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Clinical Trial Results:
A randomised, double-blind, placebo- and active-controlled parallel group study to assess the efficacy of 12 weeks of once daily treatment of two doses of orally inhaled tiotropium + olodaterol fixed dose combination (delivered by the Respimat® inhaler) in patients with moderate to severe Chronic Obstructive Pulmonary Disease (COPD)

Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.

Summary
EudraCT number	2013-002243-29
Trial protocol	FI GB CZ ES DK BE
Global end of trial date	24 Nov 2014

Results information
Results version number	v1(current)
This version publication date	06 Apr 2016
First version publication date	06 Apr 2016
Other versions

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

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Trial information

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Sponsor protocol code

1237.25

ISRCTN number

US NCT number

NCT01964352

WHO universal trial number (UTN)

Sponsor organisation name

Boehringer Ingelheim

Sponsor organisation address

Binger Strasse 173, Ingelheim am Rhein, Germany, 55216

Public contact

Boehringer Ingelheim Pharma GmbH & Co. KG, QRPE Processes and Systems Coordination, Clinical Trial, +1 8002430127, clintriage.rdg@boehringer-ingelheim.com

Scientific contact

Boehringer Ingelheim Pharma GmbH & Co. KG, QRPE Processes and Systems Coordination, Clinical Trial, +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

13 Jan 2015

Is this the analysis of the primary completion data?

Yes

Primary completion date

31 Oct 2014

Global end of trial reached?

Yes

Global end of trial date

24 Nov 2014

Was the trial ended prematurely?

Main objective of the trial

This trial was 1 of 2 randomised, double-blind, placebo- and active-controlled parallel group Phase IIIb trials with identical protocols (replicate trials with BI trial numbers 1237.25 and 1237.26) The objective of this trial was to evaluate maximal treatment effect in forced expiratory volume in one second (FEV1) response and St. George’s Respiratory Questionnaire (SGRQ) total score and safety after 12 weeks of treatment with 2 different doses of tiotropium + olodaterol fixed dose combination solution (2.5/5μg and 5/5μg) delivered by the RESPIMAT® inhaler by comparison with placebo in patients with moderate to severe 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 for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct.

Background therapy

Evidence for comparator

Actual start date of recruitment

29 Nov 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 42

Country: Number of subjects enrolled

Canada: 58

Country: Number of subjects enrolled

Czech Republic: 45

Country: Number of subjects enrolled

Denmark: 58

Country: Number of subjects enrolled

Finland: 52

Country: Number of subjects enrolled

Germany: 159

Country: Number of subjects enrolled

South Africa: 64

Country: Number of subjects enrolled

Spain: 81

Country: Number of subjects enrolled

United Kingdom: 49

Country: Number of subjects enrolled

United States: 446

Worldwide total number of subjects

1054

EEA total number of subjects

486

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)

505

From 65 to 84 years

541

85 years and over

Subject disposition

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Recruitment details

814 were entered and randomized. One patient randomized to Tiotropium 5 μg was not treated. One patient entered the study with 2 different patient numbers. This patient was counted twice in the randomized set but only once in the treated set. Thus a total of 812 unique patients were treated.

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, Carer, Data analyst, Assessor

Are arms mutually exclusive

Yes

Placebo

Arm description

Once daily 2 puffs solution of placebo for inhalation with Respimat

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

2 actuations once daily in the morning. Dose not applicable.

Tiotropium 5 μg

Arm description

Once daily 2 puffs solution of 2.5 μg tiotropium for inhalation with Respimat

Arm type

Active comparator

Investigational medicinal product name

Tiotropium Bromide

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

2 actuations once daily in the morning, for a total dose of 5 μg.

Tiotropium 2.5 μg+ Olodaterol 5 μg

Arm description

Once daily 2 puffs solution of 1.25 μg tiotropium / 2.5 μg olodaterol for inhalation with Respimat as a fixed combination with a single inhaler.

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

2 actuations once daily in the morning for a total dose of 5 μg

Investigational medicinal product name

Tiotropium Bromide

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

2 actuations once daily in the morning for a total dose of 2.5 μg

Tiotropium 5 μg + Olodaterol 5 μg

Arm description

Once daily 2 puffs solution of 2.5 μg tiotropium / 2.5 μg olodaterol for inhalation with Respimat as a fixed combination with a single inhaler.

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

2 actuations once daily in the morning, for a total dose of 5 μg.

Investigational medicinal product name

Tiotropium Bromide

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

2 actuations once daily in the morning, for a total dose of 5 μg.

Number of subjects in period 1 ^[1]	Placebo	Tiotropium 5 μg	Tiotropium 2.5 μg+ Olodaterol 5 μg	Tiotropium 5 μg + Olodaterol 5 μg
Started	204	203	202	203
Completed	178	192	196	195
Not completed	26	11	6	8
Adverse event, serious fatal	-	2	-	-
Consent withdrawn by subject	4	2	1	-
Adverse event, non-fatal	13	1	4	3
Lost to follow-up	1	-	-	1
Lack of efficacy	6	-	-	-
Protocol deviation	2	4	-	2
Other than stated above	-	2	1	2

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 randomized after successfully completing the screening period and received at least one of the trial medication.

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Once daily 2 puffs solution of placebo for inhalation with Respimat

Reporting group title

Tiotropium 5 μg

Reporting group description

Once daily 2 puffs solution of 2.5 μg tiotropium for inhalation with Respimat

Reporting group title

Tiotropium 2.5 μg+ Olodaterol 5 μg

Reporting group description

Once daily 2 puffs solution of 1.25 μg tiotropium / 2.5 μg olodaterol for inhalation with Respimat as a fixed combination with a single inhaler.

