Clinical Trial Results:
A randomised, double-blind, 5 treatment arms, 4-period, incomplete cross-over study to determine the effect of 6 weeks treatment of orally inhaled tiotropium + olodaterol fixed dose combination (FDC) (2.5 / 5 µg; and 5 / 5 µg) (delivered by the Respimat® Inhaler) compared with tiotropium (5 µg), olodaterol (5 µg ) and placebo (delivered by the Respimat® Inhaler) on lung hyperinflation and exercise endurance time during constant work rate cycle ergometry in patients with Chronic Obstructive Pulmonary Disease (COPD) [MORACTO™ 2]

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

Summary
EudraCT number	2011-004659-37
Trial protocol	BE DE AT IT
Global end of trial date	20 Nov 2013

Results information
Results version number	v2(current)
This version publication date	23 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

1237.13

ISRCTN number

US NCT number

NCT01533922

WHO universal trial number (UTN)

Sponsor organisation name

Boehringer Ingelheim

Sponsor organisation address

Binger Strasse 173, 55216 Ingelheim am Rhein, Germany,

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

02 Dec 2013

Is this the analysis of the primary completion data?

Yes

Primary completion date

20 Nov 2013

Global end of trial reached?

Yes

Global end of trial date

20 Nov 2013

Was the trial ended prematurely?

Main objective of the trial

The primary objectives of this study are: 1) To compare the effects of orally inhaled tiotropium + olodaterol fixed dose combination (2.5 / 5 μg ; 5 / 5 μg) with tiotropium (5 μg), olodaterol (5 μg) and placebo on lung hyperinflation at rest and during constant work rate exercise in patients with COPD. Lung hyperinflation will be assessed by measurement of inspiratory capacity (IC). 2) To compare the effects of orally inhaled tiotropium + olodaterol fixed dose combination (2.5 / 5 μg ; 5 / 5 μg) with tiotropium (5 μg), olodaterol (5 μg) and placebo on constant work rate exercise tolerance after 6 weeks of treatment in patients with COPD. Exercise tolerance will be assessed by measurement of symptom-limited endurance time at rest and during constant work rate cycle ergometry.

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. Administration of rescue medication was allowed at any point during the study as medically needed. Open-label salbutamol/albuterol MDI (100 μg per puff) was provided as rescue medication by BI.

Background therapy

Evidence for comparator

Actual start date of recruitment

06 Mar 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 38

Country: Number of subjects enrolled

Austria: 41

Country: Number of subjects enrolled

Germany: 69

Country: Number of subjects enrolled

Italy: 44

Country: Number of subjects enrolled

Canada: 18

Country: Number of subjects enrolled

New Zealand: 16

Country: Number of subjects enrolled

Australia: 52

Country: Number of subjects enrolled

Argentina: 18

Country: Number of subjects enrolled

Chile: 15

Country: Number of subjects enrolled

United States: 70

Worldwide total number of subjects

381

EEA total number of subjects

192

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)

216

From 65 to 84 years

165

85 years and over

Subject disposition

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Recruitment details

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 inclusion/exclusion criteria. Subjects were not randomised to trial treatment if any one of the specific entry criteria were violated. Of the enrolled 381 pts, 295 pts entered study.

Period 1 title

Overall trial (treatment 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

Placebo QD

Arm description

Oral inhalation of placebo, 2 puffs from the Respimat inhaler, once daily, in the morning.

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

Placebo inhalation solution, delivered once daily via the respimat Inhaler in the morning.

Olodaterol 5 μg QD

Arm description

Oral inhalation of Olodaterol fixed dose 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 5 μg

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

Olodaterol 5 μg inhalation solution, delivered once daily via the respimat Inhaler in the morning.

Tiotropium 5 μg QD

Arm description

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

Arm type

Active comparator

Investigational medicinal product name

Tiotropium 5 μg

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

Tiotropium 5 μg inhalation solution, delivered once daily via the respimat Inhaler in the morning.

Tiotropium + Olodaterol 2.5/5 μg QD

Arm description

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

Arm type

Experimental

Investigational medicinal product name

Tiotropium 2.5 μg / Olodaterol 5 μg_FDC

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

Tio+Olo fixed dose combination (FDC) 2.5/5 μg inhalation solution, delivered once daily via the respimat Inhaler in the morning.

Tiotropium + Olodaterol 5/5 μg QD

Arm description

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

Arm type

Experimental

Investigational medicinal product name

Tiotropium 5 μg / Olodaterol 5 μg_FDC

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

Tio+Olo FDC 5/5 μg inhalation solution, delivered once daily via the respimat Inhaler in the morning.

Number of subjects in period 1	Placebo QD	Olodaterol 5 μg QD	Tiotropium 5 μg QD	Tiotropium + Olodaterol 2.5/5 μg QD	Tiotropium + Olodaterol 5/5 μg QD
Started	222	217	227	223	226
Completed	212	214	216	219	222
Not completed	10	3	11	4	4
Other reason not defined above	-	-	1	1	-
Consent withdrawn by subject	3	1	3	1	1
Adverse event, non-fatal	7	2	5	2	3
Lack of efficacy	-	-	1	-	-
Protocol deviation	-	-	1	-	-

Period 2 title

Overall trial by sequence

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Are arms mutually exclusive

Yes

Tio+Olo 2.5/5 / Tio+Olo 5/5 / Tio / Olo

Arm description

Patients received a total of four treatments, and each treatment period is separated by a washout period of 21 days. The treatments administered orally via the respimat inhaler, once daily, in the morning were: • Fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg • Fixed dose combination (FDC) of Tiotropium 5 μg and Olodaterol 5 μg • Tiotropium fixed dose 5 μg • Olodaterol fixed dose 5 μg

Arm type

treatment sequence

Investigational medicinal product name

Tiotropium 2.5 μg / Olodaterol 5 μg_FDC

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

Tio+Olo Fixed Dose Combination (FDC) 2.5/5 μg inhalation solution delivered once daily via respimat inhaler

