Macrolide Azithromycin to Prevent Rapid Worsening of Symptoms Associated With Chronic Obstructive Pulmonary Disease

Pulmonary Disease, Chronic Obstructive Clinical Trial

Official title:

Effect of Chronic Macrolide Administration on the Frequency and Severity of COPD Exacerbations

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00325897
• Other study ID #: 0510M76766
• Secondary ID: U10HL074424-03
• Status: Completed
• Phase: N/A
• Start date: March 2006
• Est. completion date: July 2010

Study information

• Verified date: October 2019
• Source: University of Minnesota
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine if long-term administration of a macrolide antibiotic will reduce worsening of symptoms among individuals with chronic obstructive pulmonary disease (COPD).

Description:

BACKGROUND:

The prevalence, morbidity, mortality, and treatment cost of COPD are high and increasing. COPD is the sixth leading cause of death worldwide and is the only condition in the top 10 causes of death that has an increasing prevalence and mortality. The cost of health care for patients with COPD in the U.S. is approximately $6.5 billion per year; acute exacerbations account for between 31% and 68% of that cost. Macrolide antibiotics may reduce the frequency and/or severity of COPD exacerbations, as a result of their antibacterial properties and anti-inflammatory effects. Long-term administration of macrolide antibiotics in patients with a number of other pulmonary disorders has resulted in clinically important improvements. It is hypothesized that administration of a macrolide antibiotic (azithromycin) for 1 year, when added to usual care, will decrease the frequency and severity of COPD exacerbations. If this hypothesis is correct, the proposed treatment is also expected to reduce the mortality of COPD patients.

DESIGN NARRATIVE:

This is a prospective, randomized, double-blind, placebo-controlled study that will enroll 1130 patients with at least moderately severe COPD who, based on clinical indicators, have an increased likelihood of experiencing an acute exacerbation during the study period. Patients will be monitored monthly, including careful assessments of possible macrolide-related side effects. The exclusion criteria for this study will include a variety of conditions or medications that are known to adversely interact with macrolides. The primary endpoint of this study is time until the first acute COPD exacerbation. The secondary endpoints include macrolide-related side effects, the incidence of macrolide-resistant bacterial colonization, quality of life, and cost-effectiveness.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1142
• Est. completion date: July 2010
• Est. primary completion date: June 2010
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years and older

Eligibility

Inclusion Criteria:

• Clinical diagnosis of at least moderate Chronic Obstructive Pulmonary Disease (COPD), as defined by the following Global Initiative for COPD (GOLD) criteria:

1. Post-bronchodilator forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) ratio of less than 70%

2. Post-bronchodilator FEV1 less than 80% predicted, with or without chronic symptoms

• Cigarette consumption of 10 pack-years or more (may or may not be active smokers)

• Meets one or more of the following four conditions:

1. Current, or history of, supplemental O2 use

2. Received a course of systemic corticosteroids for respiratory problems within 1 year prior to study entry

3. Visited an emergency department for a COPD exacerbation within 1 year prior to study entry

4. Hospitalized for a COPD exacerbation within 1 year prior to study entry

• Willing to make return visits

• Available by telephone for duration of study

• Minimum of 4 weeks from the most recent acute exacerbation (have not received a course of systemic corticosteroids, an increased dose of chronically administered systemic corticosteroids, and/or antibiotics for an acute exacerbation for a minimum of 4 weeks from the time of study entry)

Exclusion Criteria:

• Diagnosis of asthma

• Diagnosis other than COPD that results in the patient being either medically unstable, or having a predicted life expectancy less than 3 years

• Special patient groups (i.e., prisoners, pregnant women, or institutionalized patients)

• Women who are at risk of becoming pregnant during the study (pre-menopausal) and who refuse to use acceptable birth control (i.e., hormone-based oral or barrier contraceptive) for the duration of the study

• History of hypersensitivity to any macrolide antibiotic

• Taking any of the following medications:

