Efficacy and Safety of Intravenous-to-oral Lefamulin, a Pleuromutilin Antibiotic, for the Treatment of Community-acquired Bacterial Pneumonia: The Phase III Lefamulin Evaluation Against Pneumonia (LEAP 1) Trial

Abstract

Background: Lefamulin, a pleuromutilin antibiotic, is active against pathogens commonly causing community-acquired bacterial pneumonia (CABP). The Lefamulin Evaluation Against Pneumonia (LEAP 1) study was a global noninferiority trial to evaluate the efficacy and safety of lefamulin for the treatment of CABP.

Methods: In this double-blind study, adults with CABP of Pneumonia Outcomes Research Team risk class ≥III were randomized 1:1 to receive lefamulin at 150 mg intravenously (IV) every 12 hours or moxifloxacin at 400 mg IV every 24 hours. After 6 doses, patients could be switched to an oral study drug if prespecified improvement criteria were met. If methicillin-resistant Staphylococcus aureus was suspected, either linezolid or placebo was added to moxifloxacin or lefamulin, respectively. The US Food and Drug Administration primary endpoint was an early clinical response (ECR) 96 ± 24 hours after the first dose of the study drug in the intent-to-treat (ITT) population (noninferiority margin, 12.5%). The European Medicines Agency co-primary endpoints were an investigator assessment of clinical response (IACR) 5-10 days after the last dose of the study drug in the modified ITT (mITT) and clinically evaluable (CE) populations (noninferiority margin, 10%).

Results: There were 551 patients randomized (n = 276 lefamulin; n = 275 moxifloxacin). Lefamulin was noninferior to moxifloxacin for ECR (87.3% vs 90.2%, respectively; difference -2.9%, 95% confidence interval [CI] g -8.5 to 2.8) and IACR (mITT, 81.7% vs 84.2%, respectively; difference -2.6%, 95% CI -8.9 to 3.9; CE, 86.9% vs 89.4%, respectively; difference -2.5%, 95% CI -8.4 to 3.4). Rates of study drug discontinuation due to treatment-emergent adverse events were 2.9% for lefamulin and 4.4% for moxifloxacin.

Conclusions: Lefamulin was noninferior to moxifloxacin for the primary efficacy endpoints and was generally safe and well tolerated.

Clinical trials registration: NCT02559310.

Keywords: antibiotic; lefamulin; moxifloxacin; pleuromutilin; pneumonia.

Figure 1.

Patient disposition. See Table 1 for definitions of the patient populations. Abbreviations: CABP, community-acquired bacterial pneumonia; CE, clinically evaluable; IACR, investigator assessment of clinical response; ITT, intent-to-treat; microITT, microbiological ITT; microITT-2, microbiological ITT-2; mITT, modified ITT; MRSA, methicillin-resistant Staphylococcus aureus; TOC, test of cure. ^aMet the criteria for CABP, received at least the prespecified minimal amount of the intended dose of the study drug and minimum duration of treatment, IACR not indeterminate, did not receive a concomitant antibacterial therapy (other than adjunctive linezolid) that is potentially effective against CABP pathogens (except in the case of clinical failure), and had no other confounding factors that interfered with the outcome assessment.

Figure 2.

Lefamulin met the primary endpoints of noninferiority vs moxifloxacin: (A) FDA primary endpoint and (B) EMA primary endpoints. See Table 1 for definitions of the patient populations. Abbreviations: CE, clinically evaluable; CI, confidence interval; ECR, early clinical response; EMA, European Medicines Agency; FDA, Food and Drug Administration; IACR, investigator assessment of clinical response; ITT, intent-to-treat; mITT, modified ITT; TOC, test of cure. ^aNoninferiority of lefamulin for the FDA primary endpoint was concluded if the lower limit of the 2-sided 95% CI for the observed difference in ECR responder rates between treatment groups was greater than −12.5%. ^bNoninferiority of lefamulin for the EMA co-primary endpoints was concluded if the lower limit of the 2-sided 95% CI for the observed difference in IACR success rates between the treatment groups was greater than −10% for both the mITT and CE populations.

Figure 3.

Responder (ECR) and success (IACR) rates by PORT risk class. Abbreviations: CI, confidence interval; ECR, early clinical response; IACR, investigator assessment of clinical response; ITT, intent-to-treat; mITT, modified ITT; NE, not evaluable due to n < 10; PORT, Pneumonia Outcomes Research Team.

Figure 4.

Outcome by subpopulation: (A) ECR in ITT population and (B) IACR in mITT population. Minor ATS severity criteria were defined as the presence of ≥3 of the following at baseline: respiratory rate ≥30 breaths/min, oxygen saturation <90% or partial pressure of arterial oxygen <60 mmHg, blood urea nitrogen ≥20 mg/dL, white blood cell count <4000 cells/mm³, confusion, multilobar infiltrates, platelet count <100 000 cells/mm³, temperature <36°C, and systolic blood pressure <90 mmHg. CURB-65 criteria were defined as blood urea nitrogen >19 mg/dL, respiratory rate ≥30 breaths/min, blood pressure <90 mmHg systolic or ≤60 mmHg diastolic, and age ≥65 years. Abbreviations: ATS, American Thoracic Society; CI, confidence interval; CURB-65, confusion of new onset; ECR, early clinical response; IACR, investigator assessment of clinical response; ITT, intent-to-treat; mITT, modified ITT; NE, not evaluable due to n < 10; SIRS, systemic inflammatory response syndrome. ^aNational Kidney Foundation categories of renal impairment were determined by Cockcroft-Gault (30) using baseline central laboratory serum creatinine. ^bPrior antibiotic use within 72 hours before randomization, as reported on the case report form.