Investigational medicinal product name

Tiotropium 5 μg / Olodaterol 5 μg_FDC

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

Tio+Olo FDC 5/5 μg inhalation solution delivered once daily via respimat inhaler

Investigational medicinal product name

Tiotropium 5 μg

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

Tiotropium 5 μg inhalation solution delivered once daily via respimat inhaler

Investigational medicinal product name

Olodaterol 5 μg

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

Olodaterol 5 μg inhalation solution delivered once daily via respimat inhaler

Tio+Olo 5/5 / Tio / Olo / placebo

Arm description

Patients received a total of four treatments, and each treatment period is separated by a washout period of 21 days. The treatments administered orally via the respimat inhaler, once daily, in the morning were: • Fixed dose combination (FDC) of Tiotropium 5 μg and Olodaterol 5 μg • Tiotropium fixed dose 5 μg • Olodaterol fixed dose 5 μg • Oral inhalation of placebo

Arm type

treatment sequence

Investigational medicinal product name

Tiotropium 5 μg / Olodaterol 5 μg_FDC

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

Tio+Olo FDC 5/5 μg inhalation solution delivered once daily via respimat inhaler

Investigational medicinal product name

Tiotropium 5 μg

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

Tiotropium 5 μg inhalation solution delivered once daily via respimat inhaler

Investigational medicinal product name

Olodaterol 5 μg

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

Olodaterol 5 μg inhalation solution, delivered once daily via the respimat Inhaler

Investigational medicinal product name

placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

placebo inhalation solution, delivered once daily via the respimat Inhaler

Tio / Olo / placebo / Tio+Olo 2.5/5

Arm description

Patients received a total of four treatments, and each treatment period is separated by a washout period of 21 days. The treatments administered orally via the respimat inhaler, once daily, in the morning were: • Tiotropium fixed dose 5 μg • Olodaterol fixed dose 5 μg • Oral inhalation of placebo • Fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg

Arm type

treatment sequence

Investigational medicinal product name

Tiotropium 5 μg

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

Tiotropium 5 μg inhalation solution delivered once daily via respimat inhaler

Investigational medicinal product name

Olodaterol 5 μg

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

Olodaterol 5 μg inhalation solution delivered once daily via respimat inhaler

Investigational medicinal product name

placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

Placebo inhalation solution delivered once daily (QD) via respimat inhaler

Investigational medicinal product name

Tiotropium 2.5 μg / Olodaterol 5 μg_FDC

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

Tio+Olo Fixed Dose Combination (FDC) 2.5/5 μg inhalation solution delivered once daily via respimat inhaler

Olo / placebo / Tio+Olo 2.5/5 / Tio+Olo 5/5

Arm description

Patients received a total of four treatments, and each treatment period is separated by a washout period of 21 days. The treatments administered orally via the respimat inhaler, once daily, in the morning were: • Olodaterol fixed dose 5 μg • Oral inhalation of placebo • Fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg • Fixed dose combination (FDC) of Tiotropium 5 μg and Olodaterol 5 μg One patient received Tio 5 instead of Olo 5 by mistake.

Arm type

treatment sequence

Investigational medicinal product name

Olodaterol 5 μg

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

Olodaterol 5 μg inhalation solution delivered once daily via respimat inhaler

Investigational medicinal product name

placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

Placebo inhalation solution delivered once daily (QD) via respimat inhaler

Investigational medicinal product name

Tiotropium 2.5 μg / Olodaterol 5 μg_FDC

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

Tio+Olo Fixed Dose Combination (FDC) 2.5/5 μg inhalation solution delivered once daily via respimat inhaler

Investigational medicinal product name

Tiotropium 5 μg / Olodaterol 5 μg_FDC

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

Tio+Olo FDC 5/5 μg inhalation solution delivered once daily via respimat inhaler

placebo / Tio+Olo 2.5/5 / Tio+Olo 5/5 / Tio

Arm description

Patients received a total of four treatments, and each treatment period is separated by a washout period of 21 days. The treatments administered orally via the respimat inhaler, once daily, in the morning were: • Oral inhalation of placebo • Fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg • Fixed dose combination (FDC) of Tiotropium 5 μg and Olodaterol 5 μg • Tiotropium fixed dose 5 μg

Arm type

treatment sequence

Investigational medicinal product name

placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

placebo inhalation solution, delivered once daily via the respimat Inhaler

Investigational medicinal product name

Tiotropium 2.5 μg / Olodaterol 5 μg_FDC

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

Tio+Olo Fixed Dose Combination (FDC) 2.5/5 μg inhalation solution delivered once daily via respimat inhaler

Investigational medicinal product name

Tiotropium 5 μg / Olodaterol 5 μg_FDC

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

Tio+Olo FDC 5/5 μg inhalation solution delivered once daily via respimat inhaler

Investigational medicinal product name

Tiotropium 5 μg

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

Tiotropium 5 μg inhalation solution delivered once daily via respimat inhaler

Number of subjects in period 2	Tio+Olo 2.5/5 / Tio+Olo 5/5 / Tio / Olo	Tio+Olo 5/5 / Tio / Olo / placebo	Tio / Olo / placebo / Tio+Olo 2.5/5	Olo / placebo / Tio+Olo 2.5/5 / Tio+Olo 5/5	placebo / Tio+Olo 2.5/5 / Tio+Olo 5/5 / Tio
Started	59	59	60	58	59
Received Placebo	0 ^[1]	49	57	57	59
Received Olo 5	51	52	57	57	0 ^[2]
Received Tio 5	54	58	59	1 ^[3]	54
Received Tio+Olo 2.5/5	59	0 ^[4]	52	55	56
Received Tio+Olo 5/5	58	59	0 ^[5]	53	56
Completed	49	47	50	53	53
Not completed	10	12	10	5	6
Other reason not defined above	2	-	1	-	-
Consent withdrawn by subject	3	1	2	2	1
Adverse event, non-fatal	5	8	6	3	4
Protocol deviation	-	3	-	-	1
Lack of efficacy	-	-	1	-	-