Reporting group title

Tiotropium 5 μg + Olodaterol 5 μg

Reporting group description

Once daily 2 puffs solution of 2.5 μg tiotropium / 2.5 μg olodaterol for inhalation with Respimat as a fixed combination with a single inhaler.

Reporting group values	Placebo	Tiotropium 5 μg	Tiotropium 2.5 μg+ Olodaterol 5 μg	Tiotropium 5 μg + Olodaterol 5 μg	Total
Number of subjects	204	203	202	203	812
Age categorical
Units: Subjects
Age Continuous \|
Treated set (TS) which included all randomised patients who received at least one dose of trial medication represents the baseline analysis population.
Units: years
arithmetic mean (standard deviation)	65.1 ( 8.3 )	64.9 ( 8.2 )	64.7 ( 8.2 )	64.7 ( 8.9 )	-
Gender, Male/Female
Treated set (TS) which included all randomised patients who received at least one dose of trial medication represents the baseline analysis population.
Units: participants
Female	77	79	86	89	331
Male	127	124	116	114	481

End points

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Reporting group title

Placebo

Reporting group description

Once daily 2 puffs solution of placebo for inhalation with Respimat

Reporting group title

Tiotropium 5 μg

Reporting group description

Once daily 2 puffs solution of 2.5 μg tiotropium for inhalation with Respimat

Reporting group title

Tiotropium 2.5 μg+ Olodaterol 5 μg

Reporting group description

Once daily 2 puffs solution of 1.25 μg tiotropium / 2.5 μg olodaterol for inhalation with Respimat as a fixed combination with a single inhaler.

Reporting group title

Tiotropium 5 μg + Olodaterol 5 μg

Reporting group description

Once daily 2 puffs solution of 2.5 μg tiotropium / 2.5 μg olodaterol for inhalation with Respimat as a fixed combination with a single inhaler.

Primary: FEV1 AUC0-3h response (change from baseline)

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End point title

FEV1 AUC0-3h response (change from baseline)

End point description

Forced expiratory volume in one second (FEV1) Area under the curve (AUC) 0-3h was calculated as the area under the FEV1-time curve from 0 to 3h post-dose using the trapezoidal rule, divided by the duration (3h) to report in litres. FEV1 AUC0-3h response was defined as FEV1 AUC0-3h minus baseline FEV1. The adjusted mean and standard error (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. The Full Analysis set (FAS) included all patients in the TS who had a baseline and at least one postbaseline measurement for any of the primary efficacy endpoints.

End point type

Primary

End point timeframe

baseline and 12 weeks

End point values	Placebo	Tiotropium 5 μg	Tiotropium 2.5 μg+ Olodaterol 5 μg	Tiotropium 5 μg + Olodaterol 5 μg
Number of subjects analysed	204 ^[1]	203 ^[2]	202 ^[3]	202 ^[4]
Units: Liter
arithmetic mean (standard error)	-0.014 ( 0.014 )	0.205 ( 0.013 )	0.285 ( 0.013 )	0.316 ( 0.013 )

Notes
[1] - FAS including patients with available endpoint data at week 12
[2] - FAS including patients with available endpoint data at week 12
[3] - FAS including patients with available endpoint data at week 12
[4] - FAS including patients with available endpoint data at week 12

Statistical analysis 1

Statistical analysis description

Placebo vs. Tiotropium 5 μg + Olodaterol 5 μg. FEV1 AUC0-3h response was defined as FEV1 AUC0-3h minus baseline FEV1. The adjusted mean and standard error (SE) are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Placebo v Tiotropium 5 μg + Olodaterol 5 μg

Number of subjects included in analysis

406

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed Effects Model for Repeated Measure

Parameter type

Mean difference (net)

Point estimate

0.331

Confidence interval

level

95%

sides

2-sided

lower limit

0.293

upper limit

0.369

Variability estimate

Standard error of the mean

Dispersion value

0.019

Statistical analysis 2

Statistical analysis description

Tiotropium 5 μg vs. Tiotropium 5 μg + 5 μg Olodaterol. FEV1 AUC0-3h response was defined as FEV1 AUC0-3h minus baseline FEV1. The adjusted mean and SE)are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Tiotropium 5 μg v Tiotropium 5 μg + Olodaterol 5 μg

Number of subjects included in analysis

405

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed Effects Model for Repeated Measure

Parameter type

Mean difference (net)

Point estimate

0.111

Confidence interval

level

95%

sides

2-sided

lower limit

0.075

upper limit

0.148

Variability estimate

Standard error of the mean

Dispersion value

0.019

Statistical analysis 3

Statistical analysis description

Placebo vs. Tiotropium 2.5 μg + Olodaterol 5 μg. FEV1 AUC0-3h response was defined as FEV1 AUC0-3h minus baseline FEV1. The adjusted mean and SE are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Placebo v Tiotropium 2.5 μg+ Olodaterol 5 μg

Number of subjects included in analysis

406

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed Effects Model for Repeated Measure

Parameter type

Mean difference (net)

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

0.262

upper limit

0.337

Variability estimate

Standard error of the mean

Dispersion value

0.019

Statistical analysis 4

Statistical analysis description

Tiotropium 5 μg vs. Tiotropium 2.5 μg + Olodaterol 5 μg. FEV1 AUC0-3h response was defined as FEV1 AUC0-3h minus baseline FEV1. The adjusted mean and SE are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Tiotropium 5 μg v Tiotropium 2.5 μg+ Olodaterol 5 μg

