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Is 5-day oral lefamulin noninferior to 7-day oral moxifloxacin in the management of community-acquired bacterial pneumonia?
In this randomized clinical trial that included 738 patients, the early clinical response at 96 hours (within a 24-hour window) after the first dose of study drug was 90.8% in the lefamulin group and 90.8% in the moxifloxacin group, a difference that met the noninferiority margin of 10%.
This study demonstrated the noninferiority of oral lefamulin to oral moxifloxacin for the treatment of community-acquired bacterial pneumonia.
New antibacterials are needed to treat community-acquired bacterial pneumonia (CABP) because of growing antibacterial resistance and safety concerns with standard care.
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.
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.
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.
ClinicalTrials.gov Identifier: NCT02813694; European Clinical Trials Identifier: 2015-004782-92
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Corresponding Author: Jennifer Schranz, MD, Nabriva Therapeutics US Inc, 1000 Continental Dr, Ste 600, King of Prussia, PA 19406 (email@example.com).
Accepted for Publication: September 5, 2019.
Published Online: September 27, 2019. doi:10.1001/jama.2019.15468
Author Contributions: Dr Moran had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Alexander, Goldberg, Das, Gasink, Spera, Sweeney, Paukner, Wicha, Gelone, Schranz.
Acquisition, analysis, or interpretation of data: Alexander, Goldberg, Das, Moran, Sandrock, Gasink, Spera, Sweeney, Paukner, Gelone, Schranz.
Drafting of the manuscript: Alexander, Das, Sandrock, Paukner, Gelone, Schranz.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Goldberg, Das, Sandrock, Gasink, Spera, Sweeney, Gelone.
Obtained funding: Gelone.
Administrative, technical, or material support: Moran, Paukner.
Supervision: Alexander, Gasink, Paukner, Gelone, Schranz.
Conflict of Interest Disclosures: Drs Alexander, Spera, Paukner, Gelone, and Schranz and Ms Goldberg and Mr Wicha are employees of and own stock in Nabriva Therapeutics plc. Dr Das reported serving as a consultant to AntibioTx, Archaogen, Boston Pharmaceuticals, Cempra, ContraFect, IterumTx, Nabriva Therapeutics, Paratek, Tetraphase, Theravance, UTILITY, Wockhardt, and Zavante. Dr Moran reported receiving grants from Contrafect and Nabriva Therapeutics. Dr Sandrock reported serving as a consultant to Allergan and Nabriva Therapeutics; receiving grants from the National Institutes of Health and the Health Resources and Services Administration; and receiving nonfinancial support from the State of California. Dr Gasink was an employee of and held stock options in Nabriva Therapeutics plc when the study was performed. Ms Sweeney was an employee of and held stock options in Nabriva Therapeutics plc when the study was performed; and reported serving as a consultant to Nabriva Therapeutics and VenatoRX Pharmaceuticals. No other disclosures were reported.
Funding/Support: The study was funded by Nabriva Therapeutics.
Role of the Funders/Sponsor: Nabriva Therapeutics was responsible for the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation and review of the manuscript. Nabriva Therapeutics did not have the right to veto or suppress publication. All authors were responsible for data interpretation and drafting of the manuscript. The approval and decision to submit the manuscript for publication were the responsibility of the coauthors, led by Dr Schranz.
Meeting Presentations: These data were presented, in part, as an oral presentation for abstract LB6 at IDWeek 2018 (October 4, 2018; San Francisco, California) and as mini-oral eposter O1068 at the 29th European Congress of Clinical Microbiology and Infectious Diseases (April 16, 2019; Amsterdam, the Netherlands).
Data Sharing Statement: See Supplement 3.
Additional Contributions: We thank Werner Heilmayer, PhD, an employee of Nabriva Therapeutics GmbH, for coordinating drug dose schedules during the study. We thank Lycely del C. Sepulveda-Torres, PhD, and Michael S. McNamara, MS (both with C4 MedSolutions LLC, a CHC Group company), for the medical writing and editorial support, which were contracted and paid for by Nabriva Therapeutics.
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