Conditions: Community Acquired Pneumonia
Keywords: Pneumonia CABP CAP Community acquired bacterial pneumonia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 738
Healthy volunteers: no

Brief summary:
This study evaluates the safety and efficacy of lefamulin, a pleuromutilin, for the treatment of adults with moderate community-acquired bacterial pneumonia

Detailed description:
Lefamulin is a potent, semi-synthetic antibacterial belonging to a novel class known as the pleuromutilins. The oral dosage form of lefamulin is 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.

Arms:
arm 1: oral lefamulin, 600mg arm 2: oral moxifloxacin, 400mg

Interventions: intervention 1: lefamulin intervention 2: Moxifloxacin
Intervention descriptions: intervention 1: antibacterial agent intervention 2: antibacterial agent

Protocol document:
Prot_001.pdf: 
Nabriva Therapeutics AG 
Clinical Protocol NAB-BC-3781-3102 
 
 
V3.0:  17-Mar-2016 
Page 1 of 102 
Confidential Information 
 
 
 
 
 
 
 
 
 
Clinical Protocol No. NAB-BC-3781-3102 
 
 
A Phase 3, Randomized, Double-Blind, Double-Dummy Study to Compare 
the Efficacy and Safety of Oral Lefamulin (BC-3781) Versus Oral 
Moxifloxacin in Adults With Community-Acquired Bacterial Pneumonia 
 
 
US IND 125546 (Oral) 
 
EudraCT Number 2015-004782-92 
 
 
 
 
 
 
 
Protocol Status 
Version 
Date 
Original 
1.0 
21-Dec-2015 
Amendment 1 
2.0 
17-Feb-2016 
Amendment 2 
3.0 
17-Mar-2016 
 
 
 
 
 
 
 
 
 
The information contained herein is the property of Nabriva Therapeutics AG and may not be 
produced, published, or disclosed to others without written authorization of Nabriva 
Therapeutics AG. 
 


Nabriva Therapeutics AG 
Clinical Protocol NAB-BC-3781-3102 
 
 
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SPONSOR RELATED CONTACT DETAILS 
A Phase 3, Randomized, Double-Blind, Double-Dummy Study to Compare the Efficacy 
and Safety of Oral Lefamulin (BC-3781) Versus Oral Moxifloxacin in Adults With 
Community-Acquired Bacterial Pneumonia 
(Protocol NAB-BC-3781-3102 with Amendments 1 and 2) 
Sponsor: 
Nabriva Therapeutics AG 
Leberstraße 20 
1110 Vienna 
Austria 
Sponsor’s Study Managers: 
Patricia Spera, PhD 
Nabriva Therapeutics US, Inc. 
1000 Continental Drive, Suite 600 
King of Prussia, PA  19406 
USA 
Tel:  +1 610 816 6656 
Cell: +1 610 209 5574 
Email: patricia.spera@nabriva.com 
 
Claudia Lell, PhD 
Nabriva Therapeutics AG 
Leberstraße 20 
1110 Vienna 
Austria 
Tel:  +43 1 74093 1242 
Cell:  +43 664 9631469 
Email:  claudia.lell@nabriva.com 
Sponsor’s Medical Officer: 
 
Leanne Gasink, MD 
Senior Director, Clinical Development and Medical Affairs 
Nabriva Therapeutics AG  
Nabriva Therapeutics US, Inc. 
1000 Continental Drive, Suite 600 
King of Prussia, PA  19406 
USA 
Tel:  +1 610 816 6658 
Cell:  +1 215 880 6689 
Email: leanne.gasink@nabriva.com 
Covance’s Medical Officer: 
Norberto E. Soto, MD 
Senior Medical Director 
Clinical Development Services  
Covance, Inc. 
206 Carnegie Center 
Princeton, NJ  08540 
USA 
Tel:  +1 609 419 2529 
Cell:  +1 609 216 2430 
RightFax: +1 609 419 2803 
Email:  Norberto.Soto@Covance.com 
 




Nabriva Therapeutics AG 
Clinical Protocol NAB-BC-3781-3102 
 
 
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INVESTIGATOR SIGNATURE PAGE 
A Phase 3, Randomized, Double-Blind, Double-Dummy Study to Compare the Efficacy 
and Safety of Oral Lefamulin (BC-3781) Versus Oral Moxifloxacin in Adults With 
Community-Acquired Bacterial Pneumonia 
(Protocol NAB-BC-3781-3102 with Amendments 1 and 2) 
In conducting this clinical study, I agree to be responsible for: 
• Ensuring that the clinical investigation is conducted according to the World Medical 
Association Declaration of Helsinki in its revised edition (Fortaleza, Brazil, October 
2013), the guidelines of International Conference on Harmonization (ICH) Good Clinical 
Practice (GCP) (CPMP/ICH/135/95), the signed Form Food and Drug Administration 
(FDA) 1572 Statement of Investigator (applies to all studies conducted under a United 
States Investigational New Drug Application) and other applicable local and national 
laws and requirements. 
• Protecting the rights, safety, and welfare of subjects under my care. 
• Maintaining control of the drugs under investigation. 
I also agree to conduct the study as detailed in the protocol and in accordance with Nabriva 
Therapeutics AG guidelines and all applicable government regulations.  These guidelines and 
regulations include, but are not limited to: 
• Permission to allow Nabriva Therapeutics AG and regulatory agencies to inspect study 
facilities and pertinent records at reasonable times and in a reasonable manner, which 
ensures subject confidentiality.  If I am notified that this study is to be inspected by a 
regulatory agency, I will notify Nabriva Therapeutics AG as soon as possible thereafter 
(no later than 1 week). 
• Submission of the proposed clinical investigation, including the protocol, the informed 
consent documents, and any other subject materials required for study conduct, to a duly 
constituted Independent Ethics Committee (IEC)/Institutional Review Board (IRB) for 
approval, and acquisition of written approval for each, prior to the use of the study drug. 
• Obtaining written informed consent only after ensuring that the subject, or his/her legal 
representative, is competent to make the decision, understands what is contained in the 
informed consent document, and is consenting voluntarily.  Written informed consent 
will be obtained prior to administration of study drug or any non-routine study-related 
procedures; the document contains all the essential elements of consent and has been 
previously approved by the sponsor and IEC/IRB.  Reference of written informed consent 
will be provided in source documentation. 
• Submission of any protocol amendment to the IEC/IRB.  If the protocol amendment 
change(s) increase risk to the study population, full IEC/IRB written approval must be 
obtained prior to implementation.  For changes that do not involve increased risk or affect 
the validity of the investigation or the subject's rights, prior IEC/IRB approval may be 
obtained by expedited review. 


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• Adherence to the study protocol.  Documentation and explanation of individual post-
enrollment protocol deviations will be recorded in the source documentation at the site 
and be provided to Nabriva Therapeutics AG. 
• Notification to Nabriva Therapeutics AG of all serious adverse events, regardless of 
relationship to study drug, as specified in the protocol.  Notification to the IEC/IRB of 
serious adverse events as specified in the protocol and per additional guidelines as 
provided by the IEC/IRB. 
• Notification to IEC/IRB of all unanticipated problems within the timeframe provided by 
the IEC/IRB.  For the purposes of this study, unanticipated problems are defined as any 
incident, experience, or subject outcome that meets all of the following criteria: (1) 
unexpected; (2) related or possibly related to participation in the study; (3) and suggests 
that the research places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known. 
• Provision of adequate study oversight by personally conducting or supervising the 
investigation, including, but not limited to: allotting sufficient time to properly conduct 
and complete the study within the agreed upon time period; having available an adequate 
number of qualified staff and adequate facilities for the expected duration of the study 
and to conduct the study properly and safely; and ensuring that all persons assisting with 
the study are adequately informed about the protocol and the investigational product(s) 
and are capable of performing their study-related duties and functions.  Qualifications of 
individuals assigned responsibility for the administration of the investigational product 
will be compliant with state and local law or national regulations, as applicable. 
• Submission of timely progress reports to the IEC/IRB and Nabriva Therapeutics AG at 
appropriate intervals not to exceed 1 year and submission of a final report to the IEC/IRB 
within the timeframe set by the IEC/IRB, but not later than 3 months after the completion 
or termination of the clinical investigation.  
• Maintenance of accurate source records from which case report forms are completed as 
well as drug accountability records that show the receipt and disposition (on an overall 
and per subject basis) of all study drug(s) shipped to the investigator by Nabriva 
Therapeutics AG. 
In addition, I agree to provide all the information requested in the eCRF presented to me by 
Nabriva Therapeutics AG by carefully following the completion guidelines provided as part 
of the eCRF. 
If I opt to terminate my participation in the study, the foregoing shall equally apply. 
 
 
 
 
Investigator’s Name (Please Print) 
 
 
 
 
 
Investigator’s Signature 
 
Date 
 


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AMENDMENT 2:  17-MAR-2016 
Amendment 2 addresses an inconsistency within the protocol.  In accordance with Appendix 
4 to the protocol, the use of strong P-glycoprotein inhibitors during study participation is 
prohibited.  Thus, progesterone-containing products (such as oral contraceptives) are 
prohibited.  In addition to revising the inclusion criterion associated with use of oral 
contraceptives, wording was added to the prohibited medications section for emphasis.  
These changes were made to the study synopsis, as applicable.  Added text is bolded; deleted 
text is struck through.   
Section 4.1 − Inclusion Criteria 
#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, 
oral contraceptive plus condom) 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. 
Section 6.9 – Prohibited Medications 
Bullet #6 
• 
Strong p-glycoprotein inhibitors (see Appendix 4) [NOTE:  The use of contraceptives 
containing progesterone is not permitted.] 
 
AMENDMENT 1:  17-FEB-2016 
Amendment 1 addresses revisions to the protocol requested by the US Food and Drug 
Administration (FDA) at the Type C Meeting held on 27-Jan-2016 with respect to the non-
inferiority (NI) margin.  The change in NI margin resulted in the change of other statistical 
parameters including the randomization ratio and sample size.   
In addition, FDA requested (1) an increase in the number of subjects with a PORT Risk Class 
of III or IV; (2) methicillin-resistant Staphylococcus aureus (MRSA) be added to the list of 
pathogens that would exclude study eligibility; and (3) an increase in the number of 
pharmacokinetic sampling time points (i.e., the 8-9 h PK time point, which was previously 
optional for all subjects, is now required for inpatients and optional for outpatients).  An 
increase in the number of subjects with PORT Risk Class III or IV resulted in a change of the 
outcome rates used for determination of the sample size.  
These revisions were made to the protocol sections noted below as well as to the study 
synopsis and the Schedule of Assessments and Procedures (Table 1).  Added text is bolded; 
deleted text is struck through. 


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Section 3 – STUDY DESIGN 
Paragraph 1, Sentences 2 & 3:  The planned enrollment is 573 738 subjects (382 369 subjects 
in the lefamulin group and 191 369 subjects in the moxifloxacin group) with PORT Risk 
Class II, III, or IV.  Eligible subjects will be randomized 2 1:1 to lefamulin or moxifloxacin, 
using an interactive response technology (IRT).   
Section 4.2 – Exclusion Criteria 
Exclusion criterion #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). 
Section 5.3 – Randomization 
Paragraph 1, Sentence 1:  Qualified subjects will be randomized to receive lefamulin or 
moxifloxacin in a 2 1:1 allocation ratio.   
Paragraph 2, Sentence 3:  A minimum of 25 50% of the total number of subjects randomized 
will have a PORT Risk Class of III or IV. 
Section 6.14 – Sample Collection for Pharmacokinetic Analysis 
Footnote “c” has been added to Table 5 (Sample Collection Time Points for the 
Determination of Lefamulin Plasma Concentrations following Oral Administration) in 
reference to the 8-9 h PK collection time point after the first dose of study drug, as follows: 
c: The 8-9h sample is required for inpatients.  The 8-9 h sample is optional for outpatients; 
however, should be obtained if logistically feasible. 
Section 9.2 – Sample Size Determination 
A total of 573 738 subjects will be randomized in a ratio of 21:1 (lefamulin:moxifloxacin) 
resulting in 382 369 subjects in the lefamulin arm and 191 369 in the moxifloxacin arm in 
this study.  The total number of subjects included in this study is sufficient to achieve the 
primary and secondary study objectives based on statistical considerations. 
Retrospective analyses of clinical study data for patients with CABP of varying severity as 
well as 2 recent clinical trials in CABP indicate the point estimates for an ECR responder at 
Days 3-5 range from 72% to 81% (FDA, 2011; Cempra, 2015a Barrera et al., 2016; 
Cempra, 2015b; Oldach et al., 2015).  Thus, it is reasonable to assume that in a prospective 
study of subjects with CABP, the proportion of subjects who are responders for ECR at 
96 ± 24 hours post first dose of study drug will be approximately 77 79%.   
The primary efficacy analysis variables used for NI analyses for the Marketing Authorization 
Application (MAA) to the EMA will be the proportion of subjects with an IACR of Success 
at TOC in the mITT and CE-TOC Analysis Sets.  In recent clinical studies, IACR success 
rates at the TOC Visit in the CE Analysis Set ranged from 77% to 93% (Cempra, 2015b) and 
in the ITT Analysis Set ranged from 85% to 89% depending on the antibiotics under study 
and the severity of the CABP.  Based on these data, an 87 85% IACR success rate in the CE-
TOC Analysis Set was chosen for determination of the sample size.  The success rate is 


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expected to be about 5% lower in the mITT Analysis set.  It is expected that <1% of subjects 
will be excluded from the mITT Analysis Set and thus, the sample size determination 
assumes the same number of subjects in the ITT and mITT Analysis Sets. 
Utilizing an anticipated ECR responder rate of 77 79% in the ITT Analysis Set, a 2 1:1 
randomization ratio, a two-sided alpha of 0.025, and a continuity corrected Z-test with 
unpooled variance, a sample size of 573 738 subjects (382 369 subjects in the lefamulin 
group and 191 369 in the moxifloxacin group) provides 90% power to establish the NI of 
lefamulin to moxifloxacin for ECR using a NI margin of 12.5 10.0% at the ECA.  Assuming 
an IACR success of 82 80% and 87 85% in the mITT and CE-TOC Analysis Sets, 
respectively, and a clinical evaluability rate of 80%, there is 80 91% power for demonstration 
of NI for IACR at the TOC Visit using a 10% NI margin. 
The calculated power in each analysis set for the primary and secondary outcomes is 
provided in Table 6 below. 
Table 6. 
Power Calculations for the Primary and Secondary Efficacy 
Outcomes 
 
Primary Outcome (FDA) 
(ECR 96 ± 24 hours After the First 
Dose of Study Drug) 
Secondary Outcome  
(Investigator’s Assessment of Clinical Response 
at TOC- Primary for EMA) 
Analysis Set 
ITT 
mITT 
CE-TOC 
NI Margin 
12.5 10% 
10% 
10% 
N 
573 738 (382:191 369:369) 
573 738 
459 590 
Outcome Rate 
77 79% 
82 80% 
87 85% 
Evaluability Rate 
NA 
NA 
80% 
Power 
90% 
80 91 % 
81 91% 
CE = clinically evaluable; ITT = intent to treat; mITT = modified ITT; TOC = test of cure 
Section 9.4.4 – Pharmacokinetic Analysis Variables 
Paragraph 1, Sentence 3:  Individual AUC values from Day 1 and Day 4 [i.e., 96  ±  24 hours 
post first dose] (collected pre-dose, 1-2 h post dose and 3-4 h post dose, and an optional time 
point at 8-9 h post dose [8-9 h post dose is required for inpatients; optional for 
outpatients]) will be used for the PK/PD analysis.   
Section 9.6.1 – Primary Efficacy Analysis 
Paragraph 3, Sentence 4:  If the lower limit of the 95 % CI for the difference in responder 
rates in the ITT Analysis Set is greater than -12.5% -10.0 %, the null hypothesis will be 
rejected and the NI of lefamulin to moxifloxacin will be concluded.   
In addition, the Sponsor has made the following revisions to the original protocol to provide 
clarity and to align this protocol with the Phase 3 IV/Oral Protocol (NAB-BC-3781-3101) for 
the treatment of CABP.  These changes will assist in statistical analysis at the time of 
submission for marketing approval.  These revisions were made to the protocol sections 
noted below as well as to the study synopsis and the Schedule of Assessments and 
Procedures (Table 1). Added text is bolded; deleted text is struck through.  None of these 
changes are expected to affect subject safety or the interpretation of study results. 


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Section 6.5 – Vital Signs and Oxygen Saturation 
[Rationale: Collection of supplemental oxygen therapy data has been added to the protocol 
and eCRF.]  
New paragraph (Paragraph 2) was added: 
In addition, if the subject is receiving supplemental oxygen therapy, the amount given 
will be recorded in the eCRF. 
Section 6.7 – Arterial Blood Gases 
[Rationale:  FiO2 is not being collected on the eCRF as part of the results of arterial blood 
gases.] 
Study sites are not required to measure arterial blood gases (PaO2, PaCO2) (and FiO2) or pH.  
However, if these data are available, they should be recorded in the eCRF.   
Section 6.15.8 – Nasopharyngeal Specimen 
[Rationale:  All S. pneumoniae will be tested.  H. influenzae testing will depend on validation 
of procedures using samples collected early in the trial.  It is possible that only some subjects 
will have testing for H. influenzae performed.] 
Paragraph 1, Sentences 1 and 2:  A nasopharyngeal specimen (1 swab) will be obtained at 
Screening and sent to the central laboratory/specialty laboratory for S. pneumoniae and H. 
influenzae culture, susceptibility testing, as well as identification by PCR.  Culture, 
susceptibility testing, as well as identification by PCR, may also be performed for 
H. influenzae.   
Section 7.5 – Other Reportable Events 
[Rationale:  All subjects who meet the criteria for potential Hy’s Law, regardless of whether 
it is an SAE, will complete the Hy’s Law eCRF.] 
• Potential Hy’s Law (PHL) [Sentences 1 and 2] 
The investigator is responsible for prompt reporting of any patients who has had both (1) 
AST or ALT > 3 x ULN and (2) total bilirubin > 2 x ULN at any point in the study (i.e., 
meets criteria for Potential Hy’s Law), unless the event is already reported as an SAE.  The 
investigator must complete the Hy’s Law eCRF.   
Section 9.4.4 – Pharmacokinetic Analysis Variables 
[Rationale:  PK analysis will include lefamulin’s main metabolite, BC-8041; also edits made 
to popPK anlaysis.] 
Paragraph 1, Sentence 2:  Calculated PK will enable descriptive statistical analysis of PK 
variables such as the maximum observed drug concentration (Cmax) and area under the 
concentration-time curve (AUC) for lefamulin and its main metabolite, BC-8041.   
Paragraph 1, Sentence 4: The population PK analysis based on population PK as well as a 
PK/PD analysis will be reported separately. 


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Section 9.4.5 – Other Variables 
[Rationale: A description of the disk inhibition zone diameter which would qualify as 
development of decreasing susceptibility is provided.]  
• Development of Decreasing Susceptibility: Increase in MIC (≥ 4x) or 6 mm decrease 
from baseline in disk inhibition zone diameter to the study drug received for a 
pathogen isolated at baseline and subsequently isolated from a blood or lower respiratory 
tract specimen. 
Section 9.7 – Safety Analyses 
[Rationale:  Across the lefamulin clinical development program, corrected QT interval will 
be summarized using the Frederica formula only.]  
Paragraph 5, Sentence 1:  Change from baseline to each scheduled evaluation and the overall 
worst post-baseline for RR interval, PR interval, QRS interval, QT interval, QT interval 
corrected with Bazzett, and QT interval corrected with Fridericia from the ECG will be 
summarized for each treatment group with the mean, standard deviation, minimum value, 
and maximum value. 
Section 19 - List of References 
Zeitlinger et al, 2014 (poster presentation) has been published in J Antimicrob Chemother.  
Reference and citations throughout the protocol have been updated to Zeitlinger et al, 2016. 
Cempra, 2015a (press release) has been published in Lancet.  Reference and citations 
throughout protocol have been updated to Barrera et al., 2016.  [Cempra, 2015b is now 
referenced and cited as Cempra, 2015.] 
In addition, the Sponsor has made correction of typographical errors (e.g., definition of ELF), 
updated information (e.g., increase in number of clinical isolates tested [Section 1.3, 
Paragraph 3, Sentence 1:  >13,400 vs. 13,600]), and consistency in formatting. 


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SYNOPSIS 
Study Title:  A Phase 3, Randomized, Double-Blind, Double-Dummy Study to Compare the 
Efficacy and Safety of Oral Lefamulin (BC-3781) Versus Oral Moxifloxacin in Adults With 
Community-Acquired Bacterial Pneumonia (Protocol NAB-BC-3781-3102 with 
Amendments 1 and 2). 
Study Objectives: 
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). 
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 ME-
TOC 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. 
Additional Objectives 
• Evaluate the Early Clinical Response by baseline pathogen in the microITT Analysis Set. 
• Evaluate the Investigator’s Assessment of Clinical Response at the End of Treatment 
(EOT) (i.e., within 2 days after the last dose of study drug) and at LFU in the mITT and 
CE Analysis Sets (CE-EOT for IACR at EOT and CE-LFU for IACR at LFU). 
• Evaluate the Investigator’s Assessment of Clinical Response by baseline pathogen at 
TOC and LFU in the microITT and ME- Analysis Sets (ME-TOC for IACR at TOC and 
ME-LFU for IACR at LFU). 
• Evaluate the By-Subject Microbiologic Response at TOC in the microITT and ME-TOC 
Analysis Sets. 
• Evaluate the Early Clinical Response PLUS improvement in vital signs in the ITT 
Analysis Set. 


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• Evaluate the plasma pharmacokinetics (PK) of lefamulin and its main metabolite, 
BC-8041, in the PK Analysis Set. 
• Explore a variety of health utilization variables and an investigational patient reported 
outcome (PRO) measure in subjects receiving lefamulin compared with subjects 
receiving comparator. 
Study Population: 
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 


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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 


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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). 


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• 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. 
Duration of Study:  Each subject will participate for approximately 4-5 weeks. 
Drug Products:  Drug products will be supplied as follows: 
Drug Product 
Route 
Dosage Form/Strength 
Lefamulin 
PO 
600 mg of lefamulin as a yellow oval film coated immediate-release tablet 
Moxifloxacin 
PO 
400 mg of moxifloxacin as an over-encapsulated film-coated tablet 
 
Study Drug Assignment:  Subjects will be randomized in a 1:1 ratio to either lefamulin or 
moxifloxacin. 
Study Drug Administration:  The duration of blinded study drug administration will be 
7 days.  Subjects randomized to lefamulin will receive oral lefamulin 600 mg q12h for 5 days 
(10 doses) and oral moxifloxacin placebo q24h for 7 days (7 doses).  Subjects randomized to 
moxifloxacin will receive oral moxifloxacin 400 mg q24h for 7 days (7 doses) and oral 
lefamulin placebo q12h for 5 days (10 doses).   
On Day 1, study personnel will administer the first dose of study drug at the study site to all 
subjects as soon as possible after the diagnosis of CABP and completion of all required 


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Day 1 procedures as outlined in Table 1.  While subjects are hospitalized, all doses of study 
drug will be administered by hospital staff or study personnel.   
For Outpatients, or in the event a subject is discharged from the hospital during the study 
drug administration period, an adequate supply of study drug will be dispensed for self-
administration at home.  Subjects will be provided instructions regarding the dosing 
schedule.  Subjects may self-administer oral study drug at home with the following 
exception:  Study personnel will advise subjects who are Outpatients that they must return to 
the study site to assess CABP signs and symptoms at 96 ± 24 hours after the first dose of 
study drug.  Study personnel will inform Outpatients as to the timing of this required study 
site visit.  Subjects will be advised not to take their first dose of study drug at home that day, 
rather to bring their blister packs (used and unused) to the study site, where they will take 
their dose while supervised so that specific assessments can be performed both prior to and 
after taking the dose (i.e., ECGs and PK). 
On Study Day 1, if q12h dosing is not feasible, the 1st and 2nd doses may be administered as 
close as 8 hours apart, in order to allow 2 doses to be given on Day 1.  In this circumstance, 
the subject’s dosing schedule should be adjusted on Day 2 to a regular q12h morning and 
evening schedule.  Subsequently, every effort should be made to maintain a q12h dosing 
schedule.  When this is not possible, it is acceptable to administer doses within 4 hours of the 
scheduled dosing time (i.e., a minimum of 8 hours between doses). 
Study drug should be administered at least 1 hour before a meal or 2 hours after a meal.  
However, in the event that a subject has taken any of the following − antacids containing 
aluminum, products containing iron, or multivitamins containing zinc − study drug should be 
administered 2 hours before or 4 hours after consuming any of these medications.  Doses 
should be administered with approximately 240 mL (8 ounces) of water.  
Blinding:  Study drug will be blinded using a double-dummy technique.   
A member(s) of the Sponsor’s Clinical Pharmacology group (or designee) will be unblinded 
to treatment assignment, as appropriate, in order to perform PK/PD assessments.  A Data 
Monitoring Committee (DMC) will review study data by treatment group in accordance with 
the DMC Charter.  In addition, as needed to meet regulatory reporting requirements on a 
country-by-country basis, designated pharmacovigilance personnel may be unblinded to 
treatment status of individual subjects.  In this circumstance, and if there are no other 
concerns, neither the Sponsor nor the study personnel will be unblinded to treatment status. 
Study Design:  This multicenter, multinational, randomized, double-blind, double-dummy, 
active-controlled efficacy and safety study in subjects with CABP will be conducted at 
approximately 160 centers.  The planned enrollment is 738 subjects (369 subjects in the 
lefamulin group and 369 subjects in the moxifloxacin group) with PORT Risk Class II, III, or 
IV.  Eligible subjects will be randomized 1:1 to lefamulin or moxifloxacin, using an 
interactive response technology (IRT).  Subject randomization will be stratified according to 
PORT Risk Class (Risk Class II vs. III/IV), geographic region (US vs. ex-US), and prior 
(single dose) short-acting antibiotic therapy for CABP vs. none.   