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: This was a randomised, 5 treatment sequence and 4-period incomplete block cross-over trial. In each treatment sequence the subject received only 4 treatments. Thus, the subject completed all 4 treatment arms and this milestone represent the number of subjects who did not received 5th treatment, ie., the placebo.
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: This was a randomised, 5 treatment sequence and 4-period incomplete block cross-over trial. In each treatment sequence the subject received only 4 treatments. Thus, the subject completed all 4 treatment arms and this milestone represent the number of subjects who did not received 5th treatment, ie., the Olo 5.
[3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: This was a randomised, 5 treatment sequence and 4-period incomplete block cross-over trial. In each treatment sequence the subject received only 4 treatment. One subject received Tio 5 instead of Olo 5 by mistake.Thus, this milestone represent the number of subjects who received 5th treatment, ie., the Tio 5 instead of Olo 5 by mistake.
[4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: This was a randomised, 5 treatment sequence and 4-period incomplete block cross-over trial. In each treatment sequence the subject received only 4 treatment.Thus, the subject completed all treatment arms and this milestone represent the number of subjects who did not received 5th treatment, ie., the Tio+Olo 2.5/5.
[5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: This was a randomised, 5 treatment sequence and 4-period incomplete block cross-over trial. In each treatment sequence the subject received only 4 treatments. Thus, the subject completed all 4 treatment arms and this milestone represent the number of subjects who did not received 5th treatment, ie., the Tio+Olo 5/5.

Baseline characteristics

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Reporting group title

Overall trial (treatment period)

Reporting group description

A randomised, double-blind, placebo controlled, 5 treatment, 4-period, incomplete, crossover study. Each treatment period was separated by a washout period of 21 days. The 5 treatments, administered orally via the respimat inhaler, once daily, in the morning were: • Oral inhalation of placebo • Olodaterol fixed dose 5 μg • Tiotropium fixed dose 5 μg • Fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg • Fixed dose combination (FDC) of Tiotropium 5 μg and Olodaterol 5 μg Treatment sequence is not considered as a factor which may affect the treatment effect due to sufficient washout period added between treatment cycles. As a result, we only display baseline characteristics as a whole population, but not by treatment sequence.

Notes
[1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects 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 of the trial medication.

Reporting group values	Overall trial (treatment period)	Total
Number of subjects	295	295
Age categorical
Units: Subjects
Adults (18-64 years)	165	165
From 65-84 years	130	130
Age continuous
Treated Set (TS) : This patient set included all patients of the Randomised Set (RS : patients who signed the informed consent form and were also randomised, regardless of whether the patient was treated with study medication or not) who were dispensed study medication and were documented to have taken at least 1 dose of study medication.
Units: years
arithmetic mean (standard deviation)	62.2 ± 7.5	-
Gender categorical
Units: Subjects
Female	82	82
Male	213	213

End points

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Reporting group title

Placebo QD

Reporting group description

Oral inhalation of placebo, 2 puffs from the Respimat inhaler, once daily, in the morning.

Reporting group title

Olodaterol 5 μg QD

Reporting group description

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

Reporting group title

Tiotropium 5 μg QD

Reporting group description

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

Reporting group title

Tiotropium + Olodaterol 2.5/5 μg QD

Reporting group description

Reporting group title

Tiotropium + Olodaterol 5/5 μg QD

Reporting group description

Reporting group title

Tio+Olo 2.5/5 / Tio+Olo 5/5 / Tio / Olo

Reporting group description

Reporting group title

Tio+Olo 5/5 / Tio / Olo / placebo

Reporting group description

Patients received a total of four treatments, and each treatment period is separated by a washout period of 21 days. The treatments administered orally via the respimat inhaler, once daily, in the morning were: • Fixed dose combination (FDC) of Tiotropium 5 μg and Olodaterol 5 μg • Tiotropium fixed dose 5 μg • Olodaterol fixed dose 5 μg • Oral inhalation of placebo

Reporting group title

Tio / Olo / placebo / Tio+Olo 2.5/5

Reporting group description

Patients received a total of four treatments, and each treatment period is separated by a washout period of 21 days. The treatments administered orally via the respimat inhaler, once daily, in the morning were: • Tiotropium fixed dose 5 μg • Olodaterol fixed dose 5 μg • Oral inhalation of placebo • Fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg

Reporting group title

Olo / placebo / Tio+Olo 2.5/5 / Tio+Olo 5/5

Reporting group description

Patients received a total of four treatments, and each treatment period is separated by a washout period of 21 days. The treatments administered orally via the respimat inhaler, once daily, in the morning were: • Olodaterol fixed dose 5 μg • Oral inhalation of placebo • Fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg • Fixed dose combination (FDC) of Tiotropium 5 μg and Olodaterol 5 μg One patient received Tio 5 instead of Olo 5 by mistake.

Reporting group title

placebo / Tio+Olo 2.5/5 / Tio+Olo 5/5 / Tio

Reporting group description

Patients received a total of four treatments, and each treatment period is separated by a washout period of 21 days. The treatments administered orally via the respimat inhaler, once daily, in the morning were: • Oral inhalation of placebo • Fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg • Fixed dose combination (FDC) of Tiotropium 5 μg and Olodaterol 5 μg • Tiotropium fixed dose 5 μg

Primary: Inspiratory Capacity at Rest Before Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Work Capacity

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End point title

Inspiratory Capacity at Rest Before Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Work Capacity

End point description

Inspiratory capacity (IC) at rest before constant work rate cycle ergometry to symptom limitation at 75% maximal work capacity (Wcap). Wcap was defined as the maximum work rate achieved for at least 30 seconds during the incremental cycle ergometry performed at Visit 1. The presented means are adjusted means from the MMRM (Mixed Effects Model Repeated Measures) model. Full analysis set (FAS): This patient set included all patients in the Treated Set (TS) who had the study baseline and at least 1 evaluable post-dose measurement for 1 of the primary endpoints. Assignment to the FAS was done after implementation of any data handling rules,which set measurements to missing.