Number of subjects included in analysis

405

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed Effects Model for Repeated Measure

Parameter type

Mean difference (net)

Point estimate

0.08

Confidence interval

level

95%

sides

2-sided

lower limit

0.044

upper limit

0.116

Variability estimate

Standard error of the mean

Dispersion value

0.018

Statistical analysis 5

Statistical analysis description

Placebo vs. Tiotropium 5 μg. FEV1 AUC0-3h response was defined as FEV1 AUC0-3h minus baseline FEV1. The adjusted mean and SE are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Placebo v Tiotropium 5 μg

Number of subjects included in analysis

407

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed Effects Model for Repeated Measure

Parameter type

Mean difference (net)

Point estimate

0.219

Confidence interval

level

95%

sides

2-sided

lower limit

0.181

upper limit

0.258

Variability estimate

Standard error of the mean

Dispersion value

0.02

Statistical analysis 6

Statistical analysis description

Tiotropium 2.5 μg + Olodaterol 5 μg vs. Tiotropium 5 μg + Olodaterol 5 μg. FEV1 AUC0-3h response was defined as FEV1 AUC0-3h minus baseline FEV1. The adjusted mean and SE are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Tiotropium 2.5 μg+ Olodaterol 5 μg v Tiotropium 5 μg + Olodaterol 5 μg

Number of subjects included in analysis

404

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0872

Method

Mixed Effects Model for Repeated Measure

Parameter type

Mean difference (net)

Point estimate

0.031

Confidence interval

level

95%

sides

2-sided

lower limit

-0.005

upper limit

0.067

Variability estimate

Standard error of the mean

Dispersion value

0.018

Primary: Trough FEV1 response (change from baseline)

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End point title

Trough FEV1 response (change from baseline)

End point description

Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours). It was calculated as the mean of the 2 FEV1 measurements performed 23 h and at 23 h 50 min after inhalation of study medication at day 85. Trough FEV1 response was defines as trough FEV1 minus baseline FEV1. 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.

End point type

Primary

End point timeframe

baseline and 12 weeks

End point values	Placebo	Tiotropium 5 μg	Tiotropium 2.5 μg+ Olodaterol 5 μg	Tiotropium 5 μg + Olodaterol 5 μg
Number of subjects analysed	198 ^[5]	200 ^[6]	201 ^[7]	200 ^[8]
Units: Liter
arithmetic mean (standard error)	0.001 ( 0.014 )	0.135 ( 0.014 )	0.151 ( 0.013 )	0.163 ( 0.013 )

Notes
[5] - FAS including patients with available endpoint data at week 12
[6] - FAS including patients with available endpoint data at week 12
[7] - FAS including patients with available endpoint data at week 12
[8] - FAS including patients with available endpoint data at week 12

Statistical analysis 1

Statistical analysis description

Placebo vs. Tiotropium 5 μg + Olodaterol 5 μg. Trough FEV1 response was defines as trough FEV1 minus baseline FEV1. The adjusted mean (SE) are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Placebo v Tiotropium 5 μg + Olodaterol 5 μg

Number of subjects included in analysis

398

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed Effects Model for Repeated Measure

Parameter type

Mean difference (net)

Point estimate

0.162

Confidence interval

level

95%

sides

2-sided

lower limit

0.0124

upper limit

0.2

Variability estimate

Standard error of the mean

Dispersion value

0.019

Statistical analysis 2

Statistical analysis description

Tiotropium 5 μg vs. Tiotropium 5 μg + Olodaterol 5 μg. Trough FEV1 response was defines as trough FEV1 minus baseline FEV1. The adjusted mean (SE) are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Tiotropium 5 μg v Tiotropium 5 μg + Olodaterol 5 μg

Number of subjects included in analysis

400

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1381

Method

Mixed Effects Model for Repeated Measure

Parameter type

Mean difference (net)

Point estimate

0.028

Confidence interval

level

95%

sides

2-sided

lower limit

-0.009

upper limit

0.066

Variability estimate

Standard error of the mean

Dispersion value

0.019

Statistical analysis 3

Statistical analysis description

Placebo vs. Tiotropium 2.5 μg + Olodaterol 5 μg. Trough FEV1 response was defines as trough FEV1 minus baseline FEV1. The adjusted mean (SE) are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Placebo v Tiotropium 2.5 μg+ Olodaterol 5 μg

Number of subjects included in analysis

399

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed Effects Model for Repeated Measure

Parameter type

Mean difference (net)

Point estimate

0.15

Confidence interval

level

95%

sides

2-sided

lower limit

0.113

upper limit

0.188

Variability estimate

Standard error of the mean

Dispersion value

0.019

Statistical analysis 4

Statistical analysis description

Tiotropium 5 μg vs. Tiotropium 2.5 μg + Olodaterol 5 μg. Trough FEV1 response was defines as trough FEV1 minus baseline FEV1. The adjusted mean (SE) are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Tiotropium 5 μg v Tiotropium 2.5 μg+ Olodaterol 5 μg

Number of subjects included in analysis

401

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3872

Method

Mixed Effects Model for Repeated Measure

Parameter type

Mean difference (net)

Point estimate

0.017

Confidence interval

level

95%

sides

2-sided

lower limit

-0.021

upper limit

0.054

Variability estimate

Standard error of the mean

Dispersion value

0.019

Statistical analysis 5

Statistical analysis description

Placebo vs. Tiotropium 5 μg. Trough FEV1 response was defines as trough FEV1 minus baseline FEV1. The adjusted mean (SE) are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Placebo v Tiotropium 5 μg

