Cardiovascular Function in COPD Patients

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03055988
• Collaborator: (none)
• Enrollment: 76
• Locations: 10
• Arms: 2
• Actual Duration (Months): 11.9
• Patients Per Site: 7.6
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

The objectives of the study are to explore the effect of treatment with tiotropium + olodaterol fixed dose combination (FDC) compared to fluticasone propionate + salmeterol FDC on:

• reversal of left ventricular diastolic dysfunction assessed with cardiac magnetic resonance (CMR) imaging,

• measures of arterial stiffness assessed by CMR and pulse wave analysis (PWA),

• reduction of hyperinflation assessed with body plethysmography and

• post dose spirometry.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Disease, Chronic Obstructive	Drug: Tiotropium; Drug: Olodaterol; Drug: Fluticasone propionate; Drug: Salmeterol	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 76 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: An Exploratory, Randomised, Double-blind, Double-dummy, Active-controlled, Two Period Cross-over Study to Investigate the Effect of 6 Weeks Treatment of Orally Inhaled Tiotropium + Olodaterol Fixed Dose Combination (FDC) Delivered by the Respimat® Inhaler With Fluticasone Propionate + Salmeterol FDC Delivered by the Accuhaler® Inhaler, on Left Ventricular Function and Arterial Stiffness in Patients With Chronic Obstructive Pulmonary Disease (COPD)
• Actual Study Start Date: Mar 29, 2017
• Actual Primary Completion Date: Mar 5, 2018
• Actual Study Completion Date: Mar 26, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tiotropium/Olodaterol Fixed Dose Combination	Drug: Tiotropium; Fixed Dose Combination; Other Names: INSPIOLTO, SPIOLTO, STIOLTO, VAHELVA, YANIMO ; Drug: Olodaterol; Fixed Dose Combination; Other Names: INSPIOLTO, SPIOLTO, STIOLTO, VAHELVA, YANIMO
Active Comparator: Fluticasone Propionate + Salmeterol Fixed Dose Combination	Drug: Fluticasone propionate; Fixed Dose Combination; Drug: Salmeterol; Fixed Dose Combination

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Left Ventricular End Diastolic Volume Index (LVEDVI) in the 6th Week of Treatment [Baseline and 6 weeks]

   LVEDVI is normalised left ventricular end diastolic volume, divided by body surface area. Baseline was defined as the value obtained during the assessment performed in a week prior to Visit 2 (Day 1). The change from baseline was calculated as the value obtained in a week prior to Visits 3 and 4 (end of each treatment periods) minus the baseline value.

Secondary Outcome Measures

1. Change From Baseline in Aortic Distensibility After 6 Weeks of Treatment [Baseline and 6 weeks]

   Change from baseline in aortic distensibility is presented. Aortic distensibility measurements as measure of arterial stiffness were derived from cine images acquired at end-expiration in planes perpendicular to the thoracic aorta at the level of the pulmonary artery (ascending and descending section of thoracic aorta), abdominal aorta, and perpendicularly to the main, right, and left pulmonary arteries.

2. Change From Baseline in Pulmonary Artery Pulsatility After 6 Weeks of Treatment [Baseline and 6 weeks]

   Change from baseline in pulmonary artery pulsatility (PAP) is presented. Pulmonary artery pulsatility measurements as measure of arterial stiffness were derived from cine images acquired at end-expiration in planes perpendicular to the thoracic aorta at the level of the pulmonary artery (ascending and descending section of thoracic aorta), abdominal aorta, and perpendicularly to the main, right, and left pulmonary arteries.

3. Change From Baseline in Central Systolic Pressure After 6 Weeks of Treatment [Baseline and 6 weeks]

   Change from baseline in central systolic pressure is presented.

4. Change From Baseline in Pulse Pressure After 6 Weeks of Treatment [Baseline and 6 weeks]

   Change from baseline in pulse pressure is presented.

5. Change From Baseline in Aortic Augmentation Index After 6 Weeks of Treatment [Baseline and 6 weeks]

   Change from baseline in aortic augmentation index is presented. Augmentation index was derived from brachial pulse wave separation analysis as augmentation pressure (pressure difference between the reflection wave to the ejection wave) divided by central pulse pressure (at the central aortic site) multiplied by 100.

