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

• ClinicalTrials.gov Identifier: NCT00325897
• Recruitment Status: Completed
• First Posted: May 15, 2006
• Results First Posted: June 7, 2012
• Last Update Posted: November 18, 2019
• Sponsor: University of Minnesota
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): University of Minnesota

Tracking Information

• First Submitted Date: May 12, 2006
• First Posted Date: May 15, 2006
• Results First Submitted Date: August 18, 2011
• Results First Posted Date: June 7, 2012
• Last Update Posted Date: November 18, 2019
• Study Start Date: March 2006
• Actual Primary Completion Date: June 2010 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 7, 2015)

Time Until First Occurrence of Acute Chronic Obstructive Pulmonary Disease (COPD) Exacerbation [ Time Frame: 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 "

• Original Primary Outcome Measures (submitted: May 12, 2006): time until first occurrence of acute COPD exacerbation (measured over a 1-year treatment period)

Current Secondary Outcome Measures (submitted: August 25, 2016)

• Exacerbations/Patient Year [ Time Frame: 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 "
• Number of Emergency Department Visits as a Result of Acute Exacerbations [ Time Frame: Measured monthly for 12 months ]
• Number of Hospital Admissions as a Result of Acute Exacerbations [ Time Frame: Measured monthly for 12 months ]
• Change in Age-adjusted Hearing Threshold [ Time Frame: 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 [ Time Frame: Baseline ]
  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.
• Incidence of Macrolide-resistant Bacterial Colonization of the Nasopharynx or Sputum [ Time Frame: 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.

Original Secondary Outcome Measures (submitted: May 12, 2006)

• number of occurrences of acute exacerbations
• number of emergency department visits as a result of acute exacerbations
• number of hospital admissions as a result of acute exacerbations
• number of hospital days as a result of acute exacerbations
• incidence of presumed macrolide-related side-effects
• incidence of presumed macrolide-related side effects that require cessation of treatment
• incidence of macrolide-resistant bacterial colonization of the nasopharynx or sputum
• incidence of pneumonia or acute bronchitis
• quality of life
• cost-effectiveness (all measured over a 12-month period)

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Macrolide Azithromycin to Prevent Rapid Worsening of Symptoms Associated With Chronic Obstructive Pulmonary Disease
• Official Title: Effect of Chronic Macrolide Administration on the Frequency and Severity of COPD Exacerbations
• 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.

• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Prevention
• Condition: Pulmonary Disease, Chronic Obstructive

Intervention

• Drug: Macrolide Antibiotic (Azithromycin)
  Azithromycin (daily capsule, 250 mg for 12 months)
  Other Names:

  • Zithromax
  • Zmax
• Drug: Placebo
  Placebo taken on a daily basis
  Other Name: sugar pill

Study Arms

• Active Comparator: Azithromycin, 250 mg
  Macrolide Antibiotic (Azithromycin)
  Intervention: Drug: Macrolide Antibiotic (Azithromycin)
• Placebo Comparator: Placebo
  Inactive
  Intervention: Drug: Placebo

