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 plus 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	2009-010669-22
Trial protocol	NO SE ES SK BE DE HU IE AT GB
Global end of trial date	11 Nov 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

1237.6

ISRCTN number

US NCT number

NCT01431287

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 8002430127, clintriage.rdg@boehringer-ingelheim.com

Scientific contact

QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 8002430127, 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

09 Dec 2013

Is this the analysis of the primary completion data?

Yes

Primary completion date

26 Apr 2013

Global end of trial reached?

Yes

Global end of trial date

11 Nov 2013

Was the trial ended prematurely?

Main objective of the trial

The primary 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

Hungary: 68

Country: Number of subjects enrolled

Brazil: 178

Country: Number of subjects enrolled

Canada: 140

Country: Number of subjects enrolled

Colombia: 76

Country: Number of subjects enrolled

Croatia: 26

Country: Number of subjects enrolled

India: 94

Country: Number of subjects enrolled

Japan: 318

Country: Number of subjects enrolled

China: 362

Country: Number of subjects enrolled

Taiwan: 87

Country: Number of subjects enrolled

Russian Federation: 68

Country: Number of subjects enrolled

Romania: 72

Country: Number of subjects enrolled

Serbia: 99

Country: Number of subjects enrolled

Turkey: 128

Country: Number of subjects enrolled

United States: 643

Country: Number of subjects enrolled

South Africa: 122

Country: Number of subjects enrolled

Norway: 129

Country: Number of subjects enrolled

Slovakia: 22

Country: Number of subjects enrolled

Spain: 131

Country: Number of subjects enrolled

Sweden: 106

Country: Number of subjects enrolled

United Kingdom: 65

Country: Number of subjects enrolled

Austria: 108

Country: Number of subjects enrolled

Belgium: 101

Country: Number of subjects enrolled

Germany: 346

Country: Number of subjects enrolled

Ireland: 29

Worldwide total number of subjects

3518

EEA total number of subjects

1203

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)

1804

From 65 to 84 years

1706

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, 17 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 specialist sites which would then ensure that they (the subjects) met all strictly implemented 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 oral 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. One patient who was randomised to the Tiotropium 5 ug arm was not treated. Consequently, number of subjects that started is 507 but only 506 reported to ensure consistent reporting with baseline characteristics that includes only treated patients.

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 oral 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

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 oral 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

2.5 µg once daily with oral 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 oral 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 oral 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	510	507	506	508	507
Completed	412	409	410	445	430
Not completed	98	98	96	63	77
Adverse event, serious fatal	8	4	8	6	8
Consent withdrawn by subject	29	30	34	19	29
Adverse event, non-fatal	51	53	45	27	33
Lost to follow-up	-	3	2	3	1
Protocol deviation	6	6	5	6	5
not specified	4	2	2	2	1

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

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	510	507	506	508	507	2538
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)	64.7 ( 8.3 )	63.9 ( 8.7 )	63.5 ( 8.7 )	64.1 ( 7.6 )	62.7 ( 8.4 )	-
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	132	146	134	140	158	710
Male	378	361	372	368	349	1828

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

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	507 ^[1]	504 ^[2]	500 ^[3]	506 ^[4]	502 ^[5]
Units: litre(s)
least squares mean (standard error)	0.136 ( 0.009 )	0.125 ( 0.009 )	0.165 ( 0.009 )	0.256 ( 0.009 )	0.268 ( 0.009 )

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

1009

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

0.108

upper limit

0.157

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

1002

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

0.078

upper limit

0.127

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

1013

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

0.096

upper limit

0.145

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

1010

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

adjusted mean difference

Point estimate

0.131

Confidence interval

level

95%

sides

2-sided

lower limit

0.106

upper limit

0.155

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

1006

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

adjusted mean difference

Point estimate

0.091

Confidence interval

level

95%

sides

2-sided

lower limit

0.066

upper limit

0.115

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

1008

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3394

Method

Mixed models analysis

Parameter type

adjusted mean difference

Point estimate

0.012

Confidence interval

level

95%

sides

2-sided

lower limit

-0.013

upper limit

0.036

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

1006

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

adjusted mean difference

Point estimate

0.143

Confidence interval

level

95%

sides

2-sided

lower limit

0.118

upper limit

0.167

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

1007

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0173

Method

Mixed models analysis

Parameter type

adjusted mean difference

Point estimate

0.03

Confidence interval

level

95%

sides

2-sided

lower limit

0.005

upper limit

0.054

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

1011

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.421

Method

Mixed models analysis

Parameter type

adjusted mean difference

Point estimate

-0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.035

upper limit

0.014

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

1004

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

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 number of patients used in the FAS analysis for different endpoint will vary.

End point type

Primary

End point timeframe

1 hours(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	503 ^[6]	499 ^[7]	498 ^[8]	500 ^[9]	497 ^[10]
Units: litre(s)
least squares mean (standard error)	0.057 ( 0.009 )	0.062 ( 0.009 )	0.096 ( 0.009 )	0.125 ( 0.009 )	0.145 ( 0.009 )

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

Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. 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

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

Number of subjects included in analysis

1000

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

0.063

upper limit

0.113

Variability estimate

Standard error of the mean

Dispersion value

0.013

T+O 5/5 vs Tio 5

Statistical analysis description

Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. 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

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

Number of subjects included in analysis

995

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.05

Confidence interval

level

95%

sides

2-sided

lower limit

0.024

upper limit

0.075

Variability estimate

Standard error of the mean

Dispersion value

0.013

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 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

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

Number of subjects included in analysis

1003

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.067

Confidence interval

level

95%

sides

2-sided

lower limit

0.042

upper limit

0.092

Variability estimate

Standard error of the mean

Dispersion value

0.013

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 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

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

Number of subjects included in analysis

999

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

0.037

upper limit

0.087

Variability estimate

Standard error of the mean

Dispersion value

0.013

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 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

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

Number of subjects included in analysis

998

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0231

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.029

Confidence interval

level

95%

sides

2-sided

lower limit

0.004

upper limit

0.054

Variability estimate

Standard error of the mean

Dispersion value

0.013

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 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

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

Number of subjects included in analysis

997

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1073

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.021

Confidence interval

level

95%

sides

2-sided

lower limit

-0.004

upper limit

0.046

Variability estimate

Standard error of the mean

Dispersion value

0.013

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 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

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

Number of subjects included in analysis

996

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.083

Confidence interval

level

95%

sides

2-sided

lower limit

0.058

upper limit

0.108

Variability estimate

Standard error of the mean

Dispersion value

0.013

Tio 5 vs Olo 5

Statistical analysis description

Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. 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

1001

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0029

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.038

Confidence interval

level

95%

sides

2-sided

lower limit

0.013

upper limit

0.063

Variability estimate

Standard error of the mean

Dispersion value

0.013

Tio 2.5 vs Olo 5

Statistical analysis description

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

Number of subjects included in analysis

1002

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6939

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.005

Confidence interval

level

95%

sides

2-sided

lower limit

-0.02

upper limit

0.03

Variability estimate

Standard error of the mean

Dispersion value

0.013

Tio 5 vs Tio 2.5

Statistical analysis description

Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. 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 Tiotropium (Tio) 2.5 µg

