Study to Compare Lefamulin to Moxifloxacin (With or Without Linezolid) for the Treatment of Adults With Pneumonia (LEAP)

A Phase 3, Randomized, Double-Blind, Double-Dummy Study to Compare the Efficacy and Safety of Lefamulin (BC 3781) Versus Moxifloxacin (With or Without Adjunctive Linezolid) in Adults With Community-Acquired Bacterial Pneumonia

This study evaluates the safety and efficacy of lefamulin, a pleuromutilin, for the treatment of adults with moderate to severe community-acquired bacterial pneumonia.

Study Overview

• Status: Completed
• Conditions: Community Acquired Pneumonia
• Intervention / Treatment: Drug: lefamulin; Drug: Moxifloxacin; Drug: Linezolid

Detailed Description

Lefamulin is a potent, semi-synthetic antibacterial belonging to a novel class known as the pleuromutilins. Both the intravenous (IV) and oral dosage forms of lefamulin are under investigation in this study. Lefamulin's in vitro antibacterial profile includes the most important bacterial pathogens causing respiratory tract infection (RTI). The antibacterial spectrum comprises S. pneumoniae, H. influenzae, M. catarrhalis, the atypical respiratory pathogens L. pneumophila, C. pneumoniae, and M. pneumoniae, S. aureus including MRSA and CA-MRSA, ß-haemolytic streptococci including S. pyogenes and S. agalactiae, and Enterococcus faecium including vancomycin-resistant enterococci (VRE). Moreover, as demonstrated in cross-resistance studies, lefamulin remains active against clinical isolates resistant to the following antimicrobial(s) (classes): macrolides, lincosamides, streptogramin B, oxazolidinones, tetracyclines, ß lactams, quinolones, trimethoprim-sulfametoxazole, mupirocin, and vancomycin.