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Subjects will be consented for the study prior to study assessments being performed and 
confirmation of eligibility.  Screening assessments will be performed within 24 hours before 
first dose of study drug.   
Subjects will be assessed for response at the following time points during the study: 
• Early Clinical Assessment (ECA):  96 ± 24 hours after the first dose of study drug. 
• End of Treatment (EOT):  within 2 days after the last dose of study drug (NOTE: every 
attempt should be made to conduct the EOT visit within 1 day after the last dose of study 
drug.  However, if this is not logistically feasible [e.g., visit would need to be conducted 
over a weekend], then conducting the visit within 2 days is acceptable.). 
• Test of Cure (TOC):  5-10 days after the last dose of study drug. 
• Late Follow Up (LFU):  Day 30 (± 3 days). 
 
An overview of the study design is provided in Figure 1 below. 
Figure 1. 
Study Design Overview 
 
 
Assessment of the 4 cardinal symptoms of CABP (dyspnea, cough, purulent sputum 
production, and chest pain) will be conducted daily; an assessment at 96 ± 24 hours after the 
first dose of study drug will determine Early Clinical Response (ECR) (as defined in the 
Primary Objective - FDA).  NOTE:  ECR will be determined programmatically based upon 
the Investigator’s assessment of the 4 cardinal symptoms of CABP; the decision to maintain 
the subject on study drug therapy will be made by the Investigator, based on all available 
data and his or her best clinical judgment. In addition, the Investigator’s Assessment of 
Clinical Response (IACR) will be performed at the EOT, TOC and LFU visits (Success, 
Failure and Indeterminate at EOT and TOC; Sustained Success, Relapse and Indeterminate at 
LFU).   


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Microbiological assessments will be performed at Screening, and then subsequently 
throughout the study as clinically indicated.  Samples will be taken for Gram’s staining, for 
diagnostic tests (serology, urine antigen tests, molecular tests), and for culture and 
antimicrobial susceptibility testing.  Subjects who have confirmed S. aureus bacteremia must 
be withdrawn from the study. 
Safety will be assessed by monitoring vital signs, ECG measurements, safety laboratory 
parameters, and recording of adverse events (AEs).  A Data Monitoring Committee (DMC) 
will review the safety data throughout the study.  
Blood samples for PK analyses will be collected from all subjects.  
Exploratory evaluation of a variety of health utilization variables (e.g., length of hospital 
stay, duration of antibiotic therapy, discharge status, discharge destination) as well as a PRO 
instrument (SF-12) will be administered.  The schedule of study procedures is provided 
immediately following the synopsis (Table 1:  Schedule of Assessments and Procedures). 
Statistical Considerations: 
Sample Size:  Utilizing an anticipated ECR responder rate of 79% in the ITT Analysis Set, 
1:1 randomization ratio (lefamulin:moxifloxacin) and a two-sided alpha of 0.025, a sample 
size of 738 subjects (369 subjects in the lefamulin group and 369 in the moxifloxacin group) 
provides 90% power to establish the non-inferiority (NI) of lefamulin to moxifloxacin for 
ECR using a NI margin of 10.0 % at the ECA.  Assuming an IACR success rate of 80% and 
85% in the mITT and CE-TOC Analysis Sets, respectively, and a clinical evaluability rate of 
80%, there is 91% power for demonstration of NI for IACR at the TOC Visit using a 10% NI 
margin. 
Treatment Comparison of Interest:  All comparisons will be for lefamulin vs. comparator 
therapy (moxifloxacin). 
Analysis Populations: 
• Intent-to-treat (ITT) Analysis Set:  All randomized subjects regardless of whether or not 
the subject received study drug. A subject is considered randomized when an IRT-
generated randomization number has been assigned. 
• Modified ITT (mITT) Analysis Set: All randomized subjects who receive any amount of 
study drug. Subjects are analyzed based on the randomized (i.e., assigned) treatment 
group. 
• Microbiological ITT (microITT) Analysis Set:  All subjects in the ITT Analysis Set who 
have at least 1 baseline “typical” bacterial pathogen known to cause CABP, Legionella 
pneumophila from an appropriate microbiological specimen, or who have CABP caused 
by Mycoplasma pneumoniae or Chlamydophila pneumoniae.  
• Clinically Evaluable (CE) Analysis Sets (CE-EOT, CE-TOC, and CE-LFU):  A subset of 
the ITT Analysis Set that will include subjects who meet the criteria for CABP described 
in Inclusion criteria Nos. 3 - 7, and who received at least the pre-specified minimal 
amount of the intended dose of study drug and duration of treatment, do not have an 


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indeterminate response based on the IACR (at EOT for the CE-EOT Analysis Set,  at 
TOC for the CE-TOC Analysis Set. and at LFU for the CE-LFU Analysis Set), did not 
receive concomitant antibacterial therapy that is potentially effective against CABP 
pathogens (except in the case of clinical failure) from the first dose of study drug through 
the EOT Visit (CE-EOT Analysis Set),  through the TOC Visit (CE-TOC Analysis Set) 
and through the LFU Visit (CE-LFU Analysis Set), and for whom there are no other 
confounding factors that interfere with the assessment of the outcome.  
• Microbiologically Evaluable (ME) Analysis Sets (ME-EOT, ME-TOC, and ME-LFU):  
Subjects who meet the criteria for both the microITT and the CE-EOT (ME-EOT) 
Analysis Sets, the CE-TOC (ME-TOC) Analysis Set or CE-LFU (ME-LFU) Analysis 
Set.  
• Safety Analysis Set:  All randomized subjects who receive any amount of study drug. 
Subjects are analyzed based on the study drug actually received. All safety analyses will 
be conducted in this population. 
• Pharmacokinetic Analysis Set:  All subjects who receive any amount of study drug will 
be included in the formal analysis of PK parameters providing they have at least 1 
evaluable PK sample. 
Variables for Analysis 
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. 


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- 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 non-
study 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. 
Secondary Efficacy Analysis Variables 
Efficacy will be assessed by ECR, IACR and by Microbiological Response.  
Microbiological Assessment 
The By-Pathogen Microbiological Response will be assessed using the categories for 
outcome in the microITT and ME analysis sets as follows: 
• Success includes: 
− Eradication:  the baseline causative pathogen was absent from repeat culture(s). 
− Presumed Eradication:  the IACR was Success, and culture was not repeated.  
• Failure includes: 
− Persistence:  the baseline causative pathogen was isolated in repeat culture(s).  
− Presumed Persistence:  the IACR was Failure and a culture was not repeated. 


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• Indeterminate:  
− The IACR was Indeterminate and a culture was not repeated. 
Safety Analysis Variables 
Safety will be assessed by monitoring vital signs, ECG measurements, clinical laboratory 
parameters, and AEs. 
Pharmacokinetic Analysis Variables 
Population PK modeling will be performed to determine the model-predicted plasma 
concentration time curves of lefamulin for each subject.  Calculated PK parameters will 
enable descriptive statistical analysis of PK variables such as the maximum observed drug 
concentration (Cmax) and area under the concentration-time curve (AUC) for lefamulin.   
Individual AUC values from Day 1 [all subjects] and Day 4 [Inpatients] or 96  ±  24 hours 
post first dose [Outpatients] (collected pre-dose, 1-2 h post dose and 3-4 h post dose, and a 8-
9 h post dose (the 8-9 h sample is required for inpatients and optional for outpatients) will be 
used for the PK/PD analysis.  The PK analysis based on population PK as well as a PK/PD 
analysis will be reported separately. 
Other Variables 
Exploratory evaluation of a variety of health utilization variables (e.g., length of hospital 
stay, duration of antibiotic therapy, discharge status, discharge destination) as well as a PRO 
instrument will be performed. 
Statistical Methods: 
A 2-sided unstratified 95 % confidence interval (CI) for the observed difference between 
treatment groups (lefamulin minus moxifloxacin) in ECR responder rates at 96 ± 24 hours 
post first dose will be calculated using a continuity corrected Z-statistic.  Non-inferiority for 
the primary efficacy analysis variable (FDA) will be concluded if the lower limit of the 
2-sided 95% CI is greater than –10.0% in the ITT Analysis Set. 
For the efficacy outcome measure of IACR of Success at TOC in the mITT and CE-TOC 
Analysis Sets, unstratified 95% CIs will be calculated using a continuity corrected Z-statistic 
(FDA secondary efficacy outcome).  For the primary analysis for the EMA, a stratified (for 
the randomization stratification factors) 2-sided 95% CIs will be calculated using the method 
of Miettinen and Nurminen.  Non-inferiority for the primary efficacy analysis variable 
(EMA) will be concluded if the lower limit of the 2-sided stratified 95% CI is greater than -
10% for both the mITT and CE-TOC Analysis Sets. 
The number and percentage of subjects with an ECR of Responder at 96 ± 24 hours will also 
be presented for the microITT Analysis Set, and a 2-sided unstratified 95% CI for the 
difference in responder rate will be calculated using a continuity-corrected Z-statistic.  
However, the formal test of NI will be conducted in the weighted (based on the inverse 
variance of each effect size) pooled population from this study and a second study in CABP. 


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The incidence of treatment-emergent AEs (TEAEs), serious AEs (SAEs), deaths, and 
discontinuations of study drug due to an AE or SAE will be summarized by System Organ 
Class (SOC) and Preferred Term according to the Medical Dictionary for Regulatory 
Activities (MedDRA), by relationship to study drug, and by severity.  The incidence of 
potentially clinically significant laboratory results, vital signs, and ECGs will be summarized. 


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Table 1. 
Schedule of Assessments and Procedures 
Assessment or Procedure 
Screening/ 
Baseline a 
Study Drug Administration 
    EOT d 
Visit 
Follow-up Visits 
Day 1b 
Day 2 
Day 3 
Days 4 to 7 c 
TOC e 
LFU f 
Informed consent form completed g 
X 
 
 
 
 
 
 
 
Verify inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
Medical and surgical history 
X 
 
 
 
 
 
 
 
Determine PORT Risk Class 
X 
 
 
 
 
 
 
 
Height and weight 
X 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
Prior and concomitant medications 
X 
X 
X 
X 
Daily 
X 
X 
X 
Vital signs including oxygen saturation and supplemental oxygen i 
X 
X 
X 
X 
Daily 
X 
X 
 
CABP signs and symptoms j 
X 
X 
X 
X 
Daily j 
X 
X 
X 
AEs and SAEs k 
X 
X 
X 
X 
Daily 
X 
X 
X 
12-lead ECG l 
X 
X 
 
 
Day 4 m 
 
 
 
Physical examination n 
X 
 
 
 
Day 4 o 
X 
X 
 
Hematology, clinical chemistry, urinalysis, procalcitonin (Central Lab) p 
X h 
 
 
Day 4 q 
X 
X 
 
Urine and serum pregnancy tests r 
X 
X 
 
 
 
 
 
 
CXR or CT scan 
X 
 
 
 
 
 
 
 
Arterial blood gases (PaO2, PaCO2) and pH [optional; record data if available] 
if clinically indicated 
Calculate CrCl (Cockcroft-Gault formula) 
X 
if clinically indicated 
Urine sample for L. pneumophila and S. pneumoniae antigen tests 
X h 
 
 
 
 
 
 
Blood sample for serologic tests for M. pneumoniae, C. pneumoniae, and L. pneumophila s 
X h 
 
 
 
 
 
X 
Blood sample for culture t 
X h 
if clinically indicated 
Respiratory sample for Gram’s stain and culture u 
X h 
if clinically indicated 
Pleural fluid and/or bronchoalveolar lavage (BAL) sample for Gram’s stain and culture v 
if clinically indicated 
Oropharyngeal and nasopharyngeal samples w 
X h 
 
 
 
 
 
 
Administer SF-12 health status questionnaire  
X h 
 
 
 
 
X 
 
Study drug administration x 
 
X 
X 
X 
Daily 
 
 
 
Blood samples for PK analyses 
 
Day 1y 
 
 
Day 4 y 
 
 
 
Investigator’s Assessment of Clinical Response (IACR) z 
 
 
 
 
 
X 
X 
X 
NOTE:  Hospitalization is not a requirement for this study.  However, all subjects, including Outpatients, must be evaluated at the investigational site by study personnel at the following 
time points/visits:  Screening/Baseline; Day 1; Day 4 / 96 ± 24 hours after the first dose of study drug; EOT; TOC; and LFU. 


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a: 
Perform Screening/Baseline assessments within 24 hours before the first dose of study drug.  Administration of study drug should begin as soon as possible after the diagnosis of 
CABP.  See Footnote x.  Assessments performed as part of routine standard of care prior to consent (e.g., chest X-ray, blood culture) may be used to satisfy study screening 
requirements; however, no study specific procedures may be performed prior to informed consent. 
b: 
Day 1 is the first day of study drug administration; subsequent study days are consecutive calendar days.  Assessments/ procedures on Day 1 should be performed prior to first dose. 
c: 
INPATIENTS will be assessed daily while hospitalized; thus, data required for ECR Assessment (96 ± 24 hours after the first dose of study drug) will be collected.  
 
OUTPATIENTS must have a visit at the study site that is 96 ± 24 hours after the first dose of study drug to assess CABP signs and symptoms for calculation of ECR.  Study 
personnel will inform subjects as to the timing of this visit during the course of daily telephone contact.  In addition to the assessment of CABP signs/symptoms, subjects will also have 
the following procedures/assessments performed at that study site visit:  ECGs, physical examination, AE monitoring, review of concomitant medications, vital signs, oxygen 
saturation, and blood sampling for PK analysis and safety laboratory evaluations.  Importantly, study personnel will advise OUTPATIENTS not to take their first dose of study drug at 
home that day, rather to bring their blister packs (used and unused) to the study site where they will take their dose while supervised; thus, specific assessments can be performed both 
prior to and after taking the dose (i.e., ECGs and PK).  See Footnotes i, k, l, m, o, p, and y below for details. 
d: 
Perform End of Treatment (EOT) assessments at the study site within 1 day (up to 2 days permitted) after the last dose of study drug or at the time of premature discontinuation of study 
drug or early withdrawal from study.  EOT assessments resulting from premature discontinuation of study drug should be done in place of the regular study visit on Days 1 to 7. 
e: 
Perform Test of Cure (TOC) assessments at the study site 5–10 days after the last dose of study drug.  All subjects will have a TOC Visit irrespective of early clinical failure or receipt 
of an alternative antibiotic.   
f: 
Perform Late Follow Up (LFU) assessments at the study site on Day 30 ± 3 days.  All subjects will have a LFU Visit irrespective of early clinical failure or receipt of an alternative 
antibiotic.   
g: 
Obtain informed consent before initiating any study-specific assessments or procedures. 
h: 
Assessment or procedure may occur at either Screening OR prior to the first dose of study drug on Day 1 once eligibility has been determined. 
i: 
All subjects will have vital signs and O2 saturation evaluated at Screening/Baseline and Day 1.  If screening/baseline and Day 1 occur on the same calendar day, vital signs and O2 
saturation do not need to be repeated. All subjects will also have assessments at EOT and TOC; at LFU, vital signs should be performed if medically indicated.  If EOT and the last day 
of study drug are the same day, vital signs do not need to be repeated, they may be recorded once on that day (i.e., as part of the EOT assessment).  Record the vital signs associated 
with the highest temperature after the first dose of study drug. 
 
INPATIENTS:  Vital signs, O2 saturation, and supplemental O2 usage will be measured daily.  If multiple vital signs are taken on a study day, the highest temperature and the vital signs 
associated with that high temperature will be recorded.   
OUTPATIENTS: In addition to the above time points, vital signs, O2 saturation and, if applicable, supplemental O2 usage will be measured at the study visit scheduled 96 ± 24 hours 
after the first dose of study drug.   
j: 
Study personnel will evaluate signs and symptoms of CABP at Baseline, daily while on study therapy, and at EOT, TOC, and LFU Visits. NOTE:  If Screening and Day 1 are the same 
day, signs and symptoms of CABP do not need to be repeated on Day 1.  If EOT and the last day of study drug are the same day, signs and symptoms of CABP should be done only 
once on that day (i.e., as part of the EOT assessment).  Signs and symptoms are not obtained at TOC or LFU if the subject was previously deemed to have an IACR of Failure. 
 
OUTPATIENTS:  Study personnel will contact subjects daily by telephone to track signs and symptoms of CABP; however, subjects must report to the study site for the 
assessment of CABP signs/symptoms 96 ± 24 hours after the first dose of study drug.  See Footnote c.   
k: 
Record AEs from the signing of the ICF through TOC and SAEs from signing of the ICF through LFU.  Study personnel will follow unresolved AEs and SAEs present at LFU until 
resolution or stabilization.  In addition, study personnel will monitor AEs for OUTPATIENTS in conjunction with daily telephone contacts for CABP signs/symptoms and at the study 
site visit 96 ± 24 hours after the first dose of study drug.  See Footnote c. 
l: 
At each required time point, ECGs should be recorded in triplicate within a 5-minute interval.  The subject should be stabilized in a supine position for 5 min before recording the 
ECG.  If Screening and Day 1 are on the same day, the Screening ECG can serve as the Day 1 ECG prior to the first dose of study drug; an additional ECG must be performed 1-3 hours 
after administration of first dose.  See Footnote m.   
m:  INPATIENTS:  The Day 4 ECG in triplicate is required prior to the first dose of study drug and again within 1-3 hours after the first dose of study drug. 
 
OUTPATIENTS:  The Day 4 ECG can be performed at the required study site visit 96 ± 24 hours after the first dose.  See Footnote c.  The Day 4 ECG in triplicate is required prior to 
the first dose of study drug and again within 1-3 hours after the first dose of study drug.   
n: 
A complete physical examination is performed at Baseline and directed physical examinations are performed thereafter.  


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o: 
INPATIENTS:  On Day 4, a directed physical examination will be performed.. 
OUTPATIENTS:  A directed physical examination will be performed at the study site visit scheduled 96 ± 24 hours after the first dose.  See Footnote c.    
p: 
Blood samples sent to the local laboratory for the purposes of determining study eligibility must be repeated and sent to the central laboratory following enrollment. Collect blood 
and/or urine at LFU only if subject had an abnormal (high/low flag) result at TOC.   
q: 
INPATIENTS:  On Day 4, blood and urine samples will be collected for safety laboratory evaluations. 
OUTPATIENTS: Blood and urine samples will be collected for safety laboratory evaluations at the study site visit scheduled 96 ± 24 hours after the first dose.  See Footnote c.   
r: 
A urine pregnancy test will be performed at the site on all females unless surgically sterile or at least 2 years post-menopausal.  A negative urine pregnancy test is required prior to 
randomization.  Serum must be collected on Day 1 prior to 1st dose and sent to the central lab for confirmatory testing. 
s: 
Blood to be collected and sent to central laboratory for serologic tests for M. pneumoniae, C. pneumoniae and L. pneumophila.   
t: 
Collect blood samples (2 sets via peripheral venipuncture) for microbiologic culture and susceptibility testing at the local/regional lab at Baseline and as clinically indicated during the 
study.  Repeat blood cultures after a positive result until sterilization is documented.  If possible, subjects who are discontinued from study drug due to confirmed MRSA or MSSA 
bacteremia should have blood samples collected for microbiologic culture prior to switching to alternate appropriate therapy.  All organisms isolated from blood cultures which are not 
considered contaminants will be sent to the central laboratory for confirmatory identification and susceptibility testing. 
u: 
All lower respiratory tract and expectorated sputum samples should be sent to the local/regional laboratory for Gram’s stain, culture and susceptibility testing.  A sputum sample will be 
taken at Screening for Gram’s staining, culture and susceptibility testing at the local/regional laboratory.  If a subject is unable to produce an adequate (> 25 polymorphonuclear [PMN] 
cells AND < 10 squamous epithelial cells per LPF) sputum sample at Screening, a specimen should be obtained, if possible, within 24 hours after the first dose of study drug. Gram’s 
stain and culture results from the local/regional laboratory will be recorded in the eCRF. Slides (stained and unstained) will also be sent to the central laboratory for a confirmatory 
reading of the Gram’s stain.  If possible, subjects who are discontinued from study drug due to clinical failure should have repeat cultures collected for microbiologic culture prior to 
switching to alternate appropriate therapy.  All organisms isolated from sputum samples, which are not considered contaminants, will be sent to the central laboratory for confirmatory 
identification and susceptibility testing.  In addition, a portion of all Baseline sputum samples must be frozen until sent to the central laboratory for quantitative PCR.  Subjects with a 
urinary antigen positive for Legionella spp. will also have a portion of their sputum sample sent frozen to the central laboratory for isolation of L. pneumophila. 
v: 
Collect pleural fluid samples and/or BAL only if medically indicated.  Gram’s stain samples, culture, and test the isolated pathogens for susceptibility.  Pathogens isolated from pleural 
fluid and/or BAL samples will be sent to the central laboratory for confirmatory identification and susceptibility testing.  If possible, pleural fluid samples should be incubated in blood 
culture bottles for optimal pathogen recovery. 
w: An oropharyngeal specimen (2 swabs) and a nasopharyngeal specimen (1 swab) will be collected and frozen until sent to the central laboratory.  The oropharyngeal specimen will be 
used for culture of M. pneumoniae and identification by PCR.  The nasopharyngeal specimen will be used for culture and identification by PCR of S. pneumoniae, and potentially, H. 
influenzae.   
x: 
Study personnel will administer the first dose of study drug at the study site, as soon as possible after the diagnosis of CABP and completion of all required pre-dose Day 1 procedures. 
On Day 1, if q12h dosing is not feasible, the 1st and 2nd doses may be administered as close as 8 hours apart, in order to allow 2 doses to be given on Day 1.  In this circumstance, the 
subject’s dosing schedule should be adjusted on Day 2 to a regular q12h morning and evening schedule.  Subsequently, every effort should be made to maintain a q12h dosing schedule.  
When this is not possible, it is acceptable to administer doses within 4 hours of the scheduled dosing time (i.e., a minimum of 8 hours between doses).  For Outpatients, or in the event a 
subject is discharged from the hospital during the study drug administration period, an adequate supply of study drug will be dispensed for self-administration at home.  Subjects will be 
provided instructions regarding the dosing schedule.  Subjects may self-administer oral study drug at home with the following exception:  Study personnel will advise subjects who are 
Outpatients that they must return to the study site to assess CABP signs and symptoms at 96 ± 24 hours after the first dose of study drug.  See Footnote c.  Administration of study drug 
may occur on the same calendar day as EOT, and if so will be completed before EOT assessments begin. 
y: 
Collect blood samples for PK analysis relative to the first dose of study drug.  Blood will be collected within 1 h pre-dose, 1-2 h post dose, and 3-4 h post dose, and 8-9 h post dose.  
INPATIENTS:  PK sampling should occur on Day 4 but, if not feasible, it can be done relative to the first dose on Day 5; the 8-9 h post dose is required.  OUTPATIENTS:  PK 
sampling will be done during the 96 ± 24 hours post 1st dose visit. The 8-9 h post dose sample is optional; however, it should be obtained if logistically feasible.   
z: 
Investigator to determine IACR - Success, Failure or Indeterminate (i.e., subject lost to follow up) at EOT and TOC and Sustained Success, Relapse or Indeterminate at LFU.  The 
Investigator will not determine Clinical Response at TOC or LFU if the subject was previously deemed to have an IACR of Failure. 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation 
Definition 
24 h AUC/MIC 
24 h AUC over the MIC 
24 h AUCELF/MIC ratio 
AUC at site of infection over the MIC 
ABPI 
Association of British Pharmaceutical Industry 
ABSSSI 
Acute bacterial skin and skin structure infection 
ADME 
Absorption, Distribution, Metabolism, and Elimination 
AE 
Adverse event 
AGP 
α1-acid glycoprotein 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATS 
American Thoracic Society 
AUC 
Area under the drug concentration–time curve 
BAL 
Bronchoalveolar Lavage 
BP 
Blood pressure 
C 
Celsius 
CABP 
Community-acquired bacterial pneumonia 
CA-MRSA 
Community-acquired MRSA 
CBC 
Complete blood count 
CDC 
Centers for Disease Control and Prevention 
CE 
Clinically Evaluable 
CE-EOT 
Clinically Evaluable at End-of-Treatment 
CE-LFU 
Clinically Evaluable at Late Follow Up 
CE-TOC 
Clinically Evaluable at Test-of-Cure 
CFR 
Code of Federal Regulation 
CFU 
Colony Forming Unit 
CI 
Confidence interval 
Cmax 
Maximum observed plasma concentration 
Cmin 
Minimum observed plasma concentration 
CNS 
Central Nervous System 
CrCl 
Creatinine clearance 
CS 
Clinically significant 
CT 
Computerized tomography 
CXR 
Chest x-ray 
CV [%] 
Coefficient of variation [%] 
CYP3A4 
Cytochrome P450 3A4 
DMC 
Data Monitoring Committee 
DSS 
Drug Safety Services 
ECA 
Early Clinical Assessment 