6. Change From Baseline in Functional Residual Capacity Body Plethysmography (FRCpleth) % Predicted After 6 Weeks of Treatment [Baseline and 6 weeks]

   Change from Baseline in Functional Residual Capacity Body Plethysmography (FRCpleth) % predicted is presented. Functional residual capacity, percent predicted is a lung volume at the end of normal expiration assessed/measured by body plethysmography and compared to predicted capacity for such subject, if nonsmoker and without a disease which could compromise their ventilator function, to give a percentage predicted.

7. Change From Baseline in 1.5 Hour Post Dose Forced Expiratory Volume in 1st Second (FEV1) After 6 Weeks of Treatment [Baseline and 6 weeks]

   Change from baseline in 1.5 hour post dose Forced Expiratory Volume in 1st second (FEV1) is presented.

8. Change From Baseline in 1.5 Hour Post Dose Forced Vital Capacity (FVC) After 6 Weeks of Treatment [Baseline and 6 weeks]

   Change from baseline in 1.5 hour post dose Forced Vital Capacity (FVC) is presented.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

• All patients must sign an informed consent consistent with International Council on Harmonisation - Good Clinical Practice (ICH-GCP) guidelines prior to participation in the trial, which includes medication washout and restrictions.

• All patients must have a diagnosis of chronic obstructive pulmonary disease for which they are treated with one or more long-acting inhaled bronchodilators prior to enrolment and must meet the following spirometric criteria:

Patients must have stable airway obstruction with a post-bronchodilator Forced Expiratory Volume in 1st second (FEV1) < 70% of predicted normal calculated with European Coal and Steel Community (ECSC) formulas, and a post-bronchodilator FEV1/Forced Vital Capacity (FVC)< 70% at Visit 1

• Patients with hyperinflation at rest defined as Functional Residual capacity (FRC) > 120 % predicted, with post-bronchodilator reversibility greater than and equal to 7,5 % predicted at Visit 1.

• Male or female patients between 40 and 75 years of age (inclusive) on day of signing informed consent.

• Patients with a smoking history of more than 10 pack years.

• Patients with Modified Medical Research Council (mMRC) Dyspnoea score > 1 at Visit 1.

• Patients must be able to perform technically acceptable pulmonary function tests (spirometry and body plethysmography), Cardiac Magnetic Resonance (CMR), brachial blood pressure measurements with Pulse Wave Analysis (PWA) and other tests during the study period as required in the protocol.

• Patients must be able to inhale medication in a competent manner from the Respimat and Accuhaler inhalers and from a metered dose inhaler (MDI).

Exclusion criteria:

• Patients with a significant disease other than Chronic Obstructive Pulmonary Disease (COPD).

• Patients with a clinically relevant abnormal baseline haematology, blood chemistry, or creatinine.

• Patients with a diagnosis of asthma.

• Patients with a COPD exacerbation in the 6 weeks prior to screening (Visit 1) and patients who experience COPD exacerbation or respiratory tract infection during the washout phase prior to randomisation.

• A history of myocardial infarction, cerebrovascular event or coronary artery intervention other than Coronary Artery Bypass Graft (CABG) within 1 year of screening.

• Abnormal and clinically significant 12-lead Electrocardiogram (ECG).

• Hospitalized for heart failure within the past year. Current severe heart failure (New York Heart Association (NYHA) class IV. Ejection fraction <= 40% from Cardiac Magnetic Resonance (CMR) baseline assessment.

• Patients with systolic blood pressure > 140mmHg and/or diastolic blood pressure > 90mmHg at Visit 1.

• A diagnosis of thyrotoxicosis.

• Known active tuberculosis, cardiac sarcoidosis.

• Any malignancy unless free of disease for at least five years.

• A history of cystic fibrosis.

• Clinically evident bronchiectasis.

• Patients with severe emphysema requiring endobronchial interventions within 6 months prior to screening.

• A history of significant alcohol or drug abuse.

• Patients who have undergone thoracotomy with pulmonary resection.

• Patients being treated with any oral ß-adrenergics.

• Patients being treated with oral corticosteroid medication within 6 weeks prior to Visit 1.

• Patients being prescribed long-term home oxygen treatment.

• Patients who have completed a pulmonary rehabilitation program in the six weeks prior to the screening visit or patients who are currently in a pulmonary rehabilitation program.

• Patients who have taken an investigational drug within one month or six half lives (whichever is greater) prior to screening visit.

