD MDI; BFF MDI 320/9.6 μg vs Symbicort TBH, noninferiority)

End point type

Secondary

End point timeframe

over 24 weeks

End point values	BFF MDI 320/9.6 μg	BFF MDI 160/9.6 μg	FF MDI 9.6 μg	BD MDI 320 μg	Symbicort TBH 400/12 μg
Number of subjects analysed	655	637	641	206	218
Units: scores on a scale
least squares mean (confidence interval 95%)	-1.5 (-1.8 to -1.2)	-1.7 (-2.0 to -1.4)	-1.3 (-1.6 to -1.0)	-0.9 (-1.4 to -0.3)	-1.4 (-1.9 to -0.9)

No statistical analyses for this end point

Other pre-specified: Substudy: 12-hour PFT endpoint FEV1 AUC0-12

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End point title

Substudy: 12-hour PFT endpoint FEV1 AUC0-12 ^[11]

End point description

Substudy: 12-hour PFT (Pulmonary Function Test) endpoint FEV1 (Forced Expiratory Volume) AUC0-12 (Area under the Curve 0-12)

End point type

Other pre-specified

End point timeframe

at Week 12

Notes
[11] - 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 subjects on Symbicort TBH 400ug Arm, did not participate in the Sub-Study

End point values	BFF MDI 320/9.6 μg	BFF MDI 160/9.6 μg	FF MDI 9.6 μg	BD MDI 320 μg
Number of subjects analysed	160	167	162	47
Units: Liter
least squares mean (confidence interval 95%)	0.135 (0.107 to 0.163)	0.124 (0.097 to 0.152)	0.117 (0.089 to 0.145)	0.024 (-0.028 to 0.075)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug

Adverse event reporting additional description

Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 30 weeks, which includes screening and follow up (14 days after last dose of study drug).