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Abbreviation 
Definition 
ECG 
Electrocardiogram 
ECR 
Early Clinical Response 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ELF 
Epithelial Lining Fluid 
EMA 
European Medicines Agency 
EOT 
End-of-Treatment 
ESBL 
Extended-spectrum β-lactamase  
EU 
European Union 
F 
Fahrenheit 
fAUC 
Area under the concentration-time curve of the unbound fraction of the 
drug 
FDA 
US Food and Drug Administration  
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
hERG 
Human ether a go go related Gene 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
Heart rate 
HSA 
Human serum albumin 
IAC 
Interim Analysis Committee 
IACR 
Investigator’s Assessment of Clinical Response 
IC50 
Half-maximal inhibitory concentration 
ICF 
Informed Consent 
ICH 
International Conference on Harmonization 
ICU 
Intensive Care Unit  
IDSA 
Infectious Diseases Society of America 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio  
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ITT 
Intent-to-Treat 
IV 
Intravenous 
K3EDTA 
Tripotassium ethylene diamine tetraacetic acid 
LFU 
Late Follow-up 
LLQ 
Lower limit of quantification  
MAA 
Marketing Authorization Application 
LPF 
Low power field 
ME 
Microbiologically Evaluable 
MedDRA 
Medical Dictionary for Regulatory Activities 
ME-EOT 
Microbiologically Evaluable at End-of-Treatment 


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Abbreviation 
Definition 
ME-LFU 
Microbiologically Evaluable at Late Follow Up 
ME-TOC 
Microbiologically Evaluable at Test-of-Cure 
mg 
Milligram 
MIC 
Minimum inhibitory concentration  
MIC90 
Concentration of drug required to inhibit growth of 90% of pathogens 
microITT 
Microbiological Intent-to-Treat 
mITT 
Modified Intent-to-Treat 
mL 
Milliliter 
mm 
Millimeter 
mmHg 
Millimeter of mercury 
MRSA 
Methicillin-resistant Staphylococcus aureus 
ms 
Millisecond 
MSSA 
Methicillin-susceptible Staphylococcus aureus 
n 
Group size, number of replicates 
NaCl 
Sodium chloride 
NCS 
Not clinically significant 
NI 
Non-inferiority 
NOAEL 
No Observed Adverse Effect Level  
O2 
Oxygen 
Pa O2 
Partial Pressure of Arterial Oxygen 
PCR 
Polymerase Chain Reaction 
PCS 
Potentially clinically significant 
PD 
Pharmacodynamics 
p-gp 
p-glycoprotein 
Ph. Eur. 
European Pharmacopoeia 
PHL 
Potential Hy’s Law 
PK 
Pharmacokinetic 
PMN 
Polymorphonuclear 
PO 
By mouth (oral) 
PORT 
Pneumonia Outcomes Research Team 
PRO 
Patient-reported outcome 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time  
PV 
Pharmacovigilance 
q12h 
Every 12 hours  
q24h 
Every 24 hours  
QA 
Quality Assurance 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected according to Fridericia 
ΔQTcF 
QTcF change from baseline 


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Abbreviation 
Definition 
rRNA 
Ribosomal ribonucleic acid 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SENTRY 
SENTRY Antimicrobial Surveillance Program 
SOC 
System organ class 
STD 
Sexually Transmitted Diseases  
SUSAR 
Suspected Unexpected Serious Adverse Event 
T> MIC 
Time plasma concentration exceeds the MIC 
t1/2 
Half-life 
TEAE 
Treatment-emergent adverse event 
TOC 
Test-of-Cure 
tRNA 
Transfer ribonucleic acid 
ULN 
Upper Limit of Normal 
US 
United States  
USP 
United States Pharmacopeia 
VRE 
Vancomycin-resistant enterococcus 
WBC 
White Blood Cell Count  
NOTE:  Table includes a comprehensive list of abbreviations used in lefamulin regulatory documents. 
 
 
 


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TABLE OF CONTENTS 
SPONSOR RELATED CONTACT DETAILS .........................................................................2 
PROTOCOL REVIEW AND APPROVAL FORM ..................................................................3 
INVESTIGATOR SIGNATURE PAGE ...................................................................................4 
AMENDMENT 2:  17-MAR-2016 ............................................................................................6 
AMENDMENT 1:  17-FEB-2016 .............................................................................................6 
SYNOPSIS ...............................................................................................................................11 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................26 
TABLE OF CONTENTS .........................................................................................................30 
1 
INTRODUCTION ...........................................................................................................34 
1.1 
Background of the Disease and Treatment Options ..............................................34 
1.2 
Background on Lefamulin and the Pleuromutilins ................................................35 
1.3 
Mechanism of Action and Non-Clinical Pharmacology ........................................35 
1.4 
Nonclinical Pharmacokinetics and Safety .............................................................37 
1.5 
Summary of Clinical Data .....................................................................................39 
1.5.1 
Pharmacokinetics in Humans .......................................................................39 
1.5.2 
Efficacy ........................................................................................................41 
1.5.3 
Safety ...........................................................................................................41 
2 
STUDY OBJECTIVES ....................................................................................................42 
2.1 
Primary Objectives.................................................................................................42 
2.2 
Secondary Objectives.............................................................................................43 
2.3 
Additional Objectives ............................................................................................43 
3 
STUDY DESIGN.............................................................................................................43 
3.1 
Study Rationale ......................................................................................................45 
4 
STUDY POPULATION ..................................................................................................45 
4.1 
Inclusion Criteria ...................................................................................................45 
4.2 
Exclusion Criteria ..................................................................................................47 
5 
STUDY DRUG ADMINISTRATION ............................................................................49 
5.1 
Selection of Lefamulin Doses ................................................................................49 
5.2 
Selection of Comparator ........................................................................................50 
5.3 
Randomization .......................................................................................................51 
5.4 
Study Drug Treatment............................................................................................51 
5.5 
Blinding..................................................................................................................52 
5.6 
Unblinding of Therapy Assignments .....................................................................52 
5.7 
Adherence ..............................................................................................................53 
5.8 
Occupational Safety ...............................................................................................53 
6 
STUDY ASSESSMENTS AND PROCEDURES ...........................................................53 
6.1 
Inpatient and Outpatient Assessments ...................................................................54 


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6.1.1 
Outpatient Visit for ECR Assessment and Other Site Procedures ...............54 
6.2 
Medical/Surgical History and Physical Examination ............................................55 
6.3 
PORT Risk Class Assessment ...............................................................................55 
6.4 
Electrocardiograms ................................................................................................57 
6.5 
Vital Signs and Oxygen Saturation ........................................................................57 
6.6 
Chest X-Ray or CT Scan........................................................................................58 
6.7 
Arterial Blood Gases ..............................................................................................58 
6.8 
Prior and Concomitant Medications ......................................................................58 
6.8.1 
Prior Medications .........................................................................................58 
6.8.2 
Concomitant Medication ..............................................................................58 
6.9 
Prohibited Medications ..........................................................................................59 
6.10 
Nonpharmacologic Treatments and Procedures ....................................................60 
6.11 
Assessment of Clinical Signs and Symptoms of CABP ........................................60 
6.12 
Investigator’s Assessment of Clinical Response (IACR) ......................................62 
6.12.1 
Investigator’s Assessment of Clinical Response (IACR) at End of 
Treatment and Test of Cure .........................................................................62 
6.12.2 
Investigator’s Assessment of Clinical Response (IACR) at Late Follow 
Up .................................................................................................................62 
6.13 
Clinical Laboratory Tests (Safety) .........................................................................63 
6.14 
Sample Collection for Pharmacokinetic Analysis .................................................63 
6.14.1 
Sample Collection Methodology .................................................................64 
6.14.2 
Assay Methodology .....................................................................................64 
6.15 
Microbiological Assessment ..................................................................................65 
6.15.1 
Sputum Samples...........................................................................................65 
6.15.2 
Bronchoalveolar Lavage Samples (BAL) ....................................................65 
6.15.3 
Pleural Fluid Samples ..................................................................................66 
6.15.4 
Blood Cultures .............................................................................................66 
6.15.5 
Serological Testing ......................................................................................66 
6.15.6 
Urine Antigen Test .......................................................................................66 
6.15.7 
Oropharyngeal Specimen .............................................................................66 
6.15.8 
Nasopharyngeal Specimen ...........................................................................67 
6.16 
Health Utilization and Patient Reported Outcome.................................................67 
6.17 
Food and Beverage Restrictions ............................................................................67 
6.18 
Discontinuation from Treatment or Study .............................................................67 
6.18.1 
Discontinuation from Treatment ..................................................................67 
6.18.2 
Discontinuation from Study .........................................................................68 
6.18.3 
Individual Stopping Criteria ........................................................................68 
6.18.4 
Lost to Follow-up .........................................................................................69 
7 
ADVERSE EVENTS .......................................................................................................69 


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7.1 
Assessment of Severity (Intensity) ........................................................................70 
7.2 
Assessment of Relationship to Study Drug ...........................................................70 
7.3 
Serious Adverse Events .........................................................................................71 
7.4 
Symptoms of the Disease Under Study .................................................................73 
7.5 
Other Reportable Events ........................................................................................73 
8 
DRUG SUPPLIES ...........................................................................................................74 
8.1 
Lefamulin (BC-3781).............................................................................................74 
8.2 
Moxifloxacin ..........................................................................................................74 
8.3 
Placebo ...................................................................................................................74 
8.3.1 
Packaging and Labeling ...............................................................................74 
8.3.2 
Storage of Study Drugs ................................................................................74 
8.3.3 
Product Accountability ................................................................................74 
9 
STATISTICAL ANALYSIS ...........................................................................................75 
9.1 
Treatment Comparison of Interest .........................................................................75 
9.2 
Sample Size Determination....................................................................................75 
9.3 
Analysis Populations ..............................................................................................76 
9.3.1 
Intent-to-Treat Analysis Set (ITT) ...............................................................76 
9.3.2 
Modified Intent-to-Treat Analysis Set (mITT) ............................................77 
9.3.3 
Safety Analysis Set ......................................................................................77 
9.3.4 
Microbiological Intent-to-Treat Analysis Set (microITT) ...........................77 
9.3.5 
Clinically Evaluable Analysis Set ................................................................77 
9.3.6 
Microbiologically Evaluable Analysis Set ...................................................77 
9.3.7 
Pharmacokinetic Analysis Set......................................................................77 
9.4 
Criteria for Evaluation ...........................................................................................78 
9.4.1 
Primary Efficacy Analysis Variable ............................................................78 
9.4.2 
Secondary Efficacy Analysis Variables .......................................................78 
9.4.2.1 
Clinical Outcome ...............................................................................78 
9.4.2.2 
Microbiological Assessment ..............................................................78 
9.4.3 
Safety Analysis Variables ............................................................................79 
9.4.4 
Pharmacokinetic Analysis Variables ...........................................................79 
9.4.5 
Other Variables ............................................................................................79 
9.5 
Demographic and Baseline Characteristics ...........................................................80 
9.6 
Efficacy Analysis ...................................................................................................80 
9.6.1 
Primary Efficacy Analysis ...........................................................................81 
9.6.2 
Secondary Efficacy Analyses ......................................................................82 
9.6.3 
Additional Efficacy Analyses ......................................................................83 
9.7 
Safety Analysis ......................................................................................................83 
9.8 
Handling of Missing Data ......................................................................................84 
9.9 
Pharmacokinetic Analyses .....................................................................................84 


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9.10 
Health Utilization Variables and Patient Reported Outcome ................................85 
10 STUDY MONITORING .................................................................................................85 
10.1 
Clinical Monitoring ................................................................................................85 
10.2 
Independent Data Monitoring Committee (DMC) ................................................85 
11 IEC/IRB APPROVAL .....................................................................................................86 
12 ETHICAL CONDUCT OF THE STUDY .......................................................................86 
13 INFORMED CONSENT .................................................................................................86 
14 QUALITY ASSURANCE AND QUALITY CONTROL ...............................................87 
15 DATA HANDLING AND RECORD KEEPING ...........................................................87 
15.1 
Data Handling ........................................................................................................87 
15.2 
Subject Confidentiality ..........................................................................................88 
15.3 
Computer Systems .................................................................................................88 
15.4 
Data Entry ..............................................................................................................88 
15.5 
Data Validation ......................................................................................................89 
15.6 
Record Keeping .....................................................................................................89 
16 TERMINATION OF STUDY .........................................................................................89 
17 FINANCING AND INSURANCE ..................................................................................90 
18 PUBLICATION POLICY ...............................................................................................90 
19 LIST OF REFERENCES .................................................................................................92 
20 APPENDICES .................................................................................................................96 
 
 
 


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1 
INTRODUCTION 
1.1 Background of the Disease and Treatment Options  
Community-acquired bacterial pneumonia (CABP) is a commonly occurring serious 
infection that requires systemic antibiotic therapy and is associated with substantial 
morbidity, mortality, and considerable healthcare costs.  It is the leading cause of death from 
infectious diseases in the United States (US) and, when combined with influenza, remains the 
eighth leading cause of death in the US (CDC, 2013).  In Europe, there are 44 cases of CABP 
for every 1 000 patients treated in a single general practice (Lim et al., 2009), while in the 
US, 5.6 million cases of CABP lead to as many as 1.1 million hospitalizations and > 53 000 
deaths annually (CDC, 2013). 
Community-acquired bacterial pneumonia is more common in the elderly, with an incidence 
that is 2- to 4-times greater in those > 60 years of age than in those ≤ 50 years.  The mortality 
rate in the US and Europe is < 1 % for individuals with CABP that do not require 
hospitalization; however, the average mortality rate is 12 % to 14 % among those 
hospitalized (Fine et al., 1996; Fine et al., 1997; Lim et al, 2009).  Individuals who are 
admitted to the intensive care unit (ICU), who are bacteremic, or who are admitted from a 
nursing home, have a mean mortality rate of 30% to 40% (Mandell et al., 2007; Lim et al., 
2009). 
The most common organisms of CABP identified by culture include Streptococcus 
pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Moraxella catarrhalis, and 
selected Gram-negative pathogens.  The incidence of CABP due to atypical pathogens — 
Mycoplasma pneumoniae, Chlamydophila pneumoniae, and Legionella pneumophila — lies 
between 20% and 28% depending on the region (Arnold et al., 2007). 
The emergence of pathogens resistant to antimicrobials has become an increasingly 
complicating factor in the selection of empiric therapy for CABP.  Antimicrobial 
susceptibility data for respiratory pathogens in the US reveal high rates of resistance among 
S. pneumoniae and H. influenzae.  A surveillance program conducted between 2008 and 2010 
in the US showed that, of 3 329 S. pneumoniae strains, 21.1 % were penicillin non-
susceptible or resistant.  Increases in an already elevated resistance rate for erythromycin 
(38.4% to 41.7%) were also observed in the same study (Pfaller et al., 2012).  Recent global 
surveillance studies have revealed increased resistance to fluoroquinolones in all monitored 
bacterial species with the exception of S. pneumoniae and H. influenzae (Dalhoff, 2012). 
M. pneumoniae is a common pathogen of respiratory tract infection in children and 
adolescents and can cause serious pneumonia and extra-pulmonary complications (Waites 
and Talkington, 2004).  Current preferred treatment is with a macrolide antibiotic.  In recent 
years, however, many countries have reported the isolation of clinically drug-resistant strains, 
the main mechanism of resistance being a mutation in the 23S ribosomal ribonucleic acid 
(rRNA) gene which is the target of macrolide antibiotic action.  These resistant isolates 
remain susceptible to fluoroquinolones or tetracyclines, but use of these antibiotics is limited 
in children (Liu et al., 2014). 


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S. aureus, including methicillin-resistant S. aureus (MRSA), has emerged as an important 
pathogen in CABP.  In a retrospective analysis that included hospitalized patients with 
microbiologically-confirmed CABP, approximately 25.5% of these patients were culture-
positive for S. aureus and, among these patients, 6.3% had MRSA isolated (Kollef et al., 
2005).  In general, the hospitalized patients with pneumonia due to S. aureus in this study 
had an increased mortality rate.  These findings correlate with recent case series of CABP 
due to community-acquired MRSA (CA-MRSA), which describe severe, necrotizing 
pneumonia in previously healthy young individuals (Francis et al, 2005; Hidron et al., 2009).  
Optimal management for these patients is not yet clear, and even the best available treatment 
may still result in poor outcomes (Gillet et al., 2007).  Therefore, there is a need for more 
treatment options for CABP caused by MRSA. 
1.2 Background on Lefamulin and the Pleuromutilins 
Lefamulin is a potent, semi-synthetic antibacterial belonging to a novel class known as the 
pleuromutilins.  The oral formulation of lefamulin is under investigation in this study.  The 
first marketed representative of the pleuromutilin class for human use is retapamulin 
(GlaxoSmithKline), approved in 2007 in the US (AltabaxP®) for the topical treatment of 
impetigo and in Europe (Altargo®) for the topical short-term treatment of impetigo and 
infected small lacerations, abrasions or sutured wounds.  Tiamulin (Denagard®) and 
valnemulin (Econor®), two other semi-synthetic pleuromutilin derivatives, have been used 
systemically in veterinary medicine for many years. 
1.3 Mechanism of Action and Non-Clinical Pharmacology 
Lefamulin is a prokaryotic protein synthesis inhibitor.  Its novel mode of action is mediated 
by a unique interaction with the central part of domain V of 23S rRNA, subsequently 
preventing the correct positioning of the CCA-ends of transfer ribonucleic acid (tRNA) for 
peptide transfer (Davidovich et al., 2007).  The uniqueness of this mechanism implies a very 
low probability of cross-resistance with other antibacterial classes. 
Lefamulin’s in vitro antibacterial profile covers the most important bacterial pathogens 
causing community acquired bacterial pneumonia (CABP) acute bacterial skin and skin 
structure infection (ABSSSI) and sexually transmitted diseases (STD).  The antibacterial 
spectrum comprises S. aureus including MRSA and CA-MRSA, ß-haemolytic streptococci 
including S. pyogenes and S. agalactiae, Enterococcus faecium including vancomycin-
resistant enterococci (VRE), S. pneumoniae, H. influenzae, M. catarrhalis, the atypical 
respiratory pathogens L. pneumophila, C. pneumoniae, and M. pneumoniae, and organisms 
causing STD such as Neisseria gonorrhoeae, Chlamydia trachomatis, 
Mycoplasma genitalium among others.  Moreover, lefamulin remains active against clinical 
isolates resistant to the following antimicrobial(s) (classes):  macrolides, lincosamides, 
streptogramin B, oxazolidinones, tetracyclines, ß-lactams, quinolones, trimethoprim-
sulfamethoxazole, mupirocin, and vancomycin as demonstrated in cross-resistance studies.  
The only exceptions are the rarely encountered Staphylococcus spp. producing the Cfr-
methyltransferase and the Vga(A)-efflux pump, where lefamulin showed reduced activity.  
Although some linezolid-resistant isolates have a minimum inhibitory concentration (MIC) 
of >1 µg/mL for lefamulin, no consistent cross-resistance could be observed with linezolid.  


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Multiple interaction sites with the ribosomal target are the most likely explanation for the 
observed low mutation frequency of below 10-11.  In vitro resistance development was a slow 
and stepwise process with resistant S. aureus clones being selected at sub-MIC levels only 
after 22-42 passages, whereas no stable resistant clones could be selected for S. pyogenes and 
S. pneumoniae. 
Susceptibility testing of lefamulin was performed with >13,600 contemporary clinical 
isolates including >7800 staphylococcal strains (including MRSA and methicillin-susceptible 
S. aureus [MSSA] strains) collected from patients world-wide, including the SENTRY 
Antimicrobial Surveillance Program (SENTRY) in 2010 (Paukner et al, 2013).  Lefamulin 
demonstrated in vitro antibacterial activity (MIC90) against the most relevant respiratory 
pathogens including S. pneumoniae (0.25 µg/mL), H. influenzae (2 µg/mL), M. catarrhalis 
(0.25 µg/mL), L. pneumophila (0.5 µg/mL), M. pneumoniae (0.006 µg/mL), and 
C. pneumoniae (0.04 µg/mL).  When compared with other antibiotics used to treat bacterial 
pneumonia such as macrolides, ß-lactams, fluoroquinolones or doxycycline, lefamulin was 
among the most active compounds in vitro irrespective of resistance phenotype present in 
S. pneumoniae or H. influenzae.  Furthermore, lefamulin showed complete activity (100% 
susceptibility) against S. pneumoniae that are resistant to macrolides (36.2-37.4%; SENTRY 
2010) or to levofloxacin (1.0-1.1%; SENTRY 2010) (Sader et al., 2012; Paukner et al., 
2013).  
Analysis of in vitro bacterial-killing properties suggested that lefamulin exhibits bactericidal 
activity against S. pneumoniae and H. influenzae, while it is predominantly a bacteriostatic 
agent against S. aureus.  In vivo, the extent of bacterial killing in neutropenic mice was 
excellent for most strains of S. pneumoniae and moderate for strains of S. aureus. 
The potential for synergy/antagonism of lefamulin with various currently marketed 
antibiotics was evaluated using the broth microdilution technique according to CLSI (M7-
A9, 2012) for S. aureus (n = 6), S. pneumoniae (n = 6), ß-hemolytic S. pyogenes (n = 3), 
S. agalactiae (n = 3), H. influenzae (n = 6), Enterobacteriaceae (n = 10) and P. aeruginosa 
(n = 2).  Lefamulin was largely indifferent/additive when combined with other antibacterial 
agents and did not exhibit an antagonistic effect with any antibiotic against any bacterial 
strains tested, including those with important resistance phenotypes (e.g., MRSA and ESBL).   
No apparent synergy was observed with the exception of a trend towards synergy observed 
against S. aureus isolates when lefamulin was combined with doxycycline (in 5 of 6 tested 
isolates) and for all S. pneumoniae isolates (6 of 6 tested isolates) when lefamulin was 
combined with aztreonam.  Based on studies completed to date, there is no potential concern 
if lefamulin is used in combination with other antibacterial agents.  
Lefamulin accumulated 30- to 50-fold in murine macrophages at clinically relevant 
concentrations of 1 and 5 µg/mL.  The antimicrobial potency of lefamulin was unaffected by 
lung surfactant. 
A number of animal infection models have established the in vivo efficacy of lefamulin, 
including the septicemia, thigh infection, and pneumonia models in mice.  Lefamulin has 
proven to be highly efficacious against S. aureus (MSSA and MRSA) and S. pneumoniae 
(penicillin-susceptible and penicillin-resistant S. pneumoniae).  Evaluation of the 


