Trial Outcomes & Findings for Cardiovascular Function in COPD Patients (NCT NCT03055988)

NCT ID: NCT03055988

Last Updated: 2019-08-16

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 76 participants
• Primary outcome timeframe: Baseline and 6 weeks
• Results posted on: 2019-08-16

Participant Flow

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.

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.

Participant milestones

Measure	FluticasonePropionate+SalmeterolFDC/ Tiotropium+OlodaterolFDC 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.	Tiotropium+OlodaterolFDC/ FluticasonePropionate+SalmeterolFDC 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 1 STARTED	38	38
Period 1 COMPLETED	37	33
Period 1 NOT COMPLETED	1	5
Period 2 STARTED	37	33
Period 2 COMPLETED	36	31
Period 2 NOT COMPLETED	1	2

Reasons for withdrawal

Measure	FluticasonePropionate+SalmeterolFDC/ Tiotropium+OlodaterolFDC 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.	Tiotropium+OlodaterolFDC/ FluticasonePropionate+SalmeterolFDC 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 1 Adverse Event	0	1
Period 1 Lost to Follow-up	1	0
Period 1 Withdrawal by Subject	0	4
Period 2 Adverse Event	0	1
Period 2 Other than listed	1	1

Baseline Characteristics

Cardiovascular Function in COPD Patients

Baseline characteristics by cohort

Measure	Total Patients n=76 Participants 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.
Age, Continuous	61.86 Years STANDARD_DEVIATION 7.13 • n=5 Participants
Sex: Female, Male Female	31 Participants n=5 Participants
Sex: Female, Male Male	45 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	76 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	1 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants
Race (NIH/OMB) White	75 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline and 6 weeks

Population: 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)

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.

Outcome measures

Measure	Fluticasone Propionate + Salmeterol FDC (F+S 1000/100) n=59 Participants 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.	Tiotropium + Olodaterol FDC (T+O 5/5) n=59 Participants 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.
Change From Baseline in Left Ventricular End Diastolic Volume Index (LVEDVI) in the 6th Week of Treatment	2.855 Millilitre/ meter^2 (mL/m^2) Standard Error 1.137	2.317 Millilitre/ meter^2 (mL/m^2) Standard Error 1.136

SECONDARY outcome

Timeframe: Baseline and 6 weeks

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

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.

Outcome measures

Measure	Fluticasone Propionate + Salmeterol FDC (F+S 1000/100) n=57 Participants 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.	Tiotropium + Olodaterol FDC (T+O 5/5) n=57 Participants 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.
Change From Baseline in Aortic Distensibility After 6 Weeks of Treatment	-0.006 Percentage/millimeter of mercury(%/mmHg) Standard Error 0.036	-0.005 Percentage/millimeter of mercury(%/mmHg) Standard Error 0.036

SECONDARY outcome

Timeframe: Baseline and 6 weeks

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

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.

Outcome measures

Measure	Fluticasone Propionate + Salmeterol FDC (F+S 1000/100) n=57 Participants 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.	Tiotropium + Olodaterol FDC (T+O 5/5) n=57 Participants 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.
Change From Baseline in Pulmonary Artery Pulsatility After 6 Weeks of Treatment	-0.175 Percentage of PAP (%) Standard Error 1.837	1.105 Percentage of PAP (%) Standard Error 1.836

SECONDARY outcome

Timeframe: Baseline and 6 weeks

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

Change from baseline in central systolic pressure is presented.

Outcome measures

Measure	Fluticasone Propionate + Salmeterol FDC (F+S 1000/100) n=58 Participants 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.	Tiotropium + Olodaterol FDC (T+O 5/5) n=58 Participants 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.
Change From Baseline in Central Systolic Pressure After 6 Weeks of Treatment	0.202 mmHg Standard Error 1.559	2.271 mmHg Standard Error 1.559

SECONDARY outcome

Timeframe: Baseline and 6 weeks

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

Change from baseline in pulse pressure is presented.

Outcome measures

Measure	Fluticasone Propionate + Salmeterol FDC (F+S 1000/100) n=58 Participants 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.	Tiotropium + Olodaterol FDC (T+O 5/5) n=58 Participants 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.
Change From Baseline in Pulse Pressure After 6 Weeks of Treatment	0.170 mmHg Standard Error 1.014	0.579 mmHg Standard Error 1.014

SECONDARY outcome

Timeframe: Baseline and 6 weeks

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

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.