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.0

Reporting group title

BFF MDI 320/9.6 μg

Reporting group description

Budesonide Formoterol Fumarate Metered Dose Inhalation 320/9.6 μg

Reporting group title

BFF MDI 160/9.6 μg

Reporting group description

Budesonide Formoterol Fumarate Metered Dose Inhalation 160/9.6 μg

Reporting group title

FF MDI 9.6 μg

Reporting group description

Formoterol Fumarate Metered Dose Inhalation 9.6 μg

Reporting group title

BD MDI 320 μg

Reporting group description

Budesonide Metered Dose Inhalation 320 μg

Reporting group title

Symbicort TBH 400/12 μg

Reporting group description

Symbicort Turbuhaler 400/12 μg

Serious adverse events	BFF MDI 320/9.6 μg	BFF MDI 160/9.6 μg	FF MDI 9.6 μg	BD MDI 320 μg	Symbicort TBH 400/12 μg
Total subjects affected by serious adverse events
subjects affected / exposed	42 / 655 (6.41%)	45 / 637 (7.06%)	72 / 644 (11.18%)	15 / 206 (7.28%)	20 / 219 (9.13%)
number of deaths (all causes)	3	2	2	0	2
number of deaths resulting from adverse events	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	0 / 644 (0.00%)	1 / 206 (0.49%)	0 / 219 (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
Brain cancer metastatic
subjects affected / exposed	0 / 655 (0.00%)	1 / 637 (0.16%)	0 / 644 (0.00%)	0 / 206 (0.00%)	0 / 219 (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
Breast cancer male
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	1 / 644 (0.16%)	0 / 206 (0.00%)	0 / 219 (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
Bronchial carcinoma
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	0 / 644 (0.00%)	1 / 206 (0.49%)	0 / 219 (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
Gastric neoplasm
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	1 / 644 (0.16%)	0 / 206 (0.00%)	0 / 219 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung neoplasm malignant
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	1 / 644 (0.16%)	0 / 206 (0.00%)	0 / 219 (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
Mesothelioma
subjects affected / exposed	1 / 655 (0.15%)	0 / 637 (0.00%)	0 / 644 (0.00%)	0 / 206 (0.00%)	0 / 219 (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
Metastases to liver
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	0 / 644 (0.00%)	1 / 206 (0.49%)	0 / 219 (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
Metastatic carcinoma of the bladder
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	1 / 644 (0.16%)	0 / 206 (0.00%)	0 / 219 (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
Non-small cell lung cancer
subjects affected / exposed	0 / 655 (0.00%)	1 / 637 (0.16%)	0 / 644 (0.00%)	0 / 206 (0.00%)	0 / 219 (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
Pancreatic carcinoma metastatic
subjects affected / exposed	1 / 655 (0.15%)	0 / 637 (0.00%)	0 / 644 (0.00%)	0 / 206 (0.00%)	0 / 219 (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
Prostate cancer
subjects affected / exposed	1 / 655 (0.15%)	0 / 637 (0.00%)	0 / 644 (0.00%)	0 / 206 (0.00%)	0 / 219 (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
Transitional cell carcinoma
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	0 / 644 (0.00%)	0 / 206 (0.00%)	1 / 219 (0.46%)
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
Vascular disorders
Arteriosclerosis
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	1 / 644 (0.16%)	0 / 206 (0.00%)	0 / 219 (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
Haematoma
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	1 / 644 (0.16%)	0 / 206 (0.00%)	0 / 219 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypertensive emergency
subjects affected / exposed	0 / 655 (0.00%)	1 / 637 (0.16%)	0 / 644 (0.00%)	0 / 206 (0.00%)	0 / 219 (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
Peripheral artery thrombosis
subjects affected / exposed	0 / 655 (0.00%)	1 / 637 (0.16%)	0 / 644 (0.00%)	0 / 206 (0.00%)	0 / 219 (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
Peripheral ischaemia
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	1 / 644 (0.16%)	0 / 206 (0.00%)	0 / 219 (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
Thrombophlebitis superficial
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	1 / 644 (0.16%)	0 / 206 (0.00%)	0 / 219 (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
General disorders and administration site conditions
Chest discomfort
subjects affected / exposed	1 / 655 (0.15%)	0 / 637 (0.00%)	0 / 644 (0.00%)	0 / 206 (0.00%)	0 / 219 (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
Chest pain
subjects affected / exposed	1 / 655 (0.15%)	0 / 637 (0.00%)	0 / 644 (0.00%)	0 / 206 (0.00%)	0 / 219 (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
Death
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	0 / 644 (0.00%)	0 / 206 (0.00%)	1 / 219 (0.46%)
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
Incarcerated hernia