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pharmacokinetic/pharmacodynamic (PK/PD) target associated with efficacy was performed 
using a neutropenic murine thigh and lung infection model.  The major parameters driving 
efficacy for both S. aureus and S. pneumoniae were the 24 h area under the drug 
concentration–time curve (AUC) over the MIC (24 h AUC/MIC) followed by the duration of 
time plasma concentrations exceeded the MIC (T > MIC).  The activity of the drug was only 
minimally diminished in immunocompromised mice in comparison to immuno-competent 
mice.  In lung infections caused by S. pneumoniae or S. aureus, lefamulin showed enhanced 
activity when compared to the outcome in the murine thigh infection model.  Investigations 
of the exposure levels in the epithelial lining fluid (ELF) in mice were consistent with the 
observed good efficacy against lung infections.  For the PK/PD analyses, the plasma 24 h 
fAUC/MIC ratio, as well as the AUC at site of infection over the MIC (24 h AUCELF/MIC 
ratio), were evaluated on the basis of murine lung infections caused by S. pneumoniae and S. 
aureus.  
1.4 Nonclinical Pharmacokinetics and Safety 
Pharmacokinetic studies after oral and IV administration demonstrated a dose proportional 
systemic exposure of lefamulin in all species tested.  Moderate to high plasma protein 
binding of 73 % to 88 % in humans and 61 % to 81 % in animals was observed.  However, 
lefamulin displayed low binding affinity to the 2 major drug binding human plasma proteins 
(human serum albumin [HSA] and α1-acid glycoprotein [AGP]) and, despite the observed 
moderate to high protein binding, its in vitro antimicrobial activity was maintained in the 
presence of serum.  This is suggestive of a weak and loose association of the drug with 
plasma proteins and probably explains the rapid tissue distribution observed across the 
species, including humans.  Quantitative whole body autoradiography in rats after IV bolus 
administration showed rapid distribution into tissues and organs consistent with the apparent 
low protein binding affinity observed in vitro.  The concentrations measured in the majority 
of the tissues including skin and soft tissues and lungs were higher compared to the amounts 
measured in blood.  
In vitro metabolic stability testing of lefamulin predicted a mild to moderate influence of 
Phase I reactions by CYP450 enzymes on its overall metabolism, while Phase II metabolism 
will have only a very limited effect.  Using isolated recombinant CYP450 isoenzymes, 
CYP3A4 and 3A5 were identified as lefamulin metabolizing enzymes.  Lefamulin did not 
inhibit CYP1A, 2B6, 2C9, 2C19, 2D6, 2C8, or 2E1 to a clinically relevant extent.  Lefamulin 
was identified as a p-glycoprotein (p-gp) substrate and a p-gp inhibitor and was capable of 
saturating its own efflux in Caco-2 cells.  This observation is in-line with the observed dose-
dependent increase in bioavailability, as seen in the oral single ascending dose study in 
humans (NAB-BC-3781-1101).  Lefamulin did not induce CYP1A2 and CYP3A4 in human 
hepatocytes.  Consequently, it is not expected that lefamulin will induce CYP1A2 and 
CYP3A4 or p-gp in a clinical setting. 
All data obtained so far suggest that the non-renal route of excretion drives the clearance of 
lefamulin.  Fecal excretion in the bile (and/or via the gut mucosa) is likely the most important 
route of elimination for this compound, as confirmed by a mass balance study in rats, 
showing 96 % total recovery, mainly in feces (82 %) and urine (14 %).  Furthermore, all 


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intra-organ radioactivities approached the lower limit of quantification (LLQ) within 72 h, 
indicating a total elimination of the drug and/or its metabolites.  
The safety of lefamulin has been investigated in a number of safety pharmacology and 
toxicology studies conducted in vitro and in vivo in different rodent and non-rodent animal 
species.  Safety and toxicology studies have been performed to support oral and IV use in 
human.  Studies include acute and repeated dose toxicity, local tolerance and genotoxicity 
testing, development and reproductive toxicity, safety pharmacology, and PK/toxicokinetic 
profiling in rodent and non-rodent species.  No clear differences between male and female 
animals were seen in toxicity or absorption, distribution, metabolism, and elimination 
(ADME) studies.  
Lefamulin did not show any effects on the central and autonomic nervous system in rats or 
on the respiratory system in cynomolgus monkeys.  A potential for QT/QTc interval 
prolongation was noted after a single IV dose of 40 mg/kg.  In vitro IKr (hERG) assays and a 
study using rabbit Purkinje fibers showed a potential for QT/QTc prolongation, but did not 
demonstrate any pro-arrhythmic potential for lefamulin at clinically relevant concentrations. 
Four-week, IV, repeat-dose toxicity studies in rats and monkeys resulted in NOAELs of 75 
and 120 mg/kg daily dose, respectively, the highest doses tested.  The NOAEL in pivotal 4-
week oral repeat-dose toxicity studies in rats and cynomolgus monkeys was 300 and 
70 mg/kg daily dose, respectively.  In both species, the pivotal repeat-dose toxicity studies 
did not indicate any systemic target organ toxicity. 
Intravenous administration to rats resulted in local effects at the infusion site.  These 
reversible local effects are likely induced by inflammatory irritation caused by the indwelling 
catheter together with lefamulin.  The effect might have been more pronounced due to the 
small vessel size and the lower blood flow/volume in rats.  Intravenous administrations to 
monkeys up to and including 120 mg/kg/day did not show any signs of local intolerance. 
Oral administrations in monkeys up to and including 70 mg/kg/day were well tolerated by the 
gastrointestinal (GI) tract.  Doses of 200 mg/kg/day caused emetic periods and diarrhea 
associated with body weight loss and poor physical condition.  Gastrointestinal tract 
intolerability following oral dosing of 600 and 450 mg/kg/day was also described in rats.  
The dose of 70 mg/kg/day corresponds to 4 200 mg daily in 60 kg humans and exceeds the 
maximum intended daily dose of 1 200 mg.  Lefamulin did not evidence any genotoxic 
potential, as demonstrated by in vitro and in vivo mutagenicity and clastogenicity assays. 
No treatment-related changes were noted in female or male reproductive organs of rats or 
monkeys following 14 or 28 days repeated dosing.  Embryo-fetal development toxicity 
studies with lefamulin performed in rats and rabbits did not indicate a potential for 
teratogenicity and the corresponding NOAELs were set at the highest doses tested, 100 and 
60 mg/kg/day (IV), respectively.  Fertility studies performed in rats did not show any adverse 
effect on reproductive indices and the NOAEL was established at 75 mg/kg/day (IV), the 
highest dose tested in both genders.  


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BC-8041, the main human metabolite of lefamulin, did not demonstrate a potential for 
QT/QTc prolongation (hERG assay) or genotoxicity (Ames and mouse lymphoma assay), 
and exhibited no teratogenicity in a rat embryo-fetal development toxicity study. 
The safety and toxicology program provided sufficient and pertinent information on the 
safety profile of lefamulin and its main human metabolite, BC-8041, concluding that the drug 
candidate has no indices of toxicity in animals that would preclude its use in humans.  These 
studies are described in more detail in the Investigator’s Brochure. 
1.5 Summary of Clinical Data 
Lefamulin has been administered as single or multiple-doses orally and by IV infusions to 
healthy subjects in 17 completed Phase 1 studies and IV to subjects with ABSSSI in a 
completed Phase 2 study.  In these studies, lefamulin was found to be well tolerated at the 
doses that exceed those to be used in the current study (i.e., 600 mg per oral administration).  
In the 17 Phase 1 studies, 321 male and female healthy subjects were exposed to lefamulin, 
12 of whom were ≥ 65 years of age.  In the Phase 2 study, 141 subjects (95 male, 46 female) 
were exposed to lefamulin, 7 of whom were ≥ 65 years of age (4 in the 100 mg group, 3 in 
the 150 mg group) (Prince et al., 2010; Prince et al., 2013; Wicha et al., 2010; Zeitlinger et 
al., 2011).  
1.5.1 
Pharmacokinetics in Humans 
Tissue distribution studies in healthy volunteers showed rapid lefamulin distribution 
achieving therapeutic exposures in relevant target tissues for the treatment of both respiratory 
tract and skin infections following IV and PO administration.  Following a single 150 mg IV 
infusion, lefamulin showed higher exposure in epithelial lining fluid (ELF) as compared to 
the penetration into skin tissues (Zeitlinger et al., 2016).  This pattern of tissue distribution 
has also been observed in ELF of mice.  Therefore, the exposures in plasma and in ELF were 
used for the determination of the AUC/MIC ratio for target attainment analyses.  
The plasma concentration-time curve of intravenously administered lefamulin in humans 
showed a multi-phasic decline.  Following the end of infusion (i.e., the maximal 
concentration [Cmax]), there is a rapid distribution phase over 0.5 h followed by an extended 
elimination phase with a mean half-life (t1/2) of 8.6 h to 11.8 h.  The major elimination route 
for lefamulin was non-renal.  There were no statistically significant effects of age, 
demographics (body weight, height, or body mass index) or gender on the PK parameters of 
lefamulin.  In addition, no significant influence of the health status on the total body 
clearance or drug distribution of lefamulin was observed.  
Oral administered lefamulin is characterized by a plasma concentration time curve with a 
rapid absorption describing a bimodal peak, suggesting a mixed order absorption.  The initial 
peak plasma concentration occurs 20-60 minutes after administration, followed by a second 
peak observed between 1-4 hours after dosing. Following every 12 hour intravenous infusion 
or oral administration, steady-state is achieved after two days and thereafter, trough levels 
(Cmin) remain consistently linear throughout the duration of the treatment. After oral 


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administration of an immediate-release (IR) tablet containing 600 mg of lefamulin, exposure 
— as measured by AUC (the driver of efficacy) — was equivalent to a 150 mg IV dose, the 
higher of 2 doses evaluated in the Phase 2 study of lefamulin in the treatment of ABSSSI 
(NAB-BC-3781-2001) (Wicha et al., 2013).  
Lefamulin was best absorbed when taken on an empty stomach. A food-effect study 
involving administration of lefamulin to healthy female and male volunteers under fasting 
conditions and with a high-fat meal indicated an effect of food on the absorption process and 
bioavailability of lefamulin. The CI90 % for both Cmax and AUC were outside of the 
recommended acceptance range of 80 %-125 %. While the reduced Cmax is seen as not 
clinically relevant in terms of efficacy, the effect of the decreased AUC was evaluated using 
PK/PD analysis. Exposure response (PK/PD) analysis based on an oral popPK model, robust 
surveillance data, and pre-clinically derived free plasma AUC/MIC ratio targets against 
S. pneumoniae and S. aureus showed a high probability of success of ≥ 99.4 % regardless of 
food. However, in the simulation of lung exposures in ELF (AUCELF/MIC) using the 
modified popPK model overall probability dropped down to ≥ 85.6 % in the fed population 
on Day 1, with a morning and an evening dose after a high fat, high calorie meal. Although 
we believe that the probability analysis based on the simulated fed state data represent a 
worst case scenario for oral absorption and that the prediction of ELF exposures might be 
underestimated, to mitigate any risk associated with co-administration of oral lefamulin with 
food during the Phase 3 oral trial, we plan to recommend in the protocol that study drug be 
administered at least 1 hour before a meal or 2 hours after a meal.  
Overall, lefamulin metabolism is low.  In general, the PK profiles of the metabolites in 
plasma resemble the profiles of the parent drug, resulting in similar or shorter terminal t1/2 
values.  BC-8041 was the only metabolite that could be identified exceeding the limit of 
10 % of total drug related systemic exposure at steady-state when lefamulin was given orally.  
Therefore, accumulation of any metabolite is unlikely.  BC-8041 exposure at steady-state in 
humans at lefamulin therapeutic doses is covered by toxicology studies in the cynomolgus 
monkey.  In drug-interaction studies performed with lefamulin, no issues of clinical 
significance have been identified so far.  In drug-interaction studies with midazolam or 
ketoconazole, lefamulin can be classified as having only a weak interaction with CYP3A 
after IV administration.  Oral co-administration of ketoconazole and lefamulin resulted in a 
moderate interaction, likely as a result of a reduced first-pass effect in the gut wall.  Based on 
the current safety profile of lefamulin and its main metabolite, BC-8041, it is not expected 
that a drug-drug interaction with potent CYP3A and p-gp inhibitors will be of sufficient 
clinical significance to justify a dose adjustment.  
Most recently, a Phase 1 study (NAB-BC 3781-1107) evaluating the safety, absolute and 
relative bioavailability, and the potential effect of co-administration of food on the 
pharmacokinetics of lefamulin administered as a 600 mg immediate release tablet compared 
with the IV formulation and a capsule formulation containing lefamulin API was completed. 
This study demonstrates that the AUC of lefamulin achieved with the 600 mg IR tablet 
formulation in the fasted state is comparable with that observed following administration of a 
150 mg IV dose. A lower Cmax (901 ng/mL), AUC0-inf (6 630 ng·h/mL), and bioavailability 
(21.0% versus 25.8 %) were observed with the 600 mg IR tablet in the fed compared with the 
fasted state. 


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1.5.2 
Efficacy 
The efficacy of lefamulin in humans has been demonstrated in a Phase 2 study of 
207 subjects with ABSSSI comparing 2 lefamulin doses (100 mg and 150 mg IV) with 
vancomycin (≥ 1000 mg) over 5-14 days.  This study enrolled subjects with moderate to 
severe skin infection, excluding any subjects with minor and uncomplicated infection.  In 
total, 90.8 % of subjects in the modified ITT population had S. aureus infection; 69.1 % of 
subjects had MRSA.  
In all populations evaluated, lefamulin 100 mg (IV) and 150 mg (IV) demonstrated 
consistently high clinical and microbiological success rates at several time points including 
the Early Clinical Response visit (Day 3) and Test of Cure (TOC), and 7 to 14 days after the 
completion of therapy (modified ITT population: 82.0 % and 82.4 % for 100 mg and 150 mg 
q12h treatment arms, respectively; 82.4 % for vancomycin).   
There were no significant differences in clinical success rates and microbiological 
eradication rates when assessed by baseline pathogen, particularly S. aureus and MRSA.  
Furthermore, no development of decreasing susceptibility was observed for lefamulin during 
the study (Paukner et al., 2012; Prince et al., 2013; Rubino et al., 2015).  
1.5.3 
Safety 
No changes in safety laboratory parameters, blood pressure (BP), heart rate (HR), or body 
temperature in any subject at any session in any study were of clinical concern.  After IV 
administration, pain and erythema at the infusion site were the most frequently reported 
findings.  The oral administration of lefamulin was generally well tolerated; infrequent mild 
and reversible gastrointestinal findings (nausea, abdominal pain and diarrhea) were reported.  
There were no systemic AEs of clinical concern and no drug-related SAEs in any study 
conducted to date.  None of the subjects met withdrawal or stopping criteria.    
In the Phase 2 study in subjects with ABSSSI, lefamulin (100 mg and 150 mg) administered 
intravenously over 5 to 14 days was generally well tolerated.  The incidence of treatment-
emergent adverse events (TEAEs) considered related to study drug was comparable across 
lefamulin treatment arms (34 % and 39 % in the 100 and 150 mg groups, respectively) versus 
subjects treated with vancomycin (53 %).  The types of TEAEs were consistent with a subject 
population under treatment for ABSSSI.  The most frequently reported treatment-related 
TEAEs in subjects receiving lefamulin were headache, nausea, and diarrhea.  Phlebitis at the 
infusion site was reported in 4 subjects in the lefamulin 100 mg group and 2 subjects in the 
150 mg group.  There was no increased incidence of phlebitis with increased dose.  The most 
frequently reported treatment-related TEAEs for the vancomycin group were headache, 
nausea, pruritus, generalized pruritus, and diarrhea.  All other related TEAEs were reported 
by 3 or fewer subjects in each treatment group.   
In the Phase 2 study, study drug was discontinued due to an AE for 6 subjects (8 events).  
These AEs were hyperhidrosis, vomiting, headache, respiratory failure (an SAE), cellulitis, 
infusion site pain, and dyspnea in the lefamulin groups; and drug eruption in the vancomycin 
group.  Six of these 8 events were considered related to study drug (hyperhidrosis, vomiting, 


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headache, infusion site pain, and dyspnea in the lefamulin groups and drug eruption in the 
vancomycin group).  Five subjects experienced an SAE; none was considered related to study 
drug.  These SAEs were abscess, respiratory failure, and cellulitis in the lefamulin groups; 
and accidental overdose (narcotics) and convulsion in the vancomycin group (Prince et al., 
2013). 
The effect of lefamulin on the cardiac conduction parameters of RR, QT, and QTcF has been 
closely monitored in all clinical studies.  A Cmax-dependent, predictable, and reproducible 
prolongation of the QT/QTcF interval has been observed.  A thorough analysis of ECGs in 
the Phase 2 study demonstrated that lefamulin prolonged cardiac depolarization and 
repolarization duration, but otherwise had a similar cardiac safety profile to that of 
vancomycin based on evaluations of 12-lead ECGs.  Therefore, it is expected that lefamulin 
will not produce large effects on cardiac de- and repolarization duration.  No drug-related 
cardiac AE — such as increase in ectopic ventricular activity or other cardiac arrhythmia — 
or clinically relevant ECG findings was reported during the conduct of the studies.  None of 
the protocol-defined stopping criteria (i.e., QTcF > 500 ms and ΔQTcF > 60 ms) was reached 
in any clinical study.  
In summary, the results of the Phase 2 study provide the first proof of concept for the 
systemic use of a pleuromutilin antibiotic in subjects and support the further clinical 
evaluation of lefamulin for therapy of serious infections.  Pharmacokinetic/ 
pharmacodynamic analyses suggest that lefamulin 150 mg IV q12h is an efficacious dosing 
regimen for Phase 3 studies.  Based on available safety data, lefamulin 150 mg IV q12h 
produced therapeutic exposures and demonstrated an acceptable benefit/risk profile for the 
treatment of infected subjects.  Oral doses of 600 mg lefamulin produced similar systemic 
exposures to 150 mg IV with a similar benefit/risk profile and were well tolerated in Phase 1 
studies with no signs or symptoms of clinical concern.  
This is the first Phase 3 study to be conducted in subjects with CABP to be treated only with 
oral administration of pleuromutilin antibiotic.  Subjects will receive treatment with either 
lefamulin or moxifloxacin, a standard of care treatment for CABP.  
2 
STUDY OBJECTIVES 
2.1 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). 


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2.2 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 ME-
TOC 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. 
2.3 Additional Objectives 
• Evaluate the Early Clinical Response by baseline pathogen in the microITT Analysis Set. 
• Evaluate the Investigator’s Assessment of Clinical Response at the End of Treatment 
(EOT) (i.e., within 2 days after the last dose of study drug) and at LFU in the mITT and 
CE Analysis Sets (CE-EOT for IACR at EOT and CE-LFU for IACR at LFU). 
• Evaluate the Investigator’s Assessment of Clinical Response by baseline pathogen at 
TOC and LFU in the microITT and ME Analysis Sets (ME-TOC for IACR at TOC and 
ME-LFU for IACR at LFU). 
• Evaluate the By-Subject Microbiologic Response at TOC in the microITT and ME-TOC 
Analysis Sets. 
• Evaluate the Early Clinical Response PLUS improvement in vital signs in the ITT 
Analysis Set. 
• Evaluate the plasma pharmacokinetics (PK) of lefamulin and its main metabolite, 
BC-8041, in the PK Analysis Set. 
• Explore a variety of health utilization variables and an investigational patient reported 
outcome (PRO) measure in subjects receiving lefamulin compared with subjects 
receiving comparator. 
 
3 
STUDY DESIGN 
This multicenter, multinational, randomized, double-blind, double-dummy, active-controlled 
efficacy and safety study in subjects with CABP will be conducted at approximately 160 
centers.  The planned enrollment is 738 subjects (369 subjects in the lefamulin group and 369 
subjects in the moxifloxacin group) with PORT Risk Class II, III, or IV.  Eligible subjects 
will be randomized 1:1 to lefamulin or moxifloxacin, using an interactive response 
technology (IRT).  Subject randomization will be stratified according to PORT Risk Class 
(Risk Class II vs. III/IV), geographic region (US vs. ex-US), and prior (single dose) short-
acting antibiotic therapy for CABP vs. none.   


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Subjects will be consented for the study prior to study assessments being performed and 
confirmation of eligibility (see Section 4).  Screening assessments will be performed within 
24 hours before first dose of study drug.   
Subjects will be assessed for response at the following time points during the study: 
• Early Clinical Assessment (ECA):  96 ± 24 hours after the first dose of study drug. 
• End of Treatment (EOT):  within 2 days after the last dose of study drug (NOTE: every 
attempt should be made to conduct the EOT visit within 1 day after the last dose of study 
drug.  However, if this is not logistically feasible [e.g., visit would need to be conducted 
over a weekend], then conducting the visit within 2 days is acceptable.). 
• Test of Cure (TOC):  5-10 days after the last dose of study drug. 
• Late Follow Up (LFU):  Day 30 (±3 days). 
 
As discussed in detail in Section 6.11, assessment of the 4 cardinal symptoms of CABP 
(dyspnea, cough, purulent sputum production, and chest pain) will be conducted daily; an 
assessment at 96 ± 24 hours after the first dose of study drug will determine Early Clinical 
Response (ECR) (as defined in the Primary Objective - FDA).  NOTE:  ECR will be 
determined programmatically based upon the Investigator’s assessment of the 4 cardinal 
symptoms of CABP; the decision to maintain the subject on study drug therapy will be made 
by the Investigator, based on all available data and his or her best clinical judgment.  In 
addition, as discussed in Section 6.12, the Investigator’s Assessment of Clinical Response 
(IACR) will be performed at the EOT, TOC and LFU visits (Success, Failure and 
Indeterminate at EOT and TOC; Sustained Success, Relapse and Indeterminate at LFU).   
Microbiological assessments will be performed at Screening, and throughout the study as 
clinically indicated (see Section 6.15).  Samples will be taken for Gram’s staining, for 
diagnostic tests (serology, urine antigen tests, molecular tests), and for culture and 
antimicrobial susceptibility testing.  Subjects who have confirmed S. aureus bacteremia must 
be withdrawn from the study.   
Safety will be assessed by monitoring vital signs and oxygen saturation, ECG measurements, 
safety laboratory parameters, and recording of adverse events (AEs) (see Sections 6.5, 6.4, 
6.13, and 7).  A Data Monitoring Committee (DMC) will review the safety data throughout 
the study (see Section 10.2).  
Blood samples for PK analyses will be collected from all subjects (see Section 6.14).  
Exploratory evaluation of a variety of health utilization variables (e.g., length of hospital 
stay, duration of antibiotic therapy, discharge status, discharge destination) as well as a PRO 
instrument (SF-12) will be administered.  The schedule of study procedures and an overview 
of study designs are provided in the synopsis (Table 1. Schedule of Assessments and 
Procedures and Figure 1. Study Design Overview). 


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3.1 Study Rationale 
Lefamulin (BC-3781), a semi-synthetic pleuromutilin, represents a new class of antibiotics 
for systemic use in the treatment of bacterial infections in humans.  Based on the antibacterial 
spectrum, safety and tolerability and PK in several Phase 1 and Phase 2 clinical studies, 
lefamulin should be a viable option for the treatment of CABP.  The adverse event profile 
observed in Phase 1 and 2 studies conducted to date demonstrates that lefamulin is well 
tolerated when administered IV at single doses up to 400 mg and q12h dosing for up to 
10 days.  Also, the oral safety profile observed in studies conducted to date demonstrates that 
600 mg of lefamulin is well tolerated when administered as single and repeat doses.  In the 
first study in which a systemically available pleuromutilin antibiotic was administered to a 
patient population, Study NAB-BC-3781-2001, lefamulin was found to be safe and effective 
in treating skin and skin structure infections and supported the continued clinical evaluation 
of lefamulin for serious infections.  In animal models of lung infections caused by 
S. pneumoniae or S. aureus, lefamulin showed enhanced activity when compared to the 
outcome in the murine thigh infection model.  Tissue distribution studies in healthy 
volunteers showed rapid lefamulin distribution, achieving therapeutic exposures in relevant 
target tissues for the treatment of both respiratory tract and skin infections.  Following a 
single 150 mg IV infusion, lefamulin showed higher exposure in epithelial lining fluid (ELF) 
as compared to the penetration into skin tissues (Zeitlinger et al., 2016).  Lefamulin is 
therefore being examined further in subjects with CABP. 
This study will examine whether lefamulin is non-inferior to moxifloxacin for the treatment 
of CABP in adults ≥ 18 years of age.  The comparison between lefamulin and comparator 
will be made with respect to the following assessments:  ECR (96 ± 24 hours after the first 
dose of study drug), as well as IACR at TOC.  The study will also compare safety between 
treatment groups and evaluate PK parameters of lefamulin in this population.  
This protocol is designed to address both the FDA and European Medicines Agency (EMA) 
regulatory requirements for the development of antibacterial agents to treat CABP, which 
differ regarding the preferred primary endpoint.  The EMA supports assessment of clinical 
response by Investigators at a test of cure (TOC) visit, while the FDA adopted assessment of 
clinical signs and symptoms of CABP on Days 3 to 5 as the recommended primary endpoint.  
To adequately accommodate these differences, 2 separate regional Statistical Analysis Plans 
(SAPs) will be utilized to analyze the data collected during this study.   
4 
STUDY POPULATION 
4.1 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. 