• Patients with known hypersensitivity to ß-adrenergics drugs, anticholinergic drugs, fluticasone propionate or to any of the excipients, Benzalkonium chloride (BAC), Disodium edentate (EDTA) or Lactose monohydrate (which contains milk proteins) or any other component of the Respimat® or Accuhaler® delivery systems.

• Women who are pregnant, nursing, or who plan to become pregnant while in the trial.

• Women of childbearing potential not using highly effective methods of birth control.

• Patients who have previously been enrolled in this study or are currently enrolled in another study.

• Patient who are unable to comply with pulmonary medication restrictions prior to randomisation

• Patients with pacemakers and metal implants (i.e. vascular clips and stents, metal silver in patient's eye) and patients with claustrophobia, due to contraindications for CMR.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	CIMS Studienzentrum Bamberg GmbH	Bamberg		Germany	96049
2	Klinische Forschung Berlin GbR	Berlin		Germany	10787
3	Universitätsklinikum Bonn AöR	Bonn		Germany	53105
4	Praxis Dr. med. Claus Keller	Frankfurt		Germany	60389
5	IKF Pneumologie GmbH & Co. KG	Frankfurt		Germany	60596
6	Pneumologisches Forschungsinstitut an der LungenClinic Grosshansdorf GmbH	Großhansdorf		Germany	22927
7	Thoraxklinik-Heidelberg gGmbH am Universitätsklinikum Heidelberg	Heidelberg		Germany	69126
8	KLB Gesundheitsforschung Lübeck GmbH	Lübeck		Germany	23552
9	Universitätsmedizin der Johannes Gutenberg-Universität Mainz	Mainz		Germany	55131
10	RoMed Kliniken	Rosenheim		Germany	83022

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

• Statistical Analysis Plan - Mar 13, 2018
• Study Protocol - Nov 30, 2017

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT03055988
• Other Study ID Numbers: 1237.36; 2015-002641-66
• First Posted: Feb 16, 2017
• Last Update Posted: Aug 16, 2019
• Last Verified: Jul 1, 2019

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Lung Diseases; Pulmonary Disease, Chronic Obstructive; Fluticasone; Xhance; Tiotropium Bromide; Salmeterol Xinafoate; Olodaterol

Study Results

Participant Flow

Recruitment Details	Randomised, double-blind, active-controlled, two-period cross-over study in patients with chronic obstructive pulmonary disease (COPD) to investigate effect of 6-week treatment of tiotropium + olodaterol fixed dose combination (FDC) with fluticasone propionate + salmeterol FDC orally inhaled by the Respimat® and Accuhaler® inhaler respectively.
Pre-assignment Detail	All patients were screened for eligibility to participate in the trial. Patients attended specialist sites which would then ensured that all patients met all inclusion/exclusion criteria. Patients were not to be randomized to trial treatment if any one of the specific entry criteria were not met.

Arm/Group Title	FluticasonePropionate+SalmeterolFDC/ Tiotropium+OlodaterolFDC	Tiotropium+OlodaterolFDC/ FluticasonePropionate+SalmeterolFDC
Arm/Group Description	Patients orally inhaled total 2 inhalations daily (one inhalation in the morning and evening) via Accuhaler® inhaler of 1000 microgram (μg) fluticasone propionate + 100 μg salmeterol dry powder for inhalation (F+S 1000/100) (500 μg / 50 μg per actuation) for 6-week treatment in period 1 and patients orally inhaled 2 inhalations once daily (in the morning) via Respimat® inhaler of 5 μg tiotropium + 5 μg olodaterol inhalation solution (T+O 5/5) (2.5 μg /2.5 μg per actuation) for 6-weeks treatment in period 2. There was no washout between treatments.	Patients orally inhaled 2 inhalations once daily (in the morning) via Respimat® inhaler of 5 μg tiotropium + 5 μg olodaterol inhalation solution (T+O 5/5) (2.5 μg /2.5 μg per actuation) for 6-week treatment in period 1 and patients orally inhaled total 2 inhalations daily (one inhalation in the morning and evening) via Accuhaler® inhaler of 1000 microgram (μg) fluticasone propionate + 100 μg salmeterol dry powder for inhalation (F+S 1000/100) (500 μg / 50 μg per actuation) for 6-weeks treatment in period 2. There was no washout between treatments.
Period Title: Period 1
STARTED	38	38
COMPLETED	37	33
NOT COMPLETED	1	5
Period Title: Period 1
STARTED	37	33
COMPLETED	36	31
NOT COMPLETED	1	2