Number of subjects included in analysis

997

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0097

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.033

Confidence interval

level

95%

sides

2-sided

lower limit

0.008

upper limit

0.058

Variability estimate

Standard error of the mean

Dispersion value

0.013

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 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 will 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	507 ^[11]	504 ^[12]	500 ^[13]	506 ^[14]	502 ^[15]
Units: litre(s)
least squares mean (standard error)
Day 1	0.196 ( 0.009 )	0.135 ( 0.009 )	0.164 ( 0.009 )	0.228 ( 0.009 )	0.229 ( 0.009 )
Day 85	0.153 ( 0.009 )	0.165 ( 0.009 )	0.187 ( 0.009 )	0.272 ( 0.009 )	0.297 ( 0.009 )
Day 365	0.105 ( 0.01 )	0.105 ( 0.01 )	0.124 ( 0.01 )	0.223 ( 0.009 )	0.237 ( 0.01 )

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

Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. 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

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

Number of subjects included in analysis

1009

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0095

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.033

Confidence interval

level

95%

sides

2-sided

lower limit

0.008

upper limit

0.058

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

1002

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

0.04

upper limit

0.09

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

1013

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0112

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.033

Confidence interval

level

95%

sides

2-sided

lower limit

0.007

upper limit

0.058

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

Statistical analysis description

Comparison groups

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

Number of subjects included in analysis

1010

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

0.068

upper limit

0.119

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

1006

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

0.09

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

1008

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9514

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.001

Confidence interval

level

95%

sides

2-sided

lower limit

-0.024

upper limit

0.026

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

1006

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.094

Confidence interval

level

95%

sides

2-sided

lower limit

0.069

upper limit

0.119

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

1007

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0131

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

-0.032

Confidence interval

level

95%

sides

2-sided

lower limit

-0.057

upper limit

-0.007

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

1011

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

-0.086

upper limit

-0.036

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

1004

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0243

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.029

Confidence interval

level

95%

sides

2-sided

lower limit

0.004

upper limit

0.054

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

1009

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.145

Confidence interval

level

95%

sides

2-sided

lower limit

0.119

upper limit

0.17

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

1002

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

0.085

upper limit

0.136

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

Statistical analysis description

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

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

Number of subjects included in analysis

1013

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

0.144

Variability estimate

Standard error of the mean

Dispersion value

0.013

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 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

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

Number of subjects included in analysis

1010

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.106

Confidence interval

level

95%

sides

2-sided

lower limit

0.081

upper limit

0.132

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

1006

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.085

Confidence interval

level

95%

sides

2-sided

lower limit

0.059

upper limit

0.11

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

1008

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.047

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.026

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

0.051

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

1006

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

0.107

upper limit

0.158

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

1007

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0083

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.034

Confidence interval

level

95%

sides

2-sided

lower limit

0.009

upper limit

0.06

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

1011

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3329

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.013

Confidence interval

level

95%

sides

2-sided

lower limit

-0.013

upper limit

0.038

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

1004

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0958

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.022

Confidence interval

level

95%

sides

2-sided

lower limit

-0.004

upper limit

0.047

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

1009

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

0.105

upper limit

0.158

Variability estimate

Standard error of the mean

Dispersion value

0.014

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

1002

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

0.086

upper limit

0.139

Variability estimate

Standard error of the mean

Dispersion value

0.014

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

1013

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.118

Confidence interval

level

95%

sides

2-sided

lower limit

0.092

upper limit

0.144

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

Comparison groups

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

Number of subjects included in analysis

1010

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.118

Confidence interval

level

95%

sides

2-sided

lower limit

0.092

upper limit

0.144

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

1006

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.098

Confidence interval

level

95%

sides

2-sided

lower limit

0.072

upper limit

0.125

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

1008

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3008

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.014

Confidence interval

level

95%

sides

2-sided

lower limit

-0.012

upper limit

0.04

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

1006

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

0.105

upper limit

0.158

Variability estimate

Standard error of the mean

Dispersion value

0.014

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

1007

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1484

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.007

upper limit

0.046

Variability estimate

Standard error of the mean

Dispersion value

0.014

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

1011

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9981

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.026

upper limit

0.027

Variability estimate

Standard error of the mean

Dispersion value

0.014

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

1004

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.148

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.007

upper limit

0.046

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

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End point title

Trough FEV1 response on Days 15, 43, 85, 169 and 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 number of patients used in the FAS analysis for different endpoint will 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	503 ^[16]	499 ^[17]	498 ^[18]	500 ^[19]	497 ^[20]
Units: litre(s)
least squares mean (standard error)
Day 15	0.083 ( 0.009 )	0.085 ( 0.009 )	0.112 ( 0.009 )	0.147 ( 0.009 )	0.148 ( 0.009 )
Day 43	0.07 ( 0.009 )	0.085 ( 0.009 )	0.103 ( 0.009 )	0.146 ( 0.009 )	0.15 ( 0.009 )
Day 85	0.047 ( 0.009 )	0.081 ( 0.009 )	0.088 ( 0.009 )	0.129 ( 0.009 )	0.147 ( 0.009 )
Day 169	0.034 ( 0.009 )	0.041 ( 0.009 )	0.068 ( 0.009 )	0.111 ( 0.009 )	0.119 ( 0.009 )
Day 365	0.011 ( 0.009 )	0.022 ( 0.009 )	0.04 ( 0.009 )	0.077 ( 0.009 )	0.093 ( 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

Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. 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

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

Number of subjects included in analysis

1000

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

0.04

upper limit

0.09

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

Statistical analysis description

Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. 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

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

Number of subjects included in analysis

995

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.005

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

0.061

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

Statistical analysis description

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

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

Number of subjects included in analysis

1003

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

0.089

Variability estimate

Standard error of the mean

Dispersion value

0.013

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 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

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

Number of subjects included in analysis

999

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

0.037

upper limit

0.088

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

Statistical analysis description

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

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

Number of subjects included in analysis

998

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0057

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.036

Confidence interval

level

95%

sides

2-sided

lower limit

0.01

upper limit

0.061

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

Statistical analysis description

Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. 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

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

Number of subjects included in analysis

997

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9633

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.001

Confidence interval

level

95%

sides

2-sided

lower limit

-0.025

upper limit

0.026

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

Statistical analysis description

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

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

Number of subjects included in analysis

996

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

0.038

upper limit

0.088

Variability estimate

Standard error of the mean

Dispersion value

0.013

Tio 5 vs Olo 5 on Day 15

Statistical analysis description

Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. 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

1001

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.025

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.029

Confidence interval

level

95%

sides

2-sided

lower limit

0.004

upper limit

0.054

Variability estimate

Standard error of the mean

Dispersion value

0.013

Tio 2.5 vs Olo 5 on Day 15

Statistical analysis description

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

Number of subjects included in analysis

1002

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8949

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.002

Confidence interval

level

95%

sides

2-sided

lower limit

-0.023

upper limit

0.027

Variability estimate

Standard error of the mean

Dispersion value

0.013

Tio 5 vs Tio 2.5 on Day 15

Statistical analysis description

Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. 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 Tiotropium (Tio) 2.5 µg

Number of subjects included in analysis

997

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0351

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

0.052

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

Statistical analysis description

Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. 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

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

Number of subjects included in analysis

1000

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

0.055

upper limit

0.105

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

Statistical analysis description

Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. 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

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

Number of subjects included in analysis

995

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

0.073

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

Statistical analysis description

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

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

Number of subjects included in analysis

1003

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

0.101

Variability estimate

Standard error of the mean

Dispersion value

0.013

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 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

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

Number of subjects included in analysis

999

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

0.036

upper limit

0.086

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

Statistical analysis description

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

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

Number of subjects included in analysis

998

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0007

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.044

Confidence interval

level

95%

sides

2-sided

lower limit

0.018

upper limit

0.069

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

Statistical analysis description

Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. 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