End point type

Primary

End point timeframe

6 weeks

End point values	Placebo QD	Olodaterol 5 μg QD	Tiotropium 5 μg QD	Tiotropium + Olodaterol 2.5/5 μg QD	Tiotropium + Olodaterol 5/5 μg QD
Number of subjects analysed	211 ^[1]	214 ^[2]	213 ^[3]	214 ^[4]	219 ^[5]
Units: litre(s)
least squares mean (standard error)	2.44 ± 0.027	2.566 ± 0.027	2.571 ± 0.027	2.658 ± 0.027	2.685 ± 0.027

Notes
[1] - Full analysis Set (FAS)
[2] - FAS
[3] - FAS
[4] - FAS
[5] - FAS

Tio+Olo 5/5 QD vs Placebo QD

Statistical analysis description

The adjusted mean (SE) are obtained from fitting an MMRM model including fixed effects of treatment and period, study baseline as covariate, patient as a random effect, and compound symmetry as a covariance structure for within−patient variation. N is the number of patients contributing to the MMRM model. Difference calculated as Tiotropium + olodaterol 5/5 µg QD minus Placebo QD

Comparison groups

Placebo QD v Tiotropium + Olodaterol 5/5 μg QD

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority ^[6]

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.244

Confidence interval

level

95%

sides

2-sided

lower limit

0.191

upper limit

0.298

Variability estimate

Standard error of the mean

Dispersion value

0.027

Notes
[6] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (430) does not reflect the actual number.

Tio+Olo 5/5 QD vs Olo 5 QD

Statistical analysis description

Comparison groups

Olodaterol 5 μg QD v Tiotropium + Olodaterol 5/5 μg QD

Number of subjects included in analysis

433

Analysis specification

Pre-specified

Analysis type

superiority ^[7]

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

0.065

upper limit

0.172

Variability estimate

Standard error of the mean

Dispersion value

0.027

Notes
[7] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (433) does not reflect the actual number.

Tio+Olo 5/5 QD vs Tio 5 QD

Statistical analysis description

Comparison groups

Tiotropium 5 μg QD v Tiotropium + Olodaterol 5/5 μg QD

Number of subjects included in analysis

432

Analysis specification

Pre-specified

Analysis type

superiority ^[8]

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.114

Confidence interval

level

95%

sides

2-sided

lower limit

0.061

upper limit

0.167

Variability estimate

Standard error of the mean

Dispersion value

0.027

Notes
[8] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (432) does not reflect the actual number.

Tio+Olo 2.5/5 QD vs placebo QD

Statistical analysis description

Comparison groups

Placebo QD v Tiotropium + Olodaterol 2.5/5 μg QD

Number of subjects included in analysis

425

Analysis specification

Pre-specified

Analysis type

superiority ^[9]

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

0.164

upper limit

0.271

Variability estimate

Standard error of the mean

Dispersion value

0.027

Notes
[9] - The actual number of subjects analyzed is 214. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (425) does not reflect the actual number.

Tio+Olo 2.5/5 QD vs Olo 5 QD

Statistical analysis description

Comparison groups

Olodaterol 5 μg QD v Tiotropium + Olodaterol 2.5/5 μg QD

Number of subjects included in analysis

428

Analysis specification

Pre-specified

Analysis type

superiority ^[10]

P-value

= 0.0008

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.092

Confidence interval

level

95%

sides

2-sided

lower limit

0.038

upper limit

0.145

Variability estimate

Standard error of the mean

Dispersion value

0.027

Notes
[10] - The actual number of subjects analyzed is 214. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (428) does not reflect the actual number.

Tio+Olo 2.5/5 QD vs Tio 5 QD

Statistical analysis description

Comparison groups

Tiotropium 5 μg QD v Tiotropium + Olodaterol 2.5/5 μg QD

Number of subjects included in analysis

427

Analysis specification

Pre-specified

Analysis type

superiority ^[11]

P-value

= 0.0015

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

0.141

Variability estimate

Standard error of the mean

Dispersion value

0.027

Notes
[11] - The actual number of subjects analyzed is 214. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (427) does not reflect the actual number.

Primary: Endurance Time During Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Wcap

Top of page

End point title

Endurance Time During Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Wcap

End point description

Endurance time during constant work rate cycle ergometry (CWRCE) to symptom limitation at 75% Wcap Wcap was defined as the maximum work rate achieved for at least 30 seconds during the incremental cycle ergometry performed at Visit 1. The presented means are adjusted mean from the MMRM model.

End point type

Primary

End point timeframe

6 weeks

End point values	Placebo QD	Olodaterol 5 μg QD	Tiotropium 5 μg QD	Tiotropium + Olodaterol 2.5/5 μg QD	Tiotropium + Olodaterol 5/5 μg QD
Number of subjects analysed	209 ^[12]	208 ^[13]	209 ^[14]	212 ^[15]	212 ^[16]
Units: second(s)
geometric mean (standard error)	375.45 ± 12.037	453.38 ± 14.552	457.16 ± 14.652	474.8 ± 15.145	454.08 ± 14.474

Notes
[12] - FAS
[13] - FAS
[14] - FAS
[15] - FAS
[16] - FAS

Tio+Olo 5/5 QD / placebo QD

Statistical analysis description

The adjusted mean (SE) are obtained from fitting an MMRM model for log10 (endurance time[sec])with fixed effects of treatment and period, log10 (study baseline endurance time) as covariate, patient as a random effect, and compound symmetry as a covariance structure for within−patient variation. Mean and 95% confidence limits are transformed from log10 back to the original scale. Standard error is calculated using delta method. Ratio calculated as Tio+Olo 5/5 µg QD divided by placebo QD.

