Azithromycin Treatment vs Placebo in Children With Respiratory Syncytial Virus-Induced Respiratory Failure: A Phase 2 Randomized Clinical Trial

Abstract

Importance: Despite a high disease burden, there is no effective treatment for respiratory syncytial virus (RSV) infection.

Objectives: To determine whether administration of azithromycin (AZM) to children with RSV-induced respiratory failure is safe and to define the effect of AZM therapy on nasal matrix metalloproteinase 9 (MMP-9) levels.

Design, setting, and participants: This randomized, double-blind, placebo-controlled phase 2 trial was conducted at a single tertiary pediatric intensive care unit from February 2016 to February 2019. The study included children with RSV infection who were admitted to the pediatric intensive care unit and required respiratory support via positive pressure ventilation (invasive and noninvasive). A total of 147 children were screened; 90 were excluded for not meeting inclusion criteria, having an absent legal guardian, lacking pharmacy support, or having a language barrier and 9 declined participation, resulting in 48 patients enrolled in the study.

Intervention: Receipt of standard dose AZM (10 mg/kg/d), high-dose AZM (20 mg/kg/d), or a matching placebo of normal saline intravenously for 3 days.

Main outcomes and measures: Nasal and endotracheal samples were collected at baseline as well as at 24 hours and 48 hours after start of treatment. The secondary outcome was to determine treatment effect on clinical outcome measures, including days of positive pressure ventilation and length of hospital stay.

Results: A total of 48 patients were enrolled in the trial, with a median (range) age at randomization of 12 (1 to 125) months; 36 participants (75.0%) were younger than 2 years. Overall, 26 participants (54.2%) were boys, and 29 (60.4%) had a comorbidity. A total of 16 patients were randomized into each trial group (ie, placebo, standard-dose AZM, and high-dose AZM). Baseline demographic characteristics were comparable among the 3 groups. Both doses of AZM were safe, with no adverse events observed. No difference in nasal MMP-9 levels were observed between treatment groups. Among those who required mechanical ventilation and received high-dose AZM, endotracheal active and total MMP-9 levels were lower on day 3. Compared with baseline, active and total MMP-9 levels in endotracheal aspirates were 1.0 log lower in the high-dose AZM group (active MMP-9: 99.8% CI, -1.28 to -0.64; P < .001; total MMP-9: 99.8% CI, -1.37 to -0.57; P < .001). Patients who received high-dose AZM had fewer median (interquartile range) hospital days compared with those receiving the placebo (8 [6-14] days vs 11 [8-20] days; mean ratio estimate, 0.57; 95% CI, 0.38-0.87; P = .01).

Conclusions and relevance: In this phase 2 randomized clinical trial, both doses of AZM were safe. While nasal MMP-9 levels were unchanged among treatment groups, endotracheal MMP-9 levels were lower among those who received high-dose AZM. The positive secondary clinical outcome, while exploratory, provides insight for end points in a multicenter randomized trial.

Trial registration: ClinicalTrials.gov Identifier: NCT02707523.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Aban reported receiving grants from the National Institutes of Health, the Myasthenia Gravis Foundation of America, Alexion, argenx, Catalyst Pharmaceutical, RA Pharmaceutical, and the Transverse Myelitis Association outside the submitted work. Dr Amabalavanan reported receiving grants from the National Institutes of Health during the conduct of the study. Dr Whitley reported receiving grants from the National Institutes of Health during the conduct of the study and receiving personal fees from Gilead Sciences outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Flow Diagram of Trial

AZM indicates azithromycin.

Figure 2.. Change in MMP-9 and TIMP-1 Levels

Each panel shows the estimate of means with 99.8% CIs, whereby treatment effect is defined as the change (ie, posttreatment minus pretreatment) at each day for a given treatment. Therefore, a nonzero mean difference indicates a treatment effect for the given day and treatment (placebo vs standard-dose azithromycin [AZM] vs high-dose AZM) for the cytokines measured in the nasal and endotracheal secretions. MMP-9 indicates matrix metalloproteinase–9; and TIMP-1, tissue inhibitor of metalloproteinase–1.