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	1 / 644 (0.16%)	0 / 206 (0.00%)	0 / 219 (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
Sudden cardiac death
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	1 / 644 (0.16%)	0 / 206 (0.00%)	0 / 219 (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
Reproductive system and breast disorders
Prostatic haemorrhage
subjects affected / exposed	1 / 655 (0.15%)	0 / 637 (0.00%)	0 / 644 (0.00%)	0 / 206 (0.00%)	0 / 219 (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, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	15 / 655 (2.29%)	10 / 637 (1.57%)	29 / 644 (4.50%)	2 / 206 (0.97%)	6 / 219 (2.74%)
occurrences causally related to treatment / all	0 / 16	0 / 10	0 / 35	0 / 2	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute respiratory failure
subjects affected / exposed	2 / 655 (0.31%)	2 / 637 (0.31%)	4 / 644 (0.62%)	0 / 206 (0.00%)	1 / 219 (0.46%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 4	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	1 / 655 (0.15%)	0 / 637 (0.00%)	1 / 644 (0.16%)	0 / 206 (0.00%)	0 / 219 (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
Respiratory failure
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	1 / 644 (0.16%)	0 / 206 (0.00%)	1 / 219 (0.46%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	1 / 644 (0.16%)	0 / 206 (0.00%)	0 / 219 (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
Psychiatric disorders
Mental status changes
subjects affected / exposed	0 / 655 (0.00%)	1 / 637 (0.16%)	0 / 644 (0.00%)	0 / 206 (0.00%)	0 / 219 (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
Product issues
Device battery issue
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	1 / 644 (0.16%)	0 / 206 (0.00%)	0 / 219 (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
Injury, poisoning and procedural complications
Hip fracture
subjects affected / exposed	0 / 655 (0.00%)	1 / 637 (0.16%)	0 / 644 (0.00%)	0 / 206 (0.00%)	1 / 219 (0.46%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acetabulum fracture
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	0 / 644 (0.00%)	0 / 206 (0.00%)	1 / 219 (0.46%)
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
Dural tear
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	1 / 644 (0.16%)	0 / 206 (0.00%)	0 / 219 (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
Femur fracture
subjects affected / exposed	1 / 655 (0.15%)	0 / 637 (0.00%)	0 / 644 (0.00%)	0 / 206 (0.00%)	0 / 219 (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
Forearm fracture
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	0 / 644 (0.00%)	0 / 206 (0.00%)	1 / 219 (0.46%)
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
Lower limb fracture
subjects affected / exposed	1 / 655 (0.15%)	0 / 637 (0.00%)	0 / 644 (0.00%)	0 / 206 (0.00%)	0 / 219 (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
Radius fracture
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	0 / 644 (0.00%)	1 / 206 (0.49%)	0 / 219 (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
Rib fracture
subjects affected / exposed	1 / 655 (0.15%)	0 / 637 (0.00%)	0 / 644 (0.00%)	0 / 206 (0.00%)	0 / 219 (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
Thermal burn
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	0 / 644 (0.00%)	0 / 206 (0.00%)	1 / 219 (0.46%)
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
Upper limb fracture
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	1 / 644 (0.16%)	0 / 206 (0.00%)	0 / 219 (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
Vascular pseudoaneurysm
subjects affected / exposed	1 / 655 (0.15%)	0 / 637 (0.00%)	0 / 644 (0.00%)	0 / 206 (0.00%)	0 / 219 (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
Skull fractured base
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	1 / 644 (0.16%)	0 / 206 (0.00%)	0 / 219 (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
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	1 / 655 (0.15%)	5 / 637 (0.78%)	2 / 644 (0.31%)	1 / 206 (0.49%)	0 / 219 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 5	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	1 / 655 (0.15%)	1 / 637 (0.16%)	1 / 644 (0.16%)	2 / 206 (0.97%)	1 / 219 (0.46%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	0 / 655 (0.00%)	2 / 637 (0.31%)	2 / 644 (0.31%)	0 / 206 (0.00%)	0 / 219 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	1 / 655 (0.15%)	2 / 637 (0.31%)	1 / 644 (0.16%)	0 / 206 (0.00%)	0 / 219 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Angina unstable
subjects affected / exposed	0 / 655 (0.00%)	2 / 637 (0.31%)	1 / 644 (0.16%)	0 / 206 (0.00%)	0 / 219 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	1 / 655 (0.15%)	0 / 637 (0.00%)	1 / 644 (0.16%)	1 / 206 (0.49%)	0 / 219 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	2 / 655 (0.31%)	0 / 637 (0.00%)	1 / 644 (0.16%)	0 / 206 (0.00%)	0 / 219 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure chronic
