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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.

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PROVIDER: S-EPMC6853694 | biostudies-literature | 2019 Nov

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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.

File Thomas M TM Goldberg Lisa L Das Anita A Sweeney Carolyn C Saviski John J Gelone Steven P SP Seltzer Elyse E Paukner Susanne S Wicha Wolfgang W WW Talbot George H GH Gasink Leanne B LB

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20191101 11

<h4>Background</h4>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.<h4>Methods</h4>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) ...[more]

PMID: 30722059

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Project description:Abstract Background Lefamulin, a first in class pleuromutilin, is being developed as an IV and oral formulation for treating CABP. The second of 2 phase 3 Lefamulin Evaluation Against Pneumonia studies, LEAP 2 (NCT02813694; EudraCT 2015-004782-92) evaluating an oral 5-day regimen, is presented here. LEAP 2 complements the positive results from LEAP 1, an IV-to-oral switch study in patients with PORT Risk Class III-V. Methods In this multicenter, randomized, double-blind, double dummy study, patients with CABP were randomized to oral lefamulin 600 mg q12h for 5 days or moxifloxacin 400 mg q24h for 7 days. Adults with PORT Risk Class II–IV were eligible (?50% were to have PORT Risk Class III or IV). The US FDA primary endpoint was early clinical response (ECR) (96 ± 24 h after first dose) in the intent-to-treat (ITT) population. The EMA coprimary endpoints (FDA secondary endpoints) were investigator assessment of clinical response (IACR) at test of cure (TOC) (5–10 days after last dose) in the modified ITT (mITT) and clinically evaluable (CE) TOC populations. For FDA and EMA endpoints, noninferiority was concluded if the lower limit of the two-sided 95% CI was greater than –10% (Figure 1). Results A total of 738 patients were randomized (n = 370 lefamulin, n = 368 moxifloxacin). Five days of lefamulin was noninferior to 7 days of moxifloxacin for both FDA and EMA primary endpoints (Figure 2). Lefamulin was efficacious regardless of PORT Risk Class (ECR responder rates for PORT II, III, and IV: 91.8% [168/183], 91.0% [132/145], and 85.0% [34/40] for lefamulin; 93.1% [176/189], 90.2% [120/133], and 85.7% [36/42] for moxifloxacin, respectively). Both agents demonstrated similar ECR responder and IACR success rates across baseline CABP pathogens. Rates of serious adverse events (AEs) and AEs leading to discontinuation were low and similar between groups. Most frequently reported AEs were gastrointestinal, the majority of mild severity with few discontinuations. Conclusion Five-day oral lefamulin demonstrated noninferiority for both FDA and EMA efficacy endpoints vs. 7-day oral moxifloxacin. Both agents were safe and generally well tolerated. Lefamulin shows promise as an oral monotherapy with a complete spectrum of antibacterial activity against CABP pathogens. Disclosures E. Alexander, Nabriva: Employee and Shareholder, Salary and Stock Options. L. Goldberg, Nabriva: Employee, Employee Stock Options and Salary. A. Das, Achaogen: Consultant, Consulting fee. Cempra: Consultant, Consulting fee. Contrafect: Consultant, Consulting fee. Paratek: Consultant, Consulting fee. Tetraphase: Consultant, Consulting fee. Wockhardt: Consultant, Consulting fee. Theravance: Consultant, Consulting fee. Zavante: Consultant, Consulting fee. Utility: Consultant, Consulting fee. Former Employee of Nabriva: Employee, Salary. Nabriva: Consultant, Consulting fee. G. J. Moran, Nabriva: Scientific Advisor, Consulting fee. C. Sandrock, Nabriva: Consultant, Consulting fee. L. B. Gasink, Former Employee of Nabriva: Employee, Salary. P. Spera, Nabriva: Employee and Shareholder, Salary. C. Sweeney, Nabriva: Employee, Employee Stock Options and Salary. S. Paukner, Nabriva: Employee and Shareholder, Salary. W. W. Wicha, Nabriva: Employee and Shareholder, Salary. J. Schranz, Nabriva: Employee and Shareholder, Salary.

Project description:ImportanceNew antibacterials are needed to treat community-acquired bacterial pneumonia (CABP) because of growing antibacterial resistance and safety concerns with standard care.ObjectiveTo evaluate the efficacy and adverse events of a 5-day oral lefamulin regimen in patients with CABP.Design, setting, and participantsA 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.InterventionsPatients 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 measuresThe 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.ResultsAmong 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 relevanceAmong 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 registrationsClinicalTrials.gov Identifier: NCT02813694; European Clinical Trials Identifier: 2015-004782-92.

