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