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

• ClinicalTrials.gov Identifier: NCT01760304
• Recruitment Status: Terminated
• First Posted: January 4, 2013
• Results First Posted: June 14, 2017
• Last Update Posted: June 14, 2017
• Sponsor: Brigham and Women's Hospital
• Collaborator: AstraZeneca
• Information provided by (Responsible Party): Bartolome Celli, Brigham and Women's Hospital

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 (Clinical Trial)
• 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: January 2012
• Actual Primary Completion Date: July 2012
• Actual Study Completion Date: October 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 Name: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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

• Ages Eligible for Study: 40 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

United States, Massachusetts

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

More Information

• Responsible Party: Bartolome Celli, Lecturer in Medicine, Harvard Medical School, Brigham and Women's Hospital
• ClinicalTrials.gov Identifier: NCT01760304 History of Changes
• Other Study ID Numbers: 2011-P-001576/1; D589BL00021/ISSSYMB0033 ( Other Grant/Funding Number: AstraZeneca pharmaceuticals )
• First Posted: January 4, 2013
• Results First Posted: June 14, 2017
• Last Update Posted: June 14, 2017
• Last Verified: May 2017

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by Bartolome Celli, Brigham and Women's Hospital:

COPD

Additional relevant MeSH terms:

Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Lung Diseases; Respiratory Tract Diseases; Budesonide; Formoterol Fumarate; Budesonide, Formoterol Fumarate Drug Combination; Anti-Inflammatory Agents; Bronchodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Asthmatic Agents; Respiratory System Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Adrenergic Agonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action