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

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Prevention
• Condition: Pulmonary Disease, Chronic Obstructive
• Interventions: Drug: Macrolide Antibiotic (Azithromycin); Drug: Placebo
• Enrollment: 1142

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Azithromycin	Placebo
Arm/Group Description	Azithromycin, 250 mg	Inactive sugar pill
Period Title: Overall Study
Started	570	572
Completed	558	559
Not Completed	12	13
Reason Not Completed
Lost to Follow-up	12	13

Baseline Characteristics

Arm/Group Title		Azithromycin	Placebo	Total
Arm/Group Description		Azithromycin, 250 mg	Inactive sugar pill	Total of all reporting groups
Overall Number of Baseline Participants		570	572	1142
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	570 participants	572 participants	1142 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	277 48.6%	261 45.6%	538 47.1%
	>=65 years	293 51.4%	311 54.4%	604 52.9%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	570 participants	572 participants	1142 participants
		64.8 (8.7)	65.5 (8.4)	65.1 (8.6)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	570 participants	572 participants	1142 participants
	Female	234 41.1%	229 40.0%	463 40.5%
	Male	336 58.9%	343 60.0%	679 59.5%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	570 participants	572 participants	1142 participants
	Hispanic or Latino	11 1.9%	14 2.4%	25 2.2%
	Not Hispanic or Latino	559 98.1%	558 97.6%	1117 97.8%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB) [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	570 participants	572 participants	1142 participants
	American Indian or Alaska Native	2 0.4%	2 0.3%	4 0.4%
	Asian	6 1.1%	4 0.7%	10 0.9%
	Native Hawaiian or Other Pacific Islander	0 0.0%	2 0.3%	2 0.2%
	Black or African American	79 13.9%	89 15.6%	168 14.7%
	White	463 81.2%	457 79.9%	920 80.6%
	More than one race	20 3.5%	18 3.1%	38 3.3%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
		[1] Measure Description: All applicable categories were checked for each participant.
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	570 participants	572 participants	1142 participants
		570	572	1142

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Participants that had any follow-up data were included in analysis.

Arm/Group Title	Azithromycin	Placebo
Arm/Group Description:	Azithromycin 250 mg	Inactive sugar pill
Overall Number of Participants Analyzed	558	559
Median (95% Confidence Interval); Unit of Measure: Days
	266; (227 to 313)	174; (143 to 215)

2. Secondary Outcome

Title	Exacerbations/Patient Year
Description	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 "
Time Frame	Measured monthly until 13 months

Outcome Measure Data

Analysis Population Description

Participants with any follow-up data were analyzed.

Arm/Group Title	Azithromycin	Placebo
Arm/Group Description:	Azithromycin, 250 mg	Inactive sugar pill
Overall Number of Participants Analyzed	558	559
Measure Type: Number; Unit of Measure: exacerbations/patient year
	1.48	1.83

3. Secondary Outcome

Title	Number of Emergency Department Visits as a Result of Acute Exacerbations
Description	[Not Specified]
Time Frame	Measured monthly for 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Azithromycin	Placebo
Arm/Group Description:	Azithromycin, 250 mg	Inactive sugar pill
Overall Number of Participants Analyzed	570	572
Measure Type: Number; Unit of Measure: Visits
	199	257

4. Secondary Outcome

Title	Number of Hospital Admissions as a Result of Acute Exacerbations
Description	[Not Specified]
Time Frame	Measured monthly for 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Azithromycin	Placebo
Arm/Group Description:	Azithromycin 250 mg	Inactive sugar pill
Overall Number of Participants Analyzed	570	572
Measure Type: Number; Unit of Measure: Hospitalizations
	156	200

5. Secondary Outcome

Title	Change in Age-adjusted Hearing Threshold
Description	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.
Time Frame	Baseline and 12 months

Outcome Measure Data

Analysis Population Description

Participants with both baseline and one-year audiometry data available were analyzed.