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

Number of subjects included in analysis

997

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7755

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.004

Confidence interval

level

95%

sides

2-sided

lower limit

-0.022

upper limit

0.029

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

Statistical analysis description

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

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

Number of subjects included in analysis

996

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

0.039

upper limit

0.09

Variability estimate

Standard error of the mean

Dispersion value

0.013

Tio 5 vs Olo 5 on Day 43

Statistical analysis description

Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. 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

1001

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0118

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.032

Confidence interval

level

95%

sides

2-sided

lower limit

0.007

upper limit

0.058

Variability estimate

Standard error of the mean

Dispersion value

0.013

Tio 2.5 vs Olo 5 on Day 43

Statistical analysis description

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

Number of subjects included in analysis

1002

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2416

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.015

Confidence interval

level

95%

sides

2-sided

lower limit

-0.01

upper limit

0.04

Variability estimate

Standard error of the mean

Dispersion value

0.013

Tio 5 vs Tio 2.5 on Day 43

Statistical analysis description

Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. 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 Tiotropium (Tio) 2.5 µg

Number of subjects included in analysis

997

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1792

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.017

Confidence interval

level

95%

sides

2-sided

lower limit

-0.008

upper limit

0.043

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

Statistical analysis description

Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. 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

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

Number of subjects included in analysis

1000

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

0.074

upper limit

0.125

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

Statistical analysis description

Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. 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

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

Number of subjects included in analysis

995

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.059

Confidence interval

level

95%

sides

2-sided

lower limit

0.033

upper limit

0.084

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

Statistical analysis description

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

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

Number of subjects included in analysis

1003

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

0.057

upper limit

0.107

Variability estimate

Standard error of the mean

Dispersion value

0.013

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 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

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

Number of subjects included in analysis

999

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0002

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

0.073

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

Statistical analysis description

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

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

Number of subjects included in analysis

998

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0014

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.041

Confidence interval

level

95%

sides

2-sided

lower limit

0.016

upper limit

0.067

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

Statistical analysis description

Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. 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

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

Number of subjects included in analysis

997

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1747

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.018

Confidence interval

level

95%

sides

2-sided

lower limit

-0.008

upper limit

0.043

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

Statistical analysis description

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

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

Number of subjects included in analysis

996

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

0.04

upper limit

0.091

Variability estimate

Standard error of the mean

Dispersion value

0.013

Tio 5 vs Olo 5 on Day 85

Statistical analysis description

Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. 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

1001

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0016

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.041

Confidence interval

level

95%

sides

2-sided

lower limit

0.016

upper limit

0.066

Variability estimate

Standard error of the mean

Dispersion value

0.013

Tio 2.5 vs Olo 5 on Day 85

Statistical analysis description

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

Number of subjects included in analysis

1002

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0081

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.034

Confidence interval

level

95%

sides

2-sided

lower limit

0.009

upper limit

0.06

Variability estimate

Standard error of the mean

Dispersion value

0.013

Tio 5 vs Tio 2.5 on Day 85

Statistical analysis description

Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. 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 Tiotropium (Tio) 2.5 µg

Number of subjects included in analysis

997

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.611

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.007

Confidence interval

level

95%

sides

2-sided

lower limit

-0.019

upper limit

0.032

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

Statistical analysis description

Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. 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

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

Number of subjects included in analysis

1000

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.085

Confidence interval

level

95%

sides

2-sided

lower limit

0.059

upper limit

0.111

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

Statistical analysis description

Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. 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

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

Number of subjects included in analysis

995

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.05

Confidence interval

level

95%

sides

2-sided

lower limit

0.025

upper limit

0.076

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

Statistical analysis description

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

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

Number of subjects included in analysis

1003

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.077

Confidence interval

level

95%

sides

2-sided

lower limit

0.051

upper limit

0.102

Variability estimate

Standard error of the mean

Dispersion value

0.013

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 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

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

Number of subjects included in analysis

999

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

0.044

upper limit

0.095

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

Statistical analysis description

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

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

Number of subjects included in analysis

998

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0013

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.042

Confidence interval

level

95%

sides

2-sided

lower limit

0.016

upper limit

0.068

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

Statistical analysis description

Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. 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

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

Number of subjects included in analysis

997

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5274

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

0.034

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

Statistical analysis description

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

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

Number of subjects included in analysis

996

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

0.052

upper limit

0.103

Variability estimate

Standard error of the mean

Dispersion value

0.013

Tio 5 vs Olo 5 on Day 169

Statistical analysis description

Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. 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

1001

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0083

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.035

Confidence interval

level

95%

sides

2-sided

lower limit

0.009

upper limit

0.06

Variability estimate

Standard error of the mean

Dispersion value

0.013

Tio 2.5 vs Olo 5 on Day 169

Statistical analysis description

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

Number of subjects included in analysis

1002

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5744

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

0.033

Variability estimate

Standard error of the mean

Dispersion value

0.013

Tio 5 vs Tio 2.5 on Day 169

Statistical analysis description

Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. 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 Tiotropium (Tio) 2.5 µg

Number of subjects included in analysis

997

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0381

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.027

Confidence interval

level

95%

sides

2-sided

lower limit

0.001

upper limit

0.053

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

Statistical analysis description

Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. 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

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

Number of subjects included in analysis

1000

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

0.055

upper limit

0.108

Variability estimate

Standard error of the mean

Dispersion value

0.013

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

Statistical analysis description

Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. 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

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

Number of subjects included in analysis

995

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

0.027

upper limit

0.079

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

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

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

Number of subjects included in analysis

1003

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

0.039

upper limit

0.091

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 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

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

Number of subjects included in analysis

999

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.055

Confidence interval

level

95%

sides

2-sided

lower limit

0.029

upper limit

0.081

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

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

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

Number of subjects included in analysis

998

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0052

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.037

Confidence interval

level

95%

sides

2-sided

lower limit

0.011

upper limit

0.063

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

Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. 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

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

Number of subjects included in analysis

997

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2273

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.016

Confidence interval

level

95%

sides

2-sided

lower limit

-0.01

upper limit

0.042

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

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

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

Number of subjects included in analysis

996

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

0.045

upper limit

0.097

Variability estimate

Standard error of the mean

Dispersion value

0.013

Tio 5 vs Olo 5 on Day 365

Statistical analysis description

Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. 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

1001

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.033

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.028

Confidence interval

level

95%

sides

2-sided

lower limit

0.002

upper limit

0.055

Variability estimate

Standard error of the mean

Dispersion value

0.013

Tio 2.5 vs Olo 5 on Day 365

Statistical analysis description

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

Number of subjects included in analysis

1002

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4327

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.016

upper limit

0.037

Variability estimate

Standard error of the mean

Dispersion value

0.013

Tio 5 vs Tio 2.5 on Day 365

Statistical analysis description

Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. 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 Tiotropium (Tio) 2.5 µg

Number of subjects included in analysis

997

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1764

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.018

Confidence interval

level

95%

sides

2-sided

lower limit

-0.008

upper limit

0.044

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

Top of page

End point title

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

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	507 ^[21]	504 ^[22]	500 ^[23]	506 ^[24]	502 ^[25]
Units: litre(s)
least squares mean (standard error)
Day 1	0.341 ( 0.018 )	0.264 ( 0.018 )	0.298 ( 0.018 )	0.411 ( 0.018 )	0.397 ( 0.018 )
Day 85	0.25 ( 0.018 )	0.306 ( 0.018 )	0.326 ( 0.018 )	0.46 ( 0.018 )	0.469 ( 0.018 )
Day 169	0.231 ( 0.018 )	0.247 ( 0.018 )	0.283 ( 0.018 )	0.439 ( 0.018 )	0.429 ( 0.018 )
Day 365	0.18 ( 0.019 )	0.216 ( 0.018 )	0.198 ( 0.019 )	0.397 ( 0.018 )	0.381 ( 0.019 )

