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

Not Applicable

Completed

Conditions: Pulmonary Disease, Chronic Obstructive

Interventions: Drug: Macrolide Antibiotic (Azithromycin)
Drug: Placebo

Registration Number: NCT00325897

Lead Sponsor: University of Minnesota

Brief 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).

Detailed 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 & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 1142

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Azithromycin, 250 mg	Macrolide Antibiotic (Azithromycin)	Macrolide Antibiotic (Azithromycin)
Placebo	Placebo	Inactive

Primary Outcome Measures

Name	Time	Method
Time Until First Occurrence of Acute Chronic Obstructive Pulmonary Disease (COPD) Exacerbation	Measured monthly through 13 months	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 "

Secondary Outcome Measures

Name	Time	Method
Number of Emergency Department Visits as a Result of Acute Exacerbations	Measured monthly for 12 months
Number of Hospital Admissions as a Result of Acute Exacerbations	Measured monthly for 12 months
Exacerbations/Patient Year	Measured monthly until 13 months	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 "
Change in Age-adjusted Hearing Threshold	Baseline and 12 months	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.
Incidence of Macrolide-resistant Bacterial Colonization of the Nasopharynx or Sputum	During Course of Study (either month 3, 6, 9, or 12)	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.

Trial Locations

Locations (10): Brigham and Women's Hospital
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Boston, Massachusetts, United States
University of Maryland Baltimore
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Baltimore, Maryland, United States
Minnesota Veterans Research Inst.
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Minneapolis, Minnesota, United States
University of Alabama at Birmingham
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Birmingham, Alabama, United States
University of California at San Francisco
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San Francisco, California, United States
Denver City-County Health/Hospitals Dept.
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Denver, Colorado, United States
University of Michigan
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Ann Arbor, Michigan, United States
Temple University
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Philadelphia, Pennsylvania, United States
University of Pittsburgh
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Pittsburgh, Pennsylvania, United States
Harbor-UCLA Research & Education Inst.
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Torrance, California, United States