AZCO: Changes in Cardiac Function in COPD Patients After Administration of Budesonide/Formoterol (Symbicort®) Versus Placebo

• Sponsor: Brigham and Women's Hospital (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01760304
• Collaborator: AstraZeneca (Industry)
• Enrollment: 5
• Location: 1
• Arms: 2
• Duration (Months): 9
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

To investigate whether Budesonide/Formoterol (Symbicort ®) therapy can improve heart function at rest by decreasing lung hyperinflation in patients with COPD (Chronic Obstructive Pulmonary Disease).

Condition or Disease	Intervention/Treatment	Phase
Chronic Obstructive Pulmonary Disease (COPD)	Drug: Budesonide / Formoterol; Drug: Placebo	Phase 4

Detailed Description

Patients with moderate to advanced COPD are known to have static hyperinflation (at rest) as a consequence of expiratory flow limitation. Hyperinflation is easily detected by measuring lung volumes during standard pulmonary function testing.

Decreased Inspiratory Capacity (IC) secondary to hyperinflation has been described as a predictor of mortality in COPD, and as a limiting factor for the maximal tidal volume attained during exercise. Hyperinflation has been linked to a low cardiac output in part by limiting left ventricular ejection fraction during exercise.

Treatment with inhaled anticholinergic agents or long-acting beta agonists (LABA) and combination of the LABA formoterol and budesonide has been shown to improve IC and decrease lung hyperinflation. Bronchodilators have been shown to improve exercise endurance in COPD when combined with pulmonary rehabilitation, however the exact mechanism: improvement of lung mechanics and /or improvement in cardiac function is not well known.

Impedance cardiography (ICG) has emerged as a method to measure cardiac output without the need for invasive devices. Cardiac output measurement by impedance cardiography (CO-ICG) is a valid and reproducible method. It has been shown to have good correlation with thermodilution and the direct Fick method for the measurement of stroke volume and cardiac output.

In addition, the oxygen pulse, easily obtained by dividing the measured oxygen uptake by the heart rate (VO2/HR) provides an adequate reflection of cardiac stroke volume when the systemic extraction of oxygen is stable.

This method has been used to evaluate the effect of static and dynamic hyperinflation on cardiac function.

This pilot study is designed to be a single center (Brigham and Women's Hospital), randomized, placebo-controlled, double blind, crossover study of 14 patients (male and female 40 to 80 years old) with COPD and static hyperinflation.

The primary endpoint is the measurement of stroke volume, cardiac output and oxygen pulse at rest before and after the administration of budesonide/formoterol compared to placebo.

Study Design

• Study Type: Interventional
• Actual Enrollment: 5 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Evaluation of Changes in Cardiac Function in COPD Patients With Resting Hyperinflation After Administration of Budesonide/Formoterol (Symbicort®) Compared With Placebo
• Study Start Date: Jan 1, 2012
• Actual Primary Completion Date: Jul 1, 2012
• Actual Study Completion Date: Oct 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Budesonide / Formoterol This is a crossover study, where every patient will receive in a blinded fashion either Budesonide/Formoterol (Symbicort ® ) or placebo	Drug: Budesonide / Formoterol; Budesonide/ formoterol (B/F) 160/4.5 mcg per activation. Subject who met inclusion criteria will be have at each visit day lung function, heart function and breathlessness measurements at baseline, then they will receive 2 puffs of either Budesonide/formoterol (B/F) 160/4.5 mcg per activation (as per the randomization-crossover schema). After 45 minutes , the above measurements will be repeated.; Other Names: Symbicort ®
Placebo Comparator: Placebo This is a crossover study, where every patient will receive in a blinded fashion either Budesonide/Formoterol (Symbicort ® ) or placebo	Drug: Placebo; Each visit day lung function, heart function and breathlessness measurements at baseline, then they will receive 2 puffs of placebo (as per the randomization-crossover schema). After 45 minutes , the above measurements will be repeated.