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 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

1009

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0241

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

T+O 5/5 vs Tio 5 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

1002

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

0.051

upper limit

0.148

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 2.5/5 vs Olo 5 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

1013

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0049

Method

Mixed models analysis

Parameter type

adjusted mean difference

Point estimate

0.07

Confidence interval

level

95%

sides

2-sided

lower limit

0.021

upper limit

0.119

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 2.5/5 vs Tio 2.5 Day 1

Statistical analysis description

Comparison groups

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

Number of subjects included in analysis

1010

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 2.5/5 vs Tio 5 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

1006

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

0.064

upper limit

0.162

Variability estimate

Standard error of the mean

Dispersion value

0.025

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

1008

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5831

Method

Mixed models analysis

Parameter type

adjusted mean difference

Point estimate

-0.014

Confidence interval

level

95%

sides

2-sided

lower limit

-0.063

upper limit

0.035

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 5/5 vs Tio 2.5 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

1006

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

adjusted mean difference

Point estimate

0.133

Confidence interval

level

95%

sides

2-sided

lower limit

0.084

upper limit

0.182

Variability estimate

Standard error of the mean

Dispersion value

0.025

Tio 5 vs Olo 5 Day 1

Statistical analysis description

Comparison groups

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

Number of subjects included in analysis

1007

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0822

Method

Mixed models analysis

Parameter type

adjusted mean difference

Point estimate

-0.043

Confidence interval

level

95%

sides

2-sided

lower limit

-0.092

upper limit

0.006

Variability estimate

Standard error of the mean

Dispersion value

0.025

Tio 2.5 vs Olo 5 Day 1

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

1011

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.002

Method

Mixed models analysis

Parameter type

adjusted mean difference

Point estimate

-0.077

Confidence interval

level

95%

sides

2-sided

lower limit

-0.126

upper limit

-0.028

Variability estimate

Standard error of the mean

Dispersion value

0.025

Tio 5 vs Tio 2.5 Day 1

Statistical analysis description

Comparison groups

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

Number of subjects included in analysis

1004

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1774

Method

Mixed models analysis

Parameter type

adjusted mean difference

Point estimate

0.034

Confidence interval

level

95%

sides

2-sided

lower limit

-0.015

upper limit

0.083

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 5/5 vs Olo 5 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

1009

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

adjusted mean difference

Point estimate

0.219

Confidence interval

level

95%

sides

2-sided

lower limit

0.169

upper limit

0.268

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 5/5 vs Tio 5 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

1002

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

adjusted mean difference

Point estimate

0.143

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 2.5/5 vs Olo 5 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

1013

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

adjusted mean difference

Point estimate

0.209

Confidence interval

level

95%

sides

2-sided

lower limit

0.16

upper limit

0.258

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 2.5/5 vs Tio 2.5 Day 85

Statistical analysis description

Comparison groups

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

Number of subjects included in analysis

1010

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

0.104

upper limit

0.203

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 2.5/5 vs Tio 5 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

1006

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

adjusted mean difference

Point estimate

0.134

Confidence interval

level

95%

sides

2-sided

lower limit

0.084

upper limit

0.183

Variability estimate

Standard error of the mean

Dispersion value

0.025

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

1008

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6974

Method

Mixed models analysis

Parameter type

adjusted mean difference

Point estimate

0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.04

upper limit

0.059

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 5/5 vs Tio 2.5 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

1006

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

adjusted mean difference

Point estimate

0.163

Confidence interval

level

95%

sides

2-sided

lower limit

0.114

upper limit

0.213

Variability estimate

Standard error of the mean

Dispersion value

0.025

Tio 5 vs Olo 5 Day 85

Statistical analysis description

Comparison groups

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

Number of subjects included in analysis

1007

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0027

Method

Mixed models analysis

Parameter type

adjusted mean difference

Point estimate

0.076

Confidence interval

level

95%

sides

2-sided

lower limit

0.026

upper limit

0.125

Variability estimate

Standard error of the mean

Dispersion value

0.025

Tio 2.5 vs Olo 5 Day 85

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

1011

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0269

Method

Mixed models analysis

Parameter type

adjusted mean difference

Point estimate

0.056

Confidence interval

level

95%

sides

2-sided

lower limit

0.006

upper limit

0.105

Variability estimate

Standard error of the mean

Dispersion value

0.025

Tio 5 vs Tio 2.5 Day 85

Statistical analysis description

Comparison groups

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

Number of subjects included in analysis

1004

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4343

Method

Mixed models analysis

Parameter type

adjusted mean difference

Point estimate

0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.03

upper limit

0.069

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 5/5 vs Olo 5 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

1009

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

adjusted mean difference

Point estimate

0.198

Confidence interval

level

95%

sides

2-sided

lower limit

0.148

upper limit

0.248

Variability estimate

Standard error of the mean

Dispersion value

0.026

T+O 5/5 vs Tio 5 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

1002

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

adjusted mean difference

Point estimate

0.146

Confidence interval

level

95%

sides

2-sided

lower limit

0.096

upper limit

0.197

Variability estimate

Standard error of the mean

Dispersion value

0.026

T+O 2.5/5 vs Olo 5 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

1013

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

adjusted mean difference

Point estimate

0.208

Confidence interval

level

95%

sides

2-sided

lower limit

0.158

upper limit

0.258

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 2.5/5 vs Tio 2.5 Day 169

Statistical analysis description

Comparison groups

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

Number of subjects included in analysis

1010

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

0.143

upper limit

0.242

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 2.5/5 vs Tio 5 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

1006

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

0.106

upper limit

0.206

Variability estimate

Standard error of the mean

Dispersion value

0.025

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

1008

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.698

Method

Mixed models analysis

Parameter type

adjusted mean difference

Point estimate

-0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.06

upper limit

0.04

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 5/5 vs Tio 2.5 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

1006

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

adjusted mean difference

Point estimate

0.183

Confidence interval

level

95%

sides

2-sided

lower limit

0.132

upper limit

0.233

Variability estimate

Standard error of the mean

Dispersion value

0.026

Tio 5 vs Olo 5 Day 169

Statistical analysis description

Comparison groups

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

Number of subjects included in analysis

1007

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0442

Method

Mixed models analysis

Parameter type

adjusted mean difference

Point estimate

0.051

Confidence interval

level

95%

sides

2-sided

lower limit

0.001

upper limit

0.102

Variability estimate

Standard error of the mean

Dispersion value

0.026

Tio 2.5 vs Olo 5 Day 169

Statistical analysis description

Comparison groups

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

Number of subjects included in analysis

1011

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5514

Method

Mixed models analysis

Parameter type

adjusted mean difference

Point estimate

0.015

Confidence interval

level

95%

sides

2-sided

lower limit

-0.035

upper limit

0.065

Variability estimate

Standard error of the mean

Dispersion value

0.026

Tio 5 vs Tio 2.5 Day 169

Statistical analysis description

Comparison groups

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

Number of subjects included in analysis

1004

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1569

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 Olo 5 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