Baseline Characteristics

Arm/Group Title	Total Patients
Arm/Group Description	Patients orally inhaled total 2 inhalations daily (one inhalation in the morning and evening) via Accuhaler® inhaler of 1000 microgram (μg) fluticasone propionate + 100 μg salmeterol dry powder for inhalation (F+S 1000/100) (500 μg / 50 μg per actuation) or orally inhaled 2 inhalations once daily (in the morning) via Respimat® inhaler of 5 μg tiotropium + 5 μg olodaterol inhalation solution (T+O 5/5) (2.5 μg /2.5 μg per actuation). Patients were randomly assigned to a treatment sequence in two 6-week periods. There was no washout between treatments.
Overall Participants	76
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	61.86 (7.13)
Sex: Female, Male (Count of Participants)
Female	31 40.8%
Male	45 59.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	76 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 1.3%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	75 98.7%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Left Ventricular End Diastolic Volume Index (LVEDVI) in the 6th Week of Treatment
Description	LVEDVI is normalised left ventricular end diastolic volume, divided by body surface area. Baseline was defined as the value obtained during the assessment performed in a week prior to Visit 2 (Day 1). The change from baseline was calculated as the value obtained in a week prior to Visits 3 and 4 (end of each treatment periods) minus the baseline value.
Time Frame	Baseline and 6 weeks

Outcome Measure Data

Analysis Population Description

FullAnalysisSet (FAS)ExcludingExacerbation (FAS-EE) nested within FAS and data from patients who had an exacerbation during treatments were excluded from this set. FAS nested within treated set and included patients who had baseline measurement and at least one post-baseline measurement for primary or secondary endpoints. (Including available data)

Arm/Group Title	Fluticasone Propionate + Salmeterol FDC (F+S 1000/100)	Tiotropium + Olodaterol FDC (T+O 5/5)
Arm/Group Description	Patients orally inhaled total 2 inhalations daily (one inhalation in the morning and evening) via Accuhaler® inhaler of 1000 microgram (μg) fluticasone propionate + 100 μg salmeterol dry powder for inhalation (F+S 1000/100) (500 μg / 50 μg per actuation) for 6-week treatment period.	Patients orally inhaled 2 inhalations once daily (in the morning) via Respimat® inhaler of 5 μg tiotropium + 5 μg olodaterol inhalation solution (T+O 5/5) (2.5 μg /2.5 μg per actuation) for 6-week treatment period.
Measure Participants	59	59
Least Squares Mean (Standard Error) [Millilitre/ meter^2 (mL/m^2)]	2.855 (1.137)	2.317 (1.136)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fluticasone Propionate + Salmeterol FDC (F+S 1000/100), Tiotropium + Olodaterol FDC (T+O 5/5)
	Comments	Mixed model repeated measures (MMRM) model included treatment and period as fixed effects, patient as a random effect and baseline as covariate. Unstructured covariance structure was used for within patient variation. H0: Mean change from baseline in LVEDVI for (Tiotropium + Olodaterol) = Mean change from baseline in LVEDVI for (Fluticasone propionate + Salmeterol)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6331
	Comments
	Method	Mixed model repeated measures (MMRM)
	Comments	Kenward-Roger approximation was used to estimate denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.537
	Confidence Interval	(2-Sided) 95%; -2.779 to 1.705
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.120
	Estimation Comments	Mean difference means the treatment difference vs. F+S (i.e. T+O 5/5 - F+S 1000/100).

2. Secondary Outcome

Title	Change From Baseline in Aortic Distensibility After 6 Weeks of Treatment
Description	Change from baseline in aortic distensibility is presented. Aortic distensibility measurements as measure of arterial stiffness were derived from cine images acquired at end-expiration in planes perpendicular to the thoracic aorta at the level of the pulmonary artery (ascending and descending section of thoracic aorta), abdominal aorta, and perpendicularly to the main, right, and left pulmonary arteries.
Time Frame	Baseline and 6 weeks

Outcome Measure Data

Analysis Population Description

FAS-EE set including participants with available data for change from baseline in aortic distensibility.

