[Skip to Content]
[Skip to Content Landing]

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

Educational Objective
To learn about lefamulin for the treatment of community-acquired bacterial pneumonia.
1 Credit CME
Key Points

Question  Is 5-day oral lefamulin noninferior to 7-day oral moxifloxacin in the management of community-acquired bacterial pneumonia?

Findings  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%.

Meaning  This study demonstrated the noninferiority of oral lefamulin to oral moxifloxacin for the treatment of community-acquired bacterial pneumonia.

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

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 CME Credit™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

Article Information

Corresponding Author: Jennifer Schranz, MD, Nabriva Therapeutics US Inc, 1000 Continental Dr, Ste 600, King of Prussia, PA 19406 (jennifer.schranz@nabriva.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.

References
1.
Xu  J, Murphy  SL, Kochanek  KD, Bastian  B, Arias  E. Deaths: final data for 2016. https://www.cdc.gov/nchs/data/nvsr/nvsr67/nvsr67_05.pdf. Accessed August 26, 2019.
2.
McDermott  KW, Elixhauser  A, Sun  R. Trends in hospital inpatient stays in the United States, 2005-2014. In:  Healthcare Cost and Utilization Project Statistical Brief No. 225. Rockville, MD: Agency for Healthcare Research and Quality; 2017.
3.
Bruns  AH, Oosterheert  JJ, Cucciolillo  MC,  et al.  Cause-specific long-term mortality rates in patients recovered from community-acquired pneumonia as compared with the general Dutch population.  Clin Microbiol Infect. 2011;17(5):763-768. doi:10.1111/j.1469-0691.2010.03296.xPubMedGoogle ScholarCrossref
4.
Jain  S, Self  WH, Wunderink  RG,  et al; CDC EPIC Study Team.  Community-acquired pneumonia requiring hospitalization among US adults.  N Engl J Med. 2015;373(5):415-427. doi:10.1056/NEJMoa1500245PubMedGoogle ScholarCrossref
5.
Hines  AL, Heslin  KC, Jiang  HH, Coffey  R. Trends in observed adult inpatient mortality for high-volume conditions, 2002-2012. In:  Healthcare Cost and Utilization Project Statistical Brief No. 194. Rockville, MD: Agency for Healthcare Research and Quality; 2015.
6.
Peyrani  P, Mandell  L, Torres  A, Tillotson  GS.  The burden of community-acquired bacterial pneumonia in the era of antibiotic resistance.  Expert Rev Respir Med. 2019;13(2):139-152. doi:10.1080/17476348.2019.1562339PubMedGoogle ScholarCrossref
7.
Pfaller  MA, Farrell  DJ, Sader  HS, Jones  RN.  AWARE Ceftaroline Surveillance Program (2008-2010): trends in resistance patterns among Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the United States.  Clin Infect Dis. 2012;55(suppl 3):S187-S193. doi:10.1093/cid/cis561PubMedGoogle ScholarCrossref
8.
Paukner  S, Gelone  SP, Arends  SJR, Flamm  RK, Sader  HS.  Antibacterial activity of lefamulin against pathogens most commonly causing community-acquired bacterial pneumonia: SENTRY antimicrobial surveillance program (2015-2016).  Antimicrob Agents Chemother. 2019;63(4):e021610-e021618. doi:10.1128/AAC.02161-18PubMedGoogle ScholarCrossref
9.
Sakoulas  G. Adverse effects of fluoroquinolones: where do we stand? https://www.jwatch.org/na48248/2019/02/13/adverse-effects-fluoroquinolones-where-do-we-stand. Accessed August 26, 2019.
10.
US Food and Drug Administration. Xenleta (lefamulin): full prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211672s000,211673s000lbl.pdf. Accessed August 26, 2019.
11.
Nabriva Therapeutics. Nabriva Therapeutics receives US FDA approval of Xenleta (lefamulin) to treat community-acquired bacterial pneumonia (CABP). http://investors.nabriva.com/news-releases/news-release-details/nabriva-therapeutics-receives-us-fda-approval-xenleta. Accessed August 26, 2019.
12.
US Food and Drug Administration. FDA approves new antibiotic to treat community-acquired bacterial pneumonia. https://www.fda.gov/news-events/press-announcements/fda-approves-new-antibiotic-treat-community-acquired-bacterial-pneumonia. Accessed August 26, 2019.
13.
Paukner  S, Sader  HS, Ivezic-Schoenfeld  Z, Jones  RN.  Antimicrobial activity of the pleuromutilin antibiotic BC-3781 against bacterial pathogens isolated in the SENTRY antimicrobial surveillance program in 2010.  Antimicrob Agents Chemother. 2013;57(9):4489-4495. doi:10.1128/AAC.00358-13PubMedGoogle ScholarCrossref