subjects affected / exposed	0 / 655 (0.00%)	2 / 637 (0.31%)	1 / 644 (0.16%)	0 / 206 (0.00%)	0 / 219 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	1 / 644 (0.16%)	1 / 206 (0.49%)	0 / 219 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrioventricular block complete
subjects affected / exposed	0 / 655 (0.00%)	1 / 637 (0.16%)	0 / 644 (0.00%)	1 / 206 (0.49%)	0 / 219 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	1 / 655 (0.15%)	1 / 637 (0.16%)	0 / 644 (0.00%)	0 / 206 (0.00%)	0 / 219 (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
Coronary artery disease
subjects affected / exposed	0 / 655 (0.00%)	1 / 637 (0.16%)	1 / 644 (0.16%)	0 / 206 (0.00%)	0 / 219 (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
Arteriosclerosis coronary artery
subjects affected / exposed	0 / 655 (0.00%)	1 / 637 (0.16%)	0 / 644 (0.00%)	0 / 206 (0.00%)	0 / 219 (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
Congestive cardiomyopathy
subjects affected / exposed	0 / 655 (0.00%)	1 / 637 (0.16%)	0 / 644 (0.00%)	0 / 206 (0.00%)	0 / 219 (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
Coronary artery stenosis
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	0 / 644 (0.00%)	1 / 206 (0.49%)	0 / 219 (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
Myocardial infarction
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	0 / 644 (0.00%)	1 / 206 (0.49%)	0 / 219 (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
Nervous system disorders
Ischaemic stroke
subjects affected / exposed	0 / 655 (0.00%)	1 / 637 (0.16%)	2 / 644 (0.31%)	0 / 206 (0.00%)	1 / 219 (0.46%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	1 / 655 (0.15%)	0 / 637 (0.00%)	1 / 644 (0.16%)	0 / 206 (0.00%)	1 / 219 (0.46%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 655 (0.00%)	1 / 637 (0.16%)	1 / 644 (0.16%)	0 / 206 (0.00%)	0 / 219 (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
Carotid artery stenosis
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	1 / 644 (0.16%)	0 / 206 (0.00%)	0 / 219 (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
Embolic stroke
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	0 / 644 (0.00%)	1 / 206 (0.49%)	0 / 219 (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
Epilepsy
subjects affected / exposed	0 / 655 (0.00%)	1 / 637 (0.16%)	0 / 644 (0.00%)	0 / 206 (0.00%)	0 / 219 (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
Hypoaesthesia
subjects affected / exposed	0 / 655 (0.00%)	1 / 637 (0.16%)	0 / 644 (0.00%)	0 / 206 (0.00%)	0 / 219 (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
Intracranial aneurysm
subjects affected / exposed	0 / 655 (0.00%)	1 / 637 (0.16%)	0 / 644 (0.00%)	0 / 206 (0.00%)	0 / 219 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	1 / 644 (0.16%)	0 / 206 (0.00%)	0 / 219 (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
Eye disorders
Cataract
subjects affected / exposed	0 / 655 (0.00%)	1 / 637 (0.16%)	1 / 644 (0.16%)	0 / 206 (0.00%)	0 / 219 (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
Gastrointestinal disorders
Small intestinal obstruction
subjects affected / exposed	0 / 655 (0.00%)	1 / 637 (0.16%)	2 / 644 (0.31%)	0 / 206 (0.00%)	0 / 219 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	0 / 644 (0.00%)	0 / 206 (0.00%)	2 / 219 (0.91%)
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
Abdominal pain
subjects affected / exposed	1 / 655 (0.15%)	0 / 637 (0.00%)	0 / 644 (0.00%)	0 / 206 (0.00%)	0 / 219 (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
Colitis ischaemic
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	1 / 644 (0.16%)	0 / 206 (0.00%)	0 / 219 (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
Diverticulum intestinal
subjects affected / exposed	0 / 655 (0.00%)	1 / 637 (0.16%)	0 / 644 (0.00%)	0 / 206 (0.00%)	0 / 219 (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
Gastrointestinal ulcer
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	1 / 644 (0.16%)	0 / 206 (0.00%)	0 / 219 (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
Hiatus hernia
subjects affected / exposed	1 / 655 (0.15%)	0 / 637 (0.00%)	0 / 644 (0.00%)	0 / 206 (0.00%)	0 / 219 (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
Inflammatory bowel disease
subjects affected / exposed	1 / 655 (0.15%)	0 / 637 (0.00%)	0 / 644 (0.00%)	0 / 206 (0.00%)	0 / 219 (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
Inguinal hernia
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	0 / 644 (0.00%)	1 / 206 (0.49%)	0 / 219 (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
Pancreatitis
subjects affected / exposed	0 / 655 (0.00%)	1 / 637 (0.16%)	0 / 644 (0.00%)	0 / 206 (0.00%)	0 / 219 (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
Strangulated umbilical hernia
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	0 / 644 (0.00%)	1 / 206 (0.49%)	0 / 219 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	0 / 655 (0.00%)	1 / 637 (0.16%)	0 / 644 (0.00%)	0 / 206 (0.00%)	0 / 219 (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