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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 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. 
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. 


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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. 
 
4.2 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 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 


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• 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 


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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. 
 
5 
STUDY DRUG ADMINISTRATION 
See Section 8 for a complete description of study drugs.  Instructions for the preparation of 
study drugs will be provided in a Pharmacy Manual. 
5.1 Selection of Lefamulin Doses 
This is the first study of an all oral regimen of lefamulin in subjects with CABP.  Based on 
results obtained from in vitro, animal and human experiments conducted to date, lefamulin is 
predicted to be well tolerated and efficacious in CABP.  To further explore and validate these 
findings, a pharmacometric approach was employed to assess a lefamulin dosing regimen of 
150mg IV q12h for the treatment of subjects with CABP caused by S. pneumoniae or 
S. aureus.  This approach has been utilized previously to support dose selection decisions in 
antibacterial drug development (Bhavnani et al., 2005; Bhavnani et al., 2009; Van Wart et al., 
2009).  An oral dose of 600 mg q12h (also being used in the IV-to-Oral Phase 3 study, NAB-
BC-3781-3101) has been shown to provide similar exposure (e.g., AUC) as the 150 mg IV 
dose.  Since the primary PD driver of lefamulin efficacy is total drug exposure (AUC), 
600 mg q12h given as an oral tablet is expected to provide equivalent therapeutic coverage as 
the 150 mg IV q12h regimen.  
A population PK model describing the disposition of lefamulin, non-clinical PK/PD targets 
for lefamulin activity against S. pneumoniae and S. aureus (derived from robust surveillance 
data for both pathogens), and Monte Carlo simulation were utilized to carry out PK/PD target 
attainment analyses. 
The population PK model used to conduct Monte Carlo simulations was developed using PK 
data from 11 Phase 1 studies of subjects who received IV or oral lefamulin and 1 Phase 2 
study of infected subjects with ABSSSI who received IV lefamulin.  Importantly, this dataset 
includes data describing the disposition of lefamulin in epithelial lining fluid (ELF) (obtained 
from a Phase 1 study; the relevant site for treatment of CABP) as well as in subjects 
experiencing active infection (the Phase 2 ABSSSI study).  Thus, the data used to construct 
the population PK model, the parameter estimates and associated variability incorporated into 
the Monte Carlo simulations are reflective of patients with CABP.  
Non-clinical PK/PD targets were identified using PK/PD relationships for efficacy derived 
from data from a neutropenic murine-lung infection model.  For these analyses, focus was 


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given to median 24 h AUC ELF/MIC ratio targets for S. pneumoniae and S. aureus associated 
with a 1-log10 CFU reduction from baseline as it has been demonstrated that patients with 
CABP who attain a 1-log10 CFU reduction from baseline have a higher rate of successful 
response compared to those patients who did not attain such PK/PD targets.  Lastly, in order 
to make inferences about dose for patients with S. pneumoniae or S. aureus bacteremia 
arising from CABP, the above-described analyses were also carried out using 24 h 
fAUC/MIC ratio targets for a 1-log10 CFU reduction from baseline efficacy for both 
pathogens.  The MIC distributions utilized were based on large, contemporary isolate 
libraries that represent > 1400 S. pneumoniae and > 5500 S. aureus isolates, accrued globally.  
Based on pharmacokinetic data derived from subjects receiving lefamulin 600 mg orally in 
the fasted state, the percent probabilities of attaining the median AUCELF/MIC ratio targets 
associated with a 1-log10 CFU reduction from baseline by MIC were >95 % at a MIC of 
0.5 µg/mL for S. pneumoniae and >97 % at a MIC of 0.25 µg/mL for S. aureus.  In the fed 
state (i.e. when subjects ingest a high-calorie, high-fat meal), the percent probabilities of 
achieving similar AUCELF/MIC ratio targets were >85% and >91% for S. pneumoniae and 
S. aureus, respectively.  Based upon these analyses, oral lefamulin will be administered in the 
current study either 1 hour before a meal or 2 hours after a subject ingests a meal to mitigate 
against any potential negative effect associated with co-administration with food. 
The results obtained from PK/PD target attainment analyses using a population PK model 
describing the disposition of lefamulin, non-clinical PK/PD targets for lefamulin against 
S. pneumoniae and S. aureus, robust surveillance data, and Monte Carlo simulation support 
the selection of lefamulin 600 mg PO q12h as well-tolerated, having a high probability of 
efficacy and an appropriate dosing regimen to be studied for the treatment of adult subjects 
with CABP.   
5.2 Selection of Comparator 
The Infectious Diseases Society of America (IDSA)/American Thoracic Society (ATS) 
treatment guidelines recommend the use of an anti-pneumococcal fluoroquinolone for 
hospitalized patients (not in the ICU) with CABP.  The guidelines also recommend a 
fluoroquinolone for outpatients with certain co-morbid conditions, outpatients who have used 
antimicrobials in the previous few months, and outpatients in regions with high rates of 
macrolide-resistant S. pneumonia regardless of co-morbidities or prior antibiotic use.  The 
European Society of Clinical Microbiology and Infectious Diseases also supports the use of 
fluoroquinolones for outpatient treatment of CABP in areas with increased bacterial 
resistance rates to tetracyclines and macrolides, as well as for empiric therapy in hospitalized 
patients with CABP.  These guidelines also note that respiratory quinolones may offer 
advantages over other therapy options for Legionella infection and that moxifloxacin has the 
highest antipneumococcal activity. 
Therefore, in order to provide a robust comparison of oral lefamulin to an oral CABP 
treatment regimen that would be appropriate in multiple regions and in patients with and 
without co-morbidities, respiratory fluoroquinolones were considered the comparator of 
choice.  Moxifloxacin was chosen over other respiratory fluoroquinolones because the labels 
of other fluoroquinolones have variable dose and/or treatment durations for CABP depending 


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on the specifics of approved labels in other countries.  In addition, other respiratory 
fluoroquinolones require adjustment in settings of renal dysfunction which would complicate 
treatment regimens and create challenges with maintaining the blind.    
5.3 Randomization 
Qualified subjects will be randomized to receive lefamulin or moxifloxacin in a 1:1 
allocation ratio.  Randomization may occur following the required assessments and prior to 
administration of the first dose of study drug. 
Randomization will be stratified by PORT Risk Class (Risk Class II vs. III and IV; see 
Section 6.3), geographic region (US vs. ex-US), and prior (single dose) short-acting 
antibiotic therapy for CABP vs. none using blocked randomization via IRT.  (NOTE:  No 
more than 25 % of randomized subjects will have received a single dose of a short-acting 
antibiotic).  A minimum of 50% of the total number of subjects randomized will have a 
PORT Risk Class of III or IV.   
The randomization schedule will be generated by Nabriva (or designee).  Subjects 
randomized into the study will be assigned the treatment corresponding to the next available 
number in the respective stratum of the computer-generated randomization schedule.  Prior to 
dosing, study personnel will contact the IRT system to obtain a treatment assignment.  
Subjects are considered randomized once a randomization number has been assigned 
regardless of whether the subject receives study drug.  Randomized subjects who do not 
receive study drug or who discontinue participation in the study for any reason will not be 
replaced.   
5.4 Study Drug Treatment 
The duration of blinded study drug administration will be 7 days.   
Subjects randomized to lefamulin will receive oral lefamulin 600 mg q12h for 5 days 
(10 doses) and oral moxifloxacin placebo q24h for 7 days (7 doses).  Subjects randomized to 
moxifloxacin will receive oral moxifloxacin 400 mg q24h for 7 days (7 doses) and oral 
lefamulin placebo q12h for 5 days (10 doses).   
On Day 1, study personnel will administer the first dose of study drug at the study site to all 
subjects, as soon as possible after the diagnosis of CABP and completion of all required 
Day 1 procedures as outlined in Table 1.  While subjects are hospitalized, all doses of study 
drug will be administered by hospital staff or study personnel.   
For Outpatients, or in the event a subject is discharged from the hospital during the study 
drug administration period, an adequate supply of study drug will be dispensed for self-
administration at home.  Subjects will be provided instructions regarding the dosing 
schedule.  Subjects may self-administer oral study drug at home with the following 
exception:  Study personnel will advise subjects who are Outpatients that they must return to 
the study site to assess CABP signs and symptoms at 96 ± 24 hours after the first dose of 
study drug (see Section 6.11).  Study personnel will inform Outpatients as to the timing of 


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this required study site visit.  Subjects will be advised not to take their first dose of study 
drug at home that day, rather to bring their blister packs (used and unused) to the study site 
where they will take their dose while supervised, so that specific assessments can be 
performed both prior to and after taking the dose (see Sections 6.4 [ECGs] and 6.14 [PK]). 
On Study Day 1, if q12h dosing is not feasible, the 1st and 2nd doses may be administered as 
close as 8 hours apart, in order to allow 2 doses to be given on Day 1.  In this circumstance, 
the subject’s dosing schedule should be adjusted on Day 2 to a regular q12h morning and 
evening schedule.  Subsequently, every effort should be made to maintain a q12h dosing 
schedule.  When this is not possible, it is acceptable to administer doses within 4 hours of the 
scheduled dosing time (i.e., a minimum of 8 hours between doses). 
Study drug should be administered at least 1 hour before a meal or 2 hours after a meal.  
However, in the event that a subject has taken any of the following − antacids containing 
aluminum, products containing iron, or multivitamins containing zinc − study drug should be 
administered 2 hours before or 4 hours after consuming any of these medications.  Doses 
should be administered with approximately 240 mL (8 ounces) of water.  
The lot numbers and expiration dates of all study drugs supplied will be recorded. 
5.5 Blinding 
This is a double-blind, double-dummy study.   
The study personnel, Sponsor (except as specified), and subject will not know what study 
drug is being administered.  
Study drugs will be provided in blister packs and all study drug administration will utilize a 
“double-dummy” technique.  Details about the double-dummy design and blinding are 
provided in a Study Procedure Manual.  Lefamulin or matching placebo tablets will be 
provided by the Sponsor.  Moxifloxacin will be over encapsulated; matching placebo tablets 
will also be provided by the Sponsor.   
A member(s) of the Sponsor’s Clinical Pharmacology group (or designee) will be unblinded 
to treatment assignment, as appropriate, in order to perform PK/PD assessments.  A Data 
Monitoring Committee (DMC) will review study data by masked treatment group in 
accordance with the DMC Charter.  In addition, as needed to meet regulatory reporting 
requirements on a country-by-country basis, designated pharmacovigilance personnel may be 
unblinded to treatment status of individual patients.  In this circumstance, and if there are no 
other concerns, neither the Sponsor nor study personnel will be unblinded to treatment status.   
5.6 Unblinding of Therapy Assignments 
Unblinding of therapy assignment may be requested in an emergency if unblinding is 
considered necessary for medical management of the subject.  In such a case, the Investigator 
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The Sponsor (or designee) must document any such communication with an Investigator.  
The IRT system will record the date of any unblinding of individual therapy assignments.   
The study will be unblinded for all analyses after the study database is locked, which will 
occur after the last subject randomized in the study has completed the 30-day post treatment 
follow-up assessment period.   
5.7 Adherence 
If subjects are Inpatient, hospital staff or study personnel will administer all doses of study 
drug and will record the date and time of dosing.  In addition, for Outpatients, any doses 
administered under supervision of study personnel in conjunction with assessments/ 
procedures (e.g., PK sampling, ECGs), study personnel will also record the date and time of 
those doses. 
Outpatient subjects will be instructed to bring all used and unused blister packs to each study 
visit so that drug accountability can be reviewed by study personnel.  Study personnel will 
collect all blister packs (empty or containing unused study drug) at the EOT visit (see Section 
8.3.3).  The total number of pills dispensed on Day 1 and returned at the EOT visit will be 
recorded in the eCRF. 
5.8 Occupational Safety 
Lefamulin and moxifloxacin being used in this study are not expected to pose a significant 
occupational safety risk to study personnel under normal conditions of use and 
administration.  
A Material Safety Data Sheet describing occupational hazards and recommended handling 
precautions either will be provided to the Investigator, where this is required by local laws, or 
is available upon request from Nabriva Therapeutics AG. 
6 
STUDY ASSESSMENTS AND PROCEDURES 
A schedule of study procedures is presented in Table 1.  Subjects meeting the eligibility 
criteria listed in Section 4 may be enrolled in the study after the nature and purpose of the 
protocol have been explained and written informed consent to participate has been 
voluntarily given by the subject or the subject’s legally authorized representative in 
accordance with local regulations.   
Study personnel must complete all screening procedures after informed consent is signed and 
prior to the first dose of study drug.  Note: Assessments performed as part of routine standard 
of care prior to consent (e.g., chest X-ray, blood culture) may be used to satisfy study 
screening requirements; however, no study specific procedures may be performed prior to 
informed consent.   
During the Study Drug Administration Period, the first dose of study drug is counted as 
0 Hour on Day 1.  The Investigator should make every effort to perform procedures at the 


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scheduled times and to record the actual time of the procedures, where appropriate, in the 
subject's eCRF.   
For subjects who are screened (i.e., those with signed written informed consent) but who are 
not randomized, the reason for screening failure will be recorded. 
6.1 Inpatient and Outpatient Assessments 
As shown in the Schedule of Assessments and Procedures (see Table 1), the timing of 
assessments and procedures during the Study Drug Administration Period (Days 1-7) may 
differ between subjects who are Inpatient versus Outpatient.   
Hospitalization is not a requirement for this study (i.e., subjects do not need to be admitted to 
the hospital to participate and those who are admitted may be discharged at any time at the 
discretion of the investigator).   
While Inpatient, all assessments and procedures (including daily study drug administration) 
will be conducted at the study site/hospital in accordance with the schedule shown in Table 1 
(Screening/Baseline through LFU).  While Outpatient, the study site must contact the 
subjects by telephone daily to assess CABP signs and symptoms, assess for the presence of 
AEs, and determine changes in concomitant medications (see Sections 6.11, 7, and 6.8.2).   
All subjects, including Outpatients, must be evaluated by at the investigational site by study 
personnel at the following time points/visits:  Screening/Baseline; Day 1; 96 ± 24 hours after 
the first dose of study drug; EOT; TOC; and LFU (see Table 1).  
6.1.1 
Outpatient Visit for ECR Assessment and Other Site Procedures 
Outpatients must return to the site for a face-to-face visit with study personnel 96 ± 24 hours 
(i.e., 72 to 120 hours) after the first dose of study drug.  Study personnel will inform 
Outpatients as to the timing of this required study site visit in the course of the daily 
telephone contacts. 
The purpose of this site visit is to assess CABP signs and symptoms which will be used to 
programmatically determine the ECR, as well as to perform other procedures that cannot be 
done by telephone (i.e., ECG, blood samples for PK analysis, blood samples for safety 
assessments, vital signs, and physical examination).  
ECGs and blood samples for PK analysis must be performed within specified time windows 
before and after study drug administration.  Therefore, it is critical that the subject be 
instructed to not take their first dose of study drug at home that day, rather to bring all their 
blister packs (used and unused) to the study site.  The dose associated with the outpatient 
visit for ECR assessment and other site procedures will be taken under supervision of study 
personnel.  In addition, as discussed in Sections 5.4 and 6.17, study personnel will remind 
subjects regarding adherence to the food and supplement restrictions when scheduling this 
visit.   


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6.2 Medical/Surgical History and Physical Examination 
A medical and surgical history will be taken at Screening.  All medical history findings that 
have been present or active within the 5 years prior to enrollment will be entered into the 
eCRF regardless of clinical relevance or presence at study start.  Medical history findings 
that have not been present within the 5 years prior to enrollment will be recorded if deemed 
clinically relevant by the Investigator to the conduct of the study.  The medical history should 
include drug allergy history, past and present smoking status, influenza virus and 
pneumococcal vaccination history, as well as the presence of influenza virus infection during 
the current illness.   
A complete physical examination will be performed by the Investigator at Screening.  At the 
time points specified in Table 1, subsequent directed physical examinations will be 
performed according to standard institutional practices and must be documented in source 
documents. 
Body weight and height will be measured at Screening only.   
6.3 PORT Risk Class Assessment 
Study personnel will determine the subject’s PORT Score (Table 2) and subsequent PORT 
Risk Class (Table 3) at Screening only. 


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Table 2. 
PORT Score Determination 
Patient Characteristic 
Point Assignment 
Age 
1 point for each year of age 
Female 
–10 if yes 
Neoplastic disease history 
+30 if yes 
Liver disease 
+20 if yes 
Congestive heart failure 
+10 if yes 
Cerebrovascular disease 
+10 if yes 
Renal disease 
+10 if yes 
Altered mental status 
+20 if yes 
Respiratory rate ≥ 30 breaths/min 
+20 if yes 
Systolic blood pressure < 90 mmHg 
+20 if yes 
Temperature < 35 ºC (95 ºF) or ≥ 40 ºC (104 ºF) 
+15 if yes 
Pulse ≥125 beats/min 
+10 if yes 
pH <7.35 (from ABG) 
+30 if yes 
(+0 if ABG not obtained) 
Blood urea nitrogen > 30 mg/dL (Urea > 11 mmol/L) 
+20 if yes 
Sodium < 130 mmol/L 
+20 if yes 
Glucose ≥ 250 mg/dL (≥14 mmol/L) 
+10 if yes 
Hematocrit < 30 % 
+10 if yes 
Partial pressure of arterial O2 < 60 mmHg (from ABG if 
medically indicated) or O2 saturation < 90 % (by pulse 
oximetry) 
+10 if yes 
Pleural effusion on radiograph 
+10 if yes 
 
 
 
PORT SCORE 
Sum of Applicable Numbers 
Above 
 
Table 3. 
PORT Risk Class Determination 
PORT Risk Class 
PORT Score 
I (Ineligible for Study) 
0-50 
II  
51-70 
III 
71-90 
IV 
91-130 
V (Ineligible for Study) 
> 130 
 


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6.4 Electrocardiograms 
Triplicate 12-lead ECGs will be performed within a 5-minute interval at time points specified 
in Table 1.  The subject should be stabilized in a supine position for 5 minutes before 
recording the ECG.  ECG recordings should allow a full assessment of QT intervals.  
Machine-read values for QTc/QTcF will be evaluated for determination of eligibility at 
Screening.  If the quality of the ECG is insufficient then it must be repeated.  All ECG data 
must be reviewed by the Investigator or designee and any findings of clinical significance 
found following Screening will be recorded as AEs in the eCRF.  In addition, advice may be 
sought from appropriate cardiologists, if necessary.  ECGs will be made available to the 
Sponsor for review and will be sent to a Cardiac Core Laboratory for further evaluation.  
If Screening and Day 1 are on the same day, the Screening ECG can serve as the Day 1 ECG 
prior to the first dose of study drug; an additional ECG must be performed 1-3 hours after 
administration of first dose.   
On Day 4 (Inpatients) or 96 ± 24 hour post first dose (Outpatients), ECGs in triplicate are 
required prior to the first dose of study drug and again within 1-3 hours after the first dose of 
study drug.  Thus, Outpatients will be advised not to take their first dose of study drug at 
home that day, rather to bring their blister packs (used and unused) to the study site where 
they will take their dose while supervised so that the ECGs can be performed both prior to 
and after taking the dose.  
As discussed in detail in Section 6.18.3, if at any time the subject demonstrates an average 
QTcF value > 500 ms (mean of 3 ECGs at any time point), or an average QTcF value 
> 480 ms with a concurrent increase in average QTcF value of > 60 ms (mean of 3 post-dose 
ECGs compared to mean pre-dose ECG’s taken on that day) study drug will be discontinued.   
6.5 Vital Signs and Oxygen Saturation 
Vital signs (HR, BP, respiratory rate and body temperature) and oxygen saturation will be 
recorded at time points specified in Table 1.  Blood pressure and heart rate assessments will 
be performed according to standard practice at the clinical sites.  Vital signs associated with 
the highest temperature after the first dose of study drug will be recorded in the eCRF.   
In addition, if the subject is receiving supplemental oxygen therapy, the amount given will be 
recorded in the eCRF. 
All subjects will have vital signs and O2 saturation evaluated at Screening/Baseline and 
Day 1.  If screening/baseline and Day 1 occur on the same calendar day, vital signs and O2 
saturation do not need to be repeated.  All subjects will also have assessments at EOT and 
TOC; at LFU, vital signs should be performed if medically indicated.  If EOT and the last 
day of study drug are the same day, vital signs do not need to be repeated, they may be 
recorded once on that day (i.e., as part of the EOT assessment). 
For Inpatients, in addition to the above time points, vital signs and O2 saturation will be 
measured daily and recorded.  If multiple vital signs are taken on a study day, the highest 


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temperature and the vital signs associated with that high temperature will be recorded.  For 
Outpatients, in addition to the above time points, vital signs and saturation will be measured 
at the study visit scheduled 96 ± 24 hour after the first dose of study drug (see Section 6.1.1).   
Vital signs measurements are to be repeated if clinically significant changes or machine 
errors occur.  Out of range BP and HR will be repeated at the Investigator’s discretion.  
Semi-supine BP and HR will be measured more frequently if warranted by the clinical 
condition of the subject.   
6.6 Chest X-Ray or CT Scan 
Chest x-ray will be performed at the Screening/Baseline visit as specified in Table 1 and 
evaluated by the Investigator (or designee) to qualify a subject for enrollment; however, the 
imaging study must also be interpreted by a radiologist.  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.  The test type and date and the 
Investigator’s and radiologist’s reading/interpretation will be recorded in the eCRF.   
6.7 Arterial Blood Gases 
Study sites are not required to measure arterial blood gases (PaO2, PaCO2) or pH.  However, 
if these data are available, they should be recorded in the eCRF.   
6.8 Prior and Concomitant Medications 
Prior and concomitant medications that will be recorded include prescription medications, 
dietary supplements/vitamins, and over-the-counter medications.  Topical medications will 
be recorded only if used as treatment for an AE.  The minimum requirement is that drug 
name, indication and the stop and start dates of administration are to be recorded.  For the 
following agents, the drug dose, route and frequency will also be collected in the eCRF: 
• Systemic antibacterial agents 
• Corticosteroids 
Additionally, for systemic antibacterial agents start time and stop time will be recorded. 
6.8.1 
Prior Medications 
A medication history will be taken at Screening.  All medications taken within 1 week prior 
to Day 1 will be entered into the eCRF. 
6.8.2 
Concomitant Medication 
All concomitant medications taken during the study will be recorded in the subject's eCRF.  
In the case that additional antibiotic treatment is required for the current episode of CABP, 
the subject’s study drug will be discontinued and they will be considered to have an IACR of 


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Failure; however, subjects will continue to be followed for safety as detailed in Section 
6.18.1.  
Other systemic antibacterial agents that are potentially effective against pathogens associated 
with CABP should not be administered during the study except in the case of CABP 
treatment failure or when medically necessary for treatment of a concomitant infection.  The 
following antibacterial agents are permitted: 
• Anti-tuberculosis drugs isoniazid, ethambutol and pyrazinamide 
• Cinoxacin 
• Dapsone 
• Enoxacin 
• Fidaxomicin 
• Methenamine Mandelate 
• Metronidazole 
• Naladixic Acid 
• Nitrofurantoin 
• Norfloxacin 
• Oral Vancomycin 
Although all drugs that are metabolized by CYP3A4 are not prohibited, they should only be 
used when necessary and with appropriate subject monitoring.  In vitro studies demonstrated 
that lefamulin may inhibit the metabolism of substrates of CYP3A4; however, results 
obtained from Phase 1 drug interaction studies performed demonstrate that lefamulin has a 
marginal effect on CYP3A4 inhibition in humans and no change in lefamulin’s dose is 
required.  In addition, all drugs that are P-glycoprotein substrates are not prohibited; 
however, they should only be used when necessary and with appropriate subject monitoring. 
A list of drugs that are CYP3A4 substrates and P-glycoprotein substrates is provided in 
Appendix 3.   
Close monitoring is recommended in subjects who require medication that can reduce 
potassium levels (e.g., loop and thiazide-type diuretics, laxatives and enemas [high doses], 
corticosteroids, amphotericin B) or medication that is associated with clinically significant 
bradycardia. 
6.9 Prohibited Medications 
The following medications are prohibited:   
• Prior (within 72 hours before randomization) oral or IV antibacterials for CABP.   
- 
NOTE:  Up to 25 % of subjects may have a single dose of a short-acting antibiotic for 
the current episode of CABP within 72 hours of randomization.   