Comparison groups

Tiotropium + Olodaterol 5/5 μg QD v Placebo QD

Number of subjects included in analysis

421

Analysis specification

Pre-specified

Analysis type

superiority ^[17]

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

ratio

Point estimate

1.209

Confidence interval

level

95%

sides

2-sided

lower limit

1.132

upper limit

1.292

Variability estimate

Standard error of the mean

Dispersion value

0.041

Notes
[17] - The actual number of subjects analyzed is 212. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (421) does not reflect the actual number.

Tio+Olo 5/5 QD/ Olo 5 QD

Statistical analysis description

Comparison groups

Olodaterol 5 μg QD v Tiotropium + Olodaterol 5/5 μg QD

Number of subjects included in analysis

420

Analysis specification

Pre-specified

Analysis type

superiority ^[18]

P-value

= 0.9633

Method

Mixed models analysis

Parameter type

ratio

Point estimate

1.002

Confidence interval

level

95%

sides

2-sided

lower limit

0.937

upper limit

1.07

Variability estimate

Standard error of the mean

Dispersion value

0.034

Notes
[18] - The actual number of subjects analyzed is 212. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (420) does not reflect the actual number.

Tio+Olo 5/5 QD / Tio 5 QD

Statistical analysis description

Comparison groups

Tiotropium 5 μg QD v Tiotropium + Olodaterol 5/5 μg QD

Number of subjects included in analysis

421

Analysis specification

Pre-specified

Analysis type

superiority ^[19]

P-value

= 0.8415

Method

Mixed models analysis

Parameter type

Ratio

Point estimate

0.993

Confidence interval

level

95%

sides

2-sided

lower limit

0.93

upper limit

1.061

Variability estimate

Standard error of the mean

Dispersion value

0.033

Notes
[19] - The actual number of subjects analyzed is 212. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (421) does not reflect the actual number.

Tio+Olo 2.5/5 QD / placebo QD

Statistical analysis description

Comparison groups

Placebo QD v Tiotropium + Olodaterol 2.5/5 μg QD

Number of subjects included in analysis

421

Analysis specification

Pre-specified

Analysis type

superiority ^[20]

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Ratio

Point estimate

1.265

Confidence interval

level

95%

sides

2-sided

lower limit

1.184

upper limit

1.351

Variability estimate

Standard error of the mean

Dispersion value

0.042

Notes
[20] - The actual number of subjects analyzed is 212. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (421) does not reflect the actual number.

Tio+Olo 2.5/5 QD/ Olo 5 QD

Statistical analysis description

Comparison groups

Olodaterol 5 μg QD v Tiotropium + Olodaterol 2.5/5 μg QD

Number of subjects included in analysis

420

Analysis specification

Pre-specified

Analysis type

superiority ^[21]

P-value

= 0.1717

Method

Mixed models analysis

Parameter type

Ratio

Point estimate

1.047

Confidence interval

level

95%

sides

2-sided

lower limit

0.98

upper limit

1.119

Variability estimate

Standard error of the mean

Dispersion value

0.035

Notes
[21] - The actual number of subjects analyzed is 212. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (420) does not reflect the actual number.

Tio+Olo 2.5/5 QD/ Tio 5 QD

Statistical analysis description

Comparison groups

Tiotropium 5 μg QD v Tiotropium + Olodaterol 2.5/5 μg QD

Number of subjects included in analysis

421

Analysis specification

Pre-specified

Analysis type

superiority ^[22]

P-value

= 0.261

Method

Mixed models analysis

Parameter type

Ratio

Point estimate

1.039

Confidence interval

level

95%

sides

2-sided

lower limit

0.972

upper limit

1.11

Variability estimate

Standard error of the mean

Dispersion value

0.035

Notes
[22] - The actual number of subjects analyzed is 212. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (421) does not reflect the actual number.

Secondary: Slope of the Intensity of Breathing Discomfort During Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Wcap

Top of page

End point title

Slope of the Intensity of Breathing Discomfort During Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Wcap

End point description

Slope of the intensity of breathing discomfort during CWRCE to symptom limitation at 75% Work capacity (Wcap). The intensity of breathing discomfort was rated using the modified Borg scale with ratings from 0 (nothing at all) to 10 (maximal). Slope of breathing discomfort is defined as: (intensity of breathing discomfort at the end of exercise minus intensity of breathing discomfort at rest) / endurance time. A decrease in slope indicates improvement. The presented means are adjusted means from MMRM model.

End point type

Secondary

End point timeframe

6 weeks

End point values	Placebo QD	Olodaterol 5 μg QD	Tiotropium 5 μg QD	Tiotropium + Olodaterol 2.5/5 μg QD	Tiotropium + Olodaterol 5/5 μg QD
Number of subjects analysed	209 ^[23]	208 ^[24]	209 ^[25]	212 ^[26]	212 ^[27]
Units: Borg scale unit(s)/second
least squares mean (standard error)	0.018 ± 0.001	0.016 ± 0.001	0.016 ± 0.001	0.015 ± 0.001	0.016 ± 0.001

Notes
[23] - FAS
[24] - FAS
[25] - FAS
[26] - FAS
[27] - FAS

Tio+Olo 5/5 QD vs placebo QD

Statistical analysis description

Comparison groups

Tiotropium + Olodaterol 5/5 μg QD v Placebo QD

Number of subjects included in analysis

421

Analysis specification

Pre-specified

Analysis type

superiority ^[28]

P-value

= 0.0004

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

-0.003

Confidence interval

level

95%

sides

2-sided

lower limit

-0.004

upper limit

-0.001

Variability estimate

Standard error of the mean

Dispersion value

0.001

Notes
[28] - The actual number of subjects analyzed is 212. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (421) does not reflect the actual number.