Number of subjects included in analysis

398

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed Effects Model for Repeated Measure

Parameter type

Mean difference (net)

Point estimate

0.134

Confidence interval

level

95%

sides

2-sided

lower limit

0.096

upper limit

0.172

Variability estimate

Standard error of the mean

Dispersion value

0.019

Statistical analysis 6

Statistical analysis description

Tiotropium 2.5 μg + Olodaterol 5 μg vs. Tiotropium 5 μg + Olodaterol 5 μg. Trough FEV1 response was defines as trough FEV1 minus baseline FEV1. The adjusted mean (SE) are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Tiotropium 2.5 μg+ Olodaterol 5 μg v Tiotropium 5 μg + Olodaterol 5 μg

Number of subjects included in analysis

401

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5333

Method

Mixed Effects Model for Repeated Measure

Parameter type

Mean difference (net)

Point estimate

0.012

Confidence interval

level

95%

sides

2-sided

lower limit

-0.025

upper limit

0.049

Variability estimate

Standard error of the mean

Dispersion value

0.019

Primary: St. George’s Respiratory Questionnaire (SGRQ) total score

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End point title

St. George’s Respiratory Questionnaire (SGRQ) total score

End point description

This endpoint was evaluated based on the data from this individual trial. An additional combined endpoint is defined and analysed for trial 1237.25 and 1237.26, however due to the platform limitations those could not be provided. Results can be found on CT.gov study number: NCT02006732. The SGRQ ranges from 0 (no impairment of quality of life) to 100 (highest impairment of quality of life). 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.

End point type

Primary

End point timeframe

12 weeks treatment

End point values	Placebo	Tiotropium 5 μg	Tiotropium 2.5 μg+ Olodaterol 5 μg	Tiotropium 5 μg + Olodaterol 5 μg
Number of subjects analysed	186 ^[9]	192 ^[10]	199 ^[11]	196 ^[12]
Units: units on a scale
arithmetic mean (standard error)	42.038 ( 0.738 )	39.637 ( 0.717 )	37.916 ( 0.708 )	37.144 ( 0.71 )

Notes
[9] - FAS including patients with available endpoint data at week 12
[10] - FAS including patients with available endpoint data at week 12
[11] - FAS including patients with available endpoint data at week 12
[12] - FAS including patients with available endpoint data at week 12

Statistical analysis 1

Statistical analysis description

Placebo vs. Tiotropium 5 μg+ Olodaterol 5 μg.The adjusted mean (SE) are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Placebo v Tiotropium 5 μg + Olodaterol 5 μg

Number of subjects included in analysis

382

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed Effects Model for Repeated Measure

Parameter type

Mean difference (final values)

Point estimate

-4.894

Confidence interval

level

95%

sides

2-sided

lower limit

-6.904

upper limit

-2.884

Variability estimate

Standard error of the mean

Dispersion value

1.024

Statistical analysis 2

Statistical analysis description

Tiotropium 5 μg vs. Tiotropium 5 μg+ Olodaterol 5 μg. The adjusted mean (SE) are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Tiotropium 5 μg v Tiotropium 5 μg + Olodaterol 5 μg

Number of subjects included in analysis

388

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0136

Method

Mixed Effects Model for Repeated Measure

Parameter type

Mean difference (final values)

Point estimate

-2.493

Confidence interval

level

95%

sides

2-sided

lower limit

-4.473

upper limit

-0.513

Variability estimate

Standard error of the mean

Dispersion value

1.009

Statistical analysis 3

Statistical analysis description

Placebo vs. Tiotropium 2.5 μg + Olodaterol 5 μg. The adjusted mean (SE) are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Placebo v Tiotropium 2.5 μg+ Olodaterol 5 μg

Number of subjects included in analysis

385

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed Effects Model for Repeated Measure

Parameter type

Mean difference (final values)

Point estimate

-4.122

Confidence interval

level

95%

sides

2-sided

lower limit

-6.129

upper limit

-2.114

Variability estimate

Standard error of the mean

Dispersion value

1.023

Statistical analysis 4

Statistical analysis description

Tiotropium 5 μg vs. Tiotropium 2.5 μg+ Olodaterol 5 μg. The adjusted mean (SE) are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Tiotropium 5 μg v Tiotropium 2.5 μg+ Olodaterol 5 μg

Number of subjects included in analysis

391

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.088

Method

Mixed Effects Model for Repeated Measure

Parameter type

Mean difference (final values)

Point estimate

-1.721

Confidence interval

level

95%

sides

2-sided

lower limit

-3.698

upper limit

0.256

Variability estimate

Standard error of the mean

Dispersion value

1.008

Statistical analysis 5

Statistical analysis description

Placebo vs. Tiotropium 5 μg. The adjusted mean (SE) are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Placebo v Tiotropium 5 μg

Number of subjects included in analysis

378

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0198

Method

Mixed Effects Model for Repeated Measure

Parameter type

Mean difference (final values)

Point estimate

-2.401

Confidence interval

level

95%

sides

2-sided

lower limit

-4.419

upper limit

-0.382

Variability estimate

Standard error of the mean

Dispersion value

1.029

Statistical analysis 6

Statistical analysis description

Tiotropium 2.5 μg+ Olodaterol 5 μg vs. Tiotropium 5 μg+ Olodaterol 5 μg. The adjusted mean (SE) are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Tiotropium 2.5 μg+ Olodaterol 5 μg v Tiotropium 5 μg + Olodaterol 5 μg

Number of subjects included in analysis

395

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4415

Method

Mixed Effects Model for Repeated Measure

Parameter type

Mean difference (final values)

Point estimate

-0.772

Confidence interval

level

95%

sides

2-sided

lower limit

-2.741

upper limit

1.196

Variability estimate

Standard error of the mean

Dispersion value

1.003

Secondary: Trough forced vital capacity (FVC) response (change from baseline)

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End point title

Trough forced vital capacity (FVC) response (change from baseline)

End point description

Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours). It was calculated as the mean of the 2 FVC measurements performed 23 h and at 23 h 50 min after inhalation of study medication at day 85. Trough FVC response was defined as trough FVC minus baseline FVC. 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.