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	1 / 655 (0.15%)	0 / 637 (0.00%)	1 / 644 (0.16%)	1 / 206 (0.49%)	0 / 219 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bile duct stone
subjects affected / exposed	1 / 655 (0.15%)	0 / 637 (0.00%)	1 / 644 (0.16%)	0 / 206 (0.00%)	0 / 219 (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
Cholelithiasis
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	1 / 644 (0.16%)	0 / 206 (0.00%)	1 / 219 (0.46%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	1 / 644 (0.16%)	0 / 206 (0.00%)	0 / 219 (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
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	1 / 655 (0.15%)	0 / 637 (0.00%)	0 / 644 (0.00%)	0 / 206 (0.00%)	0 / 219 (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
Chronic kidney disease
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	1 / 644 (0.16%)	0 / 206 (0.00%)	0 / 219 (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
Hypertonic bladder
subjects affected / exposed	1 / 655 (0.15%)	0 / 637 (0.00%)	0 / 644 (0.00%)	0 / 206 (0.00%)	0 / 219 (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
Renal tubular necrosis
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	1 / 644 (0.16%)	0 / 206 (0.00%)	0 / 219 (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
Renal cyst
subjects affected / exposed	1 / 655 (0.15%)	0 / 637 (0.00%)	0 / 644 (0.00%)	0 / 206 (0.00%)	0 / 219 (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
Musculoskeletal and connective tissue disorders
Osteoarthritis
subjects affected / exposed	1 / 655 (0.15%)	0 / 637 (0.00%)	1 / 644 (0.16%)	0 / 206 (0.00%)	0 / 219 (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
Arthralgia
subjects affected / exposed	0 / 655 (0.00%)	1 / 637 (0.16%)	0 / 644 (0.00%)	0 / 206 (0.00%)	0 / 219 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arthritis
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	1 / 644 (0.16%)	0 / 206 (0.00%)	0 / 219 (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
Bursitis
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	0 / 644 (0.00%)	0 / 206 (0.00%)	1 / 219 (0.46%)
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 chest pain
subjects affected / exposed	1 / 655 (0.15%)	0 / 637 (0.00%)	0 / 644 (0.00%)	0 / 206 (0.00%)	0 / 219 (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
Tendonitis
subjects affected / exposed	1 / 655 (0.15%)	0 / 637 (0.00%)	0 / 644 (0.00%)	0 / 206 (0.00%)	0 / 219 (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
Pneumonia
subjects affected / exposed	4 / 655 (0.61%)	5 / 637 (0.78%)	6 / 644 (0.93%)	0 / 206 (0.00%)	3 / 219 (1.37%)
occurrences causally related to treatment / all	0 / 4	0 / 5	0 / 7	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal hernia gangrenous
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	0 / 644 (0.00%)	0 / 206 (0.00%)	1 / 219 (0.46%)
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
Breast abscess
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	1 / 644 (0.16%)	0 / 206 (0.00%)	0 / 219 (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
Cellulitis
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	1 / 644 (0.16%)	0 / 206 (0.00%)	0 / 219 (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
Clostridium difficile colitis
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	1 / 644 (0.16%)	0 / 206 (0.00%)	0 / 219 (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
Sepsis
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	0 / 644 (0.00%)	0 / 206 (0.00%)	1 / 219 (0.46%)
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
Staphylococcal infection
subjects affected / exposed	0 / 655 (0.00%)	1 / 637 (0.16%)	0 / 644 (0.00%)	0 / 206 (0.00%)	0 / 219 (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
Tooth abscess
subjects affected / exposed	0 / 655 (0.00%)	1 / 637 (0.16%)	0 / 644 (0.00%)	0 / 206 (0.00%)	0 / 219 (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
Cachexia
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	0 / 644 (0.00%)	0 / 206 (0.00%)	1 / 219 (0.46%)
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
Diabetes mellitus
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	1 / 644 (0.16%)	0 / 206 (0.00%)	0 / 219 (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
Diabetes with hyperosmolarity
subjects affected / exposed	1 / 655 (0.15%)	0 / 637 (0.00%)	0 / 644 (0.00%)	0 / 206 (0.00%)	0 / 219 (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
Electrolyte imbalance
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	1 / 644 (0.16%)	0 / 206 (0.00%)	0 / 219 (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
Gout
subjects affected / exposed	0 / 655 (0.00%)	0 / 637 (0.00%)	1 / 644 (0.16%)	0 / 206 (0.00%)	0 / 219 (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