Outcome Measures

Primary Outcome Measures

1. Cardiac Output [Change from Baseline and at 45 minutes after administration of study medication or placebo]

   Impedance cardiography (ICG) (BioZ Dx ICG machine, by CardioDynamics) was used to measure cardiac output without the need for invasive devices. Cardiac output measurement by impedance cardiography (CO-ICG) is a plethysmography technique using sensors to detect the properties of the blood flow in the thorax. All subjects had on each visit a baseline measurement at rest and then 45 minutes after intervention (Budesonide/formoterol or Placebo). Measurement were performed at rest for 5 minutes to obtain a steady state and the last 2 minutes were taken for analysis as an averaged value labeled as pre and post intervention. For the analysis we calculated the difference from pre and post intervention at each visit. Paired t-test was used to compare the mean+/- SD of the pre and post difference when taking the study drug vs placebo.

Secondary Outcome Measures

1. Lung Hyperinflation [Change from Baseline and after 45 minutes after administration of study medication or placebo]

   Evaluation of lung hyperinflation as determined by Pulmonary function test where Inspiratory Capacity (IC) before and 45 minutes after the administration of the budesonide/formoterol or placebo.

2. Evaluation of O2 Pulse [Change from Baseline and 45 minutes after administration of study medication or placebo]

   Evaluation of O2 Pulse is the measurement of oxygen consumption pre and post intervention

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Outpatients subjects of either sex between ages 40-80 years, with a diagnosis of COPD. COPD will be characterized as the presence of airflow obstruction with an FEV1/FVC < 0.7 (Forced Expiratory Volume at one second / Forced Vital Capacity) and a FEV1 (Forced Expiratory Volume at one second ) 80% of predicted. All patients must have lung hyperinflation as demonstrated by an increase of ≥100 ml after the administration of budesonide/formoterol. All patients must have a cigarette smoking history of more than 10 pack-years, and be able to perform all the specified procedures as required by the protocol.

Exclusion Criteria:

1. Patients with other significant diseases (recent < 6 weeks COPD exacerbation) that could place the patient at risk because of participation in the study, or which may influence the results of the study or the patients' ability to participate in the study.

2. All patients with a recent (<1 year) history of myocardial infarction, or with a recent history of heart failure (NYHA class III and IV, pulmonary edema, or patients with cardiac arrhythmias.

3. Patients on daytime oxygen therapy.

4. Patients with known active tuberculosis.

5. Patients with a history of active cancer except for non-metastatic skin cancer.

6. Patients who have undergone thoracotomy, sternotomy, major cardiopulmonary intervention (lung resection, open heart surgery, etc), or other procedure in the 6 months prior to evaluation likely to cause instability of pulmonary status.

7. Patients with upper respiratory infection in the past six weeks.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115

Sponsors and Collaborators

• Brigham and Women's Hospital
• AstraZeneca

Investigators

• Principal Investigator: Bartolome R Celli, MD, Brigham and Women's Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Bartolome Celli, Lecturer in Medicine, Harvard Medical School, Brigham and Women's Hospital
• ClinicalTrials.gov Identifier: NCT01760304
• Other Study ID Numbers: 2011-P-001576/1; D589BL00021/ISSSYMB0033
• First Posted: Jan 4, 2013
• Last Update Posted: Jun 14, 2017
• Last Verified: May 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Bartolome Celli, Lecturer in Medicine, Harvard Medical School, Brigham and Women's Hospital: COPD
• Additional relevant MeSH terms: Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Budesonide; Formoterol Fumarate