End point type

Secondary

End point timeframe

baseline and 12 weeks

End point values	Placebo	Tiotropium 5 μg	Tiotropium 2.5 μg+ Olodaterol 5 μg	Tiotropium 5 μg + Olodaterol 5 μg
Number of subjects analysed	198 ^[13]	200 ^[14]	201 ^[15]	200 ^[16]
Units: Liter
arithmetic mean (standard error)	0.025 ( 0.023 )	0.223 ( 0.023 )	0.233 ( 0.022 )	0.244 ( 0.022 )

Notes
[13] - FAS including patients with available endpoint data at week 12
[14] - FAS including patients with available endpoint data at week 12
[15] - FAS including patients with available endpoint data at week 12
[16] - FAS including patients with available endpoint data at week 12

Statistical analysis 1

Statistical analysis description

Placebo vs. Tiotropium 5 μg+ Olodaterol 5 μg. Trough FVC response was defined as trough FVC minus baseline FVC. The adjusted mean (SE) are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Placebo v Tiotropium 5 μg + Olodaterol 5 μg

Number of subjects included in analysis

398

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed Effects Model for Repeated Measure

Parameter type

Mean difference (net)

Point estimate

0.22

Confidence interval

level

95%

sides

2-sided

lower limit

0.157

upper limit

0.282

Variability estimate

Standard error of the mean

Dispersion value

0.032

Statistical analysis 2

Statistical analysis description

Tiotropium 5 μg vs. Tiotropium 5 μg+ Olodaterol 5 μg. Trough FVC response was defined as trough FVC minus baseline FVC. The adjusted mean (SE) are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Tiotropium 5 μg v Tiotropium 5 μg + Olodaterol 5 μg

Number of subjects included in analysis

400

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5052

Method

Mixed Effects Model for Repeated Measure

Parameter type

Mean difference (net)

Point estimate

0.021

Confidence interval

level

95%

sides

2-sided

lower limit

-0.041

upper limit

0.084

Variability estimate

Standard error of the mean

Dispersion value

0.032

Statistical analysis 3

Statistical analysis description

Placebo vs. Tiotropium 2.5 μg+ Olodaterol 5 μg. Trough FVC response was defined as trough FVC minus baseline FVC. The adjusted mean (SE) are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Placebo v Tiotropium 2.5 μg+ Olodaterol 5 μg

Number of subjects included in analysis

399

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed Effects Model for Repeated Measure

Parameter type

Mean difference (net)

Point estimate

0.208

Confidence interval

level

95%

sides

2-sided

lower limit

0.146

upper limit

0.271

Variability estimate

Standard error of the mean

Dispersion value

0.032

Statistical analysis 4

Statistical analysis description

Tiotropium 5 μg vs. Tiotropium 2.5 μg+ Olodaterol 5 μg. Trough FVC response was defined as trough FVC minus baseline FVC. The adjusted mean (SE) are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Tiotropium 5 μg v Tiotropium 2.5 μg+ Olodaterol 5 μg

Number of subjects included in analysis

401

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7566

Method

Mixed Effects Model for Repeated Measure

Parameter type

Mean difference (net)

Point estimate

0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.052

upper limit

0.072

Variability estimate

Standard error of the mean

Dispersion value

0.032

Statistical analysis 5

Statistical analysis description

Placebo vs. Tiotropium 5 μg. Trough FVC response was defined as trough FVC minus baseline FVC. The adjusted mean (SE) are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Placebo v Tiotropium 5 μg

Number of subjects included in analysis

398

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed Effects Model for Repeated Measure

Parameter type

Mean difference (net)

Point estimate

0.198

Confidence interval

level

95%

sides

2-sided

lower limit

0.136

upper limit

0.261

Variability estimate

Standard error of the mean

Dispersion value

0.032

Statistical analysis 6

Statistical analysis description

Tiotropium 2.5 μg+ Olodaterol 5 μg vs. Tiotropium 5 μg+ Olodaterol 5 μg. Trough FVC response was defined as trough FVC minus baseline FVC. The adjusted mean (SE) are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Tiotropium 2.5 μg+ Olodaterol 5 μg v Tiotropium 5 μg + Olodaterol 5 μg

Number of subjects included in analysis

401

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7199

Method

Mixed Effects Model for Repeated Measure

Parameter type

Mean difference (net)

Point estimate

0.011

Confidence interval

level

95%

sides

2-sided

lower limit

-0.051

upper limit

0.073

Variability estimate

Standard error of the mean

Dispersion value

0.032

Secondary: TDI focal score

Top of page

End point title

TDI focal score

End point description

This endpoint was evaluated based on the data from this individual trial. An additional combined endpoint is defined and analysed for trial 1237.25 and 1237.26, however due to the platform limitations those could not be provided. Results can be found on CT.gov study number: NCT02006732. Mahler Transitional Dyspnoea Index (TDI) focal score was performed to measure the effect of the treatment on patients' dyspnoea.(Rating scale of 3 components - change in functional impairment, change in magnitude of tasks, change in magnitude of efforts. Worst score = -9, best score = +9). The adjusted mean (SE) are obtained from fitting an MMRM model 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.