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- 
EXCEPTION:  A subject who has received > 48 hours of prior systemic antibacterial 
therapy for the current episode of CABP with unequivocal evidence of treatment 
failure (i.e., worsening signs and symptoms) and the isolation of an organism from 
blood or respiratory tract that is resistant to the prior systemic antibacterial therapy, 
provided the organism is not resistant to fluoroquinolones. 
• Agents that prolong the QT interval (see Appendix 5) 
• Systemic corticosteroids at a dose ≥ 20 mg per day (prednisone equivalent) 
• Anti-epilepsy or seizure medication 
• Strong p-glycoprotein inhibitors (see Appendix 4) [NOTE:  The use of contraceptives 
containing progesterone is not permitted.] 
• Strong CYP3A inhibitors or inducers (see Appendix 4) 
 
6.10 Nonpharmacologic Treatments and Procedures 
Nonpharmacologic treatments and procedures (e.g., surgical, diagnostic) that occur during 
the study will be entered into the eCRF, including the date and reason for the 
treatment/procedure. 
6.11 Assessment of Clinical Signs and Symptoms of CABP 
Clinical signs and symptoms of CABP will be assessed at the time points specified in 
Table 1.  Signs and symptoms are not obtained at TOC or LFU if the subject previously had 
an IACR of Failure.  
The intensity of each symptom (dyspnea, cough, sputum production, and chest pain) will be 
evaluated and recorded as absent, mild, moderate or severe based on the definitions in 
Table 4 below.  While Inpatient, all subjects will have clinical signs and symptom of CABP 
assessed daily.   
Subjects who are discharged to home will be contacted by phone to assess signs and 
symptoms of CABP daily while on study drug with the following exception:   
All subjects must have a study site visit 96 ± 24 hours after the first dose of 
study drug to assess CABP signs and symptoms.  Study personnel will inform 
Outpatients as to the timing of this required study site visit (see Section 6.1.1).   


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Table 4. 
Definitions of Symptom Intensity 
Symptom 
Absent (0) 
Mild (1) 
Moderate (2) 
Severe (3) 
Dyspnea 
Resolution (to pre-CABP 
baseline) or absence of 
dyspnea 
Dyspnea on 
exertion (e.g., 
climbing stairs) 
Dyspnea with 
normal/routine 
activities (e.g., 
walking) 
Dyspnea at rest or 
requiring oxygen 
therapy 
Cough 
Resolution (to pre-CABP 
baseline) or absence of 
cough 
Transient, does 
not interfere with 
normal activity 
Frequent, 
interferes with 
normal activity or 
sleep 
Constant, 
interferes with 
most or all activity 
or sleep 
Production of 
purulent sputum 
Resolution (to pre-CABP 
baseline) or absence of 
sputum production 
Sputum 
production rarely 
causes difficulty 
or distress 
Sputum production 
often causes 
difficulty or 
distress 
Constant difficulty 
with sputum 
production 
Chest pain 
Resolution or absence of 
chest pain related to 
CABP 
Transient, does 
not interfere with 
normal activity 
Frequent, 
interferes with 
normal activity or 
sleep 
Constant, 
interferes with 
most or all activity 
or sleep 
 
The assessment of the clinical signs and symptoms of CABP will be used to determine ECR 
which will be calculated programmatically.  The decision to maintain a subject on study 
drug therapy will be made by the Investigator, based on all available data and his or her best 
clinical judgment.  
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 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 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 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. 


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Subjects will be programmatically defined as an Indeterminate if the following criterion is 
met: 
• The symptom data are missing such that a response or non-response cannot be 
determined.  
 
6.12 Investigator’s Assessment of Clinical Response (IACR) 
The Investigator will assess Clinical Response at time points specified in Table 1. 
6.12.1 
Investigator’s Assessment of Clinical Response (IACR) at End of Treatment 
and Test of Cure 
The Investigator’s Assessment of Clinical Response will be classified as Success, Failure or 
Indeterminate at EOT and TOC based on the following criteria: 
• 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 the 
treatment of the current episode of CABP. 
- 
Bacteremia has worsened or failed to improve resulting in administration of non-
study 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. 
NOTE:  Subjects who have an IACR of Failure at EOT will not have an IACR assessed at 
TOC and will be considered to have an IACR of Failure at TOC. 
6.12.2 
Investigator’s Assessment of Clinical Response (IACR) at Late Follow Up 
For subjects who do not have an IACR of Failure at TOC, a determination of Clinical 
Response (Sustained Success, Relapse or Indeterminate) will be made at LFU based on the 
following criteria: 


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• Sustained Success:  The subject’s clinical signs and symptoms remain resolved or 
further improved such that no additional antibacterial therapy has been administered for 
the treatment of the current episode of CABP. 
• Relapse:  The subject was a Clinical Success at TOC, however, any of the following are 
met:  
- 
Clinical signs and symptoms of CABP have recurred such that additional 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 recurred such 
that additional non-study antibacterial therapy is administered for the treatment of the 
current episode of CABP. 
- 
Recurrent bacteremia resulting in administration of non-study antibacterial therapy. 
- 
Death from any cause. 
• Indeterminate: Insufficient information is available to determine Sustained Success or 
Relapse, specifically lost to follow-up. 
 
6.13 Clinical Laboratory Tests (Safety) 
Safety laboratory tests will be performed at the time points specified in Table 1 and sent to a 
Central Laboratory. Blood samples sent to the local laboratory for the purposes of 
determining study eligibility must be repeated and sent to the central laboratory following 
enrollment.  Blood and/or urine will be collected at LFU only if the subject had an abnormal 
(high/low flag) result at TOC.  Additional tests may be performed at the discretion of the 
Investigator if deemed clinically appropriate.  Subjects treated as outpatients must agree to 
return to the site for blood draws as indicated in Table 1 (i.e., 96 ± 24 hour post first dose [see 
Section 6.1.1], EOT, and TOC visits). 
A full list of the clinical laboratory tests that will be performed and analyzed can be found in 
Appendix 1.  A urine pregnancy test will be performed at the site on all females unless 
surgically sterile or at least 2 years post-menopausal.  A negative urine pregnancy test is 
required prior to randomization.  Serum must be collected on Day 1 prior to 1st dose and sent 
to the central lab for confirmatory testing. 
Any safety laboratory results outside the normal range will be repeated at the discretion of 
the Investigator and will be evaluated by the Investigator or designee as “clinically 
significant” or “not clinically significant.”  Any clinically significant value should be 
repeated as necessary and followed until resolution. 
6.14 Sample Collection for Pharmacokinetic Analysis 
Blood samples for PK analysis of lefamulin and its main metabolite, BC-8041, will be 
collected in association with the first dose of study drug on Day 1 and Day 4 (see Table 5).   


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If PK sampling for Inpatients on Day 4 is not feasible, it can be done relative to the first dose 
on Day 5.  For Outpatients, PK sampling will be done during the 96 ± 24 hours post 1st dose 
visit.  Subjects will be instructed to not take their first dose of study drug at home that day, 
rather to bring all blister packs (used and unused) to the study site.  Following collection of 
the pre-dose blood sample, subjects will take their dose of study drug under supervision of 
study personnel, and subsequent PK blood samples will be collected.   
Table 5. 
Sample Collection Time Points for the Determination of Lefamulin 
Plasma Concentrations following Oral Administration 
PK Sample Time Point 
Day 1 and Day 4 or 96 ± 24 hours post 1st dose a,b 
Within 1 h prior to the first dose of study drug 
X 
1-2 h after the first dose of study drug 
X 
3-4 h after the first dose of study drug 
X 
8-9 h after the first dose of study drug c 
X 
a: 
Day 1 [all subjects] and Day 4 [Inpatients] or 96  ±  24 hours post first dose [Outpatients] 
b: 
If Day 4 PK sampling for Inpatients is not feasible, it can be done relative to the morning dose on Day 5. 
c: 
The 8-9 h sample is required for inpatients.  The 8-9 h sample is optional for outpatients; however, it 
should be obtained if logistically feasible. 
 
NOTE:  It is essential to record the exact time of dosing on those days when PK samples are 
obtained (see Section 5.7 – Adherence).  Documentation of the exact blood sampling time 
points for population PK analysis is also essential. 
6.14.1 
Sample Collection Methodology  
Blood samples for PK analysis will be collected into tubes containing K3EDTA, immediately 
chilled on crushed ice, and then centrifuged to separate plasma.  Promptly following 
centrifugation, plasma specimens (2 aliquots: 1 for bioanalysis and 1 for backup) will be 
immediately deep frozen and stored at -20 ºC or cooler until transported to the central 
laboratory.  The total time period from blood withdrawal to storage of plasma at -20 ºC 
should not exceed 60 minutes   
Additional information and instructions for blood sample collection is provided in the 
Laboratory Manual. 
6.14.2 
Assay Methodology  
Plasma samples from subjects who received lefamulin will be analyzed for the concentration 
of lefamulin and its main metabolite, BC-8041, using a validated liquid chromatography-
tandem mass spectrometry method at the bioanalytical laboratory A&M GmbH (Bergheim, 
Germany).  Samples from subjects who did not receive lefamulin (i.e., received the 
comparator) will not be analyzed.  Scientists at the bioanalytical laboratory will be unblinded 
before bioanalysis. 


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6.15 Microbiological Assessment 
The following microbiological assessments will be performed at the time points described in 
Table 1.  Details regarding storage of samples and shipment to the central laboratory can be 
found in the Laboratory Manual. 
6.15.1 
Sputum Samples 
• A sputum sample will be taken at Screening for Gram’s staining, culture and 
susceptibility testing at the local/regional laboratory.  If a subject is unable to produce an 
adequate (> 25 polymorphonuclear (PMN) cells AND < 10 squamous epithelial cells per 
LPF) sputum sample at Screening, a repeat specimen should be obtained, if possible, 
within 24 hours after the first dose of study drug. Gram’s stain and culture results from 
the local/regional laboratory will be recorded in the eCRF. 
• If possible, subjects who are discontinued from study drug due to clinical failure should 
have repeat cultures collected for microbiologic culture prior to switching to alternate 
appropriate therapy. 
• Sputum samples will only be taken at subsequent visits when clinically indicated.  
• All organisms isolated from sputum samples which are not considered contaminants will 
be sent to the central laboratory for confirmatory identification and susceptibility testing.  
The following organisms, if isolated, will always be sent to the central laboratory for 
confirmatory identification and susceptibility testing: S. pneumoniae, S. aureus, 
S. pyogenes, Haemophilus spp., M. catarrhalis, L. pneumophila, C. pneumoniae, and 
M. pneumoniae. Further details regarding organisms which should be sent to the central 
microbiology laboratory, including a list of organisms which if isolated will be classified 
as contaminants, can be found in the Laboratory Manual. 
• Gram’s stain slides will be sent to the central laboratory for a confirmatory reading.  The 
stained slide read by the local/regional laboratory as well as an unstained slide will be 
sent to the central laboratory. 
• A portion of each Screening sputum sample taken will be frozen until shipment to the 
central laboratory.  Frozen samples will be analyzed by the central microbiological 
laboratory using real-time quantitative PCR for common CABP pathogens.  Additionally, 
for subjects who have a positive urinary antigen test for Legionella spp. the frozen 
sputum will be utilized for L. pneumophila isolation and susceptibility testing.   
6.15.2 
Bronchoalveolar Lavage Samples (BAL)  
A BAL sample is not required per the protocol and will be collected only if clinically 
indicated per the Investigator, and sent to the local/regional laboratory for Gram’s staining, 
culture and susceptibility testing.  However, if the subject undergoes a repeat bronchoscopy 
as clinically warranted per the investigator, a repeat BAL sample should be sent for Gram’s 
staining and culture.  All organisms isolated from BAL samples, which are not considered 
contaminants, will be sent to the central laboratory for confirmatory identification and 


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susceptibility testing.  Culture results from the local/regional laboratory will be recorded in 
the eCRF. 
6.15.3 
Pleural Fluid Samples 
A pleural fluid sample is not required per the protocol, and will be collected only if clinically 
indicated per the Investigator and sent to the local/regional laboratory for Gram’s staining, 
culture and susceptibility testing.  However, if the subject undergoes a repeat thoracentesis as 
clinically warranted per the Investigator, a repeat pleural fluid sample should be sent for 
Gram’s staining and culture. If possible, pleural fluid samples should be incubated in blood 
culture bottles for optimal pathogen recovery.  All organisms isolated from pleural fluid 
samples which are not considered contaminants will be sent to the central laboratory for 
confirmatory identification and susceptibility testing.  Culture results from the local/regional 
laboratory will be recorded in the eCRF. 
6.15.4 
Blood Cultures 
Two sets of blood cultures via venipuncture will be obtained at Screening and sent to the 
local/regional laboratory.  Repeat blood samples for culture should be taken as clinically 
indicated during the study.  Blood cultures should be repeated after a positive result until 
sterilization is documented.  All organisms isolated from blood cultures which are not 
considered contaminants will be sent to the central laboratory for confirmatory identification 
and susceptibility testing.  Subjects who have confirmed bacteremia should have blood 
samples collected for microbiologic culture prior to switch to alternate appropriate therapy.  
Subjects who have confirmed S. aureus bacteremia must be withdrawn from the study.  
Culture results from the local/regional laboratory will be recorded in the eCRF. 
6.15.5 
Serological Testing 
Blood samples will be collected at Screening and LFU, and sent frozen to the central 
laboratory for serologic tests for M. pneumoniae, C. pneumoniae, and L. pneumophila.   
6.15.6 
Urine Antigen Test 
A urine sample will be taken at Screening and tested at the clinical site for L. pneumophila 
and S. pneumoniae antigen.  Results will be recorded in the eCRF. Clinical sites that are 
unable to perform urinary antigen testing will send urine to the central laboratory for testing.  
Subjects who have urinary antigen test positive for L. pneumophila at Screening, or sites that 
are sending urine to the central laboratory for urinary antigen testing, will have a portion of 
the sputum sample collected at Screening sent to the central laboratory for L. pneumophila 
testing as described above (Section 6.15.1). 
6.15.7 
Oropharyngeal Specimen 
An oropharyngeal specimen (2 swabs) will be obtained at Screening and sent to the central 
laboratory/specialty laboratory for M. pneumoniae culture, susceptibility testing, as well as 
identification by PCR.  Oropharyngeal specimens must be frozen until shipment to the 
central laboratory.   


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6.15.8 
Nasopharyngeal Specimen 
A nasopharyngeal specimen (1 swab) will be obtained at Screening and sent to the central 
laboratory/specialty laboratory for S. pneumoniae culture, susceptibility testing, as well as 
identification by PCR.  Culture, susceptibility testing, as well as identification by PCR may 
also be performed for H. influenzae.  Nasopharyngeal specimens must be frozen until 
shipment to the central laboratory.   
6.16 Health Utilization and Patient Reported Outcome 
Exploratory evaluation of a variety of health utilization variables (e.g., length of hospital 
stay, duration of antibiotic therapy, discharge status, discharge destination) as well as a PRO 
instrument (SF-12) will be administered.  Details for this exploratory analysis will be 
presented in a separate SAP and results will be presented in a stand-alone clinical study 
report. 
6.17 Food and Beverage Restrictions  
Subjects should refrain from drinking alcohol throughout study drug administration period. 
In addition, as discussed in Section 5.4, study drug should be administered at least 1 hour 
before a meal or 2 hours after a meal.  However, in the event that a subject has taken any of 
the following − antacids containing aluminum, products containing iron, or multivitamins 
containing zinc − study drug should be administered 2 hours before or 4 hours after 
consuming any of these medications.   
6.18 Discontinuation from Treatment or Study 
Subjects are free to withdraw from the study at any time for any reason.  Subjects may be 
withdrawn from study at the discretion of the Principal Investigator or Sub-Investigator at 
any time.  Once a subject has been withdrawn from the study they may not be re-entered.  
Subjects who withdraw or who are withdrawn from the study will not be replaced.  If a 
subject is discontinued from treatment or from the study, the reason for discontinuation will 
be collected in the eCRF. 
6.18.1 
Discontinuation from Treatment 
A subject may be discontinued prematurely from study drug treatment for the following 
reasons: 
• Lack of efficacy (i.e., requirement for additional non-study antibacterial therapy to treat 
the current episode of CABP) 
• Adverse event 
• Withdrawal by subject [specify reason in the eCRF] 
• Lost to follow-up 


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• Physician decision (i.e., Investigator decision based on protocol violation, assessment that 
it is not in the subject’s best interest to continue, or other reason) [specify reason in the 
eCRF] 
• Sponsor decision [specify reason in the eCRF] 
If a subject is prematurely withdrawn from study drug treatment, the Investigator should 
make every effort to retain the subject in the study and perform all procedures scheduled for 
the EOT, TOC, and LFU visits.  Any subject withdrawn from treatment due to an AE, SAE, 
or clinically significant abnormal laboratory test value will be evaluated by the Investigator, 
or a monitoring physician, and will be treated and/or followed up until the symptoms or 
values have either resolved or are assessed as stable by the Investigator.  
6.18.2 
Discontinuation from Study 
A subject may be discontinued prematurely from the study for the following reasons: 
• Withdrawal by subject [specify reason in the eCRF] 
• Lost to follow-up 
• Death 
• Physician decision (i.e., assessment that it is not in the subject’s best interest to continue, 
or other reason) [specify reason in the eCRF] 
• Sponsor decision [specify reason in the eCRF] 
Every attempt will be made to contact subjects who withdraw from the study in order to 
determine their vital status (alive or dead) at Day 28.   
6.18.3 Individual Stopping Criteria 
Subjects will be withdrawn from the study drug treatment for any of the following reasons: 
• The subject demonstrates an average QTcF value > 500 ms (mean of 3 ECG’s at any time 
point) as assessed locally by the Investigator.  Such subjects should be observed until the 
ECG normalizes with repeat ECG’s taken at the discretion of the investigator. 
• The subject demonstrates an average QTcF value > 480 ms with a concurrent increase in 
average QTcF value of > 60 ms (mean of 3 post-dose ECGs compared to mean pre-dose 
ECGs taken on that day) as assessed locally by the Investigator.   
• The subject has confirmed S. aureus bacteremia.   
If a subject is prematurely withdrawn from study treatment, the Investigator should make 
every effort to retain the subject in the study and to perform all procedures scheduled for the 
EOT, TOC, and LFU visits.  Any subject withdrawn from treatment due to an AE, SAE, or 
clinically significant abnormal laboratory test value will be evaluated by the Investigator, or a 


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monitoring physician, and will be treated and/or followed up until the symptoms or values 
have either resolved or are assessed as stable by the Investigator.  
6.18.4 
Lost to Follow-up 
Every reasonable attempt should be made to retain subjects in the study. If a subject does not 
report to the study site for a scheduled visit, study personnel will make 4 contact attempts:  3 
telephone contact attempts and, if these are unsuccessful, a certified letter will be sent to the 
subject.  The subject will be considered lost to follow-up if (1) upon receipt of delivery 
confirmation of the certified letter the subject does not contact the site or (2) the certified 
letter is returned as undeliverable.  Every attempt will be made to contact subjects who 
withdraw from the study in order to determine their status (alive or dead) at Day 28. 
7 
ADVERSE EVENTS 
An adverse event (AE) is any untoward medical occurrence in a subject or clinical 
investigation subject administered a pharmaceutical product that does not necessarily have a 
causal relationship with this treatment.  An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an investigational product, whether or not related to the 
investigational medicinal product.  
Any pre-existing conditions or signs and/or symptoms present in a subject prior to the start of 
the study (i.e., before informed consent) should be recorded as medical/surgical history.  Any 
medical occurrences which are new or worsened from the time of informed consent and up to 
and including the final visit must be reported as AEs or SAEs.  All AEs and SAEs must be 
recorded irrespective of whether they are considered drug related.  NOTE:  lack of 
efficacy/clinical failure does not have to be recorded as an AE unless it is an SAE. 
Subjects will be monitored throughout the study for adverse reactions to the study 
medications and/or procedures at each study visit.  Questions will be posed in a non-leading 
manner so as not to bias the response.  In addition to questioning at specific time points, 
subjects will be encouraged to spontaneously report any AEs.  Any subject with an AE, SAE 
or clinically significant abnormal laboratory test value will be evaluated by the Investigator, 
or a monitoring physician, and will be treated and/or followed up until the symptoms or 
values have resolved or are assessed as stable by the by the Investigator.  A physician, either 
at the Investigative site or at a nearby hospital emergency room, will administer treatment of 
any SAEs.  Where appropriate, medical tests and examinations may be performed to ensure 
that an AE has fully resolved.  
Adverse events will be monitored throughout the study from the time a subject is consented 
through the TOC visit; SAEs are to be collected from the time of consent through the LFU 
visit.  Study personnel will monitor AEs for subjects who are Outpatients in conjunction with 
daily telephone contacts for CABP signs/symptoms as well as at all site visits (see Table 1).  
Study personnel will follow unresolved AEs and SAEs present at LFU until resolution or 
stabilization.    


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Whenever possible, a specific disease or syndrome rather than individual associated signs 
and symptoms should be identified by the Investigator and recorded on the subject's eCRF.  
However, if an observed or reported sign or symptom is not considered a component of a 
specific disease or syndrome by the Investigator, it should be recorded as a separate AE on 
the subject's eCRF.  
Each AE or SAE reported will be assessed for intensity and the date and time of onset (if 
available), time relationship to dosing, duration, and outcome of each event will be noted. 
Laboratory abnormalities are not considered AEs unless they are associated with clinical 
signs and symptoms or require medical intervention.  Clinically significant abnormal clinical 
laboratory findings or other abnormal assessments that are associated with the disease being 
studied, unless judged by the Investigator as more severe than expected for the subject’s 
condition, or that are present or detected at the start of the study and do not worsen, will not 
be reported as AEs or SAEs. 
The Investigator will exercise medical and scientific judgment in deciding whether an 
abnormal clinical laboratory finding or other abnormal assessment is clinically significant.  
7.1 Assessment of Severity (Intensity) 
The following definitions for rating severity (intensity) will be used: 
Mild:  
A type of AE that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere 
with usual activities of daily living 
Moderate:  
A type of AE that is usually alleviated with specific therapeutic intervention. 
The event interferes with usual activities of daily living, causing discomfort 
but the subject is still able to function 
Severe: 
The type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. 
7.2 Assessment of Relationship to Study Drug 
The Investigator will use his/her clinical judgment to explain each adverse event and 
determine its relationship, if any, to study drug treatment.  Alternative causes, such as natural 
history of the underlying diseases, concomitant therapy, other risk factors, and the temporal 
relationship of the event to the study drug will be considered and investigated.  The 
Investigator will also consult the Investigator’s Brochure in the determination of his/her 
assessment.  Causality should be assessed using the following categories: 
Not related  
The event could readily be explained by factors not involving the study 
drug and a temporal relationship with the study drug did not exist.  
Possibly Related  
There was some temporal relationship between the event and the 
administration of the study drug and the event was unlikely to be 
explained by the subject’s medical condition or other therapies. 


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Probably Related  
The temporal relationship between the event and the administration of 
the study drug was suggestive, and the event was less likely to be 
explained by the subject’s medical condition or other therapies.  
Definitely Related  The 
event 
followed 
a 
reasonable 
temporal 
sequence 
from 
administration of the study drug, followed a known or suspected 
response pattern to the study drug, was confirmed by improvement 
upon stopping the study drug (dechallenge) and reappeared upon 
repeated exposure (rechallenge).  (NOTE:  this was not to be construed 
as requiring re-exposure of the subject, however, a category of 
definitely related could only be used when recurrence was observed.). 
7.3 Serious Adverse Events 
An SAE is any untoward medical occurrence that: 
• Results in death. 
• Is life-threatening. NOTE: The term ‘life threatening’ in the definition of “serious” refers 
to an event in which the subject was at risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it was more severe.  
• Results in persistent or significant disability/incapacity. 
• Requires in subject hospitalization or prolongation of existing hospitalization. 
NOTE: Hospitalizations, which are the result of elective or previously scheduled surgery 
for pre-existing conditions, which have not worsened after entry into the study, should 
not be classified as SAEs. For example, admission for a previously scheduled ventral 
hernia repair would not be classified as an SAE; however, complication(s) resulting from 
a hospitalization for an elective or previously scheduled surgery that meet(s) serious 
criteria must be reported as SAE(s). 
• Is a congenital anomaly/birth defect. 
• Is an important medical event. 
NOTE:  Medical or scientific judgment should be exercised in deciding whether reporting 
is appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition.  These should also be considered serious.  
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse. 
 