Arm/Group Title	Fluticasone Propionate + Salmeterol FDC (F+S 1000/100)	Tiotropium + Olodaterol FDC (T+O 5/5)
Arm/Group Description	Patients orally inhaled total 2 inhalations daily (one inhalation in the morning and evening) via Accuhaler® inhaler of 1000 microgram (μg) fluticasone propionate + 100 μg salmeterol dry powder for inhalation (F+S 1000/100) (500 μg / 50 μg per actuation) for 6-week treatment period.	Patients orally inhaled 2 inhalations once daily (in the morning) via Respimat® inhaler of 5 μg tiotropium + 5 μg olodaterol inhalation solution (T+O 5/5) (2.5 μg /2.5 μg per actuation) for 6-week treatment period.
Measure Participants	57	57
Least Squares Mean (Standard Error) [Percentage/millimeter of mercury(%/mmHg)]	-0.006 (0.036)	-0.005 (0.036)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fluticasone Propionate + Salmeterol FDC (F+S 1000/100), Tiotropium + Olodaterol FDC (T+O 5/5)
	Comments	MMRM model included treatment and period as fixed effects, patient as a random effect and baseline as covariate. Unstructured covariance structure was used for within patient variation.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9817
	Comments
	Method	Mixed model repeated measures (MMRM)
	Comments	Kenward-Roger approximation was used to estimate denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.001
	Confidence Interval	(2-Sided) 95%; -0.072 to 0.074
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.036
	Estimation Comments	Mean difference means the treatment difference vs. F+S (i.e. T+O 5/5 - F+S 1000/100).

3. Secondary Outcome

Title	Change From Baseline in Pulmonary Artery Pulsatility After 6 Weeks of Treatment
Description	Change from baseline in pulmonary artery pulsatility (PAP) is presented. Pulmonary artery pulsatility measurements as measure of arterial stiffness were derived from cine images acquired at end-expiration in planes perpendicular to the thoracic aorta at the level of the pulmonary artery (ascending and descending section of thoracic aorta), abdominal aorta, and perpendicularly to the main, right, and left pulmonary arteries.
Time Frame	Baseline and 6 weeks

Outcome Measure Data

Analysis Population Description

FAS-EE set including participants with available data for change from baseline in pulmonary artery pulsatility.

Arm/Group Title	Fluticasone Propionate + Salmeterol FDC (F+S 1000/100)	Tiotropium + Olodaterol FDC (T+O 5/5)
Arm/Group Description	Patients orally inhaled total 2 inhalations daily (one inhalation in the morning and evening) via Accuhaler® inhaler of 1000 microgram (μg) fluticasone propionate + 100 μg salmeterol dry powder for inhalation (F+S 1000/100) (500 μg / 50 μg per actuation) for 6-week treatment period.	Patients orally inhaled 2 inhalations once daily (in the morning) via Respimat® inhaler of 5 μg tiotropium + 5 μg olodaterol inhalation solution (T+O 5/5) (2.5 μg /2.5 μg per actuation) for 6-week treatment period.
Measure Participants	57	57
Least Squares Mean (Standard Error) [Percentage of PAP (%)]	-0.175 (1.837)	1.105 (1.836)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fluticasone Propionate + Salmeterol FDC (F+S 1000/100), Tiotropium + Olodaterol FDC (T+O 5/5)
	Comments	MMRM model included treatment and period as fixed effects, patient as a random effect and baseline as covariate. Unstructured covariance structure was used for within patient variation.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5238
	Comments
	Method	Mixed model repeated measures (MMRM)
	Comments	Kenward-Roger approximation was used to estimate denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	1.280
	Confidence Interval	(2-Sided) 95%; -2.719 to 5.279
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.995
	Estimation Comments	Mean difference means the treatment difference vs. F+S (i.e. T+O 5/5 - F+S 1000/100).

4. Secondary Outcome

Title	Change From Baseline in Central Systolic Pressure After 6 Weeks of Treatment
Description	Change from baseline in central systolic pressure is presented.
Time Frame	Baseline and 6 weeks

Outcome Measure Data

Analysis Population Description

FAS-EE set including participants with available data for change from baseline in central systolic pressure.

