This document describes a proposed randomized controlled trial comparing the clinical success rate of Lefamulin to Moxifloxacin for the treatment of community-acquired bacterial pneumonia (CABP) among Bangladeshi adults. The primary objective is to demonstrate the superiority of Lefamulin over Moxifloxacin in clinical success rate. Secondary objectives include evaluating early clinical response, clinical response at test-of-cure, microbiological response, safety, and mortality. The trial would enroll Bangladeshi adults aged 18+ who have symptoms and signs of CABP, including radiographic evidence of pneumonia. Participants must meet inclusion criteria related to symptoms and vital signs and be appropriate for oral antibiotic therapy. Those receiving other antibiotics or with

1. Clinical success rate of Lefamulin in
comparison with Moxifloxacin for the
management of CABP among Bangladeshi
adult population: A Multicenter, Double-
blind, Randomized Control Trial

2. Background
• Community-acquired pneumonia remains ubiquitous as a major clinical concern
worldwide. Over 2.5 million deaths globally were attributed to pneumonia in 2017, with
the majority occurring in individuals 70 years of age and older (∼1.1 million) and
children under 5 years (∼800,000).
• The mortality rate is as high as 23% for patients admitted to the ICU. All patients with
comorbid illness are considered at risk for pneumonia.
• One of the most common co-morbid factors are chronic obstructive pulmonary disease
(COPD) and in older individuals, asthma can be another significant risk factor.
• Other comorbid conditions increasing the risk of developing CAP include congestive
cardiac failure, diabetes mellitus, alcoholism, hepatic, renal insufficiency, and
malignancy.

3. • For healthy outpatient adults without comorbidities, the IDSA/ATS Guideline
recommends monotherapy with amoxicillin as first line and monotherapy with either
doxycycline or a macrolide as alternatives
• For outpatient adults with comorbidities the Guideline recommends combination
therapy with amoxicillin-clavulanate plus either a macrolide (preferred) or doxycycline
OR monotherapy with respiratory fluoroquinolone.
• Recent treatment regimen suggests the alternatives to amoxicillin-based regimens which
include combination therapy with a cephalosporin plus a macrolide or doxycycline OR
monotherapy with lefamulin.
• American Guideline mentioned two newest antibiotics, omadacycline and Lefamulin.
Lefamulin is a novel semisynthetic pleuromutilin antibiotic with oral and IV formulations
approved by FDA on 19 August 2019 for the treatment of CAP.

4. • In the absence of hepatic impairment or drug interactions, lefamulin is a potential
alternative to fluoroquinolones.
• The clinical efficacy and safety of lefamulin have been studied in 2 phase III randomized
clinical trials for CABP, Lefamulin Evaluation Against Pneumonia (LEAP) 1 and LEAP 2 .
• The LEAP 1 and LEAP 2 trials were both double-blind, double dummy, parallel-group,
randomized trials that evaluated lefamulin versus moxifloxacin in adults with moderate
to severe CABP.
• Safety was assessed in all randomized patients who received any amount of study drug.
Lefamulin was noninferior to moxifloxacin in the rates of ECR as well as the EMA test-of-
cure populations in both trials.

5. Rationale
This study will examine
whether Lefamulin is
superior to Moxifloxacin
for the treatment of CABP
in Bangladeshi adults
≥ 18 years of age.
The study will also
compare safety between
treatment groups and
evaluate susceptibility of
Lefamulin in this
population.

6. Objectives
• Primary Objectives
Demonstrate the superiority of Lefamulin versus comparator with respect to the
clinical success rate in the Intent-to-Treat (ITT) Analysis Set.
Demonstrate the NI of lefamulin versus comparator with respect to the Investigator’s
Assessment of Clinical Response at Test of Cure (TOC) (i.e., 5-10 days after the last
dose of study drug) in the modified-ITT (mITT) and Clinically Evaluable at TOC (CE-
TOC) Analysis Sets.
• Secondary Objectives
Evaluate the Early Clinical Response in the Microbiological Intent-to-Treat (microITT)
Analysis Set.
Evaluate the Investigator’s Assessment of Clinical Response at TOC in the microITT
and Microbiologically Evaluable at TOC (ME-TOC) Analysis Sets.
Evaluate the By-Pathogen Microbiologic Response at TOC in the microITT and METOC
Analysis Sets.
Evaluate the safety and tolerability of lefamulin versus comparator in the Safety
Analysis Set.
Evaluate 28 day all-cause mortality in the ITT Analysis Set.

7. Clinical success rate referred to CABP to be cured
(i.e., successfully treated) if patients were alive and
met 3 conditions:
At least 2 of 4 CABP symptoms (difficulty breathing,
cough, chest pain, production of phlegm) improved, and
No CABP symptoms worsened, and
No extra antibiotics were needed to treat the infection

8. 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 (less than or equal to 7 days duration) with at least 3 of the following
symptoms consistent with a lower respiratory tract infection (new or worsening):
1. Dyspnea.
2. New or increased cough.
3. Purulent sputum production.
4. Chest pain due to pneumonia.
4. Have at least 2 of the following vital sign abnormalities:
1. 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).
2. Hypotension (systolic blood pressure < 90 mmHg).
3. Tachycardia (heart rate > 100 beats/min).
4. Tachypnea (respiratory rate > 20 breaths/min).
5. Have at least 1 other clinical sign or laboratory finding of CABP:
1. Hypoxemia (i.e., O2 saturation < 90 % on room air or while receiving supplemental
at subject's baseline requirement or PaO2 < 60 mmHg).
2. Auscultatory and/or percussion findings consistent with pneumonia (e.g., crackles,
egophony, dullness).
3. White blood cell (WBC) count > 10 000 cells/mm3 or < 4 500 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 of II, III, or IV and be an
appropriate candidate for oral antibiotic therapy as treatment for the current episode of CABP.

9. 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 a nonbacterial cause of pneumonia (e.g.,
viral pneumonia)
4.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).
5.Have confirmed or suspected pleural empyema
(does not include sterile parapneumonic
effusions).