Community-Acquired Bacterial Pneumonia

Primary Objectives • Demonstrate the non-inferiority (NI) of lefamulin versus comparator with respect to the Early Clinical Response (96 ± 24 hours after the first dose of study drug) in the Intent-to-Treat (ITT) Analysis Set (FDA endpoint). • 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 (EMA endpoint).

BC-3781 tablet

BC-3781.Ac

tablet

600

Primary Efficacy Analysis Variable
• Proportion of Responders for ECR at 96 ± 24 hours following the first dose of study drug
in the ITT Analysis Set (FDA)
- Subjects will be programmatically defined as a Responder if the following 4 criteria
are met:
◦ Alive
◦ Improvement in at least 2 of the 4 cardinal symptoms of CABP (see Section 6.11)
the subject presented with at Baseline. Improvement is defined as a decrease by
at least 1 level of severity.
◦ No worsening of any of the 4 cardinal symptoms of CABP. Worsening is defined
as an increase from Baseline by at least 1 level of severity of any symptom.
◦ Did not receive a concomitant antibiotic for the treatment of CABP.
- Subjects will be programmatically defined as a Non-Responder if any of the
following criteria are met:
◦ Did not show an improvement in at least 2 of the 4 cardinal symptoms of CABP
the subject presented with at Baseline. Improvement is defined as a decrease by
at least 1 level in severity; or
◦ Worsening of any of the 4 cardinal symptoms of CABP. Worsening is defined as
an increase from Baseline by at least 1 level in severity for any symptom; or
◦ Received a concomitant antibiotic for the treatment of CABP; or
◦ Died from any cause.
- Subjects will be programmatically defined as Indeterminate if the following
criterion is met:
◦ The symptom data are missing such that a response or non-response cannot be
determined.
• Proportion of subjects with an IACR of Success at TOC in the mITT and CE-TOC
Analysis Sets (IACR definitions are provided below) (Primary for EMA and secondary
for FDA)
- Success: The subject’s clinical signs and symptoms have resolved or improved such
that no additional antibacterial therapy is administered for the treatment of the current
episode of CABP.
- Failure: A subject is a treatment failure if any of the following is met:
◦ Signs and symptoms of CABP have not resolved, not improved, or have worsened
such that non-study antibacterial therapy is administered for the treatment of the
current episode of CABP.
◦ Measures of inflammation such as temperature or elevated WBC have worsened
or failed to improve such that non-study antibacterial therapy is administered for
treatment of the current episode of CABP.
◦ Bacteremia has worsened or failed to improve resulting in administration of nonstudy antibacterial therapy.
◦ The occurrence of an AE requiring discontinuation of study drug and institution
of non-study antibacterial therapy for the treatment of the current episode of
CABP.
◦ Death from any cause.
- Indeterminate: Insufficient information is available to determine Success or Failure,
specifically lost to follow-up.

Inclusion Criteria
Each subject must:
1. Be male or female ≥ 18 years of age.
2. Provide written informed consent and be willing and able to adhere to the study-specified
procedures and restrictions. NOTE: Consent may be provided by the subject’s legally
authorized representative in accordance with local regulations.
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 < 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
consistent with acute bacterial pneumonia). NOTE: if a chest computed tomography scan
has been performed within 48 hours of enrollment and demonstrates findings consistent
with pneumonia, it can be used in place of a chest x-ray.
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.
8. If female, meets the following criteria:
• Surgically sterile or ≥ 2 years postmenopausal, or if of childbearing potential
(including being < 2 years postmenopausal), has a negative pregnancy test, and if
participating in sexual activity that may lead to pregnancy, agrees to use an effective
dual method of contraception (e.g., condom plus diaphragm, condom plus spermicide,
intrauterine device plus spermicide) during the study and for ≥ 28 days after the last
dose of study drug. If a male partner has been surgically sterile for ≥ 1 year, a single
contraception method may be used. NOTE: The use of contraceptives containing
progesterone is not permitted.
• Agrees not to breastfeed during the study and through ≥ 28 days after the last dose of
study drug.
9. If male, meets the following criteria:
• If not surgically sterile and if participating in sexual activity that may lead to
pregnancy, agrees to use an effective dual method of contraception (e.g., condom plus
diaphragm, condom plus spermicide, intrauterine device plus spermicide, oral
contraceptive plus condom) during the study and through ≥ 28 days after the last dose
of study drug. If surgically sterile for ≥ 1 year, a single contraception method may be
used.