Arm/Group Title	Fluticasone Propionate + Salmeterol FDC (F+S 1000/100)	Tiotropium + Olodaterol FDC (T+O 5/5)
Arm/Group Description	Patients orally inhaled total 2 inhalations daily (one inhalation in the morning and evening) via Accuhaler® inhaler of 1000 microgram (μg) fluticasone propionate + 100 μg salmeterol dry powder for inhalation (F+S 1000/100) (500 μg / 50 μg per actuation) for 6-week treatment period.	Patients orally inhaled 2 inhalations once daily (in the morning) via Respimat® inhaler of 5 μg tiotropium + 5 μg olodaterol inhalation solution (T+O 5/5) (2.5 μg /2.5 μg per actuation) for 6-week treatment period.
Measure Participants	58	58
Least Squares Mean (Standard Error) [mmHg]	0.202 (1.559)	2.271 (1.559)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fluticasone Propionate + Salmeterol FDC (F+S 1000/100), Tiotropium + Olodaterol FDC (T+O 5/5)
	Comments	MMRM model included treatment and period as fixed effects, patient as a random effect and baseline as covariate. Unstructured covariance structure was used for within patient variation.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2687
	Comments
	Method	Mixed model repeated measures (MMRM)
	Comments	Kenward-Roger approximation was used to estimate denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	2.069
	Confidence Interval	(2-Sided) 95%; -1.640 to 5.779
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.853
	Estimation Comments	Mean difference means the treatment difference vs. F+S (i.e. T+O 5/5 - F+S 1000/100).

5. Secondary Outcome

Title	Change From Baseline in Pulse Pressure After 6 Weeks of Treatment
Description	Change from baseline in pulse pressure is presented.
Time Frame	Baseline and 6 weeks

Outcome Measure Data

Analysis Population Description

FAS-EE set including participants with available data for change from baseline in pulse pressure.

Arm/Group Title	Fluticasone Propionate + Salmeterol FDC (F+S 1000/100)	Tiotropium + Olodaterol FDC (T+O 5/5)
Arm/Group Description	Patients orally inhaled total 2 inhalations daily (one inhalation in the morning and evening) via Accuhaler® inhaler of 1000 microgram (μg) fluticasone propionate + 100 μg salmeterol dry powder for inhalation (F+S 1000/100) (500 μg / 50 μg per actuation) for 6-week treatment period.	Patients orally inhaled 2 inhalations once daily (in the morning) via Respimat® inhaler of 5 μg tiotropium + 5 μg olodaterol inhalation solution (T+O 5/5) (2.5 μg /2.5 μg per actuation) for 6-week treatment period.
Measure Participants	58	58
Least Squares Mean (Standard Error) [mmHg]	0.170 (1.014)	0.579 (1.014)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fluticasone Propionate + Salmeterol FDC (F+S 1000/100), Tiotropium + Olodaterol FDC (T+O 5/5)
	Comments	MMRM model included treatment and period as fixed effects, patient as a random effect and baseline as covariate. Unstructured covariance structure was used for within patient variation.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7604
	Comments
	Method	Mixed model repeated measures (MMRM)
	Comments	Kenward-Roger approximation was used to estimate denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.409
	Confidence Interval	(2-Sided) 95%; -2.264 to 3.082
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.335
	Estimation Comments	Mean difference means the treatment difference vs. F+S (i.e. T+O 5/5 - F+S 1000/100).

6. Secondary Outcome

Title	Change From Baseline in Aortic Augmentation Index After 6 Weeks of Treatment
Description	Change from baseline in aortic augmentation index is presented. Augmentation index was derived from brachial pulse wave separation analysis as augmentation pressure (pressure difference between the reflection wave to the ejection wave) divided by central pulse pressure (at the central aortic site) multiplied by 100.
Time Frame	Baseline and 6 weeks

Outcome Measure Data

Analysis Population Description

FAS-EE set including participants with available data for change from baseline in aortic augmentation index.

Arm/Group Title	Fluticasone Propionate + Salmeterol FDC (F+S 1000/100)	Tiotropium + Olodaterol FDC (T+O 5/5)
Arm/Group Description	Patients orally inhaled total 2 inhalations daily (one inhalation in the morning and evening) via Accuhaler® inhaler of 1000 microgram (μg) fluticasone propionate + 100 μg salmeterol dry powder for inhalation (F+S 1000/100) (500 μg / 50 μg per actuation) for 6-week treatment period.	Patients orally inhaled 2 inhalations once daily (in the morning) via Respimat® inhaler of 5 μg tiotropium + 5 μg olodaterol inhalation solution (T+O 5/5) (2.5 μg /2.5 μg per actuation) for 6-week treatment period.
Measure Participants	58	58
Least Squares Mean (Standard Error) [Percentage of index (%)]	1.723 (1.175)	1.404 (1.175)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fluticasone Propionate + Salmeterol FDC (F+S 1000/100), Tiotropium + Olodaterol FDC (T+O 5/5)
	Comments	MMRM model included treatment and period as fixed effects, patient as a random effect and baseline as covariate. Unstructured covariance structure was used for within patient variation.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8330
	Comments
	Method	Mixed model repeated measures (MMRM)
	Comments	Kenward-Roger approximation was used to estimate denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.320
	Confidence Interval	(2-Sided) 95%; -3.341 to 2.702
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.509
	Estimation Comments	Mean difference means the treatment difference vs. F+S (i.e. T+O 5/5 - F+S 1000/100).