Outcome measures

Measure	Fluticasone Propionate + Salmeterol FDC (F+S 1000/100) n=58 Participants 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.	Tiotropium + Olodaterol FDC (T+O 5/5) n=58 Participants 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.
Change From Baseline in Aortic Augmentation Index After 6 Weeks of Treatment	1.723 Percentage of index (%) Standard Error 1.175	1.404 Percentage of index (%) Standard Error 1.175

SECONDARY outcome

Timeframe: Baseline and 6 weeks

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

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.

Outcome measures

Measure	Fluticasone Propionate + Salmeterol FDC (F+S 1000/100) n=59 Participants 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.	Tiotropium + Olodaterol FDC (T+O 5/5) n=59 Participants 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.
Change From Baseline in Functional Residual Capacity Body Plethysmography (FRCpleth) % Predicted After 6 Weeks of Treatment	-10.211 Percentage of FRCpleth (%) Standard Error 2.066	-18.168 Percentage of FRCpleth (%) Standard Error 2.065

SECONDARY outcome

Timeframe: Baseline and 6 weeks

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

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

Outcome measures

Measure	Fluticasone Propionate + Salmeterol FDC (F+S 1000/100) n=59 Participants 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.	Tiotropium + Olodaterol FDC (T+O 5/5) n=59 Participants 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.
Change From Baseline in 1.5 Hour Post Dose Forced Expiratory Volume in 1st Second (FEV1) After 6 Weeks of Treatment	0.158 Litre (L) Standard Error 0.037	0.339 Litre (L) Standard Error 0.037

SECONDARY outcome

Timeframe: Baseline and 6 weeks

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

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

Outcome measures

Measure	Fluticasone Propionate + Salmeterol FDC (F+S 1000/100) n=59 Participants 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.	Tiotropium + Olodaterol FDC (T+O 5/5) n=59 Participants 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.
Change From Baseline in 1.5 Hour Post Dose Forced Vital Capacity (FVC) After 6 Weeks of Treatment	0.159 Litre (L) Standard Error 0.054	0.445 Litre (L) Standard Error 0.054

Adverse Events

Fluticasone Propionate + Salmeterol FDC (F+S 1000/100)

Serious events: 0 serious events

Other events: 7 other events

Deaths: 0 deaths

Tiotropium + Olodaterol FDC (T+O 5/5)

Serious events: 2 serious events

Other events: 13 other events

Deaths: 0 deaths

Serious adverse events

Measure	Fluticasone Propionate + Salmeterol FDC (F+S 1000/100) n=70 participants at risk 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.	Tiotropium + Olodaterol FDC (T+O 5/5) n=74 participants at risk 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.
Injury, poisoning and procedural complications Ligament rupture	0.00% 0/70 • From first drug administration until 21 days after last drug administration, up to 106 days. 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.	1.4% 1/74 • From first drug administration until 21 days after last drug administration, up to 106 days. 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.
Musculoskeletal and connective tissue disorders Osteoporotic fracture	0.00% 0/70 • From first drug administration until 21 days after last drug administration, up to 106 days. 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.	1.4% 1/74 • From first drug administration until 21 days after last drug administration, up to 106 days. 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.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.00% 0/70 • From first drug administration until 21 days after last drug administration, up to 106 days. 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.	1.4% 1/74 • From first drug administration until 21 days after last drug administration, up to 106 days. 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.

Other adverse events

Measure	Fluticasone Propionate + Salmeterol FDC (F+S 1000/100) n=70 participants at risk 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.	Tiotropium + Olodaterol FDC (T+O 5/5) n=74 participants at risk 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.
Infections and infestations Nasopharyngitis	2.9% 2/70 • From first drug administration until 21 days after last drug administration, up to 106 days. 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.	6.8% 5/74 • From first drug administration until 21 days after last drug administration, up to 106 days. 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.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	7.1% 5/70 • From first drug administration until 21 days after last drug administration, up to 106 days. 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.	10.8% 8/74 • From first drug administration until 21 days after last drug administration, up to 106 days. 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.

Additional Information

Boehringer Ingelheim, Call Centre

Boehringer Ingelheim

Phone: 1-800-243-0127

Email: clintriage.rdg@boehringer-ingelheim.com

Results disclosure agreements

• Principal investigator is a sponsor employee 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.
• Publication restrictions are in place

Restriction type: OTHER