1009

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

adjusted mean difference

Point estimate

0.202

Confidence interval

level

95%

sides

2-sided

lower limit

0.15

upper limit

0.253

Variability estimate

Standard error of the mean

Dispersion value

0.026

T+O 5/5 vs Tio 5 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

1002

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

adjusted mean difference

Point estimate

0.183

Confidence interval

level

95%

sides

2-sided

lower limit

0.132

upper limit

0.234

Variability estimate

Standard error of the mean

Dispersion value

0.026

T+O 2.5/5 vs Olo 5 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

1013

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

adjusted mean difference

Point estimate

0.218

Confidence interval

level

95%

sides

2-sided

lower limit

0.167

upper limit

0.269

Variability estimate

Standard error of the mean

Dispersion value

0.026

T+O 2.5/5 vs Tio 2.5 Day 365

Statistical analysis description

Comparison groups

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

Number of subjects included in analysis

1010

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

adjusted mean difference

Point estimate

0.181

Confidence interval

level

95%

sides

2-sided

lower limit

0.13

upper limit

0.232

Variability estimate

Standard error of the mean

Dispersion value

0.026

T+O 2.5/5 vs Tio 5 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

1006

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

adjusted mean difference

Point estimate

0.199

Confidence interval

level

95%

sides

2-sided

lower limit

0.148

upper limit

0.25

Variability estimate

Standard error of the mean

Dispersion value

0.026

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

1008

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5373

Method

Mixed models analysis

Parameter type

adjusted mean difference

Point estimate

-0.016

Confidence interval

level

95%

sides

2-sided

lower limit

-0.067

upper limit

0.035

Variability estimate

Standard error of the mean

Dispersion value

0.026

T+O 5/5 vs Tio 2.5 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

1006

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

adjusted mean difference

Point estimate

0.165

Confidence interval

level

95%

sides

2-sided

lower limit

0.114

upper limit

0.216

Variability estimate

Standard error of the mean

Dispersion value

0.026

Tio 5 vs Olo 5 Day 365

Statistical analysis description

Comparison groups

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

Number of subjects included in analysis

1007

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4763

Method

Mixed models analysis

Parameter type

adjusted mean difference

Point estimate

0.019

Confidence interval

level

95%

sides

2-sided

lower limit

-0.033

upper limit

0.07

Variability estimate

Standard error of the mean

Dispersion value

0.026

Tio 2.5 vs Olo 5 Day 365

Statistical analysis description

Comparison groups

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

Number of subjects included in analysis

1011

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1613

Method

Mixed models analysis

Parameter type

adjusted mean difference

Point estimate

0.037

Confidence interval

level

95%

sides

2-sided

lower limit

-0.015

upper limit

0.088

Variability estimate

Standard error of the mean

Dispersion value

0.026

Tio 5 vs Tio 2.5 Day 365

Statistical analysis description

Comparison groups

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

Number of subjects included in analysis

1004

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4908

Method

Mixed models analysis

Parameter type

adjusted mean difference

Point estimate

-0.018

Confidence interval

level

95%

sides

2-sided

lower limit

-0.069

upper limit

0.033

Variability estimate

Standard error of the mean

Dispersion value

0.026

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 defined as 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 &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	503 ^[26]	499 ^[27]	498 ^[28]	500 ^[29]	497 ^[30]
Units: litre(s)
least squares mean (standard error)
Day 15	0.163 ( 0.018 )	0.209 ( 0.018 )	0.222 ( 0.018 )	0.293 ( 0.018 )	0.285 ( 0.018 )
Day 43	0.129 ( 0.018 )	0.206 ( 0.018 )	0.222 ( 0.018 )	0.281 ( 0.018 )	0.293 ( 0.018 )
Day 85	0.063 ( 0.018 )	0.178 ( 0.018 )	0.184 ( 0.018 )	0.246 ( 0.018 )	0.274 ( 0.019 )
Day 170	0.116 ( 0.018 )	0.163 ( 0.018 )	0.202 ( 0.018 )	0.266 ( 0.018 )	0.274 ( 0.018 )
Day 365	0.028 ( 0.019 )	0.096 ( 0.019 )	0.097 ( 0.019 )	0.198 ( 0.019 )	0.184 ( 0.019 )

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 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

1000

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

0.072

upper limit

0.173

Variability estimate

Standard error of the mean

Dispersion value

0.026

T+O 5/5 vs Tio 5 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

995

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0154

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.063

Confidence interval

level

95%

sides

2-sided

lower limit

0.012

upper limit

0.113

Variability estimate

Standard error of the mean

Dispersion value

0.026

T+O 2.5/5 vs Olo 5 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

1003

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.13

Confidence interval

level

95%

sides

2-sided

lower limit

0.08

upper limit

0.181

Variability estimate

Standard error of the mean

Dispersion value

0.026

T+O 2.5/5 vs Tio 2.5 Day 15

Statistical analysis description

Comparison groups

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

Number of subjects included in analysis

999

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0012

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 Tio 5 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