7. Secondary Outcome

Title	Change From Baseline in Functional Residual Capacity Body Plethysmography (FRCpleth) % Predicted After 6 Weeks of Treatment
Description	Change from Baseline in Functional Residual Capacity Body Plethysmography (FRCpleth) % predicted is presented. Functional residual capacity, percent predicted is a lung volume at the end of normal expiration assessed/measured by body plethysmography and compared to predicted capacity for such subject, if nonsmoker and without a disease which could compromise their ventilator function, to give a percentage predicted.
Time Frame	Baseline and 6 weeks

Outcome Measure Data

Analysis Population Description

FAS-EE set including participants with available data for change from baseline in FRCpleth.

Arm/Group Title	Fluticasone Propionate + Salmeterol FDC (F+S 1000/100)	Tiotropium + Olodaterol FDC (T+O 5/5)
Arm/Group Description	Patients orally inhaled total 2 inhalations daily (one inhalation in the morning and evening) via Accuhaler® inhaler of 1000 microgram (μg) fluticasone propionate + 100 μg salmeterol dry powder for inhalation (F+S 1000/100) (500 μg / 50 μg per actuation) for 6-week treatment period.	Patients orally inhaled 2 inhalations once daily (in the morning) via Respimat® inhaler of 5 μg tiotropium + 5 μg olodaterol inhalation solution (T+O 5/5) (2.5 μg /2.5 μg per actuation) for 6-week treatment period.
Measure Participants	59	59
Least Squares Mean (Standard Error) [Percentage of FRCpleth (%)]	-10.211 (2.066)	-18.168 (2.065)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fluticasone Propionate + Salmeterol FDC (F+S 1000/100), Tiotropium + Olodaterol FDC (T+O 5/5)
	Comments	MMRM model included treatment and period as fixed effects, patient as a random effect and baseline as covariate. Unstructured covariance structure was used for within patient variation.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0019
	Comments
	Method	Mixed model repeated measures (MMRM)
	Comments	Kenward-Roger approximation was used to estimate denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-7.957
	Confidence Interval	(2-Sided) 95%; -12.865 to -3.050
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.452
	Estimation Comments	Mean difference means the treatment difference vs. F+S (i.e. T+O 5/5 - F+S 1000/100).

8. Secondary Outcome

Title	Change From Baseline in 1.5 Hour Post Dose Forced Expiratory Volume in 1st Second (FEV1) After 6 Weeks of Treatment
Description	Change from baseline in 1.5 hour post dose Forced Expiratory Volume in 1st second (FEV1) is presented.
Time Frame	Baseline and 6 weeks

Outcome Measure Data

Analysis Population Description

FAS-EE set including participants with available data for change from baseline in FEV1.

Arm/Group Title	Fluticasone Propionate + Salmeterol FDC (F+S 1000/100)	Tiotropium + Olodaterol FDC (T+O 5/5)
Arm/Group Description	Patients orally inhaled total 2 inhalations daily (one inhalation in the morning and evening) via Accuhaler® inhaler of 1000 microgram (μg) fluticasone propionate + 100 μg salmeterol dry powder for inhalation (F+S 1000/100) (500 μg / 50 μg per actuation) for 6-week treatment period.	Patients orally inhaled 2 inhalations once daily (in the morning) via Respimat® inhaler of 5 μg tiotropium + 5 μg olodaterol inhalation solution (T+O 5/5) (2.5 μg /2.5 μg per actuation) for 6-week treatment period.
Measure Participants	59	59
Least Squares Mean (Standard Error) [Litre (L)]	0.158 (0.037)	0.339 (0.037)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fluticasone Propionate + Salmeterol FDC (F+S 1000/100), Tiotropium + Olodaterol FDC (T+O 5/5)
	Comments	MMRM model included treatment and period as fixed effects, patient as a random effect and baseline as covariate. Unstructured covariance structure was used for within patient variation.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed model repeated measures (MMRM)
	Comments	Kenward-Roger approximation was used to estimate denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.180
	Confidence Interval	(2-Sided) 95%; 0.121 to 0.240
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.029
	Estimation Comments	Mean difference means the treatment difference vs. F+S (i.e. T+O 5/5 - F+S 1000/100).

