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.

• Authors: Thomas M File, Lisa Goldberg, Anita Das, Carolyn Sweeney, John Saviski, Steven P Gelone, Elyse Seltzer, Susanne Paukner, Wolfgang W Wicha, George H Talbot, Leanne B Gasink
• Journal: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America (Clin Infect Dis) Vol. 69 Issue 11 Pg. 1856-1867 (11 13 2019) ISSN: 1537-6591 [Electronic] United States
• PMID: 30722059 (Publication Type: Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.

Chemical References

• Anti-Bacterial Agents
• Diterpenes
• Polycyclic Compounds
• Thioglycolates
• pleuromutilin
• lefamulin
• Linezolid
• Moxifloxacin

Topics

• Administration, Intravenous
• Adult
• Aged
• Anti-Bacterial Agents (administration & dosage, adverse effects, therapeutic use)
• Diterpenes (administration & dosage, adverse effects, therapeutic use)
• Double-Blind Method
• Female
• Humans
• Linezolid (adverse effects, therapeutic use)
• Male
• Microbial Sensitivity Tests
• Middle Aged
• Moxifloxacin (administration & dosage, adverse effects, therapeutic use)
• Pneumonia, Bacterial (drug therapy, metabolism)
• Polycyclic Compounds (administration & dosage, adverse effects, therapeutic use)
• Randomized Controlled Trials as Topic
• Thioglycolates (administration & dosage, adverse effects, therapeutic use)