Tio+Olo 5/5 QD vs Olo 5 QD

Statistical analysis description

Comparison groups

Olodaterol 5 μg QD v Tiotropium + Olodaterol 5/5 μg QD

Number of subjects included in analysis

420

Analysis specification

Pre-specified

Analysis type

superiority ^[29]

P-value

= 0.8291

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.001

upper limit

0.002

Variability estimate

Standard error of the mean

Dispersion value

0.001

Notes
[29] - The actual number of subjects analyzed is 212. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (420) does not reflect the actual number.

Tio+Olo 5/5 QD vs Tio 5 QD

Statistical analysis description

Comparison groups

Tiotropium 5 μg QD v Tiotropium + Olodaterol 5/5 μg QD

Number of subjects included in analysis

421

Analysis specification

Pre-specified

Analysis type

superiority ^[30]

P-value

= 0.857

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.002

upper limit

0.001

Variability estimate

Standard error of the mean

Dispersion value

0.001

Notes
[30] - The actual number of subjects analyzed is 212. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (421) does not reflect the actual number.

Tio+Olo 2.5/5 QD vs placebo QD

Statistical analysis description

Comparison groups

Placebo QD v Tiotropium + Olodaterol 2.5/5 μg QD

Number of subjects included in analysis

421

Analysis specification

Pre-specified

Analysis type

superiority ^[31]

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

-0.003

Confidence interval

level

95%

sides

2-sided

lower limit

-0.005

upper limit

-0.002

Variability estimate

Standard error of the mean

Dispersion value

0.001

Notes
[31] - The actual number of subjects analyzed is 212. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (421) does not reflect the actual number.

Tio+Olo 2.5/5 QD vs Olo 5 QD

Statistical analysis description

Comparison groups

Olodaterol 5 μg QD v Tiotropium + Olodaterol 2.5/5 μg QD

Number of subjects included in analysis

420

Analysis specification

Pre-specified

Analysis type

superiority ^[32]

P-value

= 0.7294

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.002

upper limit

0.001

Variability estimate

Standard error of the mean

Dispersion value

0.001

Notes
[32] - The actual number of subjects analyzed is 212. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (420) does not reflect the actual number.

Tio+Olo 2.5/5 QD vs Tio 5 QD

Statistical analysis description

Comparison groups

Tiotropium 5 μg QD v Tiotropium + Olodaterol 2.5/5 μg QD

Number of subjects included in analysis

421

Analysis specification

Pre-specified

Analysis type

superiority ^[33]

P-value

= 0.4567

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

-0.001

Confidence interval

level

95%

sides

2-sided

lower limit

-0.002

upper limit

0.001

Variability estimate

Standard error of the mean

Dispersion value

0.001

Notes
[33] - The actual number of subjects analyzed is 212. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (421) does not reflect the actual number.

Secondary: FEV1 (1 Hour Post-dose)

Top of page

End point title

FEV1 (1 Hour Post-dose)

End point description

Forced Expiratory Volume in 1 Second (FEV1) (one hour post-dose). The presented means are adjusted means from MMRM model.

End point type

Secondary

End point timeframe

6 weeks

End point values	Placebo QD	Olodaterol 5 μg QD	Tiotropium 5 μg QD	Tiotropium + Olodaterol 2.5/5 μg QD	Tiotropium + Olodaterol 5/5 μg QD
Number of subjects analysed	216 ^[34]	214 ^[35]	218 ^[36]	216 ^[37]	224 ^[38]
Units: litre(s)
least squares mean (standard error)	1.497 ± 0.013	1.689 ± 0.013	1.706 ± 0.013	1.783 ± 0.013	1.82 ± 0.013

Notes
[34] - FAS
[35] - FAS
[36] - FAS
[37] - FAS
[38] - FAS

Tio+Olo 5/5 QD vs placebo QD

Statistical analysis description

The adjusted mean (SE) are obtained from fitting an MMRM model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. Difference calculated as Tiotropium + olodaterol 5/5 µg QD minus Placebo QD

Comparison groups

Placebo QD v Tiotropium + Olodaterol 5/5 μg QD

Number of subjects included in analysis

440

Analysis specification

Pre-specified

Analysis type

superiority ^[39]

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.323

Confidence interval

level

95%

sides

2-sided

lower limit

0.293

upper limit

0.352

Variability estimate

Standard error of the mean

Dispersion value

0.015

Notes
[39] - The actual number of subjects analyzed is 224. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (440) does not reflect the actual number.

Tio+Olo 5/5 QD vs Olo 5 QD

Statistical analysis description

Comparison groups

Olodaterol 5 μg QD v Tiotropium + Olodaterol 5/5 μg QD

Number of subjects included in analysis

438

Analysis specification

Pre-specified

Analysis type

superiority ^[40]

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

0.101

upper limit

0.16

Variability estimate

Standard error of the mean

Dispersion value

0.015

Notes
[40] - The actual number of subjects analyzed is 224. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (438) does not reflect the actual number.

T+O 5/5 vs Tio 5

Statistical analysis description

Comparison groups

Tiotropium 5 μg QD v Tiotropium + Olodaterol 5/5 μg QD

Number of subjects included in analysis

442

Analysis specification

Pre-specified

Analysis type

superiority ^[41]

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.114

Confidence interval

level

95%

sides

2-sided

lower limit

0.084

upper limit

0.143

Variability estimate

Standard error of the mean

Dispersion value

0.015

Notes
[41] - The actual number of subjects analyzed is 224. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (442) does not reflect the actual number.

T+O 2.5/5 vs placebo

Statistical analysis description

Comparison groups

Placebo QD v Tiotropium + Olodaterol 2.5/5 μg QD

Number of subjects included in analysis

432

Analysis specification

Pre-specified

Analysis type

superiority ^[42]

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.286

Confidence interval

level

95%

sides

2-sided

lower limit

0.256

upper limit

0.315

Variability estimate

Standard error of the mean

Dispersion value

0.015

Notes
[42] - The actual number of subjects analyzed is 216. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (432) does not reflect the actual number.