Exclusion Criteria
Each subject must NOT:
1. Have received more than a single dose of a short-acting oral or IV antibacterial for CABP
within 72 hours before randomization (See Appendix 2).
• EXCEPTION: Subjects who have received >48 hours of prior systemic antibacterial
therapy for the current episode of CABP with unequivocal clinical evidence of
treatment failure (i.e., worsening signs and symptoms) and isolation of an organism
from blood or respiratory tract that is resistant to the prior systemic antibacterial
therapy provided the organism is not resistant is to fluoroquinolones.
2. Require concomitant systemic antibacterial therapy potentially effective against CABP
pathogens (See Section 6.9).
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., MRSA, 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. Have or be at risk for major cardiac events or dysfunction including, but not limited to,
the following:
• Known prolonged QT interval or family history of long QT syndrome
• Clinically significant hypokalemia which has not been treated prior to randomization
• Clinically unstable cardiac disease, including: unstable atrial fibrillation, symptomatic
bradycardia, unstable congestive heart failure, active myocardial ischemia, or
indwelling pacemaker
• Complete left bundle branch block
• Receipt within 7 days before enrollment of Class IA or Class III anti-arrhythmic
medication or, in the opinion of the Investigator, subject may require such medication
during the study. (Class 1A: Quinidine, Procainamide, Disopyramide; Class III:
Amiodarone, Dofetilide, Ibutilide, Sotalol)
• Receipt within 7 days before enrollment of medication that has the potential of
prolonging the QT interval or, in the opinion of the Investigator, subject may require
such medication during the study (see Appendix 5).
8. Be receiving a strong p-glycoprotein inhibitor or a strong CYP3A inducer or inhibitor
(see Appendix 4).
9. Have a history of tendon disease/disorder, myasthenia gravis, or known or suspected
central nervous system (CNS) disorders (severe cerebrovascular arteriosclerosis,
epilepsy, or other risk factors that may predispose to seizures).
10. Have a history of any hypersensitivity or allergic reaction to any fluoroquinolone, or any
drug in the pleuromutilin class (i.e., retapamulin).
11. Have severely impaired renal function, defined as estimated creatinine clearance (CrCl)
≤ 30 mL/min as calculated by the Cockcroft-Gault formula.
12. Have evidence of significant hepatic, hematologic, or immunologic disease including any
of the following:
• Known acute hepatitis, including acute viral hepatitis.
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level > 5 times
the upper limit of normal (ULN),
• Total bilirubin > 3 times the ULN (unless known Gilbert’s disease).
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level > 3 times
the upper limit of normal (ULN) and total bilirubin > 2 times the ULN.
• History of cirrhosis of the liver.
• Manifestation of end-stage liver disease, such as ascites or hepatic encephalopathy.
• Current or anticipated neutropenia (< 500 neutrophils/mm3
).
• Thrombocytopenia (< 50 000 platelets/mm3
).
• Known infection with human immunodeficiency virus and a CD4 count < 200/mm3
.
13. Have known severe immunosuppression, including but not limited to receipt of
corticosteroid therapy (≥20 mg of prednisone/day or equivalent for >4 weeks) within the
previous 8 weeks; solid organ or bone marrow transplantation within the previous 12
months; or currently receiving cytotoxic chemotherapy.
14. Have a life expectancy of ≤ 3 months because of any disease other than the current
episode of CABP (e.g., current or impending respiratory failure, acute heart failure,
shock, acute coronary syndrome, unstable arrhythmia, hypertensive emergency, clinically
relevant gastrointestinal bleeding, profound metabolic abnormality, or acute
cerebrovascular event).
15. Have participated in any study involving administration of an investigational agent or
device within 30 days or ≤ 5 terminal elimination half-lives of the previous
investigational medicinal product, whichever is longer, before enrollment.
16. Have been previously treated with lefamulin or previously enrolled in this study.
17. Have any condition that, in the opinion of the Investigator, would compromise the safety
of the subject or the quality of the data.