• Study Type: Interventional
• Enrollment (Actual): 551
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Cordoba, Argentina, X5016KEH
    • Site 3004
  • Córdoba, Argentina, X5000EPU
    • Site 3003
  • Córdoba, Argentina, X5000JRD
    • Site 3007
  • Córdoba, Argentina, X5004CDT
    • Site 3001
  • Buenos Aires
    • La Plata, Buenos Aires, Argentina, 1900
      • Site 3005
  • Santa Fe
    • Rosario, Santa Fe, Argentina, S2000CVB
      • Site 3006
• Bosnia and Herzegovina
  • Mostar, Bosnia and Herzegovina, 88000
    • Site 4003
  • Tuzla, Bosnia and Herzegovina, 75000
    • Site 4001
  • Zenica, Bosnia and Herzegovina, 72000
    • Site 4004
• Brazil
  • Minas Gerais
    • Belo Horizonte, Minas Gerais, Brazil, 30150-221
      • Site 3104
  • Rio Grande Do Sol
    • Passo Fundo, Rio Grande Do Sol, Brazil, 99010-080
      • Site 3102
  • Sao Paulo
    • Campinas, Sao Paulo, Brazil, 13059-900
      • Site 3103
    • Sao Paulo Do Rio Preto, Sao Paulo, Brazil, 15090-000
      • Site 3101
• Bulgaria
  • Gabrovo, Bulgaria, 5300
    • Site 4105
  • Lovech, Bulgaria, 5500
    • Site 4107
  • Pernik, Bulgaria, 2300
    • Site 4112
  • Ruse, Bulgaria, 7002
    • Site 4103
  • Smolyan, Bulgaria, 4700
    • Site 4108
  • Sofia, Bulgaria, 1202
    • Site 4102
  • Sofia, Bulgaria, 1233
    • Site 4101
  • Sofia, Bulgaria, 1233
    • Site 4106
  • Sofia, Bulgaria, 1606
    • Site 4110
  • Sofia, Bulgaria, 1606
    • Site 4111
  • Veliko Tarnovo, Bulgaria, 5000
    • Site 4104
  • Vidin, Bulgaria, 3700
    • Site 4109
• Georgia
  • Tbilisi, Georgia, 0101
    • Site 4206
  • Tbilisi, Georgia, 0144
    • Site 4204
  • Tbilisi, Georgia, 0144
    • Site 4205
  • Tbilisi, Georgia, 0159
    • Site 4201
  • Tbilisi, Georgia, 0186
    • Site 4202
• Hungary
  • Budapest, Hungary, 1121
    • Site 4305
  • Csorna, Hungary, 9300
    • Site 4306
  • Debrecen, Hungary, 4043
    • Site 4304
  • Farkasgyepű, Hungary, 8582
    • Site 4302
  • Miskolc, Hungary, 3529
    • Site 4307
  • Miskolc, Hungary, 3529
    • Site 4308
  • Törökbálint, Hungary, 2045
    • Site 4303
• Latvia
  • Daugavpils, Latvia, LV-5417
    • Site 4403
  • Liepaja, Latvia, LV-3414
    • Site 4401
  • Riga, Latvia, LV-1038
    • Site 4402
• Netherlands
  • Helmond, Netherlands, 5707 HA
    • Site 4602
  • Overijssel
    • Almelo, Overijssel, Netherlands, 7609 PP
      • Site 4603
• Peru
  • Lima, Peru, Lima 18
    • Site 3202
  • Lima, Peru, Lima 1
    • Site 3204
  • Lima, Peru, Lima 29
    • Site 3201
  • La Libertad
    • Trujillo, La Libertad, Peru
      • Site 3205
• Philippines
  • Iloilo City, Philippines, 5000
    • Site 2005
  • Manila, Philippines, 1012
    • Site 2004
  • Manila City, Philippines, 1000
    • Site 2003
  • Quezon City, Philippines, 1100
    • Site 2002
  • Quezon City, Philippines, 1114
    • Site 2001
• Poland
  • Lódz, Poland, 90-153
    • Site 4701
  • Wilkowice, Poland, 43-365
    • Site 4702
  • Lódzkie
    • Skierniewice, Lódzkie, Poland, 96-100
      • Site 4703
  • Mazowieckie
    • Warszawa, Mazowieckie, Poland, 02-097
      • Site 4704
• Romania
  • Bucharest, Romania, 21105
    • Site 4801
  • Bucharest, Romania, 21105
    • Site 4806
  • Bucuresti, Romania, 030303
    • Site 4810
  • Cluj-Napoca, Romania, 040000
    • Site 4811
  • Craiova, Romania, 200515
    • Site 4803
  • Craiova, Romania, 200515
    • Site 4808
  • Timisoara, Romania, 300310
    • Site 4807
  • Timisoara, Romania, 300310
    • Site 4809
  • Constanta
    • Palazu Mare, Constanta, Romania, 900002
      • Site 4802
• Russian Federation
  • Chelyabinsk, Russian Federation, 454021
    • Site 4904
  • Novosibirsk, Russian Federation, 630102
    • Site 4902
  • Smolensk, Russian Federation, 214019
    • Site 4906
  • St. Petersburg, Russian Federation, 191163
    • Site 4903
  • St. Petersburg, Russian Federation, 197706
    • Site 4901
  • Yaroslavl, Russian Federation, 150062
    • Site 4905
• Serbia
  • Belgrade, Serbia, 11000
    • Site 5002
  • Sremska Kamenica, Serbia, 11080
    • Site 5004
  • Nišavski Okrug
    • Nis, Nišavski Okrug, Serbia, 18204
      • Site 5003
  • Šumadijski Okrug
    • Kragujevac, Šumadijski Okrug, Serbia, 34000
      • Site 5001
• South Africa
  • Krugersdorp, South Africa, 1724
    • Site 5102
  • Gauteng
    • Benoni, Gauteng, South Africa, 1500
      • Site 5103
    • Pretoria, Gauteng, South Africa, 181
      • Site 5104
  • Limpopo
    • Thabazimbi, Limpopo, South Africa, 380
      • Site 5105
  • Mpumalanga
    • Middelburg, Mpumalanga, South Africa, 1050
      • Site 5101
• Thailand
  • Nonthaburi, Thailand, 10110
    • Site 2103
• Ukraine
  • Kyiv, Ukraine, 01133
    • Site 5202
  • Kyiv, Ukraine, 03680
    • Site 5205
  • Kyïv, Ukraine, 03680
    • Site 5207
  • Sumy, Ukraine, 40022
    • Site 5208
  • Zaporizhzhia, Ukraine, 69035
    • Site 5212
  • Zhytomyr, Ukraine, 10002
    • Site 5206
  • Chernivets'ka Oblast
    • Chernivtsi, Chernivets'ka Oblast, Ukraine, 58005
      • Site 5203
  • Ivano-Frankivs'ka Oblast
    • Ivano-Frankivsk, Ivano-Frankivs'ka Oblast, Ukraine, 76018
      • Site 5204
  • Kharkivs'ka Oblast
    • Kharkiv, Kharkivs'ka Oblast, Ukraine, 61124
      • Site 5201
  • Khersons'ka Oblast
    • Kherson, Khersons'ka Oblast, Ukraine, 73000
      • Site 5209
  • Odes'ka Oblast
    • Odesa, Odes'ka Oblast, Ukraine, 65025
      • Site 5211
  • Zaporiz'ka Oblast
    • Zaporizhzhia, Zaporiz'ka Oblast, Ukraine, 69118
      • Site 5210
• United States
  • Kentucky
    • Hazard, Kentucky, United States, 41701
      • Site 1006
  • Louisiana
    • Shreveport, Louisiana, United States, 71103
      • Site 1008
  • Minnesota
    • Minneapolis, Minnesota, United States, 55415
      • Site 1005
  • Montana
    • Butte, Montana, United States, 59701
      • Site 1001
  • Ohio
    • Akron, Ohio, United States, 44309
      • Site 1009
    • Dayton, Ohio, United States, 45402
      • Site 1002
  • Texas
    • Splendora, Texas, United States, 77372
      • Site 1004