Study Results

Participant Flow

Arm/Group Title	Budesonide / Formoterol , Then Placebo	Placebo Then Budesonide/Formoterol
Arm/Group Description	This is a crossover study, where every patient signed to this arm received in a blinded fashion Budesonide/Formoterol (Symbicort ® ) 160/4.5 mcg (2 inhalations) then placebo Budesonide / Formoterol: Budesonide/ formoterol (B/F) 160/4.5 mcg per activation. Subject who met inclusion criteria will be have at each visit day lung function, heart function and breathlessness measurements at baseline, then they will receive 2 puffs of Budesonide/formoterol (B/F) 160/4.5 mcg per activation (as per the randomization-crossover schema). After 45 minutes , the above measurements will be repeated.	Every patient in this arm received in a blinded fashion placebo first then Budesonide/Formoterol (Symbicort ® ) Placebo: Each visit day lung function, heart function and breathlessness measurements at baseline, then they will receive 2 puffs of placebo (as per the randomization-crossover schema). After 45 minutes , the above measurements will be repeated.
Period Title: Overall Study
STARTED	2	3
COMPLETED	2	3
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Budesonide / Formoterol First , Then Placebo	Placebo First, Then Budesonide/Formoterol	Total
Arm/Group Description	Subjects received in a blinded fashion Budesonide/Formoterol (Symbicort ® )2 inhalations (160/4.5) then placebo 2 inhalations Budesonide / Formoterol: Budesonide/ formoterol (B/F) 160/4.5 mcg per activation. Subject will have at each visit day lung function, heart function and breathlessness measurements at baseline, then they will receive 2 puffs Budesonide/formoterol (B/F) 160/4.5 mcg per activation (as per the randomization-crossover schema). After 45 minutes , the above measurements will be repeated.	Subjects received in a blinded fashion placebo 2 inhalation then Budesonide/Formoterol (Symbicort ® )2 inhalations (160/4.5) Subject will have at each visit day lung function, heart function and breathlessness measurements at baseline, then they will receive 2 puffs Placebo on visit 1 then Budesonide/formoterol (B/F) 160/4.5 msg per activation on visit 2 (as per the randomization-crossover schema). After 45 minutes , the above measurements will be repeated.	Total of all reporting groups
Overall Participants	2	3	5
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62 (7)	70 (10)	67 (9)
Sex: Female, Male (Count of Participants)
Female	0 0%	2 66.7%	2 40%
Male	2 100%	1 33.3%	3 60%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	2 100%	3 100%	5 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	2 100%	3 100%	5 100%

Outcome Measures

1. Primary Outcome

Title	Cardiac Output
Description	Impedance cardiography (ICG) (BioZ Dx ICG machine, by CardioDynamics) was used to measure cardiac output without the need for invasive devices. Cardiac output measurement by impedance cardiography (CO-ICG) is a plethysmography technique using sensors to detect the properties of the blood flow in the thorax. All subjects had on each visit a baseline measurement at rest and then 45 minutes after intervention (Budesonide/formoterol or Placebo). Measurement were performed at rest for 5 minutes to obtain a steady state and the last 2 minutes were taken for analysis as an averaged value labeled as pre and post intervention. For the analysis we calculated the difference from pre and post intervention at each visit. Paired t-test was used to compare the mean+/- SD of the pre and post difference when taking the study drug vs placebo.
Time Frame	Change from Baseline and at 45 minutes after administration of study medication or placebo

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Budesonide / Formoterol	Placebo
Arm/Group Description	In this arm patients received in a blinded fashion Budesonide/Formoterol (Symbicort ® ) first then placebo on subsequent visit (cross-over study) Budesonide / Formoterol: Budesonide/ formoterol (B/F) 160/4.5 mcg per activation. Subject who met inclusion criteria will have at each visit day lung function, heart function and breathlessness measurements at baseline, then they will receive 2 puffs of Budesonide/formoterol (B/F) 160/4.5 mcg per activation (as per the randomization-crossover schema). After 45 minutes , the above measurements will be repeated.	In this arm patients received in a blinded fashion placebo first then Budesonide/Formoterol (Symbicort ® ) on subsequent visit (cross-over study). Placebo: On visit day lung function, heart function and breathlessness measurements at baseline, then they will receive 2 puffs of placebo (as per the randomization-crossover schema). After 45 minutes , the above measurements will be repeated.
Measure Participants	5	5
Mean (95% Confidence Interval) [ml/beat]	-0.1	1.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Budesonide / Formoterol
	Comments	a paired t-test was calculated comparing baseline measures and post intervention
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.769
	Comments
	Method	2-sided paired t-test
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments	a paired t-test was calculated comparing baseline measures and post intervention
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	paired T-test
	Comments