End point type

Secondary

End point timeframe

12 weeks

End point values	Placebo	Tiotropium 5 μg	Tiotropium 2.5 μg+ Olodaterol 5 μg	Tiotropium 5 μg + Olodaterol 5 μg
Number of subjects analysed	187 ^[17]	193 ^[18]	199 ^[19]	196 ^[20]
Units: Units on a scale
arithmetic mean (standard error)	-0.113 ( 0.196 )	1.332 ( 0.192 )	1.839 ( 0.189 )	1.939 ( 0.19 )

Notes
[17] - FAS including patients with available endpoint data at week 12
[18] - FAS including patients with available endpoint data at week 12
[19] - FAS including patients with available endpoint data at week 12
[20] - FAS including patients with available endpoint data at week 12

Statistical analysis 1

Statistical analysis description

Placebo vs. Tiotropium 5 μg+ Olodaterol 5 μg. The adjusted mean (SE) are obtained from fitting an MMRM model 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

Placebo v Tiotropium 5 μg + Olodaterol 5 μg

Number of subjects included in analysis

383

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed Effects Model for Repeated Measure

Parameter type

Mean difference (final values)

Point estimate

2.052

Confidence interval

level

95%

sides

2-sided

lower limit

1.516

upper limit

2.588

Variability estimate

Standard error of the mean

Dispersion value

0.273

Statistical analysis 2

Statistical analysis description

Tiotropium 5 μg vs. Tiotropium 5 μg+ Olodaterol 5 μg. The adjusted mean (SE) are obtained from fitting an MMRM model 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 5 μg v Tiotropium 5 μg + Olodaterol 5 μg

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0246

Method

Mixed Effects Model for Repeated Measure

Parameter type

Mean difference (final values)

Point estimate

0.607

Confidence interval

level

95%

sides

2-sided

lower limit

0.078

upper limit

1.137

Variability estimate

Standard error of the mean

Dispersion value

0.27

Statistical analysis 3

Statistical analysis description

Placebo vs. Tiotropium 2.5 μg+ Olodaterol 5 μg. The adjusted mean (SE) are obtained from fitting an MMRM model 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

Placebo v Tiotropium 2.5 μg+ Olodaterol 5 μg

Number of subjects included in analysis

386

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed Effects Model for Repeated Measure

Parameter type

Mean difference (final values)

Point estimate

1.952

Confidence interval

level

95%

sides

2-sided

lower limit

1.417

upper limit

2.487

Variability estimate

Standard error of the mean

Dispersion value

0.272

Statistical analysis 4

Statistical analysis description

Tiotropium 5 μg vs. Tiotropium 2.5 μg+ Olodaterol 5 μg. The adjusted mean (SE) are obtained from fitting an MMRM model 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 5 μg v Tiotropium 2.5 μg+ Olodaterol 5 μg

Number of subjects included in analysis

392

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0599

Method

Mixed Effects Model for Repeated Measure

Parameter type

Mean difference (final values)

Point estimate

0.507

Confidence interval

level

95%

sides

2-sided

lower limit

-0.021

upper limit

1.035

Variability estimate

Standard error of the mean

Dispersion value

0.269

Statistical analysis 5

Statistical analysis description

Placebo vs. Tiotropium 5 μg. The adjusted mean (SE) are obtained from fitting an MMRM model 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

Placebo v Tiotropium 5 μg

Number of subjects included in analysis

380

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed Effects Model for Repeated Measure

Parameter type

Mean difference (final values)

Point estimate

1.445

Confidence interval

level

95%

sides

2-sided

lower limit

0.907

upper limit

1.983

Variability estimate

Standard error of the mean

Dispersion value

0.274

Statistical analysis 6

Statistical analysis description

Tiotropium 2.5 μg+ Olodaterol 5 μg vs. Tiotropium 5 μg+ Olodaterol 5 μg. The adjusted mean (SE) are obtained from fitting an MMRM model 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 2.5 μg+ Olodaterol 5 μg v Tiotropium 5 μg + Olodaterol 5 μg

Number of subjects included in analysis

395

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7081

Method

Mixed Effects Model for Repeated Measure

Parameter type

Mean difference (final values)

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.425

upper limit

0.626

Variability estimate

Standard error of the mean

Dispersion value

0.268

Secondary: FVC AUC0-3h response (change from baseline)

Top of page

End point title

FVC AUC0-3h response (change from baseline)

End point description

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.

End point type

Secondary

End point timeframe

baseline and 12 weeks

End point values	Placebo	Tiotropium 5 μg	Tiotropium 2.5 μg+ Olodaterol 5 μg	Tiotropium 5 μg + Olodaterol 5 μg
Number of subjects analysed	204 ^[21]	203 ^[22]	202 ^[23]	202 ^[24]
Units: Liter
arithmetic mean (standard error)	-0.011 ( 0.025 )	0.286 ( 0.024 )	0.387 ( 0.023 )	0.446 ( 0.023 )

Notes
[21] - FAS including patients with available endpoint data at week 12
[22] - FAS including patients with available endpoint data at week 12
[23] - FAS including patients with available endpoint data at week 12
[24] - FAS including patients with available endpoint data at week 12

Statistical analysis 1

Statistical analysis description

Placebo vs. Tiotropium 5 μg+ Olodaterol 5 μg. The adjusted mean (SE) are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Placebo v Tiotropium 5 μg + Olodaterol 5 μg

