Efficacy and safety of azithromycin versus placebo to treat lower respiratory tract infections associated with low procalcitonin: a randomised, placebo-controlled, double-blind, non-inferiority trial

Abstract

Background: Lower respiratory tract infections are frequently treated with antibiotics, despite a viral cause in many cases. It remains unknown whether low procalcitonin concentrations can identify patients with lower respiratory tract infection who are unlikely to benefit from antibiotics. We aimed to compare the efficacy and safety of azithromycin versus placebo to treat lower respiratory tract infections in patients with low procalcitonin.

Methods: We conducted a randomised, placebo-controlled, double-blind, non-inferiority trial at five health centres in the USA. Adults aged 18 years or older with clinically suspected non-pneumonia lower respiratory tract infection and symptom duration from 24 h to 28 days were eligible for enrolment. Participants with a procalcitonin concentration of 0·25 ng/mL or less were randomly assigned (1:1), in blocks of four with stratification by site, to receive over-encapsulated oral azithromycin 250 mg or matching placebo (two capsules on day 1 followed by one capsule daily for 4 days). Participants, non-study clinical providers, investigators, and study coordinators were masked to treatment allocation. The primary outcome was efficacy of azithromycin versus placebo in terms of clinical improvement at day 5 in the intention-to-treat population. The non-inferiority margin was -12·5%. Solicited adverse events (abdominal pain, vomiting, diarrhoea, allergic reaction, or yeast infections) were recorded as a secondary outcome. This trial is registered with ClinicalTrials.gov, NCT03341273.

Findings: Between Dec 8, 2017, and March 9, 2020, 691 patients were assessed for eligibility and 499 were enrolled and randomly assigned to receive azithromycin (n=249) or placebo (n=250). Clinical improvement at day 5 was observed in 148 (63%, 95% CI 54 to 71) of 238 participants with full data in the placebo group and 155 (69%, 61 to 77) of 227 participants with full data in the azithromycin group in the intention-to-treat analysis (between-group difference -6%, 95% CI -15 to 2). The 95% CI for the difference did not meet the non-inferiority margin. Solicited adverse events and the severity of solicited adverse events were not significantly different between groups at day 5, except for increased abdominal pain associated with azithromycin (47 [23%, 95% CI 18 to 29] of 204 participants) compared with placebo (35 [16%, 12 to 21] of 221; between-group difference -7% [95% CI -15 to 0]; p=0·066).

Interpretation: Placebo was not non-inferior to azithromycin in terms of clinical improvement at day 5 in adults with lower respiratory tract infection and a low procalcitonin concentration. After accounting for both the rates of clinical improvement and solicited adverse events at day 5, it is unclear whether antibiotics are indicated for patients with lower respiratory tract infection and a low procalcitonin concentration.

Funding: National Institute of Allergy and Infectious Diseases, bioMérieux.

Figure 1.. CONSORT flow diagram.

Figure 2.. Clinical improvement and solicited events among azithromycin-treated and placebo-treated subjects at Day 5.

The desirability of outcome ranking (DOOR) incorporates elements of clinical improvement and solicited adverse events while simultaneously considering the severity of those adverse events. Presented values indicate the probability of a more desirable DOOR when assigned to placebo vs. azithromycin. Probabilities above 50% indicate a more favorable DOOR with placebo treatment. Rather than reporting probabilities of adequate clinical improvement (a study endpoint), we report its absence to align the treatment-dependent directionality show in the figure.

Figure 3.. Forest plot of baseline characteristics by clinical improvement in the intent-to-treat Day 5 analysis population.

Each point estimate and error bars represent the estimate of the difference in rates of clinical improvement at Day 5 and the associated 95% CI obtained from a linear regression model. A difference in rates greater than zero favors azithromycin. Interaction p-values are obtained from an interaction Type III test where the interaction term between subgroup variable and treatment is being added to the linear regression model.