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

Non-serious adverse events	BFF MDI 320/9.6 μg	BFF MDI 160/9.6 μg	FF MDI 9.6 μg	BD MDI 320 μg	Symbicort TBH 400/12 μg
Total subjects affected by non serious adverse events
subjects affected / exposed	240 / 655 (36.64%)	201 / 637 (31.55%)	219 / 644 (34.01%)	75 / 206 (36.41%)	57 / 219 (26.03%)
Vascular disorders
Hypertension
subjects affected / exposed	14 / 655 (2.14%)	22 / 637 (3.45%)	15 / 644 (2.33%)	5 / 206 (2.43%)	4 / 219 (1.83%)
occurrences all number	14	22	15	5	5
Nervous system disorders
Headache
subjects affected / exposed	19 / 655 (2.90%)	8 / 637 (1.26%)	15 / 644 (2.33%)	3 / 206 (1.46%)	1 / 219 (0.46%)
occurrences all number	27	10	15	4	3
General disorders and administration site conditions
Fatigue
subjects affected / exposed	1 / 655 (0.15%)	1 / 637 (0.16%)	5 / 644 (0.78%)	5 / 206 (2.43%)	1 / 219 (0.46%)
occurrences all number	1	1	5	5	1
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	9 / 655 (1.37%)	9 / 637 (1.41%)	9 / 644 (1.40%)	5 / 206 (2.43%)	3 / 219 (1.37%)
occurrences all number	9	9	9	6	3
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	7 / 655 (1.07%)	15 / 637 (2.35%)	15 / 644 (2.33%)	7 / 206 (3.40%)	0 / 219 (0.00%)
occurrences all number	8	15	15	7	0
Dyspnoea
subjects affected / exposed	12 / 655 (1.83%)	11 / 637 (1.73%)	9 / 644 (1.40%)	7 / 206 (3.40%)	3 / 219 (1.37%)
occurrences all number	12	11	9	7	3
Dysphonia
subjects affected / exposed	16 / 655 (2.44%)	13 / 637 (2.04%)	3 / 644 (0.47%)	2 / 206 (0.97%)	1 / 219 (0.46%)
occurrences all number	16	13	3	2	1
Psychiatric disorders
Anxiety
subjects affected / exposed	6 / 655 (0.92%)	2 / 637 (0.31%)	4 / 644 (0.62%)	5 / 206 (2.43%)	1 / 219 (0.46%)
occurrences all number	6	2	4	5	1
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	18 / 655 (2.75%)	13 / 637 (2.04%)	18 / 644 (2.80%)	3 / 206 (1.46%)	2 / 219 (0.91%)
occurrences all number	21	14	19	3	2
Muscle spasms
subjects affected / exposed	14 / 655 (2.14%)	6 / 637 (0.94%)	6 / 644 (0.93%)	0 / 206 (0.00%)	8 / 219 (3.65%)
occurrences all number	15	6	7	0	8
Infections and infestations
Nasopharyngitis
subjects affected / exposed	40 / 655 (6.11%)	40 / 637 (6.28%)	43 / 644 (6.68%)	17 / 206 (8.25%)	14 / 219 (6.39%)
occurrences all number	46	44	46	18	18
Upper respiratory tract infection
subjects affected / exposed	25 / 655 (3.82%)	21 / 637 (3.30%)	20 / 644 (3.11%)	5 / 206 (2.43%)	3 / 219 (1.37%)
occurrences all number	27	24	20	7	3
Chronic obstructive pulmonary disease
subjects affected / exposed	16 / 655 (2.44%)	10 / 637 (1.57%)	30 / 644 (4.66%)	2 / 206 (0.97%)	6 / 219 (2.74%)
occurrences all number	17	10	36	2	6
Oral candidiasis
subjects affected / exposed	17 / 655 (2.60%)	14 / 637 (2.20%)	5 / 644 (0.78%)	3 / 206 (1.46%)	3 / 219 (1.37%)
occurrences all number	18	15	6	3	3
Bronchitis
subjects affected / exposed	16 / 655 (2.44%)	7 / 637 (1.10%)	10 / 644 (1.55%)	4 / 206 (1.94%)	2 / 219 (0.91%)
occurrences all number	17	8	10	4	2
Sinusitis
subjects affected / exposed	10 / 655 (1.53%)	9 / 637 (1.41%)	12 / 644 (1.86%)	2 / 206 (0.97%)	5 / 219 (2.28%)
occurrences all number	12	10	13	2	5