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Be male or female at least 18 years of age.
2. Provide written informed consent and be willing and able to adhere to the study-specified procedures and restrictions.

3. Have an acute illness (7 days duration) with at least 3 of the following symptoms consistent with a lower respiratory tract infection (new or worsening):

   • Dyspnea
   • New or increased cough
   • Purulent sputum production
   • Chest pain due to pneumonia

4. Have at least 2 of the following vital sign abnormalities:

   • Fever (body temperature >38.0°C (100.4°F) measured orally or equivalent temperature from an alternate body site) or hypothermia (body temperature <35.0°C (95.0°F) measured orally or equivalent temperature from an alternate body site)
   • Hypotension (systolic blood pressure <90 mmHg)
   • Tachycardia (heart rate >100 beats/min)
   • Tachypnea (respiratory rate >20 breaths/min)

5. Have at least 1 other clinical sign or laboratory finding of CABP:

   • Hypoxemia (i.e., O2 saturation <90% on room air or while receiving supplemental oxygen at subject's baseline requirement or PaO2 <60 mmHg)
   • Auscultatory and/or percussion findings consistent with pneumonia (e.g., crackles, egophony, dullness)
   • White blood cell (WBC) count >10,000 cells/mm3 or <4500 cells/mm3 or >15% immature neutrophils (bands) regardless of total WBC count
6. Have radiographically-documented pneumonia within 48 hours before enrollment (i.e., infiltrates in a lobar or multilobar distribution or diffuse opacities on chest x-ray or chest computed tomography scan consistent with acute bacterial pneumonia).
7. Have a Pneumonia Outcomes Research Team (PORT) Risk Class ≥III.