Number of subjects included in analysis

406

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed Effects Model for Repeated Measure

Parameter type

Mean difference (net)

Point estimate

0.457

Confidence interval

level

95%

sides

2-sided

lower limit

0.39

upper limit

0.524

Variability estimate

Standard error of the mean

Dispersion value

0.034

Statistical analysis 2

Statistical analysis description

Comparison groups

Tiotropium 5 μg v Tiotropium 5 μg + Olodaterol 5 μg

Number of subjects included in analysis

405

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed Effects Model for Repeated Measure

Parameter type

Mean difference (net)

Point estimate

0.16

Confidence interval

level

95%

sides

2-sided

lower limit

0.095

upper limit

0.225

Variability estimate

Standard error of the mean

Dispersion value

0.033

Statistical analysis 3

Statistical analysis description

Placebo vs. Tiotropium 2.5 μg+ Olodaterol 5 μg. The adjusted mean (SE) are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Comparison groups

Placebo v Tiotropium 2.5 μg+ Olodaterol 5 μg

Number of subjects included in analysis

406

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed Effects Model for Repeated Measure

Parameter type

Mean difference (net)

Point estimate

0.398

Confidence interval

level

95%

sides

2-sided

lower limit

0.331

upper limit

0.465

Variability estimate

Standard error of the mean

Dispersion value

0.034

Statistical analysis 4

Statistical analysis description

Comparison groups

Tiotropium 5 μg v Tiotropium 2.5 μg+ Olodaterol 5 μg

Number of subjects included in analysis

405

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0023

Method

Mixed Effects Model for Repeated Measure

Parameter type

Mean difference (net)

Point estimate

0.101

Confidence interval

level

95%

sides

2-sided

lower limit

0.036

upper limit

0.165

Variability estimate

Standard error of the mean

Dispersion value

0.033

Statistical analysis 5

Statistical analysis description

Comparison groups

Placebo v Tiotropium 5 μg

Number of subjects included in analysis

407

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed Effects Model for Repeated Measure

Parameter type

Mean difference (net)

Point estimate

0.297

Confidence interval

level

95%

sides

2-sided

lower limit

0.229

upper limit

0.365

Variability estimate

Standard error of the mean

Dispersion value

0.035

Statistical analysis 6

Statistical analysis description

Comparison groups

Tiotropium 2.5 μg+ Olodaterol 5 μg v Tiotropium 5 μg + Olodaterol 5 μg

Number of subjects included in analysis

404

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0701

Method

Mixed Effects Model for Repeated Measure

Parameter type

Mean difference (net)

Point estimate

0.059

Confidence interval

level

95%

sides

2-sided

lower limit

-0.005

upper limit

0.123

Variability estimate

Standard error of the mean

Dispersion value

0.033

Adverse events

Top of page

Timeframe for reporting adverse events

From the first drug administration to the last drug administration plus 21 days up to 112 days.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.1

Reporting group title

Treatment period placebo

Reporting group description

Once daily 2 puffs solution of placebo for inhalation with Respimat

Reporting group title

Treatment period Tiotropium 5 μg

Reporting group description

Once daily 2 puffs solution of 2.5 μg tiotropium for inhalation with Respimat

Reporting group title

Treatment period Tiotropium 2.5 μg+ Olodaterol 5 μg

Reporting group description

Once daily 2 puffs solution of 2.5 μg tiotropium for inhalation with Respimat

Reporting group title

Treatment period Tiotropium 5 μg + Olodaterol 5 μg

Reporting group description

Once daily 2 puffs solution of 2.5 μg tiotropium / 2.5 μg olodaterol for inhalation with Respimat.