All SAEs will be collected from the time of informed consent until 30 days after the last 
study treatment regardless of study drug relationship, and must be reported to Nabriva 
Therapeutics AG or their representative (Covance Pharmacovigilance & Drug Safety 
Services [PV & DSS]) within 24 hours of knowledge of the event (this refers to any AE that 
meets one or more of the aforementioned serious criteria). 


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Safety Contact Information (24 hours/day): 
 
Location 
Phone 
Fax 
United States 
+1-888-724-4908 
1-888-887-8097 
Latin America 
+55-11-3750-3900 
+0800-892-1513 
Europe 
+44-1628-548-171 
+44-1628-540028 
Asia Pacific 
+61-2-8879-2000 
+61-2-9888-8322 
 
When the SAE form is completed in EDC, Nabriva Therapeutics AG or their representative 
(Covance PV & DSS) will be notified electronically and will retrieve the form.  If the event 
meets serious criteria and it is not possible to access the system, sites must email or fax the 
completed paper SAE report form to Covance PV&DSS at drugsafety@covance.com.  The 
emailed report should include all available information requested on the SAE form.  The 
SAE form will collect data surrounding the event, e.g., the nature of the symptom(s), time of 
onset in relation to initiation of therapy, duration, intensity, and whether or not therapy was 
interrupted or discontinued.  The Investigator’s assessment of the probable cause of the event 
will also be included.  In addition, relevant medical history, concomitant medications, 
laboratory and diagnostic reports, and procedures, as well as all pertinent medical 
information related to the event, will also be collected. 
Covance PV&DSS will forward SAE queries directly to the Investigator requesting 
incomplete or missing information.  It is the Investigator’s responsibility to be diligent in 
providing this information back to the Covance PV&DSS as soon as it is available.  Initial 
reports of SAEs should never be left on telephone voicemails.  
There may be situations when an SAE has occurred and the Investigator has minimal 
information to include in the initial report to Nabriva Therapeutics AG, or their 
representative.  However, it is very important that the Investigator always makes an 
assessment of causality for every event prior to transmission of the SAE report form to 
Nabriva Therapeutics AG, or their representative.  The Investigator may change his/her 
opinion of causality in light of follow-up information, amending the SAE report form 
accordingly.  The causality assessment is one of the criteria used when determining 
regulatory reporting requirements. 
The Investigator will provide the assessment of causality as per instructions on the SAE form 
in the subject's eCRF.  SAEs that are determined by the Investigator to be related to the study 
drug must be reported even if more than 30 days after the last administration of study drug. 
The sponsor will not routinely unblind the therapy assignment for an individual subject in the 
event of a serious adverse event.  However, unblinding of an individual subject may occur if 
this information is requested by the Investigator, if the Sponsor determines that the 
information is necessary to adequately assess safety, or if this information is required for 
reporting to local regulatory authorities (see Section 5.6). 


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All serious adverse events and suspected unexpected serious adverse events (SUSARs) will 
be reported by the sponsor to the relevant competent authorities in accordance with the 
European Directive 2001/20/EC, as applicable. 
7.4 Symptoms of the Disease Under Study 
In this study, clinical signs and symptoms of pneumonia which are assessed daily per 
protocol (i.e., dyspnea, cough, sputum production, and chest pain) will not be reported as 
adverse events unless they meet the definition of a serious adverse event.  
7.5 Other Reportable Events 
Certain events that occur should be reported to the Sponsor as Other Reportable Events.  
These include the following: 
• Potential Hy’s Law (PHL) 
- 
The investigator is responsible for prompt reporting of any patients who has had both 
(1) AST or ALT > 3 x ULN and (2) total bilirubin > 2 x ULN at any point in the 
study (i.e., meets criteria for Potential Hy’s Law). The investigator must complete the 
Hy’s Law eCRF.  Liver laboratory results should be followed locally every several 
days until resolution or stabilization of the laboratory abnormalities and reported 
using an unscheduled laboratory eCRF.  If subsequent to the initial report of PHL, the 
investigator determines that the case meets serious criteria, it should be reported as an 
SAE using standard reporting procedures. 
• Pregnancy exposure (subject becomes pregnant while taking study drug) 
- 
Subjects who are pregnant at Screening are not permitted to take part in this study, 
however, Nabriva Therapeutics AG or their representative must be notified of any 
subjects that become pregnant while participating in this study (or the partner of a 
male subject).  Although pregnancy is not technically an AE, all pregnancies must be 
followed to conclusion to determine their outcome.  This information is important for 
both drug safety and public health concerns.  It is the responsibility of the Investigator 
or designee to report any pregnancy in a subject that occurs during this study to 
Nabriva Therapeutics AG or their representative.  
• Lactation exposure (subject was taking study drug while nursing an infant) 
• Accidental exposure (someone other than the study subject was exposed to study drug) 
• Overdose (subject received more than the prescribed dose of study drug within a given 
timeframe) 
• Other medication errors that potentially place subjects at a greater risk of harm than was 
previously known or recognized (e.g., study drug was administered by an incorrect 
route). 
 


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8 
DRUG SUPPLIES 
8.1 Lefamulin (BC-3781) 
The active substance being investigated in this study is lefamulin (BC-3781), present in the 
drug product as the acetate salt (BC-3781.Ac).  Physicochemical properties can be found in 
the Lefamulin Investigator’s Brochure. 
Oral lefamulin is supplied by the Sponsor as 600 mg yellow oval film coated immediate-
release tablets.  Details of the composition are provided in the Lefamulin Investigator’s 
Brochure. 
8.2 Moxifloxacin 
The oral dose of moxifloxacin is provided by the Sponsor as an over-encapsulated film 
coated tablet containing 400 mg as hydrochloride.  
Additional details regarding moxifloxacin are found in the product monograph.  
8.3 Placebo 
The following oral placebo tablets will be supplied by the Sponsor: lefamulin placebo tablet 
and moxifloxacin placebo capsule.  
Further details may be found in the Study Pharmacy Manual. 
8.3.1 
Packaging and Labeling 
Study drugs will be packaged and labeled in accordance with the applicable regulatory 
authority requirements. 
8.3.2 
Storage of Study Drugs 
Access to all study drugs at the site must be restricted to designated study personnel 
throughout the study. 
Oral study medication will be supplied in blister packs.  Two different blister packs will be 
provided: 
• Lefamulin tablets and moxifloxacin placebo capsules. 
• Over-encapsulated moxifloxacin tablets and lefamulin placebo tablets 
The two blister packs must be stored at controlled room temperature (15 to 25 °C). 
8.3.3 
Product Accountability 
The Investigator is responsible for study medication accountability, reconciliation, and record 
maintenance.  In accordance with all applicable regulatory requirements, the Investigator or 


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designated study personnel must maintain study drug accountability records throughout the 
course of the study.  This person(s) will document the amount of study drug received from 
the supplier, the amounts dispensed to subjects as well as lot numbers and expiration / retest 
date of study medications. 
At the conclusion of the study, any unused study drug will be returned to either a 
Sponsor-designated recipient or destroyed at the site after discussion with the Sponsor.  If no 
supplies remain, this will be recorded in the drug accountability section of the final 
monitoring report. 
9 
STATISTICAL ANALYSIS 
Inferential statistical analyses of the primary and secondary outcomes will be conducted as 
outlined below.  Descriptive statistics, including the numbers and percentages for categorical 
variables, and the numbers, means, standard deviations, medians, minimums, and maximums 
for continuous variables will be provided.  Additional statistical analyses, other than those 
described in this section, may be performed if deemed appropriate.  A description of the 
statistical analysis performed on the study data will be outlined in the SAP. 
As a consequence of differing regulatory requirements for the choice of primary efficacy 
analysis variable and statistical analyses of this study, 2 separate regional comprehensive 
SAPs will be prepared (FDA and EMA) and finalized before database lock and analysis of 
the data.   
Exploratory evaluation of a variety of health utilization variables (e.g., length of hospital 
stay, duration of antibiotic therapy, discharge status, discharge destination) as well as a PRO 
instrument will be performed. Details for this exploratory analysis will be presented in a 
separate SAP and results will be presented in a stand-alone clinical study report. 
9.1 Treatment Comparison of Interest 
All comparisons will be for lefamulin versus comparator therapy (moxifloxacin). 
9.2 Sample Size Determination 
A total of 738 subjects will be randomized in a ratio of 1:1 (lefamulin:moxifloxacin) 
resulting in 369 subjects in the lefamulin arm and 369 in the moxifloxacin arm in this study.  
The total number of subjects included in this study is sufficient to achieve the primary and 
secondary study objectives based on statistical considerations. 
Retrospective analyses of clinical study data for patients with CABP of varying severity as 
well as 2 recent clinical trials in CABP indicate the point estimates for an ECR responder at 
Days 3-5 range from 72% to 81% (FDA, 2011; Barrera et al., 2016; Cempra, 2015; Oldach et 
al., 2015).  Thus, it is reasonable to assume that in a prospective study of subjects with 
CABP, the proportion of subjects who are responders for ECR at 96 ± 24 hours post first dose 
of study drug will be approximately 79%.   


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The primary efficacy analysis variables used for NI analyses for the Marketing Authorization 
Application (MAA) to the EMA will be the proportion of subjects with an IACR of Success 
at TOC in the mITT and CE-TOC Analysis Sets.  In recent clinical studies, IACR success 
rates at the TOC Visit in the CE Analysis Set ranged from 77% to 93% (Cempra, 2015) and 
in the ITT Analysis Set ranged from 85% to 89% depending on the antibiotics under study 
and the severity of the CABP.  Based on these data, an 85% IACR success rate in the CE-
TOC Analysis Set was chosen for determination of the sample size.  The success rate is 
expected to be about 5% lower in the mITT Analysis set.  It is expected that <1% of subjects 
will be excluded from the mITT Analysis Set and thus, the sample size determination 
assumes the same number of subjects in the ITT and mITT Analysis Sets. 
Utilizing an anticipated ECR responder rate of 79% in the ITT Analysis Set, a 1:1 
randomization ratio, a two-sided alpha of 0.025, and a continuity corrected Z-test with 
unpooled variance, a sample size of 738 subjects (369 subjects in the lefamulin group and 
369 in the moxifloxacin group) provides 90% power to establish the NI of lefamulin to 
moxifloxacin for ECR using a NI margin of 10.0% at the ECA.  Assuming an IACR success 
of 80% and 85% in the mITT and CE-TOC Analysis Sets, respectively, and a clinical 
evaluability rate of 80%, there is 91% power for demonstration of NI for IACR at the TOC 
Visit using a 10% NI margin. 
The calculated power in each analysis set for the primary and secondary outcomes is 
provided in Table 6 below. 
Table 6. 
Power Calculations for the Primary and Secondary Efficacy 
Outcomes 
 
Primary Outcome (FDA) 
(ECR 96 ± 24 hours After the First 
Dose of Study Drug) 
Secondary Outcome  
(Investigator’s Assessment of Clinical Response at 
TOC- Primary for EMA) 
Analysis Set 
ITT 
mITT 
CE-TOC 
NI Margin 
10% 
10% 
10% 
N 
738 (369:369) 
738 
590 
Outcome Rate 
79% 
80% 
85% 
Evaluability Rate 
NA 
NA 
80% 
Power 
90% 
91 % 
91% 
CE = clinically evaluable; ITT = intent to treat; mITT = modified ITT; TOC = test of cure 
 
9.3 Analysis Populations 
9.3.1 
Intent-to-Treat Analysis Set (ITT) 
The ITT Analysis Set will consist of all randomized subjects regardless of whether or not the 
subject received study drug. A subject is considered randomized when an IRT-generated 
randomization number has been assigned. 


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9.3.2 
Modified Intent-to-Treat Analysis Set (mITT) 
The mITT Analysis Set will consist of all randomized subjects who receive any amount of 
study drug.  Subjects are analyzed based on the randomized (i.e., assigned) treatment group. 
9.3.3 
Safety Analysis Set 
The Safety Analysis Set will consist of all randomized subjects who receive any amount of 
study drug.  Subjects are analyzed based on the study drug actually received. All safety 
analyses will be conducted in this population.  
9.3.4 
Microbiological Intent-to-Treat Analysis Set (microITT) 
The microITT Analysis Set will consist of all subjects in the ITT Analysis Set who have at 
least 1 baseline “typical” bacterial pathogen known to cause CABP, Legionella pneumophila 
from an appropriate microbiological specimen, or who have CABP caused by Mycoplasma 
pneumoniae or Chlamydophila pneumoniae. 
9.3.5 
Clinically Evaluable Analysis Set  
The CE Analysis Sets (CE-EOT, CE-TOC and CE-LFU Analysis Sets) will be a subset of the 
ITT Analysis Set that will include subjects who meet the criteria for CABP described in 
Inclusion Criteria Nos. 3-7, and who received at least the pre-specified minimal amount of 
the intended dose of study drug and duration of treatment, do not have an indeterminate 
response based on the IACR (at EOT for the CE-EOT Analysis Set, at TOC for the CE-TOC 
Analysis Set and at LFU for the CE-LFU Analysis Set), did not receive concomitant 
antibacterial therapy that is potentially effective against CABP pathogens (except in the case 
of clinical failure) from the first dose of study drug through the EOT Visit (CE-EOT 
Analysis Set),  through the TOC Visit (CE-TOC Analysis Set) and through the LFU Visit 
(CE-LFU Analysis Set), and for whom there are no other confounding factors that interfere 
with the assessment of the outcome.  
9.3.6 
Microbiologically Evaluable Analysis Set 
The ME Analysis Sets (ME-EOT, ME-TOC and ME-LFU) will include all subjects who 
meet the criteria for inclusion in both the microITT and CE-EOT (ME-EOT) Analysis Sets, 
the CE-TOC (ME-TOC) Analysis Set, or the CE-LFU (ME-LFU) Analysis Set. 
9.3.7 
Pharmacokinetic Analysis Set 
All subjects who receive any amount of study drug will be included in the formal analysis of 
PK parameters providing they have at least 1 evaluable PK sample.   


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9.4 Criteria for Evaluation 
9.4.1 
Primary Efficacy Analysis Variable 
The primary efficacy variable (FDA) is the proportion of subjects in the ITT Analysis Set 
with an ECR of Responder at 96 ± 24 hours post first dose. 
Subjects will be defined as an ECR of Responder if the following 4 criteria are met: 
• Alive 
• Improvement in at least 2 of the 4 cardinal symptoms of CABP (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. 
The primary efficacy variable for the EMA (and secondary efficacy variable for the FDA) is 
the proportion of subjects with an IACR of Success at TOC in the mITT and CE-TOC 
Analysis Sets (see Section 6.12).  An IACR of Success is defined as a subject whose 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. Subjects who have an 
IACR of Failure at EOT will not have an IACR assessed at TOC and will be considered to 
have an IACR of Failure at TOC. 
9.4.2 
Secondary Efficacy Analysis Variables 
9.4.2.1 
Clinical Outcome 
The Investigator’s Assessment of Clinical Response will be evaluated in the microITT and 
ME-TOC Analysis Sets at TOC as described in Section 6.12.  ECR will be evaluated in the 
microITT Analysis Set. All-cause mortality will be evaluated in the ITT Analysis Set. 
9.4.2.2 
Microbiological Assessment 
The By-Pathogen Microbiological Response will be assessed in the micro-ITT and ME 
Analysis Sets for each causative organism using the categories for outcome as follows.  
• Success includes: 
− Eradication:  the baseline causative pathogen was absent from repeat culture(s). 
− Presumed eradication:  the IACR was Success, and culture was not repeated.  
• Failure includes: 
− Persistence:  the baseline causative pathogen was isolated in repeat culture(s).  
− Presumed persistence:  the IACR was Failure and a culture was not repeated. 


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• Indeterminate:  
- 
The IACR was Indeterminate, and culture was not repeated. 
9.4.3 
Safety Analysis Variables 
Safety will be assessed by monitoring vital signs, ECG measurements, clinical laboratory 
parameters, and AEs.  
9.4.4 
Pharmacokinetic Analysis Variables 
Population PK modeling will be performed to determine the model-predicted plasma 
concentration time curves of lefamulin for each subject.  Calculated PK will enable 
descriptive statistical analysis of PK variables such as the maximum observed drug 
concentration (Cmax) and area under the concentration-time curve (AUC) for lefamulin and its 
main metabolite, BC-8041.  Individual AUC values from Day 1 and Day 4 [i.e., 96  ±  24 
hours post first dose] (collected pre-dose, 1-2 h post dose and 3-4 h post dose, and 8-9 h post 
dose (8-9 h post dose is required for inpatients; optional for outpatients) will be used for the 
PK/PD analysis.  The population PK analysis as well as a PK/PD analysis will be reported 
separately. 
9.4.5 
Other Variables 
The Investigator’s Assessment of Clinical Response at EOT and at LFU will be evaluated in 
the mITT and CE Analysis Sets. 
The By-Subject Microbiological Response will be programmatically determined at TOC for 
each subject using the By-Pathogen Microbiological Response for each baseline causative 
pathogen.  For a subject to have a By-Subject Microbiological Response of Success, the 
response for each baseline pathogen must be Success (i.e., Eradication or Presumed 
Eradication).  If the response for any Baseline pathogen is Failure (i.e., Persistence or 
Presumed Persistence), the subject will be considered to have a By-Subject Microbiological 
Response of Failure.  A By-Subject Microbiological Response of Indeterminate will be 
assigned if all baseline pathogens have a Microbiological Response of Indeterminate. 
New bacteria isolated from respiratory or blood culture will be assessed separately from the 
outcomes listed above as follows: 
• Superinfection: 
- 
New respiratory (i.e., from sputum, pleural fluid or BAL specimen) pathogen(s) (i.e., 
pathogen(s) not present at baseline) identified in post-baseline culture(s) through the 
TOC Visit with persistent signs and symptoms of CABP (i.e., IACR of Failure at the 
TOC Visit, such that additional antibacterial therapy is necessary for the current 
episode of CABP). 
• Colonization: 
- 
New respiratory (i.e., from sputum, pleural fluid or BAL specimen) pathogen(s), (i.e., 
pathogen(s) not present at baseline) identified in at least 2 post-baseline cultures 


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through the TOC Visit but signs and symptoms of CABP have resolved, (i.e., IACR 
of Success at the TOC Visit, such that no additional antibacterial therapy is necessary 
for the current episode of CABP). 
• Development of Decreasing Susceptibility: 
- 
Increase in MIC (≥ 4x) or 6 mm decrease from baseline in disk inhibition zone 
diameter to the study drug received for a pathogen isolated at baseline and 
subsequently isolated from a blood or lower respiratory tract specimen. 
ECR plus improvement in vital signs (i.e., body temperature, blood pressure, heart rate, 
respiratory rate), if abnormal at Baseline will be evaluated in the ITT Analysis set.  If vital 
signs are normal at Baseline (i.e., not abnormal as per the definitions below), none can have 
worsened. 
Abnormal vital signs are defined as: 
• Fever: [defined as body temperature > 38.0 °C (100.4 °F) measured orally, > 38.5 °C 
(101.3 °F) measured tympanically, or > 39.0 °C (102.2 °F) measured rectally]  
• Hypothermia: [defined as body temperature < 35.0 °C (95.0 °F) measured orally, 
< 35.5 °C (95.9 °F) measured tympanically, or < 36.0 °C (96.8 °F) measured rectally] 
• Hypotension: defined as systolic blood pressure < 90 mmHg  
• Tachycardia: defined as heart rate > 100 bpm 
• Tachypnea: defined as respiratory rate > 20 breaths/min 
 
Exploratory evaluation of a variety of health utilization variables (e.g., length of hospital 
stay, duration of antibiotic therapy, discharge status, discharge destination) as well as a PRO 
instrument will be performed. Details for this exploratory analysis will be presented in a 
separate SAP and results will be presented in a stand-alone clinical study report. 
9.5 Demographic and Baseline Characteristics 
Enrollment, protocol deviations, and discontinuations from the study drug and the study will 
be summarized by treatment group.  Demographics (age, race, ethnicity and sex), medical 
and surgical history, baseline assessment of the clinical signs and symptoms, microbiological 
assessment, and study drug administration will also be summarized by treatment group.  
Differences between treatment groups will be analyzed using the chi-square or Fisher’s exact 
test for dichotomous variables and the Wilcoxon Rank Sum test for ordinal and continuous 
variables.  
9.6 Efficacy Analysis 
For all efficacy analyses, subject data will be analyzed in the group to which the subject was 
randomized.  For the stratified analysis of the primary efficacy outcome and for the primary 


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analysis for the EMA, subjects who are randomized to the wrong stratum will be analyzed in 
the stratum to which they were randomized.   
9.6.1 
Primary Efficacy Analysis 
The primary efficacy outcome (FDA) is the proportion of responders for ECR at 
96 ± 24 hours following the first dose of study drug in the ITT Analysis Set.  Each subject 
will be programmatically categorized as a Responder, Non-responder or Indeterminate based 
on data on the eCRF assessments of CABP signs and symptoms Subjects who are missing 
data required to determine an ECR or who are lost to follow up are defined as Indeterminate 
for the primary analysis and are included in the denominator for the calculation of the 
responder rate.  Thus, subjects with an ECR of Indeterminate are considered non-responders 
for the primary analysis.  The number and percentage of subjects in each treatment group in 
each response category will be reported.   
The null and alternative hypotheses are: 
H0: P1 - P2 ≤ - ∆ 
H1: P1 - P2 > - ∆ 
Where P1 = the primary efficacy outcome rate in the lefamulin group 
P2 = the primary efficacy outcome rate in the moxifloxacin group 
∆ = the non-inferiority margin 
The NI hypothesis test is a 1-sided hypothesis test performed at the 2.5 % level of 
significance.  This is based on the lower limit of the 2-sided 95 % confidence interval (CI) for 
the observed difference in the ECR (lefamulin group minus the moxifloxacin group).  The CI 
will be calculated using an unadjusted continuity corrected Z-statistic.  If the lower limit of 
the 95 % CI for the difference in responder rates in the ITT Analysis Set is greater 
than -10.0 %, the null hypothesis will be rejected and the NI of lefamulin to moxifloxacin 
will be concluded.   
Additional analyses of the primary efficacy outcome will be conducted.  ECR will be 
assessed separately across the geographic regions, prior antibiotic use, and PORT risk class 
strata.  For each geographic region, prior antibiotic use, and PORT risk class stratum, a 2-
sided 95% CI for the observed difference in ECR responder rates will be calculated for the 
ITT Analysis Set.  Sensitivity analyses of ECR include determination of a stratified 95% CI 
(adjusted for the randomization stratification factors) and considering all subjects with 
missing data (i.e., Indeterminates) at 96 ± 24 hours after the first dose of study drug as 
responders for ECR (these subjects are considered non-responders in the primary analysis).  
For the second sensitivity analysis, an unstratified 95% CI will be computed for the 
difference in the responder rates between lefamulin and moxifloxacin.  Subgroup analyses of 
the primary efficacy outcome will also be conducted for descriptive purposes and will be 
detailed in the SAP. For both ECR and IACR, additional analyses will be conducted whereby 
failures will be reclassified as Indeterminate if they received less than 48 hours of study 
medication.  