Exclusion Criteria:

1. Have received more than a single dose of a short-acting oral or IV antibacterial for CABP within 72 hours before randomization
2. Require concomitant systemic antibacterial therapy potentially effective against CABP pathogens
3. Have been hospitalized for 2 or more days within 90 days prior to the onset of symptoms or have resided in a nursing home or long-term healthcare facility within 30 days prior to the onset of symptoms. NOTE: Residence in an independent living facility is permitted.
4. Have confirmed or suspected CABP caused by a pathogen known to be resistant to any of the study drugs (e.g., Pseudomonas aeruginosa, any pathogen of the Enterobacteriaceae Family) or attributable to etiologies other than community acquired bacterial pathogens (e.g., ventilator associated pneumonia, hospital acquired bacterial pneumonia, bacterial aspiration pneumonia, Pneumocystis jiroveci pneumonia or other fungal pneumonia, viral or mycobacterial infection of the lung).
5. Have a noninfectious cause of pulmonary infiltrates (e.g., pulmonary embolism, chemical pneumonitis from aspiration, hypersensitivity pneumonia, congestive heart failure, bronchial obstruction, lung cancer, cystic fibrosis).
6. Have confirmed or suspected pleural empyema (does not include sterile parapneumonic effusions).
7. Require mechanical ventilation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lefamulin; Intravenous lefamulin with potential step-down to oral lefamulin	Drug: lefamulin; antibacterial agent; Other Names: BC-3781
Active Comparator: Moxifloxacin +/- Linezolid; Intravenous moxifloxacin with potential step-down to oral moxifloxacin +/- linezolid	Drug: Moxifloxacin; antibacterial agent; Other Names: Avelox; Drug: Linezolid; antibacterial agent; Other Names: Zyvox

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Early Clinical Response (ECR)	ECR was defined as survival with improvement in at least 2 signs and symptoms of CABP (relative to baseline), no worsening of any CABP sign or symptom, and no use of concomitant antibiotics (other than adjunctive linezolid, as allowed by the study protocol) for the treatment of CABP through the ECR assessment.	ECR was assessed 96 +/- 24 hours after the first dose of study drug.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Investigator's Assessment of Clinical Response (IACR)	IACR was defined as resolution or improvement of a subject's clinical signs and symptoms such that no additional antibacterial therapy was administered for the treatment of the current episode of CABP	IACR was assessed at the Test-of-Cure visit; 5-10 days after the last dose of study drug.
Investigator's Assessment of Clinical Response (IACR)	IACR was defined as resolution or improvement of a subject's clinical signs and symptoms such that no additional antibacterial therapy was administered for the treatment of the current episode of CABP.	IACR was assessed at the Test of Cure visit, 5 - 10 days after the last dose of study drug.

Collaborators and Investigators

• Sponsor: Nabriva Therapeutics AG
• Investigators: Study Chair: Jennifer Schranz, MD, Nabriva Therapeutics

Publications and helpful links

General Publications

• File TM Jr, Alexander E, Goldberg L, Das AF, Sandrock C, Paukner S, Moran GJ. Lefamulin efficacy and safety in a pooled phase 3 clinical trial population with community-acquired bacterial pneumonia and common clinical comorbidities. BMC Pulm Med. 2021 May 8;21(1):154. doi: 10.1186/s12890-021-01472-z.
• File TM, Goldberg L, Das A, Sweeney C, Saviski J, Gelone SP, Seltzer E, Paukner S, Wicha WW, Talbot GH, Gasink LB. 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. Clin Infect Dis. 2019 Nov 13;69(11):1856-1867. doi: 10.1093/cid/ciz090. Erratum In: Clin Infect Dis. 2020 May 23;70(11):2459.

Study record dates

Study Major Dates

• Study Start: September 1, 2015
• Primary Completion (Actual): April 1, 2017
• Study Completion (Actual): May 1, 2017

Study Registration Dates

• First Submitted: September 22, 2015
• First Submitted That Met QC Criteria: September 22, 2015
• First Posted (Estimate): September 24, 2015

Study Record Updates

• Last Update Posted (Actual): October 23, 2019
• Last Update Submitted That Met QC Criteria: October 22, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Keywords: Pneumonia; CAP; CABP; Community acquired bacterial pneumonia
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Pneumonia; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Protein Synthesis Inhibitors; Linezolid; Moxifloxacin; Lefamulin
• Other Study ID Numbers: NAB-BC-3781-3101