Publications *

• Camac ER, Voelker H, Criner GJ; COPD Clinical Research Network and the Canadian Institutes of Health Research. Impact of COPD exacerbations leading to hospitalization on general and disease-specific quality of life. Respir Med. 2021 Sep;186:106526. doi: 10.1016/j.rmed.2021.106526. Epub 2021 Jun 29.
• Leitao Filho FS, Ra SW, Mattman A, Schellenberg RS, Criner GJ, Woodruff PG, Lazarus SC, Albert R, Connett JE, Han MK, Martinez FJ, Leung JM, Paul Man SF, Aaron SD, Reed RM, Sin DD; Canadian Respiratory Research Network (CRRN). Serum IgG subclass levels and risk of exacerbations and hospitalizations in patients with COPD. Respir Res. 2018 Feb 14;19(1):30. doi: 10.1186/s12931-018-0733-z.
• Brown KE, Sin DD, Voelker H, Connett JE, Niewoehner DE, Kunisaki KM; COPD Clinical Research Network. Serum bilirubin and the risk of chronic obstructive pulmonary disease exacerbations. Respir Res. 2017 Oct 24;18(1):179. doi: 10.1186/s12931-017-0664-0.
• Wetherbee EE, Niewoehner DE, Sisson JH, Lindberg SM, Connett JE, Kunisaki KM. Self-reported alcohol intake and risk of acute exacerbations of chronic obstructive pulmonary disease: a prospective cohort study. Int J Chron Obstruct Pulmon Dis. 2015 Jul 20;10:1363-70. doi: 10.2147/COPD.S86572. eCollection 2015.
• Geiger-Brown J, Lindberg S, Krachman S, McEvoy CE, Criner GJ, Connett JE, Albert RK, Scharf SM. Self-reported sleep quality and acute exacerbations of chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2015 Feb 20;10:389-97. doi: 10.2147/COPD.S75840. eCollection 2015.
• Han MK, Tayob N, Murray S, Dransfield MT, Washko G, Scanlon PD, Criner GJ, Casaburi R, Connett J, Lazarus SC, Albert R, Woodruff P, Martinez FJ. Predictors of chronic obstructive pulmonary disease exacerbation reduction in response to daily azithromycin therapy. Am J Respir Crit Care Med. 2014 Jun 15;189(12):1503-8. doi: 10.1164/rccm.201402-0207OC.
• Albert RK, Connett J, Curtis JL, Martinez FJ, Han MK, Lazarus SC, Woodruff PG. Mannose-binding lectin deficiency and acute exacerbations of chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2012;7:767-77. doi: 10.2147/COPD.S33714. Epub 2012 Nov 23.
• Albert RK, Connett J, Bailey WC, Casaburi R, Cooper JA Jr, Criner GJ, Curtis JL, Dransfield MT, Han MK, Lazarus SC, Make B, Marchetti N, Martinez FJ, Madinger NE, McEvoy C, Niewoehner DE, Porsasz J, Price CS, Reilly J, Scanlon PD, Sciurba FC, Scharf SM, Washko GR, Woodruff PG, Anthonisen NR; COPD Clinical Research Network. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011 Aug 25;365(8):689-98. doi: 10.1056/NEJMoa1104623. Erratum In: N Engl J Med. 2012 Apr 5;366(14):1356.
• Kunisaki KM, Niewoehner DE. Antibiotic prophylaxis for chronic obstructive pulmonary disease: resurrecting an old idea. Am J Respir Crit Care Med. 2008 Dec 1;178(11):1098-9. doi: 10.1164/rccm.200808-1315ED. No abstract available.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 26, 2010): 1142
• Original Enrollment (submitted: May 12, 2006): 1130
• Actual Study Completion Date: July 2010
• Actual Primary Completion Date: June 2010 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 40 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00325897
• Other Study ID Numbers: 0510M76766; U10HL074424-03 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: University of Minnesota
• Original Responsible Party: Not Provided
• Current Study Sponsor: University of Minnesota
• Original Study Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Richard K. Albert, MD; Denver City-County Health/Hospitals Department
• Principal Investigator: William C. Bailey, MD; University of Alabama at Birmingham
• Principal Investigator: Richard Casaburi, MD, PhD; Harbor-UCLA Research & Education Institute
• Principal Investigator: John E. Connett, PhD; University of Minnesota
• Principal Investigator: Gerard J. Criner, MD; Temple University
• Principal Investigator: Stephen C. Lazarus, MD; University of California at San Francisco
• Principal Investigator: Fernando J. Martinez, MD; University of Michigan
• Principal Investigator: Dennis E. Niewoehner, MD; Minnesota Veterans Medical Research and Education Foundation
• Principal Investigator: John J. Reilly, MD; Brigham and Women's Hospital
• Principal Investigator: Steven M. Scharf, MD, PhD; University of Maryland, Baltimore
• Principal Investigator: Frank Sciurba, MD; University of Pittsburgh

• PRS Account: University of Minnesota
• Verification Date: October 2019