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For the EMA primary analysis (secondary analysis for the FDA), the number and percentage 
of subjects in each treatment group with an IACR of Success, Failure and Indeterminate (by 
definition Indeterminates are not included in the CE-TOC Analysis Set) at TOC will be 
reported in the mITT and CE-TOC Analysis.  Subjects who have an IACR of Failure at EOT 
will be considered to have an IACR of Failure at TOC.  The primary analysis for the EMA 
will utilize 2-sided stratified (for the randomization stratification factors) 95% CIs calculated 
using the method of Miettinen-Nurminen.  If the lower limit of the 95% CI for the difference 
in success rates in both the mITT and CE-TOC Analysis Sets is greater than -10%, the NI of 
lefamulin to moxifloxacin will be concluded.  Two-sided unstratified 95% CIs will be 
calculated for the difference in success rates at TOC in the mITT and CE-TOC Analysis Sets 
(FDA secondary outcome). 
Additional analyses of the EMA primary efficacy outcome will be conducted.  IACR at TOC 
will be assessed separately across the geographic regions, prior antibiotic use, and PORT risk 
class strata in the mITT and CE-TOC Analysis Sets.  For each geographic region, prior 
antibiotic use, and PORT risk class stratum, a 2-sided 95% CI for the observed difference 
success rates will be calculated for the ITT and CE-TOC Analysis Sets.  Sensitivity analyses 
of IACR include determination of unstratified 95% CI  and considering all subjects with 
missing data (i.e., Indeterminates) as successes for IACR (these subjects are considered 
failures in the EMA primary analysis).  For the second sensitivity analysis, a stratified 95% 
CI will be computed for the difference in the success rates between lefamulin and 
moxifloxacin. Subgroup analyses of the EMA primary efficacy outcome will also be 
conducted for descriptive purposes and will be detailed in the EMA SAP. 
9.6.2 
Secondary Efficacy Analyses 
The number and percentage of subjects categorized as Responder, Non-responder and 
Indeterminate for the primary FDA efficacy outcome of ECR will also be presented for the 
microITT Analysis Set and a 2-sided unstratified 95 % CI for the difference in responder rate 
will be calculated using a continuity-corrected Z-statistic.  However, the formal test of NI 
will be conducted in the weighted (based on the inverse variance of each effect size) pooled 
population from this study and a second study in CABP. 
The number and percentage of subjects in each treatment group with an IACR of Success, 
Failure and Indeterminate (by definition Indeterminates are not included in the ME-TOC 
Analysis Set) at TOC will be reported in the microITT and ME-TOC Analysis Sets.  Subjects 
who have an IACR of Failure at EOT will be considered to have an IACR of Failure at TOC.  
Two-sided unstratified 95 % CIs will be calculated for the difference in success rates.   
The By-Pathogen Microbiologic Response (by definition, subjects with an Indeterminate 
Microbiologic Response are excluded from the ME-TOC Analysis Set) will be provided for 
the microITT and ME-TOC Analysis sets at TOC. 
All-cause mortality (ACM) through Day 28 will also be summarized in the ITT Analysis Set.  
Subjects who are lost to follow-up will be considered deceased for this analysis.  A 2-sided 
unstratified 95 % CI will be calculated for the treatment difference in ACM.   


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9.6.3 
Additional Efficacy Analyses 
Additional efficacy analyses will be conducted to support the efficacy findings for the 
primary and secondary outcomes.  Confidence intervals for proportions will be determined 
for descriptive purposes, as indicated below, but no conclusions of NI will be made. 
The number and percentage of subjects who are a Responder for ECR, the number and 
percentage of subjects who have an IACR of Success at TOC, and the number and 
percentage of subjects who are a sustained response at LFU will be presented by baseline 
pathogen in the microITT Analysis Set, ME-TOC (IACR only) and ME-LFU (sustained 
success only) Analysis Sets. 
The number and percentage of subjects in each treatment group with an IACR of Success, 
Failure and Indeterminate (by definition subjects with an IACR of Indeterminate are not 
included in the CE-EOT Analysis Set) at EOT in the mITT and CE-EOT Analysis Sets.  
Two-sided unstratified 95 % CIs will be calculated for the difference in IACR success rates.  
The number and percentage of subjects with a Sustained Success, Relapse, Failure and 
Indeterminate response as assessed by the Investigator at the LFU Visit will be summarized 
for the mITT and CE-LFU Analysis Sets.  Failure is defined as a subject who had an IACR 
of Failure at the TOC Visit. 
The By-Subject Microbiologic Response (by definition, subjects with an Indeterminate 
Microbiologic Response are excluded from the ME-TOC Analysis Set) will be provided for 
the microITT and ME-TOC Analysis sets at TOC.  Two-sided unstratified 95 % CIs will be 
provided for the difference in the By-Subject Microbiologic Response success rate. 
Early Clinical Response, including improvement in vital signs at 96 ± 24 hours after the first 
dose of study drug will be derived programmatically from the eCRF assessment of CABP 
signs and symptoms data.  The number and percentage of subjects who are a Responder 
(including vital signs) will be tabulated by treatment group in the ITT Analysis Set.  A 2-
sided unstratified 95 % CI will be calculated for the treatment difference for the responder 
rate. 
9.7 Safety Analysis 
Safety will be evaluated in the Safety Analysis Set by presenting summaries of AEs, routine 
clinical laboratory evaluations, ECGs, and vital signs in the 2 treatment groups.  Subjects 
who receive the wrong study drug for their entire course of treatment will be analyzed in the 
group based on the drug received.   
Summary tables will be provided for all TEAEs.  A TEAE is defined as an AE with a start 
date and time on or after the first dose of study drug.  Adverse events will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA®).  The number and percentage of 
subjects with TEAEs will be tabulated by system organ class (SOC) and MedDRA Preferred 
Term for each treatment group and by severity and relationship to treatment. 
Adverse events leading to premature discontinuation from the study drug and serious TEAEs 
will be presented either in a table or a listing. 


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Change from baseline to each scheduled evaluation and the overall worst post-baseline in 
clinical laboratory variables will be summarized by treatment group.  The number and 
percent of subjects with treatment-emergent potentially clinically significant (PCS) 
laboratory values will be tabulated for each treatment group.  Treatment-emergent PCS 
laboratory tests are those in which the Baseline value is not PCS and the post-baseline value 
is PCS.  PCS will be defined based on the pre-specified criteria outlined in the SAP.  
Change from baseline to each scheduled evaluation and the overall worst post-baseline for 
RR interval, PR interval, QRS interval, QT interval, and QT interval corrected with 
Fridericia from the ECG will be summarized for each treatment group with the mean, 
standard deviation, minimum value, and maximum value.  The triplicate values will be 
averaged for each subject before analysis.  An outlier analysis will also be provided based on 
the worst post-baseline value. 
Descriptive statistics of vital signs and the change from baseline to each scheduled evaluation 
will be summarized by treatment group at each study visit and the worst overall post-
baseline.  The number and percent of subjects with treatment-emergent PCS values will be 
tabulated for each treatment group. 
9.8 Handling of Missing Data 
For the primary outcome measure (FDA), if any data field needed to determine ECR is 
missing, the subject will be assigned a response of Indeterminate.  Imputations for the 
missing times will be provided in the SAP. For analyses of the primary outcome, subjects 
with an indeterminate response are included in the denominator, and thus are considered 
Non-responders.  A sensitivity analysis of the primary outcome will be conducted in which 
subjects with an indeterminate response are considered Responders.   
For the outcome measure of IACR at EOT, TOC and LFU, missing data are considered as a 
response of Indeterminate.  For analysis in the ITT, mITT and microITT Analysis Sets, 
indeterminate outcomes are included in the denominator and are thus, considered clinical 
Failures.  By definition, subjects with an IACR of Indeterminate are excluded from the CE-
EOT, CE-TOC, CE-LFU, ME-EOT, ME-TOC, and ME-LFU Analysis Sets.  
A missing microbiological response is considered a presumed response based on the IACR. 
For analysis in the microITT Analysis Set, indeterminate outcomes are included in the 
denominator and are thus, considered microbiological failures.  By definition, subjects with 
an IACR of Indeterminate are excluded from the ME Analysis Sets.   
Handling of missing data for other efficacy and safety outcomes will be presented in the 
SAP. 
9.9 Pharmacokinetic Analyses 
Measured plasma concentrations of lefamulin and its main metabolite, BC-8041, will be 
summarized descriptively by the actual time point of collection.  Summary statistics in the 


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tabulation will include n, mean, standard deviation, CV [%], median, minimum and 
maximum.  
Population PK modeling will be used to determine the individual model-predicted 
concentrations of lefamulin.  Simulation of model output will enable descriptive statistical 
analysis of PK variables such as the Cmax, Cmin and AUC for lefamulin. 
A description of the population PK analysis will be described in a separate SAP.  Results of 
this analysis will be reported separately. 
9.10 Health Utilization Variables and Patient Reported Outcome 
Exploratory evaluation of a variety of health utilization variables (e.g., length of hospital 
stay, duration of antibiotic therapy, discharge status, discharge destination) as well as a PRO 
instrument, the SF-12, will be performed.  In addition, other PRO instruments may be 
utilized in this study, as feasible.  Details for this exploratory analysis will be presented in a 
separate SAP and results will be presented in a stand-alone clinical study report  
10 STUDY MONITORING 
10.1 Clinical Monitoring 
All aspects of the study will be carefully monitored by the Sponsor’s authorized individuals, 
acting as agents of the sponsor with respect to current Good Clinical Practice and Standard 
Operating Procedures for compliance with applicable government regulations.  These 
individuals will have access to all records necessary to ensure integrity of the data and will 
periodically review the progress of the study with the principal investigator. 
Frequent communication between the study site and the Sponsor is essential to ensure that 
the subject safety is monitored adequately.  The Investigator will make safety assessments on 
an ongoing basis.  The Sponsor’s medical monitor will review safety information from all 
study sites as it becomes available throughout the study.  Should any safety concerns be 
identified, the Data Monitoring Committee (DMC) will be asked to review the data and 
determine what action is recommended. 
10.2 Independent Data Monitoring Committee (DMC) 
An independent DMC will be constituted for this study to monitor important aspects of study 
conduct, including safety results on an ongoing basis.  The DMC will consist of 3 members 
who will be selected by the Sponsor but will be independent from the Sponsor.  The 
clinicians on the committee will not participate in the study as Principal or Co-investigators, 
and should be isolated from the study if their institution is a study site.  The DMC members 
receive no financial incentives for their participation, but are reimbursed only for customary 
consultative and administrative support fees.  
DMC meeting frequency and conduct is outlined in a separate DMC Charter.  An 
independent unblinded statistician will provide the committee with masked data for review 


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(treatment A versus treatment B), but will not be a member of the committee.  All members 
of the DMC will treat study data, reports, meeting discussions, and conclusions as 
confidential. 
11 IEC/IRB APPROVAL 
The Principal Investigator agrees to provide the Independent Ethics Committee 
(IEC)/Institutional Review Board (IRB) with all appropriate material, including a copy of the 
informed consent.  The study will not be initiated until the Investigator obtains written 
approval of the research plan (protocol) and the informed consent document from the 
appropriate IEC/IRB and copies of these documents are received by Nabriva Therapeutics 
AG.   
It is the Investigator’s responsibility to obtain IEC/IRB approval for all subsequent major 
changes to the protocol, in compliance with local law.  Appropriate reports on the progress of 
this study will be made by the Investigator to the IEC/IRB and Sponsor in accordance with 
applicable government regulations and in agreement with policy established by the Sponsor. 
12 ETHICAL CONDUCT OF THE STUDY 
This clinical study will be conducted in compliance with this Protocol, the guidelines of the 
World Medical Association Declaration of Helsinki in its revised edition (Fortaleza, Brazil, 
October 2013), the guidelines of International Conference on Harmonization (ICH) Good 
Clinical Practice (GCP) (CPMP/ICH/135/95), European Union (EU) Clinical Trials Directive 
2001/20/EC, EU Commission Directive 2005/28/EC, and Code of Federal Regulation (CFR) 
Title 21, CFR Part 50, 56 and 312, designated Standard Operating Procedures, and with local 
laws and regulations relevant to the use of new therapeutic agents in the country of conduct. 
13 INFORMED CONSENT 
The International Conference on Harmonization (ICH) has issued guidelines to provide 
protection for human subjects in clinical investigations.  The ICH Tripartite Guideline for 
Good Clinical Practice establishes the general requirements for informed consent. 
A properly executed, written informed consent in compliance with the terms of these 
guidelines shall be obtained from each subject before entering the study, or before 
performing any unusual or non-routine procedure in relation to the study.  The purpose of the 
study, procedures to be carried out, and potential hazards will be described to each potential 
subjects in non-technical terms.  Subjects (or their legally authorized representative) will be 
required to read, voluntarily sign, and date an informed consent form summarizing the 
discussion at Screening, and will be assured that they may withdraw from the study at any 
time without jeopardizing their medical care. 
Subjects (or their legally authorized representative) will sign and date 1 copy of the informed 
consent form which will be photocopied.  In accordance with local regulations, the original 
and copies of the signed and dated consent may be retained by the subject (or their legally 
authorized representative) and/or retained on file by the Investigator, as applicable.  


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The consent form must be approved by the appropriate IEC/IRB and Sponsor before study 
initiation at a study site.  Any subsequent changes to the approved informed consent form 
must be reviewed and approved by the appropriate IEC/IRB and Sponsor before 
implementation. 
14 QUALITY ASSURANCE AND QUALITY CONTROL 
Standard Operating Procedures belonging to Nabriva Therapeutic AG or designee(s) will be 
adhered to for all activities relevant to the quality of the study and are routinely monitored by 
the Quality Assurance (QA) Division.  
Data will undergo quality control checks prior to clinical database lock.  Sponsor-designated, 
independent monitors will be responsible for the monitoring of the study and its data within 
the eCRFs. 
A QA audit of this study may be conducted by the Sponsor or Sponsor’s designee.  The QA 
auditor will have access to all medical records, the Investigator’s study-related files and 
correspondence, information in the informed consent documentation of this study, and study 
drug storage facilities.  
An inspection of this study may be conducted by a regulatory agency.  The Investigator 
agrees to contact the Sponsor as soon as possible, but not later than within 1 week, upon 
notification of an inspection by a regulatory agency.  The Investigator agrees to allow the 
Inspector direct access to all relevant documents and to allocate his/her time and that of study 
personnel to the Inspector to discuss findings in any relevant issues.  The Investigator will 
allow Sponsor personnel to be present as an observer during a regulatory inspection, if 
requested.  
15 DATA HANDLING AND RECORD KEEPING  
15.1 Data Handling 
Data will be recorded at sites using eCRFs and reviewed by the Sponsor or designee during 
monitoring visits.  The recorded data in the EDC system will be verified with source 
documents.  All corrections or changes made to any study data must be appropriately tracked 
in an audit trail in the EDC system.  eCRFs will be considered complete when all missing, 
incorrect, and/or inconsistent data has been accounted for.  Data collected at baseline will 
only be entered into the eCRF if the subject is eligible for study participation following 
review of the data by the Investigator or designee.  
Adverse events, concomitant medication data and clinical observations will be in the 
subjects’ hospital notes, or recorded on source data forms, and will be transferred into the 
eCRF after assessment by the Investigator or designee. 
Data produced by automatic devices with original print-outs (e.g., clinical laboratory test 
results, ECG traces, BP measurements) will be included in the source documentation.  
Clinical laboratory parameters are to be reviewed, signed and dated by the Investigator or 


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designee.  Any results outside the normal range should be designated by the Investigator or 
designee as not clinically significant (NCS) or clinically significant (CS). 
15.2 Subject Confidentiality 
Investigator and his/her staff will be required to manage subject data collected for the study 
in accordance with applicable laws and regulations on personal data protection.   
US:  All US-based investigational sites and laboratories or entities providing support for this 
study, must, where applicable, comply with the Health Insurance Portability and 
Accountability Act (HIPAA) of 1996.  An investigational site that is not a Covered Entity as 
defined by HIPAA must provide documentation of this fact to Nabriva Therapeutics AG. 
EU:  Data collected during this study may be used to support the development, registration or 
marketing of lefamulin.  Nabriva Therapeutics AG will control all data collected during the 
study, and will abide by the EU Directive on Data Privacy concerning the processing and use 
of subjects’ personal data.  For the purpose of data privacy legislation, Nabriva Therapeutics 
AG will be the data controller. 
After subjects have consented to take part in the study their medical records and the data 
collected during the study will be reviewed by Nabriva Therapeutics AG or its 
representatives.  These records and data may, in addition, be reviewed by the following: 
independent auditors who validate the data on behalf of Nabriva Therapeutics AG; third 
parties with whom Nabriva Therapeutics AG may develop, register or market lefamulin; 
national or local regulatory authorities and the IRB/IECs that gave approval for this study to 
proceed. 
Subjects will be known by a unique number; however, their date of birth can also be 
collected if not in contradiction with any requirements (e.g., from IECs) and used to assist 
Nabriva Therapeutics AG to verify the accuracy of the data, for example, that the laboratory 
results are assigned to the correct subject.  The results of this study may be recorded and 
transferred to and used in other countries throughout the world, which may not afford the 
same level of protection that applies within the EU.  The purpose of any such transfer would 
be to support regulatory submissions in other countries. 
15.3 Computer Systems 
Data will be processed using a validated computer system conforming to regulatory 
requirements. 
15.4 Data Entry 
Data must be recorded using the EDC system as the study is in progress.  All study personnel 
must log into the system using their secure user name and password in order to enter, review, 
or correct study data.  These procedures must comply with the Title 21 Code of Federal 
Regulations (21 CFR Part 11) for US sites and EU Directives 2001/20/EC and 2005/28/EC 
for EU sites.  All passwords will be strictly confidential.  


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15.5 Data Validation 
Validation checks programmed within the EDC system as well as supplemental validation 
performed via review of the downloaded data will be applied to the data in order to ensure 
accurate, consistent, and reliable data.  Data identified as erroneous, or data that are missing, 
will be referred to the investigative site for resolution through data queries. 
eCRFs must be reviewed and electronically signed by the Investigator who signed the 
protocol. 
15.6 Record Keeping  
Raw data generated in connection with this study as well as an original copy of the final 
clinical study report, will be retained in archive until at least 5 years after the last approval of 
a marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 5 years have elapsed since the formal 
discontinuation of clinical development of lefamulin.  These documents will be retained for a 
longer period if required by the applicable regulatory requirements or by an agreement with 
the Sponsor.  It is the responsibility of the Sponsor to inform the Investigator/Institution as to 
when these documents no longer need to be retained. 
As required under European Directive 2005/28/EC, Article 17, all ‘essential documents’ (as 
described in the ICH GCP Guidelines) must be retained by Nabriva Therapeutics AG and the 
Investigator for at least 5 years after the completion of the clinical study.  Therefore all 
studies, independent of where they were conducted in the world, must follow this 
requirement in the event a submission is ever made in the EU.  These documents may be 
retained for a longer period, however, if required by the applicable regulatory requirements 
or by an agreement with Nabriva Therapeutics AG.  It is the responsibility of Nabriva 
Therapeutics AG to inform the Investigator as to when these documents no longer need to be 
retained.  The Investigator must obtain written permission from Nabriva Therapeutics AG 
prior to the destruction of any study document.  
The retention of investigator study records is an investigator responsibility and Nabriva 
Therapeutics AG will neither arrange nor pay for this activity. Any transfer of ownership of 
the content of the clinical trial master file is the responsibility of the investigator or site 
representative, and shall be documented.  The new owner shall assume the responsibilities set 
forth in the applicable regulations. 
These records must be made available at reasonable times for inspection and duplication, if 
required, by a properly authorized representative of the US Food and Drug Administration 
(FDA) in accordance with 21 CFR 312.68 or other national or foreign Regulatory Authorities 
in accordance with regulatory requirements.  
16 TERMINATION OF STUDY 
The Sponsor reserves the right to discontinue this study at any time. 


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17 FINANCING AND INSURANCE 
The costs necessary to perform the study will be agreed with each Investigator and will be 
documented in a separate financial agreement that will be signed by the Investigator and 
Nabriva Therapeutics AG (or designee), prior to the start of the study.  A statement regarding 
insurance/indemnity such as Association of British Pharmaceutical Industry (ABPI) should 
also be included. 
The Investigator will be required to disclose any financial arrangement whereby the value of 
the compensation for conducting the study could be influenced by the results or outcome of 
the study.  The following information will be collected: any significant payments of other 
sorts from Nabriva Therapeutics AG, (e.g., money to fund ongoing research, compensation in 
the form of equipment, retainer for ongoing consultation or honoraria); any proprietary 
interest in lefamulin; any significant equity interest in Nabriva Therapeutics AG as defined in 
21 CFR 54 2(b). 
In consideration of participation in the study, Nabriva Therapeutics AG will pay the 
Investigator or nominated payee the sums set out in the payment schedule attached to the 
Investigator agreement.  
18 PUBLICATION POLICY 
It is intended that the results of the study may be published as scientific literature.  Results 
may also be used in submissions to Regulatory Authorities.  The following conditions are to 
protect commercial confidential materials (e.g., patents, etc.), not to restrict publication. 
All information concerning lefamulin (such as patent applications, formulae, manufacturing 
processes, basic scientific data, or formulation information supplied to the Investigator by 
Nabriva Therapeutics AG and not previously published) is considered confidential by 
Nabriva Therapeutics AG and shall remain the sole property of Nabriva Therapeutics AG.  
The Investigator agrees not to use it for other purposes without Nabriva Therapeutics AG 
written consent. 
It is understood by the Investigator that Nabriva Therapeutics AG will use the information 
developed in this clinical study in connection with the development of lefamulin and, 
therefore, may be disclosed as required to other Nabriva Therapeutics AG Investigators or 
any appropriate international Regulatory Authorities.  In order to allow for the use of 
information derived from this clinical study, the Investigator understands that he/she has an 
obligation to provide Nabriva Therapeutics AG with complete test results and all data 
developed during this study. 
All manuscripts, abstracts or other modes of presentation arising from the results of the study 
must be reviewed and approved in writing by Nabriva Therapeutics AG in advance of 
submission.  The review is aimed at protecting Nabriva Therapeutics AG's proprietary 
information existing either at the date of the commencement of the study or generated during 
the study. 


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The detailed obligations regarding the publication of any data shall be set out in the 
agreement between each Investigator and Nabriva Therapeutics AG. 
 
 


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19 LIST OF REFERENCES 
 
Arnold et al., 2007. 
Arnold FW, Summersgill JT, Lajoie AS, et al. A worldwide perspective of atypical 
pathogens in community-acquired pneumonia. Am J Respir Crit Care Med. 2007; 
175(10):1086-1093. 
 
Barrera et al., 2016. 
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oral moxifloxacin for treatment of community-acquired bacterial pneumonia: a global, 
double-blind, multicentre, randomised, active-controlled, non-inferiority trial (SOLITAIRE-
ORAL). Lancet Infect Dis. 2016; Feb 4. pii: S1473-3099(16)00017-7. doi: 10.1016/S1473-
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Bhavnani et al., 2005. 
Bhavnani SM, Hammell JP, Cirincione BB, Wikler MA, Ambrose PG. Use of 
pharmacokinetic-pharmacodynamic target attainment analyses to support Phase 2 and 3 
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Bhavnani et al., 2009. 
Bhavnani SM, Lawrence L, Burak E, Ambrose PG. Clinical trial dose selection for 
dalafloxacin (DFX) for complicated skin and skin-structure infections (cSSSI). Poster 
presented at: 49th ICAAC; 2009 Sep 12-15; San Francisco, CA, USA. A1-1942. 
 
CDC, 2013. 
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death.htm (last access: 29.10.2014). 
 
Cempra, 2015. 
Cempra, Inc. 16-Jan-2015. Cempra announces positive topline phase 3 clinical results for 
intravenous solithromycin in the treatment of community-acquired bacterial pneumonia 
[Press release]. Retrieved from 
http://investor.cempra.com/releasedetail.cfm?releaseid=936994 
 
Dalhoff, 2012. 
Dalhoff A. Resistance surveillance studies: a multifaceted problem–the fluoroquinolone 
example. Infection. 2012; 40(3):239-262. 
 
Davidovich et al., 2007. 
Davidovich C, Bashan A, Auerbach-Nevo T, Yaggie RD, Gontarek RR, Yonath A. Induced-
fit tightens pleuromutilins binding to ribosomes and remote interactions enable their 
selectivity. Proc Natl Acad Sci USA. 2007; 104(11):4291-4296. 
 


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Confidential Information 
FDA, 2011. 
FDA Anti-infective Drugs Advisory Committee (03-Nov-2011). Endpoints and clinical trial 
issues in community-acquired bacterial pneumonia. Recommendations to FDA for interim 
endpoints for clinical trials in community-acquired bacterial pneumonia (document dated, 
26-Aug-2011).  Prepared by: Foundations for the National Institutes of Health Biomarkers 
Consortium Project Team. CABP Docket ID: FDA-2009D0136. Available at: 
http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/anti-
infectivedrugsadvisorycommittee/ucm275823.pdf.  
 
Fine et al., 1996. 
Fine MJ, Smith MA, Carson CA, et al. Prognosis and outcomes of patients with community-
acquired pneumonia. A meta-analysis. JAMA. 1996; 257(2):134-141. 
 
Fine et al., 1997. 
Fine MJ, Auble TE, Yealy DM, et al. A prediction rule to identify low-risk patients with 
community-acquired pneumonia. N Engl J Med. 1997; 336(4):243-250. 
 
Francis et al., 2005. 
Francis JS, Doherty MC, Lopatin U, et al. Severