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

• ClinicalTrials.gov Identifier: NCT02559310
• Recruitment Status: Completed
• First Posted: September 24, 2015
• Results First Posted: October 23, 2019
• Last Update Posted: October 23, 2019
• Sponsor: Nabriva Therapeutics AG
• Information provided by (Responsible Party): Nabriva Therapeutics AG

Tracking Information

• First Submitted Date: September 22, 2015
• First Posted Date: September 24, 2015
• Results First Submitted Date: August 28, 2019
• Results First Posted Date: October 23, 2019
• Last Update Posted Date: October 23, 2019
• Study Start Date: September 2015
• Actual Primary Completion Date: April 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 22, 2019)

Early Clinical Response (ECR) [ Time Frame: ECR was assessed 96 +/- 24 hours after the first dose of study drug. ]

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.

Original Primary Outcome Measures (submitted: September 22, 2015)

Early Clinical Response [ Time Frame: 96 hours after the first dose of study drug ]

Assessment of clinical signs and symptoms of pneumonia

Current Secondary Outcome Measures (submitted: October 22, 2019)

• Investigator's Assessment of Clinical Response (IACR) [ Time Frame: IACR was assessed at the Test-of-Cure visit; 5-10 days after the last dose of study drug. ]
  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
• Investigator's Assessment of Clinical Response (IACR) [ Time Frame: IACR was assessed at the Test of Cure visit, 5 - 10 days after the last dose of study drug. ]
  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.

Original Secondary Outcome Measures (submitted: September 22, 2015)

• Early Clinical Response in the microITT population [ Time Frame: 96 hours after the first dose of study drug ]
  Assessment of clinical signs and symptoms of pneumonia
• Investigator's Assessment of Clinical Response in the m-ITT and CE populations [ Time Frame: 5 to 10 days after last dose of study drug ]
  Assessment of clinical response
• Safety and tolerability [ Time Frame: From screening to 30 days post 1st dose ]
  Evaluation of adverse events throughout the study

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study to Compare Lefamulin to Moxifloxacin (With or Without Linezolid) for the Treatment of Adults With Pneumonia
• Official Title: 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
• Brief Summary: This study evaluates the safety and efficacy of lefamulin, a pleuromutilin, for the treatment of adults with moderate to severe community-acquired bacterial pneumonia.
• 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
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Community Acquired Pneumonia

Intervention

• Drug: lefamulin
  antibacterial agent
  Other Name: BC-3781
• Drug: Moxifloxacin
  antibacterial agent
  Other Name: Avelox
• Drug: Linezolid
  antibacterial agent
  Other Name: Zyvox

Study Arms

• Experimental: Lefamulin
  Intravenous lefamulin with potential step-down to oral lefamulin
  Intervention: Drug: lefamulin
• Active Comparator: Moxifloxacin +/- Linezolid
  Intravenous moxifloxacin with potential step-down to oral moxifloxacin +/- linezolid
  Interventions:

  • Drug: Moxifloxacin
  • Drug: Linezolid

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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 30, 2017): 551
• Original Estimated Enrollment (submitted: September 22, 2015): 738
• Actual Study Completion Date: May 2017
• Actual Primary Completion Date: April 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Bosnia and Herzegovina, Brazil, Bulgaria, Georgia, Hungary, Latvia, Netherlands, Peru, Philippines, Poland, Romania, Russian Federation, Serbia, South Africa, Thailand, Ukraine, United States

Administrative Information

• NCT Number: NCT02559310
• Other Study ID Numbers: NAB-BC-3781-3101
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Nabriva Therapeutics AG
• Original Responsible Party: Same as current
• Current Study Sponsor: Nabriva Therapeutics AG
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Chair: Jennifer Schranz, MD; Nabriva Therapeutics

• PRS Account: Nabriva Therapeutics AG
• Verification Date: October 2019