Clinical Trial Results:
A randomised, double-blind, parallel group study to assess the efficacy and safety of 52 weeks of once daily treatment of orally inhaled tiotropium + olodaterol fixed dose combination (2.5 μg / 5 μg; 5 μg / 5 μg) (delivered by the Respimat® Inhaler) compared with the individual components (2.5 μg and 5 μg tiotropium, 5 μg olodaterol) (delivered by the Respimat® Inhaler) in patients with Chronic Obstructive Pulmonary Disease (COPD).

Due to a system error, the data reported in v1 is not correct and has been removed from public view.

Summary
EudraCT number	2009-010668-40
Trial protocol	NL FI PT SI CZ DE HU DK EE IT
Global end of trial date	19 Sep 2013

Results information
Results version number	v2(current)
This version publication date	01 Jul 2016
First version publication date	01 Aug 2015
Other versions	v1 (removed from public view)
Version creation reason	Correction of full data set Data correction due to a system error in EudraCT- Results

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

1237.5

ISRCTN number

US NCT number

NCT01431274

WHO universal trial number (UTN)

Sponsor organisation name

Boehringer Ingelheim

Sponsor organisation address

Binger Strasse 173, Ingelheim am Rhein , Germany, 55216

Public contact

QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 800 2430127, clintriage.rdg@boehringer-ingelheim.com

Scientific contact

QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 800 2430127, clintriage.rdg@boehringer-ingelheim.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

05 Nov 2013

Is this the analysis of the primary completion data?

Yes

Primary completion date

06 Mar 2013

Global end of trial reached?

Yes

Global end of trial date

19 Sep 2013

Was the trial ended prematurely?

Main objective of the trial

The overall objective of this study is to assess the efficacy and safety of 52 weeks once daily treatment with orally inhaled tiotropium + olodaterol fixed dose combination ((2.5 µg / 5 µg; 5 µg / 5 µg) (delivered by the Respimat® Inhaler) compared with the individual components (2.5 and 5 μg tiotropium, 5 µg olodaterol) (delivered by the Respimat® Inhaler) in patients with Chronic Obstructive Pulmonary Disease (COPD).

Protection of trial subjects

Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time without the need to provide a reason. Close monitoring of all subjects was adhered to throughout the trial conduct. Rescue medication was allowed for all patients as required.

Background therapy

Evidence for comparator

Actual start date of recruitment

15 Sep 2011

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Slovenia: 105

Country: Number of subjects enrolled

Denmark: 150

Country: Number of subjects enrolled

Finland: 81

Country: Number of subjects enrolled

Italy: 49

Country: Number of subjects enrolled

Netherlands: 119

Country: Number of subjects enrolled

Portugal: 74

Country: Number of subjects enrolled

Bulgaria: 94

Country: Number of subjects enrolled

Czech Republic: 59

Country: Number of subjects enrolled

Estonia: 49

Country: Number of subjects enrolled

France: 80

Country: Number of subjects enrolled

Germany: 301

Country: Number of subjects enrolled

Hungary: 89

Country: Number of subjects enrolled

United States: 553

Country: Number of subjects enrolled

Australia: 22

Country: Number of subjects enrolled

Canada: 131

Country: Number of subjects enrolled

Guatemala: 110

Country: Number of subjects enrolled

India: 99

Country: Number of subjects enrolled

Japan: 279

Country: Number of subjects enrolled

Mexico: 45

Country: Number of subjects enrolled

New Zealand: 30

Country: Number of subjects enrolled

China: 316

Country: Number of subjects enrolled

Argentina: 206

Country: Number of subjects enrolled

Russian Federation: 56

Country: Number of subjects enrolled

Korea, Republic of: 175

Country: Number of subjects enrolled

Turkey: 97

Worldwide total number of subjects

3369

EEA total number of subjects

1250

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)

1703

From 65 to 84 years

1651

85 years and over

Subject disposition

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Recruitment details

A "Missing" category is unavailable for the age group breakdown of enrolled patients. Hence, 8 subjects with a missing data for age group have been added to age-category "18-64 years".

Screening details

All subjects were screened for eligibility to participate in the trial. Subjects attended one specialist site which would then ensure that they (the subjects) met all inclusion/exclusion criteria. Subjects were not to be randomised to trial treatment if any one of the specific entry criteria were violated.

Period 1 title

Treatment period (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

Are arms mutually exclusive

Yes

Olodaterol (Olo) 5 μg

Arm description

Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.

Arm type

Active comparator

Investigational medicinal product name

Olodaterol

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

5 μg Once daily with orally inhalation

Tiotropium (Tio) 2.5 μg

Arm description

Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.

Arm type

Active comparator

Investigational medicinal product name

Tiotropium

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

2.5 μg once daily with orally inhalation

Tiotropium (Tio) 5 μg

Arm description

Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.

Arm type

Active comparator

Investigational medicinal product name

Tiotropium

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

5 μg once daily with orally inhalation

Tio + Olo (T+O) 2.5 /5 μg

Arm description

Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.

Arm type

Experimental

Investigational medicinal product name

Tiotropium

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

2.5 μg once daily with orally inhalation

Investigational medicinal product name

Olodaterol

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

5 μg once daily with orally inhalation

Tio + Olo (T + O) 5/5 μg

Arm description

Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.

Arm type

Experimental

Investigational medicinal product name

Olodaterol

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

5 μg once daily with orally inhalation

Investigational medicinal product name

Tiotropium

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

5 μg once daily with orally inhalation

Number of subjects in period 1 ^[1]	Olodaterol (Olo) 5 μg	Tiotropium (Tio) 2.5 μg	Tiotropium (Tio) 5 μg	Tio + Olo (T+O) 2.5 /5 μg	Tio + Olo (T + O) 5/5 μg
Started	528	525	527	522	522
Completed	431	448	455	462	466
Not completed	97	77	72	60	56
Adverse event, serious fatal	4	6	4	7	7
Consent withdrawn by subject	29	20	17	20	11
Adverse event, non-fatal	47	31	39	23	30
Lost to follow-up	6	7	1	4	-
Protocol deviation	5	8	4	4	4
Reason other than specified above	6	5	7	2	4

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: Baseline characteristics are based on the patients who were randomised after successfully completing the screening period and received at least one dose of the trial medication.

Baseline characteristics

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Reporting group title

Olodaterol (Olo) 5 μg

Reporting group description

Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.

Reporting group title

Tiotropium (Tio) 2.5 μg

Reporting group description

Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.

Reporting group title

Tiotropium (Tio) 5 μg

Reporting group description

Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.

Reporting group title

Tio + Olo (T+O) 2.5 /5 μg

Reporting group description

Reporting group title

Tio + Olo (T + O) 5/5 μg

Reporting group description

Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.

Reporting group values	Olodaterol (Olo) 5 μg	Tiotropium (Tio) 2.5 μg	Tiotropium (Tio) 5 μg	Tio + Olo (T+O) 2.5 /5 μg	Tio + Olo (T + O) 5/5 μg	Total
Number of subjects	528	525	527	522	522	2624
Age categorical
Units: Subjects
Age continuous
Treated Set (TS): This patient set included all patients in the randomised set who were dispensed study medication and were documented to have taken any dose of study medication.
Units: years
arithmetic mean (standard deviation)	63.7 ( 8 )	64.2 ( 8.6 )	64.2 ( 8.5 )	64.1 ( 8 )	64.8 ( 8.2 )	-
Gender categorical
Treated Set (TS): This patient set included all patients in the randomised set who were dispensed study medication and were documented to have taken any dose of study medication.
Units: Subjects
Female	142	133	144	133	138	690
Male	386	392	383	389	384	1934

End points

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Reporting group title

Olodaterol (Olo) 5 μg

Reporting group description

Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.

Reporting group title

Tiotropium (Tio) 2.5 μg

Reporting group description

Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.

Reporting group title

Tiotropium (Tio) 5 μg

Reporting group description

Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.

Reporting group title

Tio + Olo (T+O) 2.5 /5 μg

Reporting group description

Reporting group title

Tio + Olo (T + O) 5/5 μg

Reporting group description

Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.

Primary: Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) (0-3h) Response on Day 169.

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End point title

Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) (0-3h) Response on Day 169.

End point description

Area under the FEV-time curve from 0 to 3h post-dose(FEV1 AUC(0-3h)) was calculated using trapezoidal rule, divided by duration(3h) to report in litres. FEV1 AUC(0-3h) response was defined as FEV1 AUC(0-3h) minus baseline FEV1. Baseline was defined as the mean of 2 pre-dose measurements performed 1h & at 10 min prior to first dose at visit 2(day1). The adjusted means(SE) were obtained by fitting MMRM model with fixed effects of treatment,planned test day,treatment-by-test day interaction, baseline & baseline-by-test day interaction,patient as random effect,& spatial power covariance structure for within-patient errors & Kenward-Roger approximation for denominator degrees of freedom.The Full analysis set(FAS) included all randomized patients, dispensed study medication,documented to have taken any dose of study medication & who had non-missing baseline & at least one non-missing post-baseline measurement for at least one primary or key secondary efficacy endpoints.

End point type

Primary

End point timeframe

1 hour (h) and at 10 minutes (min) prior to dose on the first day of randomized treatment and on Day 169 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 169

End point values	Olodaterol (Olo) 5 μg	Tiotropium (Tio) 2.5 μg	Tiotropium (Tio) 5 μg	Tio + Olo (T+O) 2.5 /5 μg	Tio + Olo (T + O) 5/5 μg
Number of subjects analysed	525 ^[1]	524 ^[2]	526 ^[3]	521 ^[4]	522 ^[5]
Units: litre(s)
least squares mean (standard error)	0.133 ( 0.008 )	0.148 ( 0.008 )	0.139 ( 0.008 )	0.241 ( 0.008 )	0.256 ( 0.008 )

Notes
[1] - Number of FAS (full analysis set) patients actually contributing to the model.
[2] - Number of FAS (full analysis set) patients actually contributing to the model.
[3] - Number of FAS (full analysis set) patients actually contributing to the model.
[4] - Number of FAS (full analysis set) patients actually contributing to the model.
[5] - Number of FAS (full analysis set) patients actually contributing to the model.

T+O 5/5 vs Olo 5

Statistical analysis description

Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Tio + Olo (T + O) 5/5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1047

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.123

Confidence interval

level

95%

sides

2-sided

lower limit

0.1

upper limit

0.146

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 5/5 vs Tio 5

Statistical analysis description

Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 5 μg

Number of subjects included in analysis

1048

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.117

Confidence interval

level

95%

sides

2-sided

lower limit

0.094

upper limit

0.14

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 2.5/5 vs Olo 5

Statistical analysis description

Tio + Olo (T+O) 2.5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1046

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.109

Confidence interval

level

95%

sides

2-sided

lower limit

0.086

upper limit

0.132

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 2.5/5 vs Tio 2.5

Statistical analysis description

Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg.The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1045

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.093

Confidence interval

level

95%

sides

2-sided

lower limit

0.07

upper limit

0.116

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 2.5/5 vs Tio 5

Statistical analysis description

Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 5 μg

Number of subjects included in analysis

1047

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.102

Confidence interval

level

95%

sides

2-sided

lower limit

0.08

upper limit

0.125

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 5/5 vs T+O 2.5/5

Statistical analysis description

Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tio + Olo (T+O) 2.5 /5 μg

Number of subjects included in analysis

1043

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2169

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.014

Confidence interval

level

95%

sides

2-sided

lower limit

-0.008

upper limit

0.037

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 5/5 vs Tio 2.5

Statistical analysis description

Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1046

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.108

Confidence interval

level

95%

sides

2-sided

lower limit

0.085

upper limit

0.13

Variability estimate

Standard error of the mean

Dispersion value

0.012

Tio 5 vs Olo 5

Statistical analysis description

Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Tiotropium (Tio) 5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1051

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5849

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.006

Confidence interval

level

95%

sides

2-sided

lower limit

-0.017

upper limit

0.029

Variability estimate

Standard error of the mean

Dispersion value

0.012

Tio 2.5 vs Olo 5

Statistical analysis description

Tiotropium (Tio) 2.5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Tiotropium (Tio) 2.5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1049

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1863

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.016

Confidence interval

level

95%

sides

2-sided

lower limit

-0.007

upper limit

0.039

Variability estimate

Standard error of the mean

Dispersion value

0.012

Tio 5 vs Tio 2.5

Statistical analysis description

Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Tiotropium (Tio) 5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1050

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4352

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

-0.009

Confidence interval

level

95%

sides

2-sided

lower limit

-0.032

upper limit

0.014

Variability estimate

Standard error of the mean

Dispersion value

0.012

Primary: Trough FEV1 response on Day 170

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End point title

Trough FEV1 response on Day 170

End point description

Trough FEV1 defined as the FEV1 value at the end of the dosing interval (24h)&calculated as mean of 2 FEV1 measurements performed at 23h &at 23h 50 min after inhalation of study medication at clinic visit on the previous day.Trough FEV1 response was defined as trough FEV1 minus baseline FEV1.Baseline was defined as mean of 2 pre-dose measurements performed 1h&at 10 min prior to administration of first dose at visit2(day 1).The adjusted means (SE) obtained by fitting mixed effect model repeated measures(MMRM) including fixed effects of treatment,planned test day,treatment-by-test day interaction,baseline&baseline-by-test day interaction,patient as random effect,&spatial power covariance structure for within-patient errors&Kenward- Roger approximation for denominator degrees of freedom.Since it is possible for patient to meet the data criterion for only a subset of the primary endpoints,it is possible that the number of patients used in the FAS analysis for different endpoint will vary.

End point type

Primary

End point timeframe

1 h and at 10 min prior to dose on the first day of randomized treatment (baseline) and at 23 h and at 23 h 50 min after inhalation of study medication on Day 170

End point values	Olodaterol (Olo) 5 μg	Tiotropium (Tio) 2.5 μg	Tiotropium (Tio) 5 μg	Tio + Olo (T+O) 2.5 /5 μg	Tio + Olo (T + O) 5/5 μg
Number of subjects analysed	519 ^[6]	519 ^[7]	520 ^[8]	518 ^[9]	521 ^[10]
Units: litre(s)
least squares mean (standard error)	0.054 ( 0.009 )	0.083 ( 0.008 )	0.065 ( 0.008 )	0.111 ( 0.008 )	0.136 ( 0.008 )

Notes
[6] - Number of FAS (full analysis set) patients actually contributing to the model.
[7] - Number of FAS (full analysis set) patients actually contributing to the model.
[8] - Number of FAS (full analysis set) patients actually contributing to the model.
[9] - Number of FAS (full analysis set) patients actually contributing to the model.
[10] - Number of FAS (full analysis set) patients actually contributing to the model.

T+O 5/5 vs Olo 5

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1040

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.082

Confidence interval

level

95%

sides

2-sided

lower limit

0.059

upper limit

0.106

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 5/5 vs Tio 5

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 5 μg

Number of subjects included in analysis

1041

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.071

Confidence interval

level

95%

sides

2-sided

lower limit

0.047

upper limit

0.094

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 2.5/5 vs Olo 5

Statistical analysis description

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1037

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.058

Confidence interval

level

95%

sides

2-sided

lower limit

0.034

upper limit

0.081

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 2.5/5 vs Tio 2.5

Statistical analysis description

Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1037

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0174

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.029

Confidence interval

level

95%

sides

2-sided

lower limit

0.005

upper limit

0.052

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 2.5/5 vs Tio 5

Statistical analysis description

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 5 μg

Number of subjects included in analysis

1038

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.046

Confidence interval

level

95%

sides

2-sided

lower limit

0.023

upper limit

0.07

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 5/5 vs T+O 2.5/5

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tio + Olo (T+O) 2.5 /5 μg

Number of subjects included in analysis

1039

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0407

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.024

Confidence interval

level

95%

sides

2-sided

lower limit

0.001

upper limit

0.048

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 5/5 vs Tio 2.5

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1040

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.053

Confidence interval

level

95%

sides

2-sided

lower limit

0.03

upper limit

0.077

Variability estimate

Standard error of the mean

Dispersion value

0.012

Tio 5 vs Olo 5

Statistical analysis description

Comparison groups

Tiotropium (Tio) 5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1039

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3326

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.012

Confidence interval

level

95%

sides

2-sided

lower limit

-0.012

upper limit

0.035

Variability estimate

Standard error of the mean

Dispersion value

0.012

Tio 2.5 vs Olo 5

Statistical analysis description

Comparison groups

Tiotropium (Tio) 2.5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1038

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0151

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.029

Confidence interval

level

95%

sides

2-sided

lower limit

0.006

upper limit

0.053

Variability estimate

Standard error of the mean

Dispersion value

0.012

Tio 5 vs Tio 2.5

Statistical analysis description

Comparison groups

Tiotropium (Tio) 5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1039

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1421

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

-0.018

Confidence interval

level

95%

sides

2-sided

lower limit

-0.041

upper limit

0.006

Variability estimate

Standard error of the mean

Dispersion value

0.012

Secondary: FEV1 AUC(0-3h) response on Day 1, Day 85, and Day 365

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End point title

FEV1 AUC(0-3h) response on Day 1, Day 85, and Day 365

End point description

FEV1 AUC(0-3h) was calculated as the area under the FEV1- time curve from 0 to 3 h post-dose using the trapezoidal rule,divided by the duration (3 h) to report in litres.FEV1 AUC(0-3h) response was defined as FEV1 AUC(0-3h) minus baseline FEV1.Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h & at 10 min prior to administration of the first dose of randomised treatment at Day1.The adjusted means (SE) were obtained by fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment,planned test day, treatment-by-test day interaction,baseline & baseline-by-test day interaction, patient as random effect, & spatial power covariance structure for within−patient errors and Kenward-Roger approximation for denominator degrees of freedom.Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints,it is possible that the number of patients used in the FAS analysis for different endpoint vary.

End point type

Secondary

End point timeframe

1 hour (h) and at 10 minutes (min) prior to dose on the first day of randomized treatment and on Days 85 and 365 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on the first day of randomized treatment and on Days 85 and 365.

End point values	Olodaterol (Olo) 5 μg	Tiotropium (Tio) 2.5 μg	Tiotropium (Tio) 5 μg	Tio + Olo (T+O) 2.5 /5 μg	Tio + Olo (T + O) 5/5 μg
Number of subjects analysed	525 ^[11]	524 ^[12]	526 ^[13]	521 ^[14]	522 ^[15]
Units: litre(s)
least squares mean (standard error)
Day 1	0.205 ( 0.009 )	0.148 ( 0.009 )	0.157 ( 0.009 )	0.226 ( 0.009 )	0.237 ( 0.009 )
Day 85	0.161 ( 0.009 )	0.176 ( 0.009 )	0.162 ( 0.009 )	0.271 ( 0.009 )	0.289 ( 0.009 )
Day 365	0.096 ( 0.009 )	0.116 ( 0.009 )	0.122 ( 0.009 )	0.214 ( 0.009 )	0.237 ( 0.009 )

Notes
[11] - Number of FAS (full analysis set) patients actually contributing to the model.
[12] - Number of FAS (full analysis set) patients actually contributing to the model.
[13] - Number of FAS (full analysis set) patients actually contributing to the model.
[14] - Number of FAS (full analysis set) patients actually contributing to the model.
[15] - Number of FAS (full analysis set) patients actually contributing to the model.

T+O 5/5 vs Olo 5 on Day 1

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1047

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0067

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.033

Confidence interval

level

95%

sides

2-sided

lower limit

0.009

upper limit

0.056

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 5/5 vs Tio 5 on Day 1

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 5 μg

Number of subjects included in analysis

1048

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.081

Confidence interval

level

95%

sides

2-sided

lower limit

0.057

upper limit

0.104

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 2.5/5 vs Olo 5 on Day 1

Statistical analysis description

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1046

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0746

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.022

Confidence interval

level

95%

sides

2-sided

lower limit

-0.002

upper limit

0.045

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 2.5/5 vs Tio 2.5 on Day 1

Statistical analysis description

Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1045

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.078

Confidence interval

level

95%

sides

2-sided

lower limit

0.054

upper limit

0.101

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 2.5/5 vs Tio 5 on Day 1

Statistical analysis description

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 5 μg

Number of subjects included in analysis

1047

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.07

Confidence interval

level

95%

sides

2-sided

lower limit

0.046

upper limit

0.093

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 5/5 vs T+O 2.5/5 on Day 1

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tio + Olo (T+O) 2.5 /5 μg

Number of subjects included in analysis

1043

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3549

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.011

Confidence interval

level

95%

sides

2-sided

lower limit

-0.013

upper limit

0.035

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 5/5 vs Tio 2.5 on Day 1

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1046

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.089

Confidence interval

level

95%

sides

2-sided

lower limit

0.065

upper limit

0.113

Variability estimate

Standard error of the mean

Dispersion value

0.012

Tio 5 vs Olo 5 on Day 1

Statistical analysis description

Comparison groups

Tiotropium (Tio) 5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1051

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

-0.048

Confidence interval

level

95%

sides

2-sided

lower limit

-0.072

upper limit

-0.025

Variability estimate

Standard error of the mean

Dispersion value

0.012

Tio 2.5 vs Olo 5 on Day 1

Statistical analysis description

Comparison groups

Tiotropium (Tio) 2.5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1049

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

-0.056

Confidence interval

level

95%

sides

2-sided

lower limit

-0.08

upper limit

-0.033

Variability estimate

Standard error of the mean

Dispersion value

0.012

Tio 5 vs Tio 2.5 on Day 1

Statistical analysis description

Comparison groups

Tiotropium (Tio) 5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1050

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5018

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.008

Confidence interval

level

95%

sides

2-sided

lower limit

-0.016

upper limit

0.032

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 5/5 vs Olo 5 on Day 85

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1047

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.128

Confidence interval

level

95%

sides

2-sided

lower limit

0.104

upper limit

0.152

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 5/5 vs Tio 5 on Day 85

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 5 μg

Number of subjects included in analysis

1048

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.126

Confidence interval

level

95%

sides

2-sided

lower limit

0.102

upper limit

0.15

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 2.5/5 vs Olo 5 on Day 85

Statistical analysis description

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1046

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.111

Confidence interval

level

95%

sides

2-sided

lower limit

0.087

upper limit

0.135

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 2.5/5 vs Tio 5 on Day 85

Statistical analysis description

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 5 μg

Number of subjects included in analysis

1047

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.109

Confidence interval

level

95%

sides

2-sided

lower limit

0.085

upper limit

0.133

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 2.5/5 vs Tio 2.5 on Day 85

Statistical analysis description

Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1045

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.096

Confidence interval

level

95%

sides

2-sided

lower limit

0.072

upper limit

0.12

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 5/5 vs T+O 2.5/5 on Day 85

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tio + Olo (T+O) 2.5 /5 μg

Number of subjects included in analysis

1043

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1569

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.017

Confidence interval

level

95%

sides

2-sided

lower limit

-0.007

upper limit

0.041

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 5/5 vs Tio 2.5 on Day 85

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1046

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.113

Confidence interval

level

95%

sides

2-sided

lower limit

0.089

upper limit

0.137

Variability estimate

Standard error of the mean

Dispersion value

0.012

Tio 5 vs Olo 5 on Day 85

Statistical analysis description

Comparison groups

Tiotropium (Tio) 5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1051

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8834

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.002

Confidence interval

level

95%

sides

2-sided

lower limit

-0.022

upper limit

0.026

Variability estimate

Standard error of the mean

Dispersion value

0.012

Tio 2.5 vs Olo 5 on Day 85

Statistical analysis description

Comparison groups

Tiotropium (Tio) 2.5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1049

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2129

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.015

Confidence interval

level

95%

sides

2-sided

lower limit

-0.009

upper limit

0.039

Variability estimate

Standard error of the mean

Dispersion value

0.012

Tio 5 vs Tio 2.5 on Day 85

Statistical analysis description

Comparison groups

Tiotropium (Tio) 5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1050

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2702

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

-0.013

Confidence interval

level

95%

sides

2-sided

lower limit

-0.037

upper limit

0.01

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 5/5 vs Olo 5 on Day 365

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1047

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.141

Confidence interval

level

95%

sides

2-sided

lower limit

0.117

upper limit

0.166

Variability estimate

Standard error of the mean

Dispersion value

0.013

T+O 5/5 vs Tio 5 on Day 365

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 5 μg

Number of subjects included in analysis

1048

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.115

Confidence interval

level

95%

sides

2-sided

lower limit

0.09

upper limit

0.139

Variability estimate

Standard error of the mean

Dispersion value

0.013

T+O 2.5/5 vs Olo 5 on Day 365

Statistical analysis description

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1046

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.119

Confidence interval

level

95%

sides

2-sided

lower limit

0.094

upper limit

0.143

Variability estimate

Standard error of the mean

Dispersion value

0.013

T+O 2.5/5 vs Tio 2.5 on Day 365

Statistical analysis description

Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1045

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.099

Confidence interval

level

95%

sides

2-sided

lower limit

0.074

upper limit

0.123

Variability estimate

Standard error of the mean

Dispersion value

0.013

T+O 2.5/5 vs Tio 5 on Day 365

Statistical analysis description

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 5 μg

Number of subjects included in analysis

1047

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.092

Confidence interval

level

95%

sides

2-sided

lower limit

0.067

upper limit

0.117

Variability estimate

Standard error of the mean

Dispersion value

0.013

T+O 5/5 vs T+O 2.5/5 on Day 365

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tio + Olo (T+O) 2.5 /5 μg

Number of subjects included in analysis

1043

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0717

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.023

Confidence interval

level

95%

sides

2-sided

lower limit

-0.002

upper limit

0.047

Variability estimate

Standard error of the mean

Dispersion value

0.013

T+O 5/5 vs Tio 2.5 on Day 365

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1046

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.121

Confidence interval

level

95%

sides

2-sided

lower limit

0.097

upper limit

0.146

Variability estimate

Standard error of the mean

Dispersion value

0.013

Tio 5 vs Olo 5 on Day 365

Statistical analysis description

Comparison groups

Tiotropium (Tio) 5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1051

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0344

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.027

Confidence interval

level

95%

sides

2-sided

lower limit

0.002

upper limit

0.051

Variability estimate

Standard error of the mean

Dispersion value

0.013

Tio 2.5 vs Olo 5 on Day 365

Statistical analysis description

Comparison groups

Tiotropium (Tio) 2.5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1049

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1126

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.005

upper limit

0.045

Variability estimate

Standard error of the mean

Dispersion value

0.013

Tio 5 vs Tio 2.5 on Day 365

Statistical analysis description

Comparison groups

Tiotropium (Tio) 5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1050

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6009

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.007

Confidence interval

level

95%

sides

2-sided

lower limit

-0.018

upper limit

0.031

Variability estimate

Standard error of the mean

Dispersion value

0.013

Secondary: Trough FEV1 response on Day 15, Day 43, Day 85, Day 169, and Day 365

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End point title

Trough FEV1 response on Day 15, Day 43, Day 85, Day 169, and Day 365

End point description

Trough FEV1 defined as the FEV1 value at the end of the dosing interval (24 hours),calculated as mean of the pre-dose measurements.Trough FEV1 response was defined as trough FEV1 minus baseline FEV1.Baseline was defined as mean of 2 pre-dose measurements performed 1h&at 10 min prior to administration of the first dose of randomised treatment at Day1.The adjusted means (SE) were obtained by MMRM model including fixed effects of treatment,planned test day, treatment-by-test day interaction, baseline&baseline-by-test day interaction,patient as random effect,&spatial power covariance structure for within-patient errors &Kenward-Roger approximation for denominator degrees of freedom.Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoint vary.

End point type

Secondary

End point timeframe

1 hour (h) and at 10 minutes (min) prior to dose on the first day of randomized treatment and on Days 85, 169 and 365 and 10 minutes (min) prior to randomized treatment on days 15 and 43.

End point values	Olodaterol (Olo) 5 μg	Tiotropium (Tio) 2.5 μg	Tiotropium (Tio) 5 μg	Tio + Olo (T+O) 2.5 /5 μg	Tio + Olo (T + O) 5/5 μg
Number of subjects analysed	519 ^[16]	519 ^[17]	520 ^[18]	518 ^[19]	521 ^[20]
Units: litre(s)
least squares mean (standard error)
Day 15	0.085 ( 0.009 )	0.101 ( 0.009 )	0.094 ( 0.009 )	0.132 ( 0.009 )	0.157 ( 0.009 )
Day 43	0.083 ( 0.009 )	0.097 ( 0.009 )	0.088 ( 0.009 )	0.12 ( 0.009 )	0.163 ( 0.009 )
Day 85	0.057 ( 0.009 )	0.077 ( 0.009 )	0.07 ( 0.009 )	0.128 ( 0.009 )	0.146 ( 0.009 )
Day 169	0.033 ( 0.009 )	0.047 ( 0.009 )	0.05 ( 0.009 )	0.094 ( 0.009 )	0.112 ( 0.009 )
Day 365	0 ( 0.009 )	0.028 ( 0.009 )	0.036 ( 0.009 )	0.075 ( 0.009 )	0.099 ( 0.009 )

Notes
[16] - Number of FAS (full analysis set) patients actually contributing to the model.
[17] - Number of FAS (full analysis set) patients actually contributing to the model.
[18] - Number of FAS (full analysis set) patients actually contributing to the model.
[19] - Number of FAS (full analysis set) patients actually contributing to the model.
[20] - Number of FAS (full analysis set) patients actually contributing to the model.

T+O 5/5 vs Olo 5 on Day 15

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1040

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.072

Confidence interval

level

95%

sides

2-sided

lower limit

0.049

upper limit

0.096

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 5/5 vs Tio 5 on Day 15

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 5 μg

Number of subjects included in analysis

1041

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.063

Confidence interval

level

95%

sides

2-sided

lower limit

0.039

upper limit

0.087

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 2.5/5 vs Olo 5 on Day 15

Statistical analysis description

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1037

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.047

Confidence interval

level

95%

sides

2-sided

lower limit

0.023

upper limit

0.07

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 2.5/5 vs Tio 2.5 on Day 15

Statistical analysis description

Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1037

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0122

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.03

Confidence interval

level

95%

sides

2-sided

lower limit

0.007

upper limit

0.054

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 2.5/5 vs Tio 5 on Day 15

Statistical analysis description

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 5 μg

Number of subjects included in analysis

1038

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0021

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.037

Confidence interval

level

95%

sides

2-sided

lower limit

0.014

upper limit

0.061

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 5/5 vs T+O 2.5/5 on Day 15

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tio + Olo (T+O) 2.5 /5 μg

Number of subjects included in analysis

1039

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0347

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.026

Confidence interval

level

95%

sides

2-sided

lower limit

0.002

upper limit

0.049

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 5/5 vs Tio 2.5 on Day 15

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1040

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.056

Confidence interval

level

95%

sides

2-sided

lower limit

0.032

upper limit

0.08

Variability estimate

Standard error of the mean

Dispersion value

0.012

Tio 5 vs Olo 5 on Day 15

Statistical analysis description

Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5μg.The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.

Comparison groups

Tiotropium (Tio) 5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1039

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4407

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.009

Confidence interval

level

95%

sides

2-sided

lower limit

-0.014

upper limit

0.033

Variability estimate

Standard error of the mean

Dispersion value

0.012

Tio 2.5 vs Olo 5 on Day 15

Statistical analysis description

Comparison groups

Tiotropium (Tio) 2.5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1038

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1777

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.016

Confidence interval

level

95%

sides

2-sided

lower limit

-0.007

upper limit

0.04

Variability estimate

Standard error of the mean

Dispersion value

0.012

Tio 5 vs Tio 2.5 on Day 15

Statistical analysis description

Comparison groups

Tiotropium (Tio) 5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1039

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5641

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

-0.007

Confidence interval

level

95%

sides

2-sided

lower limit

-0.031

upper limit

0.017

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 5/5 vs Olo 5 on Day 43

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1040

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.08

Confidence interval

level

95%

sides

2-sided

lower limit

0.057

upper limit

0.104

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 5/5 vs Tio 5 on Day 43

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 5 μg

Number of subjects included in analysis

1041

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.075

Confidence interval

level

95%

sides

2-sided

lower limit

0.051

upper limit

0.099

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 2.5/5 vs Olo 5 on Day 43

Statistical analysis description

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1037

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0018

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.038

Confidence interval

level

95%

sides

2-sided

lower limit

0.014

upper limit

0.062

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 2.5/5 vs Tio 2.5 on Day 43

Statistical analysis description

Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1037

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0517

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.024

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

0.047

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 2.5/5 vs Tio 5 on Day 43

Statistical analysis description

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 5 μg

Number of subjects included in analysis

1038

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0072

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.033

Confidence interval

level

95%

sides

2-sided

lower limit

0.009

upper limit

0.056

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 5/5 vs T+O 2.5/5 on Day 43

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tio + Olo (T+O) 2.5 /5 μg

Number of subjects included in analysis

1039

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0005

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.042

Confidence interval

level

95%

sides

2-sided

lower limit

0.019

upper limit

0.066

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 5/5 vs Tio 2.5 on Day 43

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1040

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.066

Confidence interval

level

95%

sides

2-sided

lower limit

0.042

upper limit

0.09

Variability estimate

Standard error of the mean

Dispersion value

0.012

Tio 5 vs Olo 5 on Day 43

Statistical analysis description

Comparison groups

Tiotropium (Tio) 5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1039

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6619

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.005

Confidence interval

level

95%

sides

2-sided

lower limit

-0.018

upper limit

0.029

Variability estimate

Standard error of the mean

Dispersion value

0.012

Tio 2.5 vs Olo 5 on Day 43

Statistical analysis description

Comparison groups

Tiotropium (Tio) 2.5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1038

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2401

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.014

Confidence interval

level

95%

sides

2-sided

lower limit

-0.01

upper limit

0.038

Variability estimate

Standard error of the mean

Dispersion value

0.012

Tio 5 vs Tio 2.5 on Day 43

Statistical analysis description

Comparison groups

Tiotropium (Tio) 5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1039

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4601

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

-0.009

Confidence interval

level

95%

sides

2-sided

lower limit

-0.033

upper limit

0.015

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 5/5 vs Olo 5 on Day 85

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1040

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.088

Confidence interval

level

95%

sides

2-sided

lower limit

0.064

upper limit

0.112

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 5/5 vs Tio 5 on Day 85

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 5 μg

Number of subjects included in analysis

1041

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.076

Confidence interval

level

95%

sides

2-sided

lower limit

0.052

upper limit

0.1

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 2.5/5 vs Olo 5 on Day 85

Statistical analysis description

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1037

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.07

Confidence interval

level

95%

sides

2-sided

lower limit

0.046

upper limit

0.094

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 2.5/5 vs Tio 2.5 on Day 85

Statistical analysis description

Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1037

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.051

Confidence interval

level

95%

sides

2-sided

lower limit

0.027

upper limit

0.075

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 2.5/5 vs Tio 5 on Day 85

Statistical analysis description

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 5 μg

Number of subjects included in analysis

1038

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.058

Confidence interval

level

95%

sides

2-sided

lower limit

0.034

upper limit

0.082

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 5/5 vs T+O 2.5/5 on Day 85

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tio + Olo (T+O) 2.5 /5 μg

Number of subjects included in analysis

1039

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1405

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.018

Confidence interval

level

95%

sides

2-sided

lower limit

-0.006

upper limit

0.042

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 5/5 vs Tio 2.5 on Day 85

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1040

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.069

Confidence interval

level

95%

sides

2-sided

lower limit

0.045

upper limit

0.093

Variability estimate

Standard error of the mean

Dispersion value

0.012

Tio 5 vs Olo 5 on Day 85

Statistical analysis description

Comparison groups

Tiotropium (Tio) 5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1039

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3118

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.012

Confidence interval

level

95%

sides

2-sided

lower limit

-0.012

upper limit

0.036

Variability estimate

Standard error of the mean

Dispersion value

0.012

Tio 2.5 vs Olo 5 on Day 85

Statistical analysis description

Comparison groups

Tiotropium (Tio) 2.5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1038

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1171

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.019

Confidence interval

level

95%

sides

2-sided

lower limit

-0.005

upper limit

0.043

Variability estimate

Standard error of the mean

Dispersion value

0.012

Tio 5 vs Tio 2.5 on Day 85

Statistical analysis description

Comparison groups

Tiotropium (Tio) 5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1039

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5759

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

-0.007

Confidence interval

level

95%

sides

2-sided

lower limit

-0.031

upper limit

0.017

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 5/5 vs Olo 5 on Day 169

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1040

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.079

Confidence interval

level

95%

sides

2-sided

lower limit

0.055

upper limit

0.103

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 5/5 vs Tio 5 on Day 169

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 5 μg

Number of subjects included in analysis

1041

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.062

Confidence interval

level

95%

sides

2-sided

lower limit

0.038

upper limit

0.086

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 2.5/5 vs Olo 5 on Day 169

Statistical analysis description

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1037

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.061

Confidence interval

level

95%

sides

2-sided

lower limit

0.037

upper limit

0.085

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 2.5/5 vs Tio 2.5 on Day 169

Statistical analysis description

Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1037

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0002

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.047

Confidence interval

level

95%

sides

2-sided

lower limit

0.022

upper limit

0.071

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 2.5/5 vs Tio 5 on Day 169

Statistical analysis description

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 5 μg

Number of subjects included in analysis

1038

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0004

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.044

Confidence interval

level

95%

sides

2-sided

lower limit

0.019

upper limit

0.068

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 5/5 vs T+O 2.5/5 on Day 169

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tio + Olo (T+O) 2.5 /5 μg

Number of subjects included in analysis

1039

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.136

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.018

Confidence interval

level

95%

sides

2-sided

lower limit

-0.006

upper limit

0.042

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 5/5 vs Tio 2.5 on Day 169

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1040

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.065

Confidence interval

level

95%

sides

2-sided

lower limit

0.041

upper limit

0.089

Variability estimate

Standard error of the mean

Dispersion value

0.012

Tio 5 vs Olo 5 on Day 169

Statistical analysis description

Comparison groups

Tiotropium (Tio) 5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1039

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1617

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.017

Confidence interval

level

95%

sides

2-sided

lower limit

-0.007

upper limit

0.041

Variability estimate

Standard error of the mean

Dispersion value

0.012

Tio 2.5 vs Olo 5 on Day 169

Statistical analysis description

Comparison groups

Tiotropium (Tio) 2.5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1038

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2476

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.014

Confidence interval

level

95%

sides

2-sided

lower limit

-0.01

upper limit

0.039

Variability estimate

Standard error of the mean

Dispersion value

0.012

Tio 5 vs Tio 2.5 on Day 169

Statistical analysis description

Comparison groups

Tiotropium (Tio) 5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1039

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8083

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.003

Confidence interval

level

95%

sides

2-sided

lower limit

-0.021

upper limit

0.027

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 5/5 vs Olo 5 on Day 365

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1040

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

0.075

upper limit

0.124

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 5/5 vs Tio 5 on Day 365

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 5 μg

Number of subjects included in analysis

1041

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.064

Confidence interval

level

95%

sides

2-sided

lower limit

0.039

upper limit

0.088

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 2.5/5 vs Olo 5 on Day 365

Statistical analysis description

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1037

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.076

Confidence interval

level

95%

sides

2-sided

lower limit

0.051

upper limit

0.1

Variability estimate

Standard error of the mean

Dispersion value

0.013

T+O 2.5/5 vs Tio 2.5 on Day 365

Statistical analysis description

Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1037

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.048

Confidence interval

level

95%

sides

2-sided

lower limit

0.023

upper limit

0.072

Variability estimate

Standard error of the mean

Dispersion value

0.013

T+O 2.5/5 vs Tio 5 on Day 365

Statistical analysis description

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 5 μg

Number of subjects included in analysis

1038

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0014

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.04

Confidence interval

level

95%

sides

2-sided

lower limit

0.015

upper limit

0.064

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 5/5 vs T+O 2.5/5 on Day 365

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tio + Olo (T+O) 2.5 /5 μg

Number of subjects included in analysis

1039

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0554

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.024

Confidence interval

level

95%

sides

2-sided

lower limit

-0.001

upper limit

0.048

Variability estimate

Standard error of the mean

Dispersion value

0.012

T+O 5/5 vs Tio 2.5 on Day 365

Statistical analysis description

Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 2.5 μg.. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1040

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.071

Confidence interval

level

95%

sides

2-sided

lower limit

0.047

upper limit

0.096

Variability estimate

Standard error of the mean

Dispersion value

0.012

Tio 5 vs Olo 5 on Day 365

Statistical analysis description

Comparison groups

Tiotropium (Tio) 5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1039

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0041

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.036

Confidence interval

level

95%

sides

2-sided

lower limit

0.011

upper limit

0.06

Variability estimate

Standard error of the mean

Dispersion value

0.013

Tio 2.5 vs Olo 5 on Day 365

Statistical analysis description

Comparison groups

Tiotropium (Tio) 2.5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1038

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0248

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.028

Confidence interval

level

95%

sides

2-sided

lower limit

0.004

upper limit

0.053

Variability estimate

Standard error of the mean

Dispersion value

0.013

Tio 5 vs Tio 2.5 on Day 365

Statistical analysis description

Comparison groups

Tiotropium (Tio) 5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1039

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5338

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.008

Confidence interval

level

95%

sides

2-sided

lower limit

-0.017

upper limit

0.032

Variability estimate

Standard error of the mean

Dispersion value

0.013

Secondary: Forced vital capacity (FVC) AUC (0-3h) response on Day 1, Day 85, Day 169, and Day 365

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End point title

Forced vital capacity (FVC) AUC (0-3h) response on Day 1, Day 85, Day 169, and Day 365

End point description

FVC AUC(0-3h) calculated as area under FVC-time curve from 0to3h post-dose using trapezoidal rule,divided by duration(3h) to report in litres.FVC AUC(0-3h) response defined as FVC AUC(0-3h) minus baseline FVC.Baseline was defined as mean of 2 pre-dose measurements performed 1h&at10 min prior to administration of first dose at visit2(day 1).The adjusted means (SE) were obtained by fitting MMRM model including fixed effects of treatment,planned test day,treatment-by-test day interaction,baseline&baseline-by-test day interaction,patient as random effect,&spatial power covariance structure for within-patient errors&Kenward-Roger approximation for denominator degrees of freedom.Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints,it is possible that the number of patients used in the FAS analysis for different endpoints will vary.

End point type

Secondary

End point timeframe

1 hour (h) and at 10 minutes (min) prior to dose and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on the first day of randomized treatment and on each of the days specified in the title.

End point values	Olodaterol (Olo) 5 μg	Tiotropium (Tio) 2.5 μg	Tiotropium (Tio) 5 μg	Tio + Olo (T+O) 2.5 /5 μg	Tio + Olo (T + O) 5/5 μg
Number of subjects analysed	525 ^[21]	524 ^[22]	526 ^[23]	521 ^[24]	522 ^[25]
Units: litre(s)
least squares mean (standard error)
Day 1	0.35 ( 0.017 )	0.277 ( 0.017 )	0.289 ( 0.017 )	0.4 ( 0.017 )	0.427 ( 0.017 )
Day 85	0.247 ( 0.017 )	0.318 ( 0.017 )	0.275 ( 0.017 )	0.432 ( 0.017 )	0.469 ( 0.017 )
Day 169	0.212 ( 0.017 )	0.279 ( 0.017 )	0.254 ( 0.017 )	0.386 ( 0.017 )	0.407 ( 0.017 )
Day 365	0.172 ( 0.018 )	0.241 ( 0.018 )	0.221 ( 0.018 )	0.364 ( 0.018 )	0.377 ( 0.018 )

Notes
[21] - Number of FAS (full analysis set) patients actually contributing to the model.
[22] - Number of FAS (full analysis set) patients actually contributing to the model.
[23] - Number of FAS (full analysis set) patients actually contributing to the model.
[24] - Number of FAS (full analysis set) patients actually contributing to the model.
[25] - Number of FAS (full analysis set) patients actually contributing to the model.

T+O 5/5 vs Olo 5 on Day 1

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1047

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0017

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.077

Confidence interval

level

95%

sides

2-sided

lower limit

0.029

upper limit

0.125

Variability estimate

Standard error of the mean

Dispersion value

0.024

T+O 5/5 vs Tio 5 on Day 1

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 5 μg

Number of subjects included in analysis

1048

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.138

Confidence interval

level

95%

sides

2-sided

lower limit

0.09

upper limit

0.186

Variability estimate

Standard error of the mean

Dispersion value

0.024

T+O 2.5/5 vs Olo 5 on Day 1

Statistical analysis description

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1046

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0426

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.05

Confidence interval

level

95%

sides

2-sided

lower limit

0.002

upper limit

0.098

Variability estimate

Standard error of the mean

Dispersion value

0.024

T+O 2.5/5 vs Tio 2.5 on Day 1

Statistical analysis description

Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1045

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.122

Confidence interval

level

95%

sides

2-sided

lower limit

0.074

upper limit

0.17

Variability estimate

Standard error of the mean

Dispersion value

0.024

T+O 2.5/5 vs Tio 5 on Day 1

Statistical analysis description

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 5 μg

Number of subjects included in analysis

1047

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.111

Confidence interval

level

95%

sides

2-sided

lower limit

0.063

upper limit

0.159

Variability estimate

Standard error of the mean

Dispersion value

0.024

T+O 5/5 vs T+O 2.5/5 on Day 1

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tio + Olo (T+O) 2.5 /5 μg

Number of subjects included in analysis

1043

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2661

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.027

Confidence interval

level

95%

sides

2-sided

lower limit

-0.021

upper limit

0.075

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 5/5 vs Tio 2.5 on Day 1

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1046

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.15

Confidence interval

level

95%

sides

2-sided

lower limit

0.102

upper limit

0.198

Variability estimate

Standard error of the mean

Dispersion value

0.024

Tio 5 vs Olo 5 on Day 1

Statistical analysis description

Comparison groups

Tiotropium (Tio) 5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1051

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0119

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

-0.061

Confidence interval

level

95%

sides

2-sided

lower limit

-0.109

upper limit

-0.014

Variability estimate

Standard error of the mean

Dispersion value

0.024

Tio 2.5 vs Olo 5 on Day 1

Statistical analysis description

Comparison groups

Tiotropium (Tio) 2.5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1049

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0029

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

-0.073

Confidence interval

level

95%

sides

2-sided

lower limit

-0.121

upper limit

-0.025

Variability estimate

Standard error of the mean

Dispersion value

0.024

Tio 5 vs Tio 2.5 on Day 1

Statistical analysis description

Comparison groups

Tiotropium (Tio) 5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1050

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6408

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.011

Confidence interval

level

95%

sides

2-sided

lower limit

-0.036

upper limit

0.059

Variability estimate

Standard error of the mean

Dispersion value

0.024

T+O 5/5 vs Olo 5 on Day 85

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1047

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.221

Confidence interval

level

95%

sides

2-sided

lower limit

0.173

upper limit

0.27

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 5/5 vs Tio 5 on Day 85

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 5 μg

Number of subjects included in analysis

1048

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.193

Confidence interval

level

95%

sides

2-sided

lower limit

0.145

upper limit

0.242

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 2.5/5 vs Olo 5 on Day 85

Statistical analysis description

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1046

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.185

Confidence interval

level

95%

sides

2-sided

lower limit

0.136

upper limit

0.233

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 2.5/5 vs Tio 2.5 on Day 85

Statistical analysis description

Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1045

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.114

Confidence interval

level

95%

sides

2-sided

lower limit

0.065

upper limit

0.162

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 2.5/5 vs Tio 5 on Day 85

Statistical analysis description

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 5 μg

Number of subjects included in analysis

1047

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.157

Confidence interval

level

95%

sides

2-sided

lower limit

0.108

upper limit

0.205

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 5/5 vs T+O 2.5/5 on Day 85

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tio + Olo (T+O) 2.5 /5 μg

Number of subjects included in analysis

1043

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1355

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.037

Confidence interval

level

95%

sides

2-sided

lower limit

-0.012

upper limit

0.085

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 5/5 vs Tio 2.5 on Day 85

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1046

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.151

Confidence interval

level

95%

sides

2-sided

lower limit

0.102

upper limit

0.199

Variability estimate

Standard error of the mean

Dispersion value

0.025

Tio 5 vs Olo 5 on Day 85

Statistical analysis description

Comparison groups

Tiotropium (Tio) 5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1051

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2562

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.028

Confidence interval

level

95%

sides

2-sided

lower limit

-0.02

upper limit

0.076

Variability estimate

Standard error of the mean

Dispersion value

0.025

Tio 2.5 vs Olo 5 on Day 85

Statistical analysis description

Comparison groups

Tiotropium (Tio) 2.5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1049

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0041

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.071

Confidence interval

level

95%

sides

2-sided

lower limit

0.022

upper limit

0.119

Variability estimate

Standard error of the mean

Dispersion value

0.025

Tio 5 vs Tio 2.5 on Day 85

Statistical analysis description

Comparison groups

Tiotropium (Tio) 5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1050

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0815

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

-0.043

Confidence interval

level

95%

sides

2-sided

lower limit

-0.091

upper limit

0.005

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 5/5 vs Olo 5 on Day 169

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1047

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.195

Confidence interval

level

95%

sides

2-sided

lower limit

0.149

upper limit

0.242

Variability estimate

Standard error of the mean

Dispersion value

0.024

T+O 5/5 vs Tio 5 on Day 169

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 5 μg

Number of subjects included in analysis

1048

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.153

Confidence interval

level

95%

sides

2-sided

lower limit

0.107

upper limit

0.199

Variability estimate

Standard error of the mean

Dispersion value

0.024

T+O 2.5/5 vs Olo 5 on Day 169

Statistical analysis description

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1046

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.174

Confidence interval

level

95%

sides

2-sided

lower limit

0.128

upper limit

0.221

Variability estimate

Standard error of the mean

Dispersion value

0.024

T+O 2.5/5 vs Tio 2.5 on Day 169

Statistical analysis description

Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1045

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.107

Confidence interval

level

95%

sides

2-sided

lower limit

0.061

upper limit

0.154

Variability estimate

Standard error of the mean

Dispersion value

0.024

T+O 2.5/5 vs Tio 5 on Day 169

Statistical analysis description

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 5 μg

Number of subjects included in analysis

1047

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.132

Confidence interval

level

95%

sides

2-sided

lower limit

0.086

upper limit

0.178

Variability estimate

Standard error of the mean

Dispersion value

0.024

T+O 5/5 vs T+O 2.5/5 on Day 169

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tio + Olo (T+O) 2.5 /5 μg

Number of subjects included in analysis

1043

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3727

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.021

Confidence interval

level

95%

sides

2-sided

lower limit

-0.025

upper limit

0.067

Variability estimate

Standard error of the mean

Dispersion value

0.024

T+O 5/5 vs Tio 2.5 on Day 169

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1046

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.128

Confidence interval

level

95%

sides

2-sided

lower limit

0.082

upper limit

0.175

Variability estimate

Standard error of the mean

Dispersion value

0.024

Tio 5 vs Olo 5 on Day 169

Statistical analysis description

Comparison groups

Tiotropium (Tio) 5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1051

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0744

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.042

Confidence interval

level

95%

sides

2-sided

lower limit

-0.004

upper limit

0.089

Variability estimate

Standard error of the mean

Dispersion value

0.024

Tio 2.5 vs Olo 5 on Day 169

Statistical analysis description

Comparison groups

Tiotropium (Tio) 2.5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1049

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0047

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.067

Confidence interval

level

95%

sides

2-sided

lower limit

0.021

upper limit

0.114

Variability estimate

Standard error of the mean

Dispersion value

0.024

Tio 5 vs Tio 2.5 on Day 169

Statistical analysis description

Comparison groups

Tiotropium (Tio) 5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1050

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2945

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

-0.025

Confidence interval

level

95%

sides

2-sided

lower limit

-0.071

upper limit

0.022

Variability estimate

Standard error of the mean

Dispersion value

0.024

T+O 5/5 vs Olo 5 on Day 365

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1047

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.205

Confidence interval

level

95%

sides

2-sided

lower limit

0.155

upper limit

0.255

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 5/5 vs Tio 5 on Day 365

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 5 μg

Number of subjects included in analysis

1048

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.156

Confidence interval

level

95%

sides

2-sided

lower limit

0.107

upper limit

0.206

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 2.5/5 vs Olo 5 on Day 365

Statistical analysis description

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1046

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.192

Confidence interval

level

95%

sides

2-sided

lower limit

0.142

upper limit

0.242

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 2.5/5 vs Tio 2.5 on Day 365

Statistical analysis description

Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1045

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.124

Confidence interval

level

95%

sides

2-sided

lower limit

0.074

upper limit

0.174

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 2.5/5 vs Tio 5 on Day 365

Statistical analysis description

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 5 μg

Number of subjects included in analysis

1047

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.144

Confidence interval

level

95%

sides

2-sided

lower limit

0.094

upper limit

0.193

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 5/5 vs T+O 2.5/5 on Day 365

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tio + Olo (T+O) 2.5 /5 μg

Number of subjects included in analysis

1043

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6103

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.013

Confidence interval

level

95%

sides

2-sided

lower limit

-0.037

upper limit

0.062

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 5/5 vs Tio 2.5 on Day 365

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1046

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.137

Confidence interval

level

95%

sides

2-sided

lower limit

0.087

upper limit

0.186

Variability estimate

Standard error of the mean

Dispersion value

0.025

Tio 5 vs Olo 5 on Day 365

Statistical analysis description

Comparison groups

Tiotropium (Tio) 5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1051

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0559

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.049

Confidence interval

level

95%

sides

2-sided

lower limit

-0.001

upper limit

0.098

Variability estimate

Standard error of the mean

Dispersion value

0.025

Tio 2.5 vs Olo 5 on Day 365

Statistical analysis description

Comparison groups

Tiotropium (Tio) 2.5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1049

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0073

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.068

Confidence interval

level

95%

sides

2-sided

lower limit

0.018

upper limit

0.118

Variability estimate

Standard error of the mean

Dispersion value

0.025

Tio 5 vs Tio 2.5 on Day 365

Statistical analysis description

Comparison groups

Tiotropium (Tio) 5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1050

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4368

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

-0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.07

upper limit

0.03

Variability estimate

Standard error of the mean

Dispersion value

0.025

Secondary: Trough FVC response on Day 15, Day 43, Day 85, Day 170, and Day 365

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End point title

Trough FVC response on Day 15, Day 43, Day 85, Day 170, and Day 365

End point description

Trough FVC defined as the FVC value at the end of the dosing interval (24 hours),calculated as mean of the pre-dose measurements.Trough FVC response defined as trough FVC minus baseline FVC. Baseline was defined as mean of 2 pre-dose measurements performed 1h&at 10min prior to administration of first dose at visit 2(day 1).The adjusted means (SE) were obtained by fitting MMRM including fixed effects of treatment,planned test day,treatment-by-test day interaction,baseline and baseline-by-test day interaction,patient as random effect, &spatial power covariance structure for within-patient errors &Kenward-Roger approximation for denominator degrees of freedom. Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.

End point type

Secondary

End point timeframe

1 h and at 10 min prior to dose on the first day of randomized treatment (baseline), day 85, day 365, at 10 min pre-dose on day 15 and 43 and at 23 h and at 23 h 50 min after inhalation of study medication on Day 170.

End point values	Olodaterol (Olo) 5 μg	Tiotropium (Tio) 2.5 μg	Tiotropium (Tio) 5 μg	Tio + Olo (T+O) 2.5 /5 μg	Tio + Olo (T + O) 5/5 μg
Number of subjects analysed	519 ^[26]	519 ^[27]	520 ^[28]	518 ^[29]	521 ^[30]
Units: litre(s)
least squares mean (standard error)
Day 15	0.149 ( 0.018 )	0.222 ( 0.018 )	0.22 ( 0.018 )	0.27 ( 0.018 )	0.296 ( 0.018 )
Day 43	0.15 ( 0.018 )	0.206 ( 0.018 )	0.213 ( 0.018 )	0.254 ( 0.018 )	0.318 ( 0.018 )
Day 85	0.077 ( 0.018 )	0.168 ( 0.018 )	0.144 ( 0.018 )	0.23 ( 0.018 )	0.265 ( 0.018 )
Day 170	0.093 ( 0.017 )	0.184 ( 0.017 )	0.169 ( 0.017 )	0.225 ( 0.017 )	0.246 ( 0.017 )
Day 365	0.014 ( 0.018 )	0.114 ( 0.018 )	0.108 ( 0.018 )	0.155 ( 0.018 )	0.191 ( 0.018 )

Notes
[26] - Number of FAS (full analysis set) patients actually contributing to the model.
[27] - Number of FAS (full analysis set) patients actually contributing to the model.
[28] - Number of FAS (full analysis set) patients actually contributing to the model.
[29] - Number of FAS (full analysis set) patients actually contributing to the model.
[30] - Number of FAS (full analysis set) patients actually contributing to the model.

T+O 5/5 vs Olo 5 on Day 15

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1040

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.147

Confidence interval

level

95%

sides

2-sided

lower limit

0.098

upper limit

0.196

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 5/5 vs Tio 5 on Day 15

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 5 μg

Number of subjects included in analysis

1041

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0023

Method

Mixed models analysis

Parameter type

Adjusted mean difference

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

0.025

T+O 2.5/5 vs Olo 5 on Day 15

Statistical analysis description

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1037

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.121

Confidence interval

level

95%

sides

2-sided

lower limit

0.072

upper limit

0.17

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 2.5/5 vs Tio 2.5 on Day 15

Statistical analysis description

Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1037

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0545

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.048

Confidence interval

level

95%

sides

2-sided

lower limit

-0.001

upper limit

0.097

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 2.5/5 vs Tio 5 on Day 15

Statistical analysis description

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 5 μg

Number of subjects included in analysis

1038

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0456

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.05

Confidence interval

level

95%

sides

2-sided

lower limit

0.001

upper limit

0.099

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 5/5 vs T+O 2.5/5 on Day 15

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tio + Olo (T+O) 2.5 /5 μg

Number of subjects included in analysis

1039

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2949

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.026

Confidence interval

level

95%

sides

2-sided

lower limit

-0.023

upper limit

0.075

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 5/5 vs Tio 2.5 on Day 15

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1040

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0029

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.074

Confidence interval

level

95%

sides

2-sided

lower limit

0.025

upper limit

0.123

Variability estimate

Standard error of the mean

Dispersion value

0.025

Tio 5 vs Olo 5 on Day 15

Statistical analysis description

Comparison groups

Tiotropium (Tio) 5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1039

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0045

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.071

Confidence interval

level

95%

sides

2-sided

lower limit

0.022

upper limit

0.12

Variability estimate

Standard error of the mean

Dispersion value

0.025

Tio 2.5 vs Olo 5 on Day 15

Statistical analysis description

Comparison groups

Tiotropium (Tio) 2.5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1038

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0035

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.073

Confidence interval

level

95%

sides

2-sided

lower limit

0.024

upper limit

0.122

Variability estimate

Standard error of the mean

Dispersion value

0.025

Tio 5 vs Tio 2.5 on Day 15

Statistical analysis description

Comparison groups

Tiotropium (Tio) 5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1039

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9369

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

-0.002

Confidence interval

level

95%

sides

2-sided

lower limit

-0.051

upper limit

0.047

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 5/5 vs Olo 5 on Day 43

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1040

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.168

Confidence interval

level

95%

sides

2-sided

lower limit

0.119

upper limit

0.217

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 5/5 vs Tio 5 on Day 43

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 5 μg

Number of subjects included in analysis

1041

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.105

Confidence interval

level

95%

sides

2-sided

lower limit

0.056

upper limit

0.154

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 2.5/5 vs Olo 5 on Day 43

Statistical analysis description

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1037

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.103

Confidence interval

level

95%

sides

2-sided

lower limit

0.054

upper limit

0.152

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 2.5/5 vs Tio 2.5 on Day 43

Statistical analysis description

Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1037

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0585

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.047

Confidence interval

level

95%

sides

2-sided

lower limit

-0.002

upper limit

0.096

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 2.5/5 vs Tio 5 on Day 43

Statistical analysis description

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 5 μg

Number of subjects included in analysis

1038

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1042

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.041

Confidence interval

level

95%

sides

2-sided

lower limit

-0.008

upper limit

0.09

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 5/5 vs T+O 2.5/5 on Day 43

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tio + Olo (T+O) 2.5 /5 μg

Number of subjects included in analysis

1039

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0097

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.065

Confidence interval

level

95%

sides

2-sided

lower limit

0.016

upper limit

0.114

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 5/5 vs Tio 2.5 on Day 43

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1040

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.112

Confidence interval

level

95%

sides

2-sided

lower limit

0.063

upper limit

0.161

Variability estimate

Standard error of the mean

Dispersion value

0.025

Tio 5 vs Olo 5 on Day 43

Statistical analysis description

Comparison groups

Tiotropium (Tio) 5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1039

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.012

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.063

Confidence interval

level

95%

sides

2-sided

lower limit

0.014

upper limit

0.112

Variability estimate

Standard error of the mean

Dispersion value

0.025

Tio 2.5 vs Olo 5 on Day 43

Statistical analysis description

Comparison groups

Tiotropium (Tio) 2.5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1038

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.025

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.056

Confidence interval

level

95%

sides

2-sided

lower limit

0.007

upper limit

0.105

Variability estimate

Standard error of the mean

Dispersion value

0.025

Tio 5 vs Tio 2.5 on Day 43

Statistical analysis description

Comparison groups

Tiotropium (Tio) 5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1039

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7889

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.007

Confidence interval

level

95%

sides

2-sided

lower limit

-0.042

upper limit

0.056

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 5/5 vs Olo 5 on Day 85

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1040

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.187

Confidence interval

level

95%

sides

2-sided

lower limit

0.138

upper limit

0.237

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 5/5 vs Tio 5 on Day 85

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 5 μg

Number of subjects included in analysis

1041

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.121

Confidence interval

level

95%

sides

2-sided

lower limit

0.072

upper limit

0.17

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 2.5/5 vs Olo 5 on Day85

Statistical analysis description

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1037

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.153

Confidence interval

level

95%

sides

2-sided

lower limit

0.103

upper limit

0.202

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 2.5/5 vs Tio 2.5 on Day 85

Statistical analysis description

Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1037

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0134

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.062

Confidence interval

level

95%

sides

2-sided

lower limit

0.013

upper limit

0.111

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 2.5/5 vs Tio 5 on Day 85

Statistical analysis description

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 5 μg

Number of subjects included in analysis

1038

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0006

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.086

Confidence interval

level

95%

sides

2-sided

lower limit

0.037

upper limit

0.136

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 5/5 vs T+O 2.5/5 on Day 85

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tio + Olo (T+O) 2.5 /5 μg

Number of subjects included in analysis

1039

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.167

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.035

Confidence interval

level

95%

sides

2-sided

lower limit

-0.015

upper limit

0.084

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 5/5 vs Tio 2.5 on Day 85

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1040

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.097

Confidence interval

level

95%

sides

2-sided

lower limit

0.048

upper limit

0.146

Variability estimate

Standard error of the mean

Dispersion value

0.025

Tio 5 vs Olo 5 on Day 85

Statistical analysis description

Comparison groups

Tiotropium (Tio) 5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1039

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0085

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.066

Confidence interval

level

95%

sides

2-sided

lower limit

0.017

upper limit

0.115

Variability estimate

Standard error of the mean

Dispersion value

0.025

Tio 2.5 vs Olo 5 on Day 85

Statistical analysis description

Comparison groups

Tiotropium (Tio) 2.5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1038

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0003

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.09

Confidence interval

level

95%

sides

2-sided

lower limit

0.041

upper limit

0.14

Variability estimate

Standard error of the mean

Dispersion value

0.025

Tio 5 vs Tio 2.5 on Day 85

Statistical analysis description

Comparison groups

Tiotropium (Tio) 5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1039

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3332

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

-0.024

Confidence interval

level

95%

sides

2-sided

lower limit

-0.074

upper limit

0.025

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 5/5 vs Olo 5 on Day 170

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1040

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.153

Confidence interval

level

95%

sides

2-sided

lower limit

0.105

upper limit

0.201

Variability estimate

Standard error of the mean

Dispersion value

0.024

T+O 5/5 vs Tio 5 on Day 170

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 5 μg

Number of subjects included in analysis

1041

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0016

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.077

Confidence interval

level

95%

sides

2-sided

lower limit

0.029

upper limit

0.125

Variability estimate

Standard error of the mean

Dispersion value

0.024

T+O 2.5/5 vs Olo 5 on Day 170

Statistical analysis description

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1037

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.132

Confidence interval

level

95%

sides

2-sided

lower limit

0.084

upper limit

0.18

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 2.5/5 vs Tio 2.5 on Day 170

Statistical analysis description

Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1037

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0926

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.041

Confidence interval

level

95%

sides

2-sided

lower limit

-0.007

upper limit

0.089

Variability estimate

Standard error of the mean

Dispersion value

0.024

T+O 2.5/5 vs Tio 5 on Day 170

Statistical analysis description

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 5 μg

Number of subjects included in analysis

1038

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0231

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.055

Confidence interval

level

95%

sides

2-sided

lower limit

0.008

upper limit

0.103

Variability estimate

Standard error of the mean

Dispersion value

0.024

T+O 5/5 vs T+O 2.5/5 on Day 170

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tio + Olo (T+O) 2.5 /5 μg

Number of subjects included in analysis

1039

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3802

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.021

Confidence interval

level

95%

sides

2-sided

lower limit

-0.026

upper limit

0.069

Variability estimate

Standard error of the mean

Dispersion value

0.024

T+O 5/5 vs Tio 2.5 on Day 170

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1040

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0105

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.062

Confidence interval

level

95%

sides

2-sided

lower limit

0.015

upper limit

0.11

Variability estimate

Standard error of the mean

Dispersion value

0.024

Tio 5 vs Olo 5 on Day 170

Statistical analysis description

Comparison groups

Tiotropium (Tio) 5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1039

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0018

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.076

Confidence interval

level

95%

sides

2-sided

lower limit

0.028

upper limit

0.125

Variability estimate

Standard error of the mean

Dispersion value

0.025

Tio 2.5 vs Olo 5 on Day 170

Statistical analysis description

Comparison groups

Tiotropium (Tio) 2.5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1038

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0002

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.091

Confidence interval

level

95%

sides

2-sided

lower limit

0.043

upper limit

0.139

Variability estimate

Standard error of the mean

Dispersion value

0.025

Tio 5 vs Tio 2.5 on Day 170

Statistical analysis description

Comparison groups

Tiotropium (Tio) 5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1039

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5554

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

-0.014

Confidence interval

level

95%

sides

2-sided

lower limit

-0.062

upper limit

0.034

Variability estimate

Standard error of the mean

Dispersion value

0.024

T+O 5/5 vs Olo 5 on Day 365

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1040

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.178

Confidence interval

level

95%

sides

2-sided

lower limit

0.127

upper limit

0.228

Variability estimate

Standard error of the mean

Dispersion value

0.026

T+O 5/5 vs Tio 5 on Day 365

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 5 μg

Number of subjects included in analysis

1041

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0011

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.084

Confidence interval

level

95%

sides

2-sided

lower limit

0.033

upper limit

0.134

Variability estimate

Standard error of the mean

Dispersion value

0.026

T+O 2.5/5 vs Olo 5 on Day 365

Statistical analysis description

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1037

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.142

Confidence interval

level

95%

sides

2-sided

lower limit

0.091

upper limit

0.192

Variability estimate

Standard error of the mean

Dispersion value

0.026

T+O 2.5/5 vs Tio 2.5 on Day 365

Statistical analysis description

Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1037

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1112

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.041

Confidence interval

level

95%

sides

2-sided

lower limit

-0.009

upper limit

0.091

Variability estimate

Standard error of the mean

Dispersion value

0.026

T+O 2.5/5 vs Tio 5 on Day 365

Statistical analysis description

Comparison groups

Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 5 μg

Number of subjects included in analysis

1038

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0632

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.048

Confidence interval

level

95%

sides

2-sided

lower limit

-0.003

upper limit

0.098

Variability estimate

Standard error of the mean

Dispersion value

0.026

T+O 5/5 vs T+O 2.5/5 on Day 365

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tio + Olo (T+O) 2.5 /5 μg

Number of subjects included in analysis

1039

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1615

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.036

Confidence interval

level

95%

sides

2-sided

lower limit

-0.014

upper limit

0.086

Variability estimate

Standard error of the mean

Dispersion value

0.026

T+O 5/5 vs Tio 2.5 on Day 365

Statistical analysis description

Comparison groups

Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1040

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0027

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.077

Confidence interval

level

95%

sides

2-sided

lower limit

0.027

upper limit

0.127

Variability estimate

Standard error of the mean

Dispersion value

0.026

Tio 5 vs Olo 5 on Day 365

Statistical analysis description

Comparison groups

Tiotropium (Tio) 5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1039

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0003

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.094

Confidence interval

level

95%

sides

2-sided

lower limit

0.044

upper limit

0.144

Variability estimate

Standard error of the mean

Dispersion value

0.026

Tio 2.5 vs Olo 5 on Day 365

Statistical analysis description

Comparison groups

Tiotropium (Tio) 2.5 μg v Olodaterol (Olo) 5 μg

Number of subjects included in analysis

1038

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.101

Confidence interval

level

95%

sides

2-sided

lower limit

0.05

upper limit

0.151

Variability estimate

Standard error of the mean

Dispersion value

0.026

Tio 5 vs Tio 2.5 on Day 365

Statistical analysis description

Comparison groups

Tiotropium (Tio) 5 μg v Tiotropium (Tio) 2.5 μg

Number of subjects included in analysis

1039

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7925

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

-0.007

Confidence interval

level

95%

sides

2-sided

lower limit

-0.057

upper limit

0.044

Variability estimate

Standard error of the mean

Dispersion value

0.026

Adverse events

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Timeframe for reporting adverse events

All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 447 days)

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

16.1

Reporting group title

Olodaterol (5 μg)

Reporting group description

Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.

Reporting group title

Tiotropium (2.5 μg)

Reporting group description

Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.

Reporting group title

Tiotropium (5 μg)

Reporting group description

Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.

Reporting group title

Tio+Olo FDC (2.5/5 μg)

Reporting group description

Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.

Reporting group title

Tio+Olo FDC (5/5 μg)

Reporting group description

Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning

Serious adverse events	Olodaterol (5 μg)	Tiotropium (2.5 μg)	Tiotropium (5 μg)	Tio+Olo FDC (2.5/5 μg)	Tio+Olo FDC (5/5 μg)
Total subjects affected by serious adverse events
subjects affected / exposed	75 / 528 (14.20%)	66 / 525 (12.57%)	79 / 527 (14.99%)	81 / 522 (15.52%)	87 / 522 (16.67%)
number of deaths (all causes)	5	11	12	10	10
number of deaths resulting from adverse events	0	1	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma pancreas
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (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
Basal cell carcinoma
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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
Benign neoplasm of bladder
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
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
Benign ovarian tumour
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Bladder cancer
subjects affected / exposed	1 / 528 (0.19%)	1 / 525 (0.19%)	0 / 527 (0.00%)	1 / 522 (0.19%)	1 / 522 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bladder neoplasm
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
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
Bladder papilloma
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Brain neoplasm
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
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 / 1
Bronchial carcinoma
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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 / 1	0 / 0	0 / 0	0 / 0
Chronic lymphocytic leukaemia
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colon cancer
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
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
Enchondroma
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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
Gastric cancer
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	2 / 522 (0.38%)	0 / 522 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastric neoplasm
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Glioblastoma multiforme
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (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
Hepatic cancer
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Lipoma
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
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
Lung adenocarcinoma
subjects affected / exposed	1 / 528 (0.19%)	1 / 525 (0.19%)	2 / 527 (0.38%)	0 / 522 (0.00%)	0 / 522 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung adenocarcinoma metastatic
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Lung cancer metastatic
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (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 / 1	0 / 0
Lung neoplasm malignant
subjects affected / exposed	1 / 528 (0.19%)	1 / 525 (0.19%)	5 / 527 (0.95%)	3 / 522 (0.57%)	1 / 522 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 5	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 1	0 / 0
Malignant melanoma
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	2 / 527 (0.38%)	0 / 522 (0.00%)	0 / 522 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Meningioma
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (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
Metastases to bone
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Metastases to central nervous system
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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
Metastases to lymph nodes
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (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
Neuroendocrine carcinoma of the skin
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (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
Oesophageal carcinoma
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	1 / 522 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
Prostate cancer
subjects affected / exposed	2 / 528 (0.38%)	1 / 525 (0.19%)	2 / 527 (0.38%)	2 / 522 (0.38%)	0 / 522 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal cancer
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Renal cell carcinoma
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Small cell lung cancer
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
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
Small cell lung cancer metastatic
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (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
Squamous cell carcinoma of skin
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Tongue neoplasm malignant stage unspecified
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Ureteric cancer
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (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
Vascular disorders
Arterial occlusive disease
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
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
Arteriosclerosis
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Circulatory collapse
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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
Deep vein thrombosis
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
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
Hypertension
subjects affected / exposed	2 / 528 (0.38%)	0 / 525 (0.00%)	1 / 527 (0.19%)	1 / 522 (0.19%)	0 / 522 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypertensive crisis
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Hypotension
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
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
Peripheral arterial occlusive disease
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Peripheral vascular disorder
subjects affected / exposed	2 / 528 (0.38%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
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 / 1
Surgical and medical procedures
Hip arthroplasty
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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
Nasal septal operation
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	1 / 527 (0.19%)	0 / 522 (0.00%)	1 / 522 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Death
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	1 / 522 (0.19%)	1 / 522 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
Electrocution
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (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
Generalised oedema
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
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
Hernia
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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
Inflammation
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (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
Local swelling
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Malaise
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
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
Multi-organ failure
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	2 / 527 (0.38%)	0 / 522 (0.00%)	0 / 522 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (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
Sudden death
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
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 / 1
Systemic inflammatory response syndrome
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (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	2 / 528 (0.38%)	0 / 525 (0.00%)	1 / 527 (0.19%)	1 / 522 (0.19%)	1 / 522 (0.19%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Menorrhagia
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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
Pelvic adhesions
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Prostatitis
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
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
Prostatomegaly
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Uterine prolapse
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
subjects affected / exposed	2 / 528 (0.38%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Asthma
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
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
Bronchospasm
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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
Chronic obstructive pulmonary disease
subjects affected / exposed	27 / 528 (5.11%)	25 / 525 (4.76%)	24 / 527 (4.55%)	20 / 522 (3.83%)	36 / 522 (6.90%)
occurrences causally related to treatment / all	3 / 35	0 / 28	0 / 29	0 / 21	2 / 40
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 2	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	1 / 522 (0.19%)	1 / 522 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	2 / 528 (0.38%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypercapnia
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Hypoxia
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	1 / 522 (0.19%)	0 / 522 (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
Lung infiltration
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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
Organising pneumonia
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (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
Pleural effusion
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	1 / 522 (0.19%)	0 / 522 (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
Pneumonitis
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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
Pneumothorax
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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
Pneumothorax spontaneous
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
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 congestion
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (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
Pulmonary embolism
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	0 / 522 (0.00%)	3 / 522 (0.57%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary hypertension
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
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 mass
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	1 / 522 (0.19%)	1 / 522 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
Pulmonary oedema
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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
Respiratory failure
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (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 / 1	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Abnormal behaviour
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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
Bipolar disorder
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Confusional state
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (0.00%)
occurrences causally related to treatment / all	1 / 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
Depression
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Major depression
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric decompensation
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Psychotic disorder
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
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
Suicidal ideation
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (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
Suicide attempt
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (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
Investigations
Arteriogram coronary
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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 murmur
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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
Prostatic specific antigen increased
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Alcohol poisoning
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Ankle fracture
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (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
Bone fissure
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Brain contusion
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Cervical vertebral fracture
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Clavicle fracture
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (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
Contusion
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Facial bones fracture
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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
Fall
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	1 / 527 (0.19%)	2 / 522 (0.38%)	2 / 522 (0.38%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	2 / 522 (0.38%)	0 / 522 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fractured coccyx
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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
Ligament sprain
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Limb injury
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
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
Meniscus injury
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
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
Periprosthetic fracture
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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
Pneumothorax traumatic
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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
Post laminectomy syndrome
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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
Postoperative ileus
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Procedural pain
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (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
Radius fracture
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Road traffic accident
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Skull fractured base
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Subdural haematoma
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Subdural haemorrhage
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Tendon rupture
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Thermal burn
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (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
Thoracic vertebral fracture
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Wound
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	1 / 528 (0.19%)	1 / 525 (0.19%)	0 / 527 (0.00%)	1 / 522 (0.19%)	3 / 522 (0.57%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	1 / 528 (0.19%)	1 / 525 (0.19%)	1 / 527 (0.19%)	0 / 522 (0.00%)	4 / 522 (0.77%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Angina unstable
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (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
Arteriosclerosis coronary artery
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	2 / 528 (0.38%)	1 / 525 (0.19%)	2 / 527 (0.38%)	2 / 522 (0.38%)	1 / 522 (0.19%)
occurrences causally related to treatment / all	0 / 2	0 / 1	1 / 2	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrioventricular block
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Atrioventricular block complete
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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
Bradycardia
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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 arrest
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
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 / 1
Cardiac failure
subjects affected / exposed	0 / 528 (0.00%)	2 / 525 (0.38%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
Cardiac failure acute
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	1 / 522 (0.19%)	0 / 522 (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 / 1	0 / 0	0 / 0
Cardiac failure chronic
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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
Cardio-respiratory arrest
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	1 / 522 (0.19%)
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 / 1	0 / 1
Cardiomyopathy
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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
Cardiopulmonary failure
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
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 / 1
Coronary artery disease
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	2 / 527 (0.38%)	0 / 522 (0.00%)	1 / 522 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mitral valve stenosis
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Myocardial infarction
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	1 / 527 (0.19%)	1 / 522 (0.19%)	2 / 522 (0.38%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	2 / 527 (0.38%)	0 / 522 (0.00%)	0 / 522 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ventricular fibrillation
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (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
Ventricular tachycardia
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Nervous system disorders
Amyotrophic lateral sclerosis
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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 / 1	0 / 0	0 / 0
Cerebral infarction
subjects affected / exposed	1 / 528 (0.19%)	1 / 525 (0.19%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	2 / 528 (0.38%)	2 / 525 (0.38%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (0.00%)
occurrences causally related to treatment / all	0 / 2	1 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Convulsion
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Critical illness polyneuropathy
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Cubital tunnel syndrome
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Dementia
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Epilepsy
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Haemorrhagic stroke
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
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 / 1
Intracranial aneurysm
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
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
Ischaemic stroke
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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
Lacunar infarction
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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
Lumbar radiculopathy
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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
Migraine
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Multiple sclerosis
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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
Neuralgia
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Post herpetic neuralgia
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
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
Sciatica
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
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
Syncope
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (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
Transient ischaemic attack
subjects affected / exposed	0 / 528 (0.00%)	2 / 525 (0.38%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vocal cord paralysis
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (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 and lymphatic system disorders
Leukocytosis
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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
Lymphadenopathy
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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
Pancytopenia
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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 disorders
Abdominal adhesions
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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 hernia
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	1 / 522 (0.19%)
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
Abdominal pain
subjects affected / exposed	2 / 528 (0.38%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	1 / 522 (0.19%)	0 / 522 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anal fissure
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (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
Anal fistula
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Coeliac disease
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Crohn's disease
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Diarrhoea
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Diverticular perforation
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Duodenitis
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Gastric polyps
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (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 ulcer
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
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
Gastritis
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	2 / 528 (0.38%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
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
Haematemesis
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	2 / 522 (0.38%)	3 / 522 (0.57%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
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
Large intestine polyp
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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
Melaena
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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
Nausea
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
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
Pancreatic cyst
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
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
Pancreatic duct dilatation
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Pancreatitis acute
subjects affected / exposed	0 / 528 (0.00%)	2 / 525 (0.38%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 1	0 / 0
Pancreatitis chronic
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Rectal ulcer
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (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
Small intestinal obstruction
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (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
Umbilical hernia
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (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
Vomiting
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
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
Hepatobiliary disorders
Bile duct obstruction
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Bile duct stone
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (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
Biliary dilatation
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Cholangitis
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (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
Cholecystitis acute
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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
Hepatic cyst
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Jaundice cholestatic
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Psoriasis
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (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 ureteric
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (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
Haematuria
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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 colic
subjects affected / exposed	2 / 528 (0.38%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure acute
subjects affected / exposed	2 / 528 (0.38%)	0 / 525 (0.00%)	2 / 527 (0.38%)	1 / 522 (0.19%)	0 / 522 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure chronic
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
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
Urethral stenosis
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	1 / 522 (0.19%)	1 / 522 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract obstruction
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Hyperparathyroidism primary
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Musculoskeletal and connective tissue disorders
Arthritis
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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
Back pain
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	2 / 522 (0.38%)	0 / 522 (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
Bone pain
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
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
Fascial hernia
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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
Lumbar spinal stenosis
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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
Musculoskeletal pain
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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
Osteoporosis
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Spinal column stenosis
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (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
Infections and infestations
Appendicitis
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (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
Bronchitis
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	1 / 522 (0.19%)	1 / 522 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchopneumonia
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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
Cellulitis
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (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
Clostridium difficile colitis
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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
Cystitis
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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
Diverticulitis
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Extradural abscess
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
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
Gastroenteritis
subjects affected / exposed	3 / 528 (0.57%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatitis E
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
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
Infected bites
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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
Infective exacerbation of chronic obstructive airways disease
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	1 / 522 (0.19%)
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
Klebsiella sepsis
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Lobar pneumonia
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	3 / 522 (0.57%)	1 / 522 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Localised infection
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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 abscess
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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 infection
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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
Otitis media chronic
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (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
Pneumonia
subjects affected / exposed	8 / 528 (1.52%)	5 / 525 (0.95%)	5 / 527 (0.95%)	10 / 522 (1.92%)	9 / 522 (1.72%)
occurrences causally related to treatment / all	0 / 8	0 / 5	0 / 5	0 / 11	0 / 9
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	0 / 528 (0.00%)	1 / 525 (0.19%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Pneumonia pneumococcal
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
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
Pyelonephritis
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
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 / 528 (0.00%)	2 / 525 (0.38%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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 / 1	0 / 0	0 / 0
Sinusitis
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	1 / 522 (0.19%)
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 sepsis
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	1 / 522 (0.19%)
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
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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
Failure to thrive
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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
Fluid overload
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (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 / 528 (0.00%)	0 / 525 (0.00%)	1 / 527 (0.19%)	0 / 522 (0.00%)	0 / 522 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	2 / 522 (0.38%)
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
Hypoglycaemia
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	0 / 522 (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
Hyponatraemia
subjects affected / exposed	0 / 528 (0.00%)	0 / 525 (0.00%)	0 / 527 (0.00%)	1 / 522 (0.19%)	1 / 522 (0.19%)
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
Hypovolaemia
subjects affected / exposed	1 / 528 (0.19%)	0 / 525 (0.00%)	0 / 527 (0.00%)	0 / 522 (0.00%)	0 / 522 (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