14.
Waites  KB, Crabb  DM, Duffy  LB, Jensen  JS, Liu  Y, Paukner  S.  In vitro activities of lefamulin and other antimicrobial agents against macrolide-susceptible and macrolide-resistant Mycoplasma pneumoniae from the United States, Europe, and China.  Antimicrob Agents Chemother. 2017;61(2):e02008-e020016. doi:10.1128/AAC.02008-16PubMedGoogle Scholar
15.
File  TM  Jr, Goldberg  L, Das  A,  et al.  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  [published February 4, 2019].  Clin Infect Dis. doi:10.1093/cid/ciz090PubMedGoogle Scholar
16.
Mandell  LA, Wunderink  RG, Anzueto  A,  et al; Infectious Diseases Society of America; American Thoracic Society.  Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults.  Clin Infect Dis. 2007;44(suppl 2):S27-S72. doi:10.1086/511159PubMedGoogle ScholarCrossref
17.
US Food and Drug Administration. Avelox (moxifloxacin hydrochloride): full prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021085s063lbl.pdf. Accessed August 26, 2019.
18.
World Medical Association.  World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.  JAMA. 2013;310(20):2191-2194. doi:10.1001/jama.2013.281053PubMedGoogle ScholarCrossref
19.
US Food and Drug Administration. Guidance for industry and Food and Drug Administration staff: collection of race and ethnicity data in clinical trials. https://www.fda.gov/media/75453/download. Accessed August 26, 2019.
20.
US Food and Drug Administration. Guidance for industry: community-acquired bacterial pneumonia: developing drugs for treatment. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM123686.pdf. Accessed August 26, 2019.
21.
European Medicines Agency Committee for Human Medicinal Products. Addendum to the guideline on the evaluation of medicinal products indicated for treatment of bacterial infections. https://www.ema.europa.eu/documents/scientific-guideline/addendum-guideline-evaluation-medicinal-products-indicated-treatment-bacterial-infections_en.pdf. Accessed August 26, 2019.
22.
European Medicines Agency Committee for Human Medicinal Products. Guideline on the evaluation of medicinal products indicated for treatment of bacterial infections. https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-evaluation-medicinal-products-indicated-treatment-bacterial-infections-revision-2_en.pdf. Accessed September 3, 2019.
23.
Talbot  GH, Powers  JH, Fleming  TR, Siuciak  JA, Bradley  J, Boucher  H; CABP-ABSSSI Project Team.  Progress on developing endpoints for registrational clinical trials of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections: update from the Biomarkers Consortium of the Foundation for the National Institutes of Health.  Clin Infect Dis. 2012;55(8):1114-1121. doi:10.1093/cid/cis566PubMedGoogle ScholarCrossref
24.
Fine  MJ, Auble  TE, Yealy  DM,  et al.  A prediction rule to identify low-risk patients with community-acquired pneumonia.  N Engl J Med. 1997;336(4):243-250. doi:10.1056/NEJM199701233360402PubMedGoogle ScholarCrossref
25.
US Food and Drug Administration. Guidance for industry drug-induced liver injury: premarketing clinical evaluation. https://www.fda.gov/downloads/guidances/UCM174090.pdf. Accessed August 26, 2019.
26.
US Food and Drug Administration Antimicrobial Drugs Advisory Committee. Solithromycin for the treatment of community acquired bacterial pneumonia. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/UCM527691.pdf. Accessed August 26, 2019.
27.
US Food and Drug Administration. Nuzyra (omadacycline): full prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209816_209817lbl.pdf. Accessed August 26, 2019.
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_LoginSubscribe_Purchase
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_LoginSubscribe_Purchase
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right

Name Your Search

Save Search
With a personal account, you can:
  • Track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
jn-learning_Modal_SaveSearch_NoAccess_Purchase

Lookup An Activity

or

My Saved Searches

You currently have no searches saved.

With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Topics
State Requirements