998

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0061

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.071

Confidence interval

level

95%

sides

2-sided

lower limit

0.02

upper limit

0.121

Variability estimate

Standard error of the mean

Dispersion value

0.026

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

997

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7518

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

-0.008

Confidence interval

level

95%

sides

2-sided

lower limit

-0.059

upper limit

0.042

Variability estimate

Standard error of the mean

Dispersion value

0.026

T+O 5/5 vs Tio 2.5 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

996

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0034

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.076

Confidence interval

level

95%

sides

2-sided

lower limit

0.025

upper limit

0.126

Variability estimate

Standard error of the mean

Dispersion value

0.026

Tio 5 vs Olo 5 Day 15

Statistical analysis description

Comparison groups

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

Number of subjects included in analysis

1001

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0209

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.059

Confidence interval

level

95%

sides

2-sided

lower limit

0.009

upper limit

0.11

Variability estimate

Standard error of the mean

Dispersion value

0.026

Tio 2.5 vs Olo 5 Day 15

Statistical analysis description

Comparison groups

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

Number of subjects included in analysis

1002

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0708

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.047

Confidence interval

level

95%

sides

2-sided

lower limit

-0.004

upper limit

0.097

Variability estimate

Standard error of the mean

Dispersion value

0.026

Tio 5 vs Tio 2.5 Day 15

Statistical analysis description

Comparison groups

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

Number of subjects included in analysis

997

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6148

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.013

Confidence interval

level

95%

sides

2-sided

lower limit

-0.038

upper limit

0.064

Variability estimate

Standard error of the mean

Dispersion value

0.026

T+O 5/5 vs Olo 5 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

1000

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.164

Confidence interval

level

95%

sides

2-sided

lower limit

0.114

upper limit

0.215

Variability estimate

Standard error of the mean

Dispersion value

0.026

T+O 5/5 vs Tio 5 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

995

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0064

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.071

Confidence interval

level

95%

sides

2-sided

lower limit

0.02

upper limit

0.122

Variability estimate

Standard error of the mean

Dispersion value

0.026

T+O 2.5/5 vs Olo 5 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

1003

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.152

Confidence interval

level

95%

sides

2-sided

lower limit

0.102

upper limit

0.203

Variability estimate

Standard error of the mean

Dispersion value

0.026

T+O 2.5/5 vs Tio 2.5 Day 43

Statistical analysis description

Comparison groups

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

Number of subjects included in analysis

999

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0035

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.075

Confidence interval

level

95%

sides

2-sided

lower limit

0.025

upper limit

0.126

Variability estimate

Standard error of the mean

Dispersion value

0.026

T+O 2.5/5 vs Tio 5 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

998

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0233

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.059

Confidence interval

level

95%

sides

2-sided

lower limit

0.008

upper limit

0.109

Variability estimate

Standard error of the mean

Dispersion value

0.026

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

997

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6413

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.012

Confidence interval

level

95%

sides

2-sided

lower limit

-0.039

upper limit

0.063

Variability estimate

Standard error of the mean

Dispersion value

0.026

T+O 5/5 vs Tio 2.5 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

996

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0007

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.088

Confidence interval

level

95%

sides

2-sided

lower limit

0.037

upper limit

0.138

Variability estimate

Standard error of the mean

Dispersion value

0.026

Tio 5 vs Olo 5 Day 43

Statistical analysis description

Comparison groups

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

Number of subjects included in analysis

1001

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

0.043

upper limit

0.144

Variability estimate

Standard error of the mean

Dispersion value

0.026

Tio 2.5 vs Olo 5 Day 43

Statistical analysis description

Comparison groups

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

Number of subjects included in analysis

1002

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.003

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.077

Confidence interval

level

95%

sides

2-sided

lower limit

0.026

upper limit

0.127

Variability estimate

Standard error of the mean

Dispersion value

0.026

Tio 5 vs Tio 2.5 Day 43

Statistical analysis description

Comparison groups

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

Number of subjects included in analysis

997

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5159

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.017

Confidence interval

level

95%

sides

2-sided

lower limit

-0.034

upper limit

0.068

Variability estimate

Standard error of the mean

Dispersion value

0.026

T+O 5/5 vs Olo 5 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

1000

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.21

Confidence interval

level

95%

sides

2-sided

lower limit

0.159

upper limit

0.261

Variability estimate

Standard error of the mean

Dispersion value

0.026

T+O 5/5 vs Tio 5 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

995

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0006

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.089

Confidence interval

level

95%

sides

2-sided

lower limit

0.038

upper limit

0.141

Variability estimate

Standard error of the mean

Dispersion value

0.026

T+O 2.5/5 vs Olo 5 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

1003

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.183

Confidence interval

level

95%

sides

2-sided

lower limit

0.132

upper limit

0.234

Variability estimate

Standard error of the mean

Dispersion value

0.026

T+O 2.5/5 vs Tio 2.5 Day 85

Statistical analysis description

Comparison groups

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

Number of subjects included in analysis

999

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0094

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.068

Confidence interval

level

95%

sides

2-sided

lower limit

0.017

upper limit

0.119

Variability estimate

Standard error of the mean

Dispersion value

0.026

T+O 2.5/5 vs Tio 5 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

998

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0174

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.062

Confidence interval

level

95%

sides

2-sided

lower limit

0.011

upper limit

0.113

Variability estimate

Standard error of the mean

Dispersion value

0.026

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

997

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2888

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.028

Confidence interval

level

95%

sides

2-sided

lower limit

-0.023

upper limit

0.079

Variability estimate

Standard error of the mean

Dispersion value

0.026

T+O 5/5 vs Tio 2.5 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

996

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0003

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.095

Confidence interval

level

95%

sides

2-sided

lower limit

0.044

upper limit

0.146

Variability estimate

Standard error of the mean

Dispersion value

0.026

Tio 5 vs Olo 5 Day 85

Statistical analysis description

Comparison groups

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

Number of subjects included in analysis

1001

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

0.07

upper limit

0.172

Variability estimate

Standard error of the mean

Dispersion value

0.026

Tio 2.5 vs Olo 5 Day 85

Statistical analysis description

Comparison groups

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

Number of subjects included in analysis

1002

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

0.064

upper limit

0.166

Variability estimate

Standard error of the mean

Dispersion value

0.026

Tio 5 vs Tio 2.5 Day 85

Statistical analysis description

Comparison groups

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

Number of subjects included in analysis

997

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8241

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.006

Confidence interval

level

95%

sides

2-sided

lower limit

-0.045

upper limit

0.057

Variability estimate

Standard error of the mean

Dispersion value

0.026

T+O 5/5 vs Olo 5 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

1000

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.158

Confidence interval

level

95%

sides

2-sided

lower limit

0.108

upper limit

0.208

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 5/5 vs Tio 5 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

995

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0048

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.072

Confidence interval

level

95%

sides

2-sided

lower limit

0.022

upper limit

0.122

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 2.5/5 vs Olo 5 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

1003

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

0.101

upper limit

0.2

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 2.5/5 vs Tio 2.5 Day 170

Statistical analysis description

Comparison groups

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

Number of subjects included in analysis

999

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

0.053

upper limit

0.152

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 2.5/5 vs Tio 5 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

998

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0116

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.064

Confidence interval

level

95%

sides

2-sided

lower limit

0.014

upper limit

0.113

Variability estimate

Standard error of the mean

Dispersion value

0.025

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

997

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7577

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.008

Confidence interval

level

95%

sides

2-sided

lower limit

-0.042

upper limit

0.058

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 5/5 vs Tio 2.5 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

996

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

0.061

upper limit

0.16

Variability estimate

Standard error of the mean

Dispersion value

0.025

Tio 5 vs Olo 5 Day 170

Statistical analysis description

Comparison groups

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

Number of subjects included in analysis

1001

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0007

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

Tio 2.5 vs Olo 5 Day 170

Statistical analysis description

Comparison groups

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

Number of subjects included in analysis

1002

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0621

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.048

Confidence interval

level

95%

sides

2-sided

lower limit

-0.002

upper limit

0.097

Variability estimate

Standard error of the mean

Dispersion value

0.025

Tio 5 vs Tio 2.5 Day 170

Statistical analysis description

Comparison groups

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

Number of subjects included in analysis

997

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1266

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.039

Confidence interval

level

95%

sides

2-sided

lower limit

-0.011

upper limit

0.089

Variability estimate

Standard error of the mean

Dispersion value

0.025

T+O 5/5 vs Olo 5 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

1000

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

0.104

upper limit

0.209

Variability estimate

Standard error of the mean

Dispersion value

0.027

T+O 5/5 vs Tio 5 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

995

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0013

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.087

Confidence interval

level

95%

sides

2-sided

lower limit

0.034

upper limit

0.139

Variability estimate

Standard error of the mean

Dispersion value

0.027

T+O 2.5/5 vs Olo 5 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

1003

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.17

Confidence interval

level

95%

sides

2-sided

lower limit

0.118

upper limit

0.223

Variability estimate

Standard error of the mean

Dispersion value

0.027

T+O 2.5/5 vs Tio 2.5 Day 365

Statistical analysis description

Comparison groups

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

Number of subjects included in analysis

999

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

0.049

upper limit

0.154

Variability estimate

Standard error of the mean

Dispersion value

0.027

T+O 2.5/5 vs Tio 5 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

998

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0002

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

0.048

upper limit

0.153

Variability estimate

Standard error of the mean

Dispersion value

0.027

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

997

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6093

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

-0.014

Confidence interval

level

95%

sides

2-sided

lower limit

-0.066

upper limit

0.039

Variability estimate

Standard error of the mean

Dispersion value

0.027

T+O 5/5 vs Tio 2.5 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

996

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0011

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.088

Confidence interval

level

95%

sides

2-sided

lower limit

0.035

upper limit

0.14

Variability estimate

Standard error of the mean

Dispersion value

0.027

Tio 5 vs Olo 5 Day 365

Statistical analysis description

Comparison groups

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

Number of subjects included in analysis

1001

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0095

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.07

Confidence interval

level

95%

sides

2-sided

lower limit

0.017

upper limit

0.123

Variability estimate

Standard error of the mean

Dispersion value

0.027

Tio 2.5 vs Olo 5 Day 365

Statistical analysis description

Comparison groups

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

Number of subjects included in analysis

1002

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0108

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.069

Confidence interval

level

95%

sides

2-sided

lower limit

0.016

upper limit

0.121

Variability estimate

Standard error of the mean

Dispersion value

0.027

Tio 5 vs Tio 2.5 Day 365

Statistical analysis description

Comparison groups

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

Number of subjects included in analysis

997

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9627

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.001

Confidence interval

level

95%

sides

2-sided

lower limit

-0.051

upper limit

0.054

Variability estimate

Standard error of the mean

Dispersion value

0.027

Adverse events

Top of page

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 459 days).