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Olodaterol (5 μg)	Tiotropium (2.5 μg)	Tiotropium (5 μg)	Tio+Olo FDC (2.5/5 μg)	Tio+Olo FDC (5/5 μg)
Total subjects affected by non serious adverse events
subjects affected / exposed	221 / 528 (41.86%)	207 / 525 (39.43%)	210 / 527 (39.85%)	211 / 522 (40.42%)	193 / 522 (36.97%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	155 / 528 (29.36%)	144 / 525 (27.43%)	151 / 527 (28.65%)	133 / 522 (25.48%)	134 / 522 (25.67%)
occurrences all number	242	207	239	193	200
Infections and infestations
Nasopharyngitis
subjects affected / exposed	65 / 528 (12.31%)	64 / 525 (12.19%)	67 / 527 (12.71%)	64 / 522 (12.26%)	67 / 522 (12.84%)
occurrences all number	82	83	85	78	84
Upper respiratory tract infection
subjects affected / exposed	24 / 528 (4.55%)	30 / 525 (5.71%)	30 / 527 (5.69%)	40 / 522 (7.66%)	25 / 522 (4.79%)
occurrences all number	32	44	36	61	35

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Were there any global substantial amendments to the protocol? Yes

07 Oct 2011

Significant changes to the trial protocol introduced by this revision were a change in timing of Visit 7* and the addition of trough PFT measurements to this visit to ensure FEV1 AUC0-3h and trough FEV1 at Visit 7 (primary efficacy endpoints after 24 weeks of treatment) both came from the same dosing interval. Furthermore, instructions were added to report any related SAEs that occurred after the defined observational period. Note: The last amendment to the protocol dated 28-Oct-2013 has been made after the global end of trial date (19-Sep-2013). In this administrative revision, assessment days and time points were added to the lists of primary, secondary and further endpoints. Several endpoints were split into secondary and further endpoints and 10 endpoints were moved from secondary to further endpoints. The list of further endpoints concerning COPD exacerbations was extended, with any, moderate/severe, and severe COPD exacerbations to be analysed as separate endpoints. Each endpoint related to COPD exacerbations was to be analysed for the entire population and for the subset of patients with a history of exacerbation. FPI was to be regarded as a further endpoint. The TDI component scores on Day 169 originally were inadvertently left out of the list of further endpoints. As with other TDI data, these endpoints were to be examined for data from 1237.5+1237.6 combined. A definition of patients to be considered having a history of exacerbation was added. The 1-sided superiority hypothesis testing was changed to 2-sided hypothesis testing, and the corresponding 1-sided type I error rate of 0.025 was changed to 2-sided type I error rate of 0.05. Since tiotropium 5μg is a marketed product in several countries, a comparison of T+O 2.5/5 μg versus Tio 5 μg was added to the hierarchical testing sequences.

29 Aug 2012

Significant changes to the trial protocol introduced by this revision were the extension of procedures to be performed for early discontinuations (i.e. inclusion of all safety assessments as specified for the regular EOT visit), the expansion of event adjudication to include all SAEs (instead of fatal cases only), the addition of text regarding rescue treatment on days of Visit 7/7*, and the addition of a plausibility check between eDiary and RESPIMAT. FEV1 and FVC endpoints at individual time points were defined as further (instead of secondary) endpoints with actual values to be analysed instead of response. For the recording of SAEs a list of AEs that were defined as ‘always serious AEs’ was included to comply with a new BI internal procedure. The list was to come into effect for this trial once all countries and sites had received regulatory and ethics committee approval for the protocol revision. Since the trial was completed before all approvals were obtained, this SAE procedure was never implemented. Further specifications of the period during which contraception was required and a pregnancy test at the follow-up visit were added in response to an authority request. Instructions for clinical evaluation of liver injury were included to implement a new BI guideline to comply with the FDA guidance for industry ‘Drug-Induced Liver Injury: Premarketing Clinical Evaluation’.

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.

Additional combined primary and/or secondary endpoints are defined and analysed for trial 1237.5 and 1237.6, however due to the platform limitations those could not be provided. Results can be found on CT.gov study number: NCT01431274.

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) (0-3h) Response on Day 169.

Primary: Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) (0-3h) Response on Day 169.

Primary: Trough FEV1 response on Day 170

Primary: Trough FEV1 response on Day 170

Secondary: FEV1 AUC(0-3h) response on Day 1, Day 85, and Day 365

Secondary: FEV1 AUC(0-3h) response on Day 1, Day 85, and Day 365

Secondary: Trough FEV1 response on Day 15, Day 43, Day 85, Day 169, and Day 365

Secondary: Trough FEV1 response on Day 15, Day 43, Day 85, Day 169, and Day 365

Secondary: Forced vital capacity (FVC) AUC (0-3h) response on Day 1, Day 85, Day 169, and Day 365

Secondary: Forced vital capacity (FVC) AUC (0-3h) response on Day 1, Day 85, Day 169, and Day 365

Secondary: Trough FVC response on Day 15, Day 43, Day 85, Day 170, and Day 365

Secondary: Trough FVC response on Day 15, Day 43, Day 85, Day 170, and Day 365

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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