LEAP2

LEAP2

Alexander. JAMA 2019; Pubished online 27 September 2019. doi:10.1001/jama.2019.15468

Clinical Question

  • Is 5-day oral lefamulin non-inferior to 7-day oral moxifloxacin in the management of community-acquired bacterial pneumonia?

Background

  • Community Acquired Bacterial Pneumonia (CABP) is a leading cause of hospitalization and death in the United States
  • Current first-line treatments include macrolides, β-lactams, and fluoroquinolones
  • Lefamulin is the first pleuromutilin antibiotic approved for intravenous and oral use in humans
    • Mechanism of action: inhibition of protein synthesis via interactions with ribosomal RNA
  • LEAP1 demonstrated non-inferiority of lefamulin to moxifloxacin in moderate to severe CABP when initiated intravenously

Design

  • Phase 3, double-blind, double-dummy, parallel-group randomized clinical trial
  • Patients were randomized 1:1 with block size of 6 and stratified based on Pneumonia Outcomes Research Team (PORT) risk class, geographic region, and prior receipt of short-acting antibiotic therapy for CABP
  • Intention to treat (ITT) design included all randomized patients
  • Additional population analyses:
    • Modified ITT population: received any amount of study drug
    • Clinically evaluable population: at least 48 hours of study drug, no other antibacterial drugs, did not have indeterminate clinical response, and no other confounding factors
    • Microbiological ITT population: as per ITT population where pathogen identified
  • A sample size of 738 patients randomized 1:1 provided 90% power to establish lefamulin non-inferiority to moxifloxacin for early clinical response (US Food and Drug Administration)
    • 79% responder rate in both treatment groups for the ITT population
    • 10% noninferiority margin
    • 1-sided α level of .025
  • A similar power was achieved for the co-primary outcome of investigator-assessed clinical response in the modified ITT (European Medicines Agency)
  • Authors based the non-inferiority margin of 10% on observational studies which estimated a 20% effect size of no treatment vs antibacterial therapy
    • 10% margin preserves 50% of treatment effect
    • Consistent with US Food and Drug Administration and European Medicines Agency guidelines

Setting

  • 99 sites in 19 countries throughout Europe, North America, South America, Asia, and Africa
  • August 2016, to January 2018

Population

  • Inclusion:
    • Adult patients with PORT risk class II, III, or IV radiographically documented pneumonia
    • Acute illness (≤7 days)
    • 3 or more CABP symptoms (dyspnea, new or increased cough, purulent sputum production, and chest pain)
  • Exclusion:
    • More than 1 dose of a short-acting oral or intravenous antibacterial for CABP within 72 hours before randomization
    • Hospitalization for 2 days or longer within 90 days
    • Confirmed or suspected methicillin-resistant S. aureus
    • At risk of major cardiac events or dysfunction
    • Significant hepatic disease
  • 738 randomized patients
    • 685 completed treatment
  • Mean duration of exposure to treatment
    • 5.0 days for lefamulin
    • 6.7 days for moxifloxcin
  • Most commonly isolated pathogens
    • S. pneumoniae: 63.7%
    • H. influenzae: 26.6%
    • Atypicals (M. pneumoniae, L. pneumophila, and C. pneumonia): 22.3%

Intervention

  • Lefamulin
    • 600 mg orally every 12 hours for 5 days
    • Plus oral moxifloxacin placebo every 24 hours for 7 days

Control

  • Moxifloxacin
    • 400 mg orally every 24 hours for 7 days
    • Plus oral lefamulin placebo every 12 hours for 5 days