Adverse event reporting additional description

AE additional description

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	106 / 510 (20.78%)	90 / 507 (17.75%)	93 / 506 (18.38%)	87 / 508 (17.13%)	82 / 507 (16.17%)
number of deaths (all causes)	13	5	11	8	11
number of deaths resulting from adverse events	0	0	0	0	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Basal cell carcinoma
subjects affected / exposed	1 / 510 (0.20%)	1 / 507 (0.20%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	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 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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 neoplasm
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Bronchial carcinoma
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colon adenoma
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Colon cancer
subjects affected / exposed	2 / 510 (0.39%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Endometrial cancer
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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 cancer
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Hepatic cancer
subjects affected / exposed	0 / 510 (0.00%)	2 / 507 (0.39%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung adenocarcinoma
subjects affected / exposed	1 / 510 (0.20%)	1 / 507 (0.20%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	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 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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 cancer metastatic
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (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
Lung neoplasm
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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 neoplasm malignant
subjects affected / exposed	1 / 510 (0.20%)	1 / 507 (0.20%)	2 / 506 (0.40%)	2 / 508 (0.39%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Metastases to adrenals
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to central nervous system
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
Metastases to liver
subjects affected / exposed	2 / 510 (0.39%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Neoplasm prostate
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (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
Neuroendocrine carcinoma
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Non-small cell lung cancer
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	1 / 508 (0.20%)	0 / 507 (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
Oesophageal carcinoma
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (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 squamous cell carcinoma
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Oropharyngeal cancer
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	1 / 507 (0.20%)
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
Pancreatic carcinoma
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Penile cancer
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Prostate cancer
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	1 / 506 (0.20%)	2 / 508 (0.39%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Prostate cancer metastatic
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Rectal cancer
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal cancer
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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 cancer metastatic
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (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
Small cell lung cancer
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
Squamous cell carcinoma of lung
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma of skin
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (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
Squamous cell carcinoma of the tongue
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Sweat gland tumour
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (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
Transitional cell carcinoma
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Vascular disorders
Aneurysm
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (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
Aortic aneurysm
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Aortic aneurysm rupture
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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	1 / 1
Arteritis
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Deep vein thrombosis
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (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
Haemorrhage
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (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
Hypertension
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypertensive crisis
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (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
Hypotension
subjects affected / exposed	1 / 510 (0.20%)	1 / 507 (0.20%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Intermittent claudication
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (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
Leriche syndrome
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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 arterial occlusive disease
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (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
Peripheral artery aneurysm
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (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
Peripheral artery stenosis
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (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
Shock
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Thrombophlebitis
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
General disorders and administration site conditions
Chest discomfort
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	1 / 506 (0.20%)	2 / 508 (0.39%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Death
subjects affected / exposed	1 / 510 (0.20%)	1 / 507 (0.20%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
Device dislocation
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	1 / 507 (0.20%)
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
Drowning
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Generalised oedema
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (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
Medical device complication
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Multi-organ failure
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Non-cardiac chest pain
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	2 / 507 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	2 / 508 (0.39%)	0 / 507 (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
Pyrexia
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Sudden death
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Immune system disorders
Anti-neutrophil cytoplasmic antibody positive vasculitis
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	4 / 506 (0.79%)	1 / 508 (0.20%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	2 / 4	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vaginal prolapse
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
subjects affected / exposed	2 / 510 (0.39%)	2 / 507 (0.39%)	1 / 506 (0.20%)	2 / 508 (0.39%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Analgesic asthma syndrome
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (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
Atelectasis
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Bronchiectasis
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Bullous lung disease
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (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	41 / 510 (8.04%)	37 / 507 (7.30%)	33 / 506 (6.52%)	30 / 508 (5.91%)	33 / 507 (6.51%)
occurrences causally related to treatment / all	0 / 48	1 / 45	1 / 38	2 / 35	2 / 38
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 1	0 / 1
Dysphonia
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Dyspnoea
subjects affected / exposed	0 / 510 (0.00%)	2 / 507 (0.39%)	2 / 506 (0.40%)	1 / 508 (0.20%)	2 / 507 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 3	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Emphysema
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Epistaxis
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Haemoptysis
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Hydrothorax
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (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
Hypercapnia
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Hypoxia
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Nasal polyps
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (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 turbinate hypertrophy
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (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
Paranasal sinus discomfort
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Pleural effusion
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (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 aspiration
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Pneumothorax
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	3 / 506 (0.59%)	0 / 508 (0.00%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax spontaneous
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	2 / 510 (0.39%)	2 / 507 (0.39%)	0 / 506 (0.00%)	3 / 508 (0.59%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Pulmonary granuloma
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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 hypertension
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary infarction
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (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 mass
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Pulmonary oedema
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Respiratory failure
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	3 / 506 (0.59%)	0 / 508 (0.00%)	3 / 507 (0.59%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 3	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 0	0 / 0
Rhonchi
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Vocal cord polyp
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Acute stress disorder
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Aggression
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Bipolar I disorder
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Confusional state
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Conversion disorder
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Delirium
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Depression
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (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
Major depression
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (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
Blood glucose increased
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Blood pressure decreased
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Troponin T increased
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Abdominal injury
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (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
Acetabulum fracture
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Avulsion fracture
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Clavicle fracture
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (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 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Fall
subjects affected / exposed	3 / 510 (0.59%)	1 / 507 (0.20%)	0 / 506 (0.00%)	2 / 508 (0.39%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Femur fracture
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (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
Head injury
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (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
Hip fracture
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Joint dislocation
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Liver contusion
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (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 vertebral fracture
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (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
Meniscus injury
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Patella fracture
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	2 / 507 (0.39%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skull fractured base
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (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
Spinal compression fracture
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Stab wound
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Subdural haematoma
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (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
Tendon rupture
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (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
Thoracic vertebral fracture
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Traumatic haematoma
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (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 pseudoaneurysm
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (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
Congenital, familial and genetic disorders
Malformation biliary
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (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
Acute myocardial infarction
subjects affected / exposed	2 / 510 (0.39%)	1 / 507 (0.20%)	0 / 506 (0.00%)	1 / 508 (0.20%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Angina pectoris
subjects affected / exposed	3 / 510 (0.59%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Angina unstable
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (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
Aortic valve stenosis
subjects affected / exposed	0 / 510 (0.00%)	2 / 507 (0.39%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Atrial fibrillation
subjects affected / exposed	1 / 510 (0.20%)	1 / 507 (0.20%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (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 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Cardiac arrest
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	1 / 506 (0.20%)	2 / 508 (0.39%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 2	0 / 0
Cardiac disorder
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Cardiac failure
subjects affected / exposed	2 / 510 (0.39%)	0 / 507 (0.00%)	2 / 506 (0.40%)	1 / 508 (0.20%)	0 / 507 (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 / 1	0 / 0	0 / 1	0 / 0	0 / 0
Cardiac failure acute
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Cardiac failure congestive
subjects affected / exposed	1 / 510 (0.20%)	2 / 507 (0.39%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	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 / 510 (0.00%)	1 / 507 (0.20%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Coronary artery disease
subjects affected / exposed	2 / 510 (0.39%)	1 / 507 (0.20%)	3 / 506 (0.59%)	1 / 508 (0.20%)	2 / 507 (0.39%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 3	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Extrasystoles
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Ischaemic cardiomyopathy