Serious adverse events	Treatment period placebo	Treatment period Tiotropium 5 μg	Treatment period Tiotropium 2.5 μg+ Olodaterol 5 μg	Treatment period Tiotropium 5 μg + Olodaterol 5 μg
Total subjects affected by serious adverse events
subjects affected / exposed	11 / 204 (5.39%)	6 / 203 (2.96%)	4 / 202 (1.98%)	10 / 203 (4.93%)
number of deaths (all causes)	0	2	0	2
number of deaths resulting from adverse events	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm of unknown primary site
subjects affected / exposed	0 / 204 (0.00%)	0 / 203 (0.00%)	0 / 202 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Injury, poisoning and procedural complications
Accidental overdose
subjects affected / exposed	0 / 204 (0.00%)	0 / 203 (0.00%)	1 / 202 (0.50%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cervical vertebral fracture
subjects affected / exposed	0 / 204 (0.00%)	0 / 203 (0.00%)	0 / 202 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Clavicle fracture
subjects affected / exposed	0 / 204 (0.00%)	0 / 203 (0.00%)	1 / 202 (0.50%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Road traffic accident
subjects affected / exposed	0 / 204 (0.00%)	0 / 203 (0.00%)	0 / 202 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Peripheral ischaemia
subjects affected / exposed	0 / 204 (0.00%)	0 / 203 (0.00%)	1 / 202 (0.50%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Angina unstable
subjects affected / exposed	1 / 204 (0.49%)	0 / 203 (0.00%)	0 / 202 (0.00%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	2 / 204 (0.98%)	0 / 203 (0.00%)	0 / 202 (0.00%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	1 / 204 (0.49%)	0 / 203 (0.00%)	0 / 202 (0.00%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiomyopathy
subjects affected / exposed	1 / 204 (0.49%)	0 / 203 (0.00%)	0 / 202 (0.00%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic cardiomyopathy
subjects affected / exposed	1 / 204 (0.49%)	0 / 203 (0.00%)	0 / 202 (0.00%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 204 (0.00%)	1 / 203 (0.49%)	0 / 202 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	0 / 204 (0.00%)	1 / 203 (0.49%)	0 / 202 (0.00%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Convulsion
subjects affected / exposed	0 / 204 (0.00%)	0 / 203 (0.00%)	0 / 202 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lumbar radiculopathy
subjects affected / exposed	1 / 204 (0.49%)	0 / 203 (0.00%)	0 / 202 (0.00%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	0 / 204 (0.00%)	0 / 203 (0.00%)	0 / 202 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Colitis
subjects affected / exposed	0 / 204 (0.00%)	0 / 203 (0.00%)	0 / 202 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Autoimmune hepatitis
subjects affected / exposed	1 / 204 (0.49%)	0 / 203 (0.00%)	0 / 202 (0.00%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	3 / 204 (1.47%)	1 / 203 (0.49%)	1 / 202 (0.50%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 204 (0.00%)	0 / 203 (0.00%)	0 / 202 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary hypertension
subjects affected / exposed	0 / 204 (0.00%)	1 / 203 (0.49%)	0 / 202 (0.00%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	1 / 204 (0.49%)	0 / 203 (0.00%)	0 / 202 (0.00%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Acute stress disorder
subjects affected / exposed	0 / 204 (0.00%)	0 / 203 (0.00%)	0 / 202 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bipolar disorder
subjects affected / exposed	0 / 204 (0.00%)	0 / 203 (0.00%)	0 / 202 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Depression
subjects affected / exposed	0 / 204 (0.00%)	0 / 203 (0.00%)	0 / 202 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Suicide attempt
subjects affected / exposed	0 / 204 (0.00%)	0 / 203 (0.00%)	0 / 202 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Osteoarthritis
subjects affected / exposed	2 / 204 (0.98%)	1 / 203 (0.49%)	0 / 202 (0.00%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Cellulitis
subjects affected / exposed	0 / 204 (0.00%)	0 / 203 (0.00%)	1 / 202 (0.50%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	0 / 204 (0.00%)	1 / 203 (0.49%)	0 / 202 (0.00%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gangrene
subjects affected / exposed	0 / 204 (0.00%)	0 / 203 (0.00%)	1 / 202 (0.50%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal bacterial infection
subjects affected / exposed	0 / 204 (0.00%)	0 / 203 (0.00%)	0 / 202 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Localised infection
subjects affected / exposed	0 / 204 (0.00%)	0 / 203 (0.00%)	1 / 202 (0.50%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 204 (0.00%)	0 / 203 (0.00%)	0 / 202 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	0 / 204 (0.00%)	1 / 203 (0.49%)	0 / 202 (0.00%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sinusitis
subjects affected / exposed	1 / 204 (0.49%)	0 / 203 (0.00%)	0 / 202 (0.00%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Viral infection
subjects affected / exposed	1 / 204 (0.49%)	0 / 203 (0.00%)	0 / 202 (0.00%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Treatment period placebo	Treatment period Tiotropium 5 μg	Treatment period Tiotropium 2.5 μg+ Olodaterol 5 μg	Treatment period Tiotropium 5 μg + Olodaterol 5 μg
Total subjects affected by non serious adverse events
subjects affected / exposed	32 / 204 (15.69%)	25 / 203 (12.32%)	25 / 202 (12.38%)	16 / 203 (7.88%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	20 / 204 (9.80%)	19 / 203 (9.36%)	16 / 202 (7.92%)	9 / 203 (4.43%)
occurrences all number	22	21	16	10
Infections and infestations
Nasopharyngitis
subjects affected / exposed	12 / 204 (5.88%)	9 / 203 (4.43%)	9 / 202 (4.46%)	7 / 203 (3.45%)
occurrences all number	12	9	9	7

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Were there any global substantial amendments to the protocol? Yes

12 May 2014

In this administrative revision of the trial protocol, medication restrictions and washout periods for bronchodilator medications were updated to define washout periods for bronchodilator medications marketed after finalisation of original protocol. Web cast training was added for sites that did not participate in hands-on training of MasterScope equipment during the investigator meeting to ensure that at least one staff member at each site was fully trained in the use of the ERT equipment.

28 Aug 2014

In this administrative revision of the trial protocol, the hypothesis testing strategy, text describing the hypothesis testing strategy and corresponding figure were updated to maintain consistency within the project. It was made explicit that safety laboratory tests and ECGs were to be performed locally and not collected in the database, and hence would not be analysed. Further details were added to provide clear guidance on visit rescheduling for patients recovering from acute exacerbations of COPD.

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 secondary endpoints are defined and analysed for trial 1237.25 and 1237.26, however due to the platform limitations those could not be provided. Results can be found on CT.gov study number: NCT02006732.

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Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: FEV1 AUC0-3h response (change from baseline)

Primary: FEV1 AUC0-3h response (change from baseline)

Primary: Trough FEV1 response (change from baseline)

Primary: Trough FEV1 response (change from baseline)

Primary: St. George’s Respiratory Questionnaire (SGRQ) total score

Primary: St. George’s Respiratory Questionnaire (SGRQ) total score

Secondary: Trough forced vital capacity (FVC) response (change from baseline)

Secondary: Trough forced vital capacity (FVC) response (change from baseline)

Secondary: TDI focal score

Secondary: TDI focal score

Secondary: FVC AUC0-3h response (change from baseline)

Secondary: FVC AUC0-3h response (change from baseline)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

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