A Double-Blind, Randomized, Placebo-controlled Trial of Long-Term Doxycycline Therapy on Exacerbation Rate in Patients with Stable Chronic Obstructive Pulmonary Disease

Abstract

Rationale: Chronic obstructive pulmonary disease (COPD) exacerbations are a major cause of morbidity and mortality, and preventing them is a key treatment target. Long-term macrolide treatment is effective at reducing exacerbations, but there is a paucity of evidence for other antibiotic classes. Objectives: To assess whether 12-month use of doxycycline reduces the exacerbation rate in people with COPD. Methods: People with moderate to very severe COPD and an exacerbation history were recruited from three UK centers and randomized to 12 months of doxycycline 100 mg once daily or placebo. The primary study outcome was the exacerbation rate per person-year. Results: A total of 222 people were randomized. Baseline mean FEV₁ was 1.35 L (SD, 0.35 L), 52.5% predicted (SD, 15.9% predicted). The median number of treated exacerbations in the year before the study was 2 (SD, 1-4). A total of 71% of patients reported two or more exacerbations, and 81% were already prescribed inhaled corticosteroids at baseline. The COPD exacerbation rate did not differ between the groups (doxycycline/placebo rate ratio [RR], 0.86; 95% confidence interval [CI], 0.67-1.10; P = 0.23). No difference was seen if only treated exacerbations or hospitalizations were considered. In preplanned subgroup analysis, doxycycline appeared to better reduce the exacerbation rate among people with severe COPD (RR, 0.36; 95% CI, 0.15-0.85; P = 0.019) and in those with an eosinophil count <300 cells/μl (RR, 0.50; 95% CI, 0.29-0.84; P = 0.01). Health status measured by St. George's Respiratory Questionnaire was 5.2 points worse in the doxycycline group at 12 months (P < 0.007). Conclusions: Doxycycline did not significantly reduce the exacerbation rate, over 12 months, in participants with COPD who exacerbated regularly, but it may have benefitted those with more severe COPD or blood eosinophil counts <300 cells/μl. Clinical trial registered with www.clinicaltrials.gov (NCT02305940).

Keywords: antibiotic; chronic obstructive pulmonary disease; clinical trial; exacerbations; long-term.

Figure 1.

Consort diagram showing patient flow.

Figure 2.

Kaplan-Meier plot of time to first exacerbation split between doxycycline and placebo groups (see online supplement for graph stratified by site).

Figure 3.

The interaction of covariates with the effect of doxycycline. (A) Forest plot. (B) Tabulated indicating the relevant comparator for each comparison. Models are adjusted for baseline exacerbation rate in the previous year. Doxycycline reduced the exacerbation rate to a greater degree in those with severe chronic obstructive pulmonary disease (COPD) (FEV₁, 30–50% predicted) relative to very severe COPD (FEV₁ < 30% predicted) (relative risk [RR], 0.36; 95% confidence interval [CI], 0.15–0.85; P = 0.019). Doxycycline reduced the exacerbation rate to a greater degree in those with an eosinophil count <300 cells/μl relative to those with an eosinophil count ⩾300 cells/μl (RR, 0.50; 95% CI, 0.29–0.84; P = 0.01).