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (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
Left ventricular dysfunction
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Myocardial infarction
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	2 / 508 (0.39%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	1 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	1 / 506 (0.20%)	1 / 508 (0.20%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Palpitations
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (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
Supraventricular tachycardia
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Tachyarrhythmia
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (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
Ventricular fibrillation
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (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	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Nervous system disorders
Acute polyneuropathy
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (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
Carotid artery aneurysm
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Carotid artery stenosis
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (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
Cerebellar haemorrhage
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Cerebral haemorrhage
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Cerebral infarction
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	2 / 508 (0.39%)	0 / 507 (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
Cerebrovascular accident
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	2 / 506 (0.40%)	0 / 508 (0.00%)	2 / 507 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular disorder
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (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
Convulsion
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (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
Dizziness
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Epilepsy
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (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
Haemorrhage intracranial
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (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
Headache
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (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
Hypoxic-ischaemic encephalopathy
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorder
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Neuromyopathy
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (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
Presyncope
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Spondylitic myelopathy
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (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
Subarachnoid haemorrhage
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Syncope
subjects affected / exposed	1 / 510 (0.20%)	1 / 507 (0.20%)	1 / 506 (0.20%)	1 / 508 (0.20%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombotic cerebral infarction
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (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
Transient ischaemic attack
subjects affected / exposed	2 / 510 (0.39%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tremor
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (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
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (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
Haemorrhagic anaemia
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Iron deficiency anaemia
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (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
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (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
Eye disorders
Age-related macular degeneration
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (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
Cataract
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Lacrimation increased
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (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
Macular degeneration
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Retinal tear
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (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
Vision blurred
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Abdominal pain upper
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colitis ischaemic
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colitis ulcerative
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (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
Crohn's disease
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 4	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 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Diverticulum intestinal
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Duodenal ulcer haemorrhage
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Duodenal ulcer perforation
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Dysphagia
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (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
Enteritis
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Gastritis
subjects affected / exposed	0 / 510 (0.00%)	2 / 507 (0.39%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (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
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Ileus
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Inguinal hernia
subjects affected / exposed	3 / 510 (0.59%)	1 / 507 (0.20%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Inguinal hernia strangulated
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Melaena
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (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
Mesenteric artery stenosis
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Oesophageal achalasia
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Oesophageal stenosis
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (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
Oral pain
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	1 / 508 (0.20%)	0 / 507 (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
Proctalgia
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (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	0 / 510 (0.00%)	1 / 507 (0.20%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Upper gastrointestinal haemorrhage
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Hepatobiliary disorders
Bile duct stone
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Biliary colic
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Cholecystitis
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Cholecystitis acute
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	1 / 506 (0.20%)	2 / 508 (0.39%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	1 / 506 (0.20%)	1 / 508 (0.20%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Eczema
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Dysuria
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (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
Haematuria
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	1 / 508 (0.20%)	0 / 507 (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
Nephritis
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (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
Renal colic
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Renal failure acute
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	1 / 506 (0.20%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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 / 1	0 / 0	0 / 0
Renal vasculitis
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (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 and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (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
Back pain
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (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
Bone deformity
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (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
Flank pain
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Foot deformity
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (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
Intervertebral disc degeneration
subjects affected / exposed	1 / 510 (0.20%)	1 / 507 (0.20%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	1 / 506 (0.20%)	1 / 508 (0.20%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 1	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 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	2 / 508 (0.39%)	0 / 507 (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
Monarthritis
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (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 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (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
Osteoarthritis
subjects affected / exposed	2 / 510 (0.39%)	2 / 507 (0.39%)	1 / 506 (0.20%)	0 / 508 (0.00%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Periarthritis
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Spinal column stenosis
subjects affected / exposed	0 / 510 (0.00%)	3 / 507 (0.59%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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 / 0	0 / 0	0 / 0	0 / 0
Spinal osteoarthritis
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	1 / 507 (0.20%)
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
Spondylolisthesis
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (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
Synovial cyst
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Abscess
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Anal abscess
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Appendicitis perforated
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Biliary sepsis
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Bronchitis
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	2 / 507 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchopneumonia
subjects affected / exposed	2 / 510 (0.39%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Cellulitis
subjects affected / exposed	2 / 510 (0.39%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis pharyngeal
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Dermatitis infected
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Escherichia bacteraemia
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	2 / 506 (0.40%)	0 / 508 (0.00%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (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
Graft infection
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
H1N1 influenza
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Hepatitis B
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (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
Infection
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Infective exacerbation of chronic obstructive airways disease
subjects affected / exposed	2 / 510 (0.39%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	2 / 510 (0.39%)	1 / 507 (0.20%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lobar pneumonia
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Lower respiratory tract infection
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (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
Lung infection
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (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 / 1	0 / 0
Ophthalmic herpes zoster
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Pelvic abscess
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Pneumococcal sepsis
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Pneumonia
subjects affected / exposed	6 / 510 (1.18%)	6 / 507 (1.18%)	2 / 506 (0.40%)	9 / 508 (1.77%)	9 / 507 (1.78%)
occurrences causally related to treatment / all	0 / 7	0 / 8	0 / 2	0 / 9	1 / 11
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
Post procedural infection
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (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
Postoperative abscess
subjects affected / exposed	1 / 510 (0.20%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	0 / 507 (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
Pyelonephritis
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	1 / 507 (0.20%)
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
Respiratory tract infection
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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	1 / 510 (0.20%)	1 / 507 (0.20%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	0 / 507 (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
Sinusitis
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Superinfection
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Urinary tract infection
subjects affected / exposed	0 / 510 (0.00%)	1 / 507 (0.20%)	1 / 506 (0.20%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Urosepsis
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (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
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	2 / 507 (0.39%)
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
Diabetes mellitus
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	1 / 508 (0.20%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diabetic ketoacidosis
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	0 / 506 (0.00%)	0 / 508 (0.00%)	1 / 507 (0.20%)
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
Gout
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (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
Hypokalaemia
subjects affected / exposed	0 / 510 (0.00%)	0 / 507 (0.00%)	1 / 506 (0.20%)	0 / 508 (0.00%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 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	246 / 510 (48.24%)	228 / 507 (44.97%)	216 / 506 (42.69%)	223 / 508 (43.90%)	214 / 507 (42.21%)
Vascular disorders
Hypertension
subjects affected / exposed	26 / 510 (5.10%)	10 / 507 (1.97%)	10 / 506 (1.98%)	19 / 508 (3.74%)	12 / 507 (2.37%)
occurrences all number	26	10	11	22	14
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	147 / 510 (28.82%)	146 / 507 (28.80%)	132 / 506 (26.09%)	118 / 508 (23.23%)	129 / 507 (25.44%)
occurrences all number	216	226	204	168	208
Cough
subjects affected / exposed	17 / 510 (3.33%)	27 / 507 (5.33%)	25 / 506 (4.94%)	29 / 508 (5.71%)	24 / 507 (4.73%)
occurrences all number	20	29	27	30	24
Dyspnoea
subjects affected / exposed	20 / 510 (3.92%)	22 / 507 (4.34%)	27 / 506 (5.34%)	21 / 508 (4.13%)	20 / 507 (3.94%)
occurrences all number	23	27	36	22	22
Infections and infestations
Nasopharyngitis
subjects affected / exposed	66 / 510 (12.94%)	59 / 507 (11.64%)	54 / 506 (10.67%)	70 / 508 (13.78%)	61 / 507 (12.03%)
occurrences all number	87	83	72	105	82
Upper respiratory tract infection
subjects affected / exposed	32 / 510 (6.27%)	31 / 507 (6.11%)	27 / 506 (5.34%)	29 / 508 (5.71%)	29 / 507 (5.72%)
occurrences all number	43	40	32	33	38

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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: NCT01431287

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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 Days 15, 43, 85, 169 and 365

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

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

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

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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