2. Secondary Outcome

Title	Lung Hyperinflation
Description	Evaluation of lung hyperinflation as determined by Pulmonary function test where Inspiratory Capacity (IC) before and 45 minutes after the administration of the budesonide/formoterol or placebo.
Time Frame	Change from Baseline and after 45 minutes after administration of study medication or placebo

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Budesonide / Formoterol	Placebo
Arm/Group Description	In this arm patients received in a blinded fashion Budesonide/Formoterol (Symbicort ® ) first then placebo on subsequent visit (cross-over study) Budesonide / Formoterol: Budesonide/ formoterol (B/F) 160/4.5 mcg per activation. Subject who met inclusion criteria will be have at each visit day lung function, heart function and breathlessness measurements at baseline, then they will receive 2 puffs of either Budesonide/formoterol (B/F) 160/4.5 mcg per activation (as per the randomization-crossover schema). After 45 minutes , the above measurements will be repeated.	In this arm patients will received in a blinded fashion placebo first then Budesonide/Formoterol (Symbicort ® ) on subsequent visit (cross-over study) Placebo: Each visit day lung function, heart function and breathlessness measurements at baseline, then they will receive 2 puffs of placebo (as per the randomization-crossover schema). After 45 minutes , the above measurements will be repeated.
Measure Participants	5	5
Mean (95% Confidence Interval) [Liters]	0.34	-0.058

3. Secondary Outcome

Title	Evaluation of O2 Pulse
Description	Evaluation of O2 Pulse is the measurement of oxygen consumption pre and post intervention
Time Frame	Change from Baseline and 45 minutes after administration of study medication or placebo

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Budesonide / Formoterol	Placebo
Arm/Group Description	This is a crossover study, where every patient will receive in a blinded fashion either Budesonide/Formoterol (Symbicort ® ) or placebo Budesonide / Formoterol: Budesonide/ formoterol (B/F) 160/4.5 mcg per activation. Subject who met inclusion criteria will be have at each visit day lung function, heart function and breathlessness measurements at baseline, then they will receive 2 puffs of either Budesonide/formoterol (B/F) 160/4.5 mcg per activation (as per the randomization-crossover schema). After 45 minutes , the above measurements will be repeated.	This is a crossover study, where every patient will receive in a blinded fashion either Budesonide/Formoterol (Symbicort ® ) or placebo Placebo: Each visit day lung function, heart function and breathlessness measurements at baseline, then they will receive 2 puffs of placebo (as per the randomization-crossover schema). After 45 minutes , the above measurements will be repeated.
Measure Participants	5	5
Mean (95% Confidence Interval) [ml/beat]	-0.03	0.17

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Budesonide / Formoterol, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	paired t-test
	Comments

Adverse Events

Time Frame	6 months
Arm/Group Title	Budesonide / Formoterol		Placebo
Arm/Group Description	This is a crossover study, where every patient will receive in a blinded fashion either Budesonide/Formoterol (Symbicort ® ) or placebo Budesonide / Formoterol: Budesonide/ formoterol (B/F) 160/4.5 mcg per activation. Subject who met inclusion criteria will be have at each visit day lung function, heart function and breathlessness measurements at baseline, then they will receive 2 puffs of either Budesonide/formoterol (B/F) 160/4.5 mcg per activation (as per the randomization-crossover schema). After 45 minutes , the above measurements will be repeated.		This is a crossover study, where every patient will receive in a blinded fashion either Budesonide/Formoterol (Symbicort ® ) or placebo Placebo: Each visit day lung function, heart function and breathlessness measurements at baseline, then they will receive 2 puffs of placebo (as per the randomization-crossover schema). After 45 minutes , the above measurements will be repeated.
All Cause Mortality
	Budesonide / Formoterol		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/5 (0%)
Serious Adverse Events
	Budesonide / Formoterol		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/5 (0%)
Other (Not Including Serious) Adverse Events
	Budesonide / Formoterol		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/5 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.