T+O 2.5/5 vs Olo 5

Statistical analysis description

Comparison groups

Olodaterol 5 μg QD v Tiotropium + Olodaterol 2.5/5 μg QD

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority ^[43]

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

0.063

upper limit

0.123

Variability estimate

Standard error of the mean

Dispersion value

0.015

Notes
[43] - The actual number of subjects analyzed is 216. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (430) does not reflect the actual number.

T+O 2.5/5 vs Tio 5

Statistical analysis description

Comparison groups

Tiotropium 5 μg QD v Tiotropium + Olodaterol 2.5/5 μg QD

Number of subjects included in analysis

434

Analysis specification

Pre-specified

Analysis type

superiority ^[44]

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

0.047

upper limit

0.106

Variability estimate

Standard error of the mean

Dispersion value

0.015

Notes
[44] - The actual number of subjects analyzed is 216. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (434) does not reflect the actual number.

Adverse events

Top of page

Timeframe for reporting adverse events

From drug administration until 21 days after the last administration, up to 120 days.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

16.1

Reporting group title

Placebo

Reporting group description

Oral inhalation of placebo, 2 puffs from the Respimat inhaler, once daily, in the morning.

Reporting group title

Olodaterol 5 μg QD

Reporting group description

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

Reporting group title

Tiotropium 5 μg QD

Reporting group description

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

Reporting group title

Tiotropium + Olodaterol 2.5/5 QD

Reporting group description

Reporting group title

Tiotropium + Olodaterol 5/5 QD

Reporting group description

Serious adverse events	Placebo	Olodaterol 5 μg QD	Tiotropium 5 μg QD	Tiotropium + Olodaterol 2.5/5 QD	Tiotropium + Olodaterol 5/5 QD
Total subjects affected by serious adverse events
subjects affected / exposed	4 / 222 (1.80%)	3 / 217 (1.38%)	8 / 226 (3.54%)	5 / 222 (2.25%)	6 / 226 (2.65%)
number of deaths (all causes)	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Blepharal papilloma
subjects affected / exposed	0 / 222 (0.00%)	0 / 217 (0.00%)	1 / 226 (0.44%)	0 / 222 (0.00%)	0 / 226 (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 / 222 (0.00%)	0 / 217 (0.00%)	1 / 226 (0.44%)	0 / 222 (0.00%)	0 / 226 (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 skin
subjects affected / exposed	0 / 222 (0.00%)	1 / 217 (0.46%)	0 / 226 (0.00%)	1 / 222 (0.45%)	0 / 226 (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
Vascular disorders
Haematoma
subjects affected / exposed	0 / 222 (0.00%)	0 / 217 (0.00%)	0 / 226 (0.00%)	1 / 222 (0.45%)	0 / 226 (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
Surgical and medical procedures
Cardiac pacemaker insertion
subjects affected / exposed	0 / 222 (0.00%)	0 / 217 (0.00%)	0 / 226 (0.00%)	1 / 222 (0.45%)	0 / 226 (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
General disorders and administration site conditions
Chest discomfort
subjects affected / exposed	0 / 222 (0.00%)	0 / 217 (0.00%)	0 / 226 (0.00%)	0 / 222 (0.00%)	1 / 226 (0.44%)
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
Chest pain
subjects affected / exposed	0 / 222 (0.00%)	0 / 217 (0.00%)	1 / 226 (0.44%)	0 / 222 (0.00%)	0 / 226 (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
Hypothermia
subjects affected / exposed	0 / 222 (0.00%)	0 / 217 (0.00%)	0 / 226 (0.00%)	1 / 222 (0.45%)	0 / 226 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 222 (0.45%)	0 / 217 (0.00%)	0 / 226 (0.00%)	0 / 222 (0.00%)	2 / 226 (0.88%)
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
Haemoptysis
subjects affected / exposed	0 / 222 (0.00%)	0 / 217 (0.00%)	1 / 226 (0.44%)	0 / 222 (0.00%)	0 / 226 (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
Investigations
Hepatic enzyme increased
subjects affected / exposed	0 / 222 (0.00%)	0 / 217 (0.00%)	0 / 226 (0.00%)	1 / 222 (0.45%)	0 / 226 (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
Injury, poisoning and procedural complications
Animal bite
subjects affected / exposed	0 / 222 (0.00%)	0 / 217 (0.00%)	0 / 226 (0.00%)	0 / 222 (0.00%)	1 / 226 (0.44%)
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
Splenic rupture
subjects affected / exposed	0 / 222 (0.00%)	0 / 217 (0.00%)	0 / 226 (0.00%)	1 / 222 (0.45%)	0 / 226 (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 / 222 (0.00%)	0 / 217 (0.00%)	1 / 226 (0.44%)	0 / 222 (0.00%)	0 / 226 (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
Congenital cystic kidney disease
subjects affected / exposed	0 / 222 (0.00%)	0 / 217 (0.00%)	0 / 226 (0.00%)	1 / 222 (0.45%)	0 / 226 (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
Angina pectoris
subjects affected / exposed	0 / 222 (0.00%)	1 / 217 (0.46%)	0 / 226 (0.00%)	0 / 222 (0.00%)	0 / 226 (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
Angina unstable
subjects affected / exposed	0 / 222 (0.00%)	0 / 217 (0.00%)	0 / 226 (0.00%)	0 / 222 (0.00%)	1 / 226 (0.44%)
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
Bradycardia
subjects affected / exposed	1 / 222 (0.45%)	0 / 217 (0.00%)	0 / 226 (0.00%)	0 / 222 (0.00%)	0 / 226 (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
Ventricular extrasystoles
subjects affected / exposed	1 / 222 (0.45%)	0 / 217 (0.00%)	0 / 226 (0.00%)	0 / 222 (0.00%)	0 / 226 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Transient ischaemic attack
subjects affected / exposed	0 / 222 (0.00%)	1 / 217 (0.46%)	0 / 226 (0.00%)	0 / 222 (0.00%)	0 / 226 (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
Vertebrobasilar insufficiency
subjects affected / exposed	0 / 222 (0.00%)	0 / 217 (0.00%)	0 / 226 (0.00%)	1 / 222 (0.45%)	0 / 226 (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
Gastrointestinal disorders
Umbilical hernia
subjects affected / exposed	0 / 222 (0.00%)	0 / 217 (0.00%)	0 / 226 (0.00%)	0 / 222 (0.00%)	1 / 226 (0.44%)
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
Hepatobiliary disorders
Biliary tract disorder
subjects affected / exposed	1 / 222 (0.45%)	0 / 217 (0.00%)	0 / 226 (0.00%)	0 / 222 (0.00%)	0 / 226 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Infective exacerbation of chronic obstructive airways disease
subjects affected / exposed	0 / 222 (0.00%)	0 / 217 (0.00%)	1 / 226 (0.44%)	0 / 222 (0.00%)	0 / 226 (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
Kidney infection
subjects affected / exposed	0 / 222 (0.00%)	0 / 217 (0.00%)	0 / 226 (0.00%)	1 / 222 (0.45%)	0 / 226 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 222 (0.00%)	0 / 217 (0.00%)	2 / 226 (0.88%)	1 / 222 (0.45%)	0 / 226 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wound abscess
subjects affected / exposed	0 / 222 (0.00%)	0 / 217 (0.00%)	0 / 226 (0.00%)	1 / 222 (0.45%)	0 / 226 (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

