Oral Lefamulin vs Moxifloxacin for Early Clinical Response among Adults with Community-Acquired Bacterial Pneumonia: The LEAP 2 Randomized Clinical Trial

Elizabeth Alexander, Lisa Goldberg, Anita F. Das, Gregory J. Moran, Christian Sandrock, Leanne B. Gasink, Patricia Spera, Carolyn Sweeney, Susanne Paukner, Wolfgang W. Wicha, Steven P. Gelone, Jennifer Schranz

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1661-1671
Number of pages11
JournalJAMA - Journal of the American Medical Association
Volume322
Issue number17
DOIs
StatePublished - Nov 5 2019

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Bacterial Pneumonia
Randomized Controlled Trials
Pneumonia
Population
Research Personnel
Outcome Assessment (Health Care)
United States Food and Drug Administration
Vital Signs
moxifloxacin
Pharmaceutical Preparations
Nausea
Diarrhea
Clinical Trials
Safety

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Oral Lefamulin vs Moxifloxacin for Early Clinical Response among Adults with Community-Acquired Bacterial Pneumonia : The LEAP 2 Randomized Clinical Trial. / Alexander, Elizabeth; Goldberg, Lisa; Das, Anita F.; Moran, Gregory J.; Sandrock, Christian; Gasink, Leanne B.; Spera, Patricia; Sweeney, Carolyn; Paukner, Susanne; Wicha, Wolfgang W.; Gelone, Steven P.; Schranz, Jennifer.

In: JAMA - Journal of the American Medical Association, Vol. 322, No. 17, 05.11.2019, p. 1661-1671.

Research output: Contribution to journalArticle

Alexander, E, Goldberg, L, Das, AF, Moran, GJ, Sandrock, C, Gasink, LB, Spera, P, Sweeney, C, Paukner, S, Wicha, WW, Gelone, SP & Schranz, J 2019, 'Oral Lefamulin vs Moxifloxacin for Early Clinical Response among Adults with Community-Acquired Bacterial Pneumonia: The LEAP 2 Randomized Clinical Trial', JAMA - Journal of the American Medical Association, vol. 322, no. 17, pp. 1661-1671. https://doi.org/10.1001/jama.2019.15468
Alexander, Elizabeth ; Goldberg, Lisa ; Das, Anita F. ; Moran, Gregory J. ; Sandrock, Christian ; Gasink, Leanne B. ; Spera, Patricia ; Sweeney, Carolyn ; Paukner, Susanne ; Wicha, Wolfgang W. ; Gelone, Steven P. ; Schranz, Jennifer. / Oral Lefamulin vs Moxifloxacin for Early Clinical Response among Adults with Community-Acquired Bacterial Pneumonia : The LEAP 2 Randomized Clinical Trial. In: JAMA - Journal of the American Medical Association. 2019 ; Vol. 322, No. 17. pp. 1661-1671.
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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.",
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T1 - Oral Lefamulin vs Moxifloxacin for Early Clinical Response among Adults with Community-Acquired Bacterial Pneumonia

T2 - The LEAP 2 Randomized Clinical Trial

AU - Alexander, Elizabeth

AU - Goldberg, Lisa

AU - Das, Anita F.

AU - Moran, Gregory J.

AU - Sandrock, Christian

AU - Gasink, Leanne B.

AU - Spera, Patricia

AU - Sweeney, Carolyn

AU - Paukner, Susanne

AU - Wicha, Wolfgang W.

AU - Gelone, Steven P.

AU - Schranz, Jennifer

PY - 2019/11/5

Y1 - 2019/11/5

N2 - 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.

AB - 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.

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