Outcome

  • Classifications for US FDA Primary Outcome:
    • Responder
      • Alive, showed improvement in 2 or more of the 4 CABP symptoms, had no worsening of any CABP symptom, or did not receive a non-study antibacterial for the current CABP episode
    • Non-responder
      • Did not meet above criteria
    • Indeterminate
      • Lost to follow up or missing data on criteria
  • Primary outcome: defined by US Food and Drug Administration
    • Early clinical response at 96 hours (within a 24-hour window) after receipt of first dose of either study drug in the ITT population
    • Lefamulin: 90.8%
    • Moxifloxacin: 90.8%
    • Absolute Difference: 0.1% (1-sided 97.5% CI: -4.4% to ∞)
  • Co-primary outcomes: defined by European Medicines Agency)
    • Investigator-assessed clinical response at test of cure (5-10 days after last dose of study drug) in the modified ITT population
      • Lefamulin: 87.5%
      • Moxifloxacin: 89.1%
      • Difference: -1.6% (1-sided 97.5% CI: -6.3% to ∞)
  • Secondary outcomes:
    • Investigator-assessed clinical response at test of cure (5-10 days after last dose of study drug) for the clinically evaluable population
      • Lefamulin: 89.7%
      • Moxifloxacin: 93.6%
      • Difference: -3.9% (1-sided 97.5% CI: -8.2% to ∞)
  • Adverse Outcomes
    • Overall incidence of treatment-emergent adverse events was 32.6% with lefamulin and 25.0% with moxifloxacin
      • Lefamulin group
        • Diarrhea (12.2%)
        • Nausea (5.2%)
        • Vomiting (3.3%)
        • Gastrointestinal-relate treatment-emergent adverse events (17.9%)
        • Hepatobiliary events (1.1%)
        • Cardiac events (2.2%)
        • Mean QTcF change from baseline at steady state 9.5 ms
          One patient’s QTc interval increased from 440.3 ms at baseline to a maximum of 490 ms on day 5 (study drug discontinued)
        • One case of C. diff in patient successfully treated who then remained hospitalized for five days, resolved with oral vancomycin
      • Moxifloxacin group
        • Nausea (1.9%)
        • Headache (1.6%)
        • Urinary tract infection (1.6%)
        • Gastrointestinal-relate treatment-emergent adverse events (7.6%)
        • Hepatobiliary events (0.5%)
        • Cardiac events (2.4%)
        • Mean QTcF change from baseline at steady state 11.6 m
    • Serious adverse events leading to death (none considered to be related to study drug)
      • Lefamulin group
        • 3 within 28 day window
          • Acute respiratory distress (1 patient)
          • Acute myeloid lymphoma (1 patient)
          • Pulmonary edema (1 patient)
        • 2 after 28 day window
          • Acute myeloid lymphoma (1 patient)
          • Subacute aortic valve endocarditis (1 patient)
      • Moxifloxacin group
        • 3 within 28 day window
          • Respiratory failure (1 patient)
          • Natural causes (1 patient)
          • Cerebral infarction (1 patient)

Authors’ Conclusions

  • “This study demonstrated the non-inferiority of oral lefamulin to oral moxifloxacin for the treatment of community-acquired bacterial pneumonia.”

Strengths

  • Appropriate design to answer the clinical question
  • Non-inferiority methodology allows an efficient study and appropriate conclusion
  • Randomisation method and prior-concealment prevents recruitment bias
  • Stratification and block randomisation reduces uneven allocation by play of chance
  • Study sponsors were blinded to treatment allocation unless unblinding was necessary for medical management
  • The study used CABP end points defined by regulatory bodies in the United States and in Europe
  • Sponsor did not have the right to veto or suppress publication
  • Appropriate comparator drug (moxifloxacin) and duration

Weaknesses

  • Bias may have been introduced as the study sponsors were responsible for the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation and review of the manuscript
  • Results of some secondary endpoints were not reported
  • Usually Intention-To-Treat (ITT) analysis is appropriate for superiority trial designs and Per-Protocol (PP) analysis is appropriate for non-inferiority trial design
    • This trial used multiple populations and analyses, and the conclusions were in agreement, so this is unlikely to have resulted in a false conclusion
    • ITT tends to minimise differences and PP tends to exaggerate differences – when testing for no difference, the analysis should try to exaggerate any differences so that a conclusion of no difference is robustly proven
  • Authors’ self-reported limitations
    • Broad exclusion criteria may limit generalizability to certain sub-populations
    • Limited MIC data due to non-culture identification of many pathogens
    • Sample not tested for viral pathogens
    • Patients with suspected MRSA were excluded due to poor coverage with moxifloxacin
    • Overall recovery of resistant pathogens was low
    • Race/ethnicity designation may have been misclassified based on potentially inconsistent data collection methodology

The Bottom Line

  • Despite the potential sources of bias, this seems to be a generally well-designed study
  • Oral lefamulin appears to be efficacious for the treatment of CABP, albeit with a higher rate of adverse reactions, as demonstrated by this non-inferiority trial
  • Cost may be a barrier, as lefamulin will be priced at $200-300 per day of treatment
  • Lefamulin likely represents a valuable addition to our arsenal of antibiotics against CABP, but given its status of non-inferiority (and not superiority), antimicrobial stewardship may dictate that it should be reserved if possible to avoid developing resistance

External Links

Metadata

Summary author: Dan Hu
Summary date: 16 December 2019
Peer-review editor: Duncan Chambler

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