Oral Lefamulin vs Moxifloxacin for Early Clinical Response Among Adults With Community-Acquired Bacterial Pneumonia: The LEAP 2 Randomized Clinical Trial

Abstract

Importance: New antibacterials are needed to treat community-acquired bacterial pneumonia (CABP) because of growing antibacterial resistance and safety concerns with standard care.

Objective: To evaluate the efficacy and adverse events of a 5-day oral lefamulin regimen in patients with CABP.

Design, setting, and participants: A phase 3, noninferiority randomized clinical trial conducted at 99 sites in 19 countries that included adults aged 18 years or older with a Pneumonia Outcomes Research Team (PORT) risk class of II, III, or IV; radiographically documented pneumonia; acute illness; 3 or more CABP symptoms; and 2 or more vital sign abnormalities. The first patient visit was on August 30, 2016, and patients were followed up for 30 days; the final follow-up visit was on January 2, 2018.

Interventions: Patients were randomized 1:1 to receive oral lefamulin (600 mg every 12 hours for 5 days; n = 370) or moxifloxacin (400 mg every 24 hours for 7 days; n = 368).

Main outcomes and measures: The US Food and Drug Administration (FDA) primary end point was early clinical response at 96 hours (within a 24-hour window) after the first dose of either study drug in the intent-to-treat (ITT) population (all randomized patients). Responders were defined as alive, showing improvement in 2 or more of the 4 CABP symptoms, having no worsening of any CABP symptoms, and not receiving any nonstudy antibacterial drug for current CABP episode. The European Medicines Agency coprimary end points (FDA secondary end points) were investigator assessment of clinical response at test of cure (5-10 days after last dose) in the modified ITT population and in the clinically evaluable population. The noninferiority margin was 10% for early clinical response and investigator assessment of clinical response.

Results: Among 738 randomized patients (mean age, 57.5 years; 351 women [47.6%]; 360 had a PORT risk class of III or IV [48.8%]), 707 (95.8%) completed the trial. Early clinical response rates were 90.8% with lefamulin and 90.8% with moxifloxacin (difference, 0.1% [1-sided 97.5% CI, -4.4% to ∞]). Rates of investigator assessment of clinical response success were 87.5% with lefamulin and 89.1% with moxifloxacin in the modified ITT population (difference, -1.6% [1-sided 97.5% CI, -6.3% to ∞]) and 89.7% and 93.6%, respectively, in the clinically evaluable population (difference, -3.9% [1-sided 97.5% CI, -8.2% to ∞]) at test of cure. The most frequently reported treatment-emergent adverse events were gastrointestinal (diarrhea: 45/368 [12.2%] in lefamulin group and 4/368 [1.1%] in moxifloxacin group; nausea: 19/368 [5.2%] in lefamulin group and 7/368 [1.9%] in moxifloxacin group).

Conclusions and relevance: Among patients with CABP, 5-day oral lefamulin was noninferior to 7-day oral moxifloxacin with respect to early clinical response at 96 hours after first dose.

Trial registrations: ClinicalTrials.gov Identifier: NCT02813694; European Clinical Trials Identifier: 2015-004782-92.

Figure.. Patient Recruitment, Randomization, and Follow-up in the LEAP 2 Trial

ITT indicates intent to treat; LEAP 2, Lefamulin Evaluation Against Pneumonia 2. ^aThe number of patients with a Pneumonia Outcomes Research Team (PORT) risk class of II was capped at 50% of the total population; once this cap was reached, these patients were no longer assessed for study eligibility. All patients assessed for study eligibility provided informed consent. ^bOne patient did not attend the randomization visit, 1 patient did not receive study drug due to insufficient drug stock at site, 1 patient with PORT risk class II was assessed after the per-protocol cap had been met, 1 patient had prolonged QTcF at the screening visit, 2 patients were excluded by the investigator, 6 patients were excluded due to randomization error, and 1 patient was excluded for an unknown reason. ^cThe number of randomized patients who received a single dose of a short-acting antibiotic was capped at 25% of the total population; this cap was not reached and therefore this criterion had no effect on randomization. ^dPatients were discontinued from treatment because they met per protocol exclusion or study withdrawal criteria: 1 patient due to baseline and postbaseline QTcF greater than 500 ms, 2 patients due to confirmed Staphylococcus aureus bacteremia, and 1 patient due to a complete left bundle branch block. ^eMay have met more than 1 exclusion criterion. ^fAs defined by inclusion criteria 3 through 7 and exclusion criteria 3, 5, and 6 in Supplement 1. ^gAs defined by exclusion criterion 1 in Supplement 1. ^hPatient had a lung abscess diagnosed by computed tomography within hours after randomization. ⁱOne patient was diagnosed with tuberculosis on study day 1; 1 patient was diagnosed with small cell lung cancer on study day 4; 1 patient was diagnosed with squamous cell carcinoma of the lung on study day 5; 1 patient was diagnosed with tuberculosis effusion on study day 24; and 1 patient was ultimately diagnosed with tuberculosis.