9. Secondary Outcome

Title	Change From Baseline in 1.5 Hour Post Dose Forced Vital Capacity (FVC) After 6 Weeks of Treatment
Description	Change from baseline in 1.5 hour post dose Forced Vital Capacity (FVC) is presented.
Time Frame	Baseline and 6 weeks

Outcome Measure Data

Analysis Population Description

FAS-EE set including participants with available data for change from baseline in FVC.

Arm/Group Title	Fluticasone Propionate + Salmeterol FDC (F+S 1000/100)	Tiotropium + Olodaterol FDC (T+O 5/5)
Arm/Group Description	Patients orally inhaled total 2 inhalations daily (one inhalation in the morning and evening) via Accuhaler® inhaler of 1000 microgram (μg) fluticasone propionate + 100 μg salmeterol dry powder for inhalation (F+S 1000/100) (500 μg / 50 μg per actuation) for 6-week treatment period.	Patients orally inhaled 2 inhalations once daily (in the morning) via Respimat® inhaler of 5 μg tiotropium + 5 μg olodaterol inhalation solution (T+O 5/5) (2.5 μg /2.5 μg per actuation) for 6-week treatment period.
Measure Participants	59	59
Least Squares Mean (Standard Error) [Litre (L)]	0.159 (0.054)	0.445 (0.054)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fluticasone Propionate + Salmeterol FDC (F+S 1000/100), Tiotropium + Olodaterol FDC (T+O 5/5)
	Comments	MMRM model included treatment and period as fixed effects, patient as a random effect and baseline as covariate. Unstructured covariance structure was used for within patient variation.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed model repeated measures (MMRM)
	Comments	Kenward-Roger approximation was used to estimate denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.286
	Confidence Interval	(2-Sided) 95%; 0.171 to 0.400
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.057
	Estimation Comments	Mean difference means the treatment difference vs. F+S (i.e. T+O 5/5 - F+S 1000/100).

Adverse Events

Time Frame	From first drug administration until 21 days after last drug administration, up to 106 days.
Adverse Event Reporting Description	Participant flow is presented by treatment sequence whereas adverse events (AEs) are presented by treatments arms and hence the number of participant differs from the number of participant assigned in participant flow. TS was used for AEs. TS is nested within the randomised set and includes all patients who were dispensed study medication and were documented to have taken any dose of study medication.
Arm/Group Title	Fluticasone Propionate + Salmeterol FDC (F+S 1000/100)		Tiotropium + Olodaterol FDC (T+O 5/5)
Arm/Group Description	Patients orally inhaled total 2 inhalations daily (one inhalation in the morning and evening) via Accuhaler® inhaler of 1000 microgram (μg) fluticasone propionate + 100 μg salmeterol dry powder for inhalation (F+S 1000/100) (500 μg / 50 μg per actuation) for 6-week treatment period.		Patients orally inhaled 2 inhalations once daily (in the morning) via Respimat® inhaler of 5 μg tiotropium + 5 μg olodaterol inhalation solution (T+O 5/5) (2.5 μg /2.5 μg per actuation) for 6-week treatment period.
All Cause Mortality
	Fluticasone Propionate + Salmeterol FDC (F+S 1000/100)		Tiotropium + Olodaterol FDC (T+O 5/5)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/70 (0%)		0/74 (0%)
Serious Adverse Events
	Fluticasone Propionate + Salmeterol FDC (F+S 1000/100)		Tiotropium + Olodaterol FDC (T+O 5/5)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/70 (0%)		2/74 (2.7%)
Injury, poisoning and procedural complications
Ligament rupture	0/70 (0%)		1/74 (1.4%)
Musculoskeletal and connective tissue disorders
Osteoporotic fracture	0/70 (0%)		1/74 (1.4%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/70 (0%)		1/74 (1.4%)
Other (Not Including Serious) Adverse Events
	Fluticasone Propionate + Salmeterol FDC (F+S 1000/100)		Tiotropium + Olodaterol FDC (T+O 5/5)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/70 (10%)		13/74 (17.6%)
Infections and infestations
Nasopharyngitis	2/70 (2.9%)		5/74 (6.8%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	5/70 (7.1%)		8/74 (10.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.