1. Cisapride

2. Ergot derivatives

3. Pimozide

4. Disopyramide

5. Cyclosporin

6. Tacrolimus

7. Nelfinavir

8. Bromocriptine

9. Hexobarbital

• Corrected QT interval (QTc) on electrocardiogram exceeding 440 ms

• Taking rifabutin or rifampin

• Chronic hepatic insufficiency

• Chronic renal insufficiency

• Diagnosis of bronchiectasis (defined as production of greater than one-half cup of purulent sputum/day)

• If, for either ear, formal audiometric testing in a sound booth results in a pure tone average (i.e., the average of the thresholds for the 4 frequencies 1000, 2000, 3000, or 4000) exceeding 50 decibel (dB), or if the threshold at any one frequency exceeds 60 dB, then the participant will be counseled by the audiologist concerning hearing aids and/or referral to an otolaryngologist. In addition, the audiologist may discuss with the participant whether or not to continue in the study. Following the examination and counseling, the participant will also discuss whether or not to continue in the study with one of the study investigators. If it is found that a participant's pure tone average in the two ears differs by more than 15 dB, or if the difference in the two ears for any one frequency exceeds 20 dB, then the participant will not be eligible for randomization into the study unless cleared by an otolaryngologist

Related Conditions & MeSH terms

• Lung Diseases
• Pulmonary Disease, Chronic Obstructive

Intervention

Drug:
• Macrolide Antibiotic (Azithromycin)
Azithromycin (daily capsule, 250 mg for 12 months)
• Placebo
Placebo taken on a daily basis

Locations

Country	Name	City	State
United States	University of Michigan	Ann Arbor	Michigan
United States	University of Maryland Baltimore	Baltimore	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Denver City-County Health/Hospitals Dept.	Denver	Colorado
United States	Minnesota Veterans Research Inst.	Minneapolis	Minnesota
United States	Temple University	Philadelphia	Pennsylvania
United States	University of Pittsburgh	Pittsburgh	Pennsylvania
United States	University of California at San Francisco	San Francisco	California
United States	Harbor-UCLA Research & Education Inst.	Torrance	California

Sponsors (2)

Lead Sponsor	Collaborator
University of Minnesota	National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time Until First Occurrence of Acute Chronic Obstructive Pulmonary Disease (COPD) Exacerbation	Time until first occurrence of acute Chronic Obstructive Pulmonary Disease (COPD) exacerbation. Acute exacerbations are defined as a "complex of respiratory symptoms (increase or new onset) of more than one of the following: cough, sputum, wheezing, dyspnea, or chest tightness with a duration of at least three days requiring treatment with antibiotics and/or systemic steroids "	Measured monthly through 13 months
Secondary	Exacerbations/Patient Year	Acute exacerbations are defined as a "complex of respiratory symptoms (increase or new onset) of more than one of the following: cough, sputum, wheezing, dyspnea, or chest tightness with a duration of at least three days requiring treatment with antibiotics and/or systemic steroids "	Measured monthly until 13 months
Secondary	Number of Emergency Department Visits as a Result of Acute Exacerbations		Measured monthly for 12 months
Secondary	Number of Hospital Admissions as a Result of Acute Exacerbations		Measured monthly for 12 months
Secondary	Change in Age-adjusted Hearing Threshold	Assessed by audiometry for four sound frequencies (1000, 2000, 3000, 4000 Hz). The maximum was computed for each threshold in each ear for all frequencies, then the differences between visits were assessed.	Baseline and 12 months
Secondary	Incidence of Macrolide-resistant Bacterial Colonization of the Nasopharynx or Sputum	Cultures from 68% of the participants in the azithromycin group and 70% in the placebo group who were not colonized with selected respiratory pathogens at the time of enrollment but who became colonized during the course of the study were available for susceptibility testing for the incidence of macrolide-resistant bacterial colonization.	Baseline
Secondary	Incidence of Macrolide-resistant Bacterial Colonization of the Nasopharynx or Sputum	Cultures from some participants who were not colonized with selected respiratory pathogens at the time of enrollment but who became colonized during the course of the study were available for susceptibility testing for the incidence of macrolide-resistant bacterial colonization.	During Course of Study (either month 3, 6, 9, or 12)

External Links

•   Published manuscript reporting main results