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Were there any global substantial amendments to the protocol? Yes

01 Jul 2016

Clarified dose of open label Symbicort® TBH Updated synopsis, Safety endpoints, Inclusion/Exclusion Criteria.

24 Oct 2017

Updated Protocol objective, updated endpoints, clarification of statistical methods.

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from baseline in morning pre-dose trough FEV1 over 24 weeks (BFF MDI versus FF MDI)

Primary: Change from baseline in morning pre-dose trough FEV1 over 24 weeks (BFF MDI versus FF MDI)

Primary: Change from baseline in FEV1 AUC0-4 (BFF MDI vs BD MDI)

Primary: Change from baseline in FEV1 AUC0-4 (BFF MDI vs BD MDI)

Secondary: Time to first moderate or severe COPD exacerbation (BFF MDI vs FF MDI).

Secondary: Time to first moderate or severe COPD exacerbation (BFF MDI vs FF MDI).

Secondary: Percentage of subjects achieving an MCID (Minimal clinically important difference) of 4 units or more in SGRQ over 24 weeks

Secondary: Percentage of subjects achieving an MCID (Minimal clinically important difference) of 4 units or more in SGRQ over 24 weeks

Secondary: Change from baseline in morning pre-dose trough FEV1 over 24 weeks (BFF MDI vs BD MDI)

Secondary: Change from baseline in morning pre-dose trough FEV1 over 24 weeks (BFF MDI vs BD MDI)

Secondary: Peak change from baseline in FEV1 over 24 weeks (BFF MDI vs BD MDI)

Secondary: Peak change from baseline in FEV1 over 24 weeks (BFF MDI vs BD MDI)

Secondary: Change from baseline in average daily rescue Ventolin HFA use over 24 weeks (BFF MDI vs BD MDI)

Secondary: Change from baseline in average daily rescue Ventolin HFA use over 24 weeks (BFF MDI vs BD MDI)

Secondary: Time to onset of action on Day 1 - 5 Minutes (BFF MDI vs BD MDI)

Secondary: Time to onset of action on Day 1 - 5 Minutes (BFF MDI vs BD MDI)

Secondary: Time to onset of action on Day 1 - 15 Minutes (BFF MDI vs BD MDI)

Secondary: Time to onset of action on Day 1 - 15 Minutes (BFF MDI vs BD MDI)

Secondary: Time to onset of action on Day 1 - 30 Minutes (BFF MDI vs BD MDI)

Secondary: Time to onset of action on Day 1 - 30 Minutes (BFF MDI vs BD MDI)

Secondary: Time to onset of action on Day 1 - 1 Hour (BFF MDI vs BD MDI)

Secondary: Time to onset of action on Day 1 - 1 Hour (BFF MDI vs BD MDI)

Secondary: Time to onset of action on Day 1 - 2 Hours (BFF MDI vs BD MDI)

Secondary: Time to onset of action on Day 1 - 2 Hours (BFF MDI vs BD MDI)

Secondary: Time to onset of action on Day 1 - 4 Hours (BFF MDI vs BD MDI)

Secondary: Time to onset of action on Day 1 - 4 Hours (BFF MDI vs BD MDI)

Secondary: Time to CID (BFF MDI vs FF MDI)

Secondary: Time to CID (BFF MDI vs FF MDI)

Secondary: TDI focal score over 24 weeks

Secondary: TDI focal score over 24 weeks

Secondary: Change from baseline in the E-RS-Total Score over 24 weeks

Secondary: Change from baseline in the E-RS-Total Score over 24 weeks

Other pre-specified: Substudy: 12-hour PFT endpoint FEV1 AUC0-12

Other pre-specified: Substudy: 12-hour PFT endpoint FEV1 AUC0-12

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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