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

Non-serious adverse events	Placebo	Olodaterol 5 μg QD	Tiotropium 5 μg QD	Tiotropium + Olodaterol 2.5/5 QD	Tiotropium + Olodaterol 5/5 QD
Total subjects affected by non serious adverse events
subjects affected / exposed	26 / 222 (11.71%)	17 / 217 (7.83%)	20 / 226 (8.85%)	13 / 222 (5.86%)	19 / 226 (8.41%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	26 / 222 (11.71%)	17 / 217 (7.83%)	20 / 226 (8.85%)	13 / 222 (5.86%)	19 / 226 (8.41%)
occurrences all number	30	18	22	14	21

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Were there any global substantial amendments to the protocol? Yes

31 Mar 2012

Body plethysmography at Visit 1 (baseline) was introduced to characterise the patients’ static hyperinflation. Furthermore, procedures to be completed in the case of early withdrawal from the trial were specified as well as individual withdrawal criteria. It was clarified that the adjudication committee reviewed all serious adverse events (SAEs) and not only fatal SAEs. On recommendation from local (German) authorities, the trial population was restricted to patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) Stage II to III (instead of Stage II to IV) including a lower limit of FEV1 > 30% of predicted normal. For safety reasons, chronic respiratory failure was added to the exclusion criteria. A specification that SAEs needed to be reported until 21 days after the last administration of study medication was added and a list of “always serious” AEs was included to comply with a new Boehringer Ingelheim (BI) internal procedure.

16 Nov 2012

Instructions were added for the clinical evaluation of potential Drug-induced Liver Injury (DILI) to comply with FDA guidance for industry “Drug-Induced Liver Injury: Premarketing Clinical Evaluation”. The period during which a pregnancy test after end of treatment was to be performed was specified. It was clarified that mortality and SAE adjudication were to be conducted separately. Furthermore, the order of the endpoint hypothesis testing strategy was changed and the testing for the key secondary endpoint of breathing discomfort was included to be aligned with the testing strategy for the programme and for monoproducts with the FDC product.

10 Jun 2013

The definition of primary endpoint of IC was changed from being determined at isotime to being determined at rest (prior to exercise) to avoid introducing a bias. This was due to the incomplete cross-over design, which had the possibility for treatment comparisons at isotime to be at different time points. The original primary endpoint ‘IC determined at isotime’ and the original key-secondary endpoint ‘intensity of breathing discomfort at isotime' were included among the ‘further’ efficacy endpoints. The slope of the intensity of breathing discomfort during CWRCE to symptom limitation at 75% Wcap after 6 weeks of treatment and FEV1 (1 h post-dose) after 6 weeks of treatment were included as secondary endpoints (slope defined as [intensity of breathing discomfort at the end of exercise minus intensity of breathing discomfort at rest]/endurance time). FEV1 (1 h post-dose) on Day 1 of treatment, Forced Vital Capacity (FVC) (1 h post-dose) on Day 1 and after 6 weeks of treatment, and FEV1, FVC (trough) after 6 weeks of treatment were added as “further” efficacy endpoints. Intensity of breathing discomfort and intensity of leg discomfort (Borg scale) were changed to be determined at isotime and not during exercise. The trial protocol had specified that the effect of Tio+Olo FDC was to be tested at the 1-sided 0.025 level. This is the same as testing at the 2-sided 0.05 level if the treatment effect is in favour of Tio+Olo FDC compared with placebo. To aid in the interpretation of the results, 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. Statistical significance was therefore declared if hypothesis tests were significant at the 2-sided 0.05 level, the treatment effect favoured Tio+Olo FDC, and all previous hypothesis tests in the hierarchy had shown statistical superiority.

Were there any global interruptions to the trial? No

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

None reported

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Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Inspiratory Capacity at Rest Before Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Work Capacity

Primary: Inspiratory Capacity at Rest Before Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Work Capacity

Primary: Endurance Time During Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Wcap

Primary: Endurance Time During Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Wcap

Secondary: Slope of the Intensity of Breathing Discomfort During Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Wcap

Secondary: Slope of the Intensity of Breathing Discomfort During Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Wcap

Secondary: FEV1 (1 Hour Post-dose)

Secondary: FEV1 (1 Hour Post-dose)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

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