Arm/Group Title	Azithromycin, 250 mg	Placebo
Arm/Group Description:	Macrolide Antibiotic (Azithromycin) Macrolide Antibiotic (Azithromycin): Azithromycin (daily capsule, 250 mg for 12 months)	Inactive Placebo: Placebo taken on a daily basis
Overall Number of Participants Analyzed	420	426
Mean (Standard Deviation); Unit of Measure: Decibels (db)
	-1.2 (4.2)	-0.9 (4.1)

6. Secondary Outcome

Title	Incidence of Macrolide-resistant Bacterial Colonization of the Nasopharynx or Sputum
Description	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.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

Using cultures from participants who were not colonized with selected respiratory pathogens at the time of enrollment but who became colonized during the course of the study, samples were available from 68% of the participants in the azithromycin group and 70% in the placebo group among these cultures.

Arm/Group Title	Azithromycin, 250 mg	Placebo
Arm/Group Description:	Macrolide Antibiotic (Azithromycin) Macrolide Antibiotic (Azithromycin): Azithromycin (daily capsule, 250 mg for 12 months)	Inactive Placebo: Placebo taken on a daily basis
Overall Number of Participants Analyzed	44	49
Measure Type: Number; Unit of Measure: Participants
	23	28

7. Secondary Outcome

Title	Incidence of Macrolide-resistant Bacterial Colonization of the Nasopharynx or Sputum
Description	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.
Time Frame	During Course of Study (either month 3, 6, 9, or 12)

Outcome Measure Data

Analysis Population Description

Using cultures from participants who were not colonized with selected respiratory pathogens at the time of enrollment but who became colonized during the course of the study, samples were available from 68% of the participants in the azithromycin group and 70% in the placebo group among these cultures.

Arm/Group Title	Azithromycin, 250 mg	Placebo
Arm/Group Description:	Macrolide Antibiotic (Azithromycin) Macrolide Antibiotic (Azithromycin): Azithromycin (daily capsule, 250 mg for 12 months)	Inactive Placebo: Placebo taken on a daily basis
Overall Number of Participants Analyzed	47	108
Measure Type: Number; Unit of Measure: participants
	38	44

Adverse Events

Time Frame	13 months
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Azithromycin		Placebo
Arm/Group Description	Azithromycin, 250 mg		Inactive sugar pill
All-Cause Mortality
	Azithromycin		Placebo
	Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--
Serious Adverse Events
	Azithromycin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	217/570 (38.07%)		217/572 (37.94%)
Cardiac disorders
Circulatory † 1	32/570 (5.61%)	32	31/572 (5.42%)	36
Gastrointestinal disorders
Digestive † 1	15/570 (2.63%)	15	18/572 (3.15%)	21
General disorders
Other † 1	100/570 (17.54%)	113	101/572 (17.66%)	114
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasm † 1	6/570 (1.05%)	7	8/572 (1.40%)	13
Respiratory, thoracic and mediastinal disorders
Pneumonia † 1	24/570 (4.21%)	26	37/572 (6.47%)	41
COPD Exacerbation † 1	120/570 (21.05%)	145	109/572 (19.06%)	170
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, ICD-9
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Azithromycin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	500/570 (87.72%)		444/572 (77.62%)
Cardiac disorders
Circulatory † 1	34/570 (5.96%)	49	29/572 (5.07%)	42
Gastrointestinal disorders
Digestive † 1	62/570 (10.88%)	89	78/572 (13.64%)	104
General disorders
Other † 1	319/570 (55.96%)	1132	331/572 (57.87%)	1176
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasm † 1	13/570 (2.28%)	13	15/572 (2.62%)	16
Respiratory, thoracic and mediastinal disorders
Pneumonia † 1	7/570 (1.23%)	13	24/572 (4.20%)	27
COPD Exacerbation † 1	185/570 (32.46%)	566	244/572 (42.66%)	657
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, ICD-9

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Dr. Richard Albert
• Organization: Denver Health Medical Center
• Phone: 303-436-6900
• EMail: ralbert@dhha.org

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: University of Minnesota
• ClinicalTrials.gov Identifier: NCT00325897
• Other Study ID Numbers: 0510M76766; U10HL074424-03 ( U.S. NIH Grant/Contract )
• First Submitted: May 12, 2006
• First Posted: May 15, 2006
• Results First Submitted: August 18, 2011
• Results First Posted: June 7, 2012
• Last Update Posted: November 18, 2019