Project description:BackgroundLefamulin, a first-in-class pleuromutilin antibiotic approved for intravenous and oral use in adults with community-acquired bacterial pneumonia (CABP), was noninferior to moxifloxacin in the Lefamulin Evaluation Against Pneumonia (LEAP) 1 intravenous-to-oral switch study and the LEAP 2 oral-only study. Using pooled LEAP 1/2 data, we examined lefamulin efficacy/safety overall and within subgroups of patients presenting with comorbidities typical in CABP management.MethodsIn LEAP 1, adults with CABP were randomized to receive intravenous lefamulin (150 mg every 12 h) for 5‒7 days or moxifloxacin (400 mg every 24 h) for 7 days, with optional intravenous-to-oral switch if predefined improvement criteria were met. In LEAP 2, adults with CABP were randomized to receive oral lefamulin (600 mg every 12 h) for 5 days or moxifloxacin (400 mg every 24 h) for 7 days. Both studies assessed early clinical response (ECR) at 96 ± 24 h after first study drug dose and investigator assessment of clinical response (IACR) at test-of-cure (5‒10 days after last dose). Pooled analyses of the overall population used a 10% noninferiority margin.ResultsLefamulin (n = 646) was noninferior to moxifloxacin (n = 643) for ECR (89.3% vs 90.5%, respectively; difference - 1.1%; 95% CI - 4.4 to 2.2); IACR success rates at test-of-cure were similarly high (≥ 85.0%). High efficacy with both lefamulin and moxifloxacin was also demonstrated across all well-represented patient subgroups, including those with advanced age, diabetes mellitus, a history of cardiovascular diseases (e.g., hypertension, congestive heart failure, or arrhythmia) or chronic lung diseases (e.g., asthma or chronic obstructive pulmonary disease), elevated liver enzymes, or mild-to-moderate renal dysfunction. No new safety signals were identified.ConclusionsLefamulin may provide a valuable intravenous/oral monotherapy alternative to fluoroquinolones or macrolides for empiric treatment of patients with CABP, including cases of patients at risk for poor outcomes due to age or various comorbidities.Trial registrationClinicalTrials.gov LEAP 1 (NCT02559310; Registration Date: 24/09/2015) and LEAP 2 (NCT02813694; Registration Date: 27/06/2016).

Project description:BackgroundThe most frequently prescribed regimens for the treatment of hospitalized adults with suspected or documented community-acquired bacterial pneumonia (CABP), an acute bacterial infection of the pulmonary parenchyma, are ceftriaxone plus a macrolide, or a respiratory fluoroquinolone. Although these regimens are consistent with expert guidelines, there are growing concerns regarding their safety and efficacy. Omadacycline is a once-daily antibiotic with oral and intravenous (IV) formulations; it was recently approved in the United States for the treatment of adults with CABP.ObjectiveTo estimate the cost impact of shortening hospital stay or avoiding hospitalization when using a treatment with an IV and an oral formulation, such as omadacycline, versus an IV-only drug regimen, such as ceftriaxone plus a macrolide, in adults with CABP who are not candidates for respiratory fluoroquinolone therapy.MethodsWe developed 2 conceptual healthcare decision models to identify potential cost-saving opportunities in hospitalized adults with CABP who receive omadacycline versus ceftriaxone plus a macrolide. The early hospital discharge model examined the cost impact of shifting patients with CABP from inpatient treatment with ceftriaxone plus a macrolide to inpatient IV omadacycline treatment and early hospital discharge with oral omadacycline. The hospital-avoidance model examined the cost impact of omadacycline treatment in the outpatient setting in patients with CABP who have low disease severity. The models defined the upper range of the daily acquisition cost for omadacycline that conferred cost-savings relative to inpatient treatment with ceftriaxone plus a macrolide.ResultsIn the early hospital discharge model, omadacycline showed cost-savings with a 2-day hospital stay reduction if the daily cost of omadacycline was ?$836, almost twice its wholesale acquisition cost. In the hospital-avoidance model, the daily omadacycline thresholds that still conferred cost-savings relative to inpatient ceftriaxone plus a macrolide ranged from $1302 to $1334, based on a daily wholesale acquisition cost of $450 for omadacycline, depending on the potential use of the emergency department and an observation unit.ConclusionThe study findings show that the targeted use of omadacycline for the treatment of select patient populations with CABP could result in cost-savings relative to inpatient treatment with ceftriaxone plus a macrolide.

Project description:IntroductionCommunity-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP) are common complications in idiopathic inflammatory myopathy (IIM) patients, and are frequently associated with unfavorable outcome as well as prolonged antibiotic therapy. In this study, we intended to clarify whether clinical pulmonary infection score (CPIS) and multiple serum biomarkers are valuable in predicting unfavorable outcomes and prolonged antibiotic therapy in adult IIM patients complicated with CAP or HAP.MethodsData of IIM patients with CAP or HAP who were admitted to three tertiary centers from December 2010 to November 2019 were retrospectively collected. Cox proportional hazards regression analysis and logistic regression analysis were adopted to identify risk factors for unfavorable outcomes and prolonged antibiotic therapy in these patients. The predictive values of potential predictors were assessed using receiver operating characteristic analysis.ResultsThe mortality rate was 60.6% in 109 IIM patients complicated with CAP or HAP. Myositis Disease Activity Assessment Visual Analogue Scales (MYOACT) score, CPIS and timely adjustment to antibiotics based on drug susceptibility test (DST-based antibiotic) were significantly associated with long-term outcome in these patients. With an optimal cutoff value of 6.5 and area under the curve (AUC) of 0.813, CPIS was a more satisfying predictor compared with MYOACT score. The peak C-reactive protein (CRP) level, DST-based antibiotics, and complication of interstitial lung disease (ILD) were also significantly correlated with prolonged antibiotic therapy.ConclusionsIIM patients complicated with CAP or HAP frequently suffer from unfavorable outcomes. Compared with IIM disease activity, CPIS worked as a better predictor of outcome in these patients. Also, the peak CRP level during hospitalization might be valuable in predicting prolonged antibiotic therapy. The existence of ILD might impede early discontinuation of antibiotics. Timely adjustment to antibiotics based on drug susceptibility testing would decrease the mortality rate and reduce the incidence of prolonged antibiotic therapy.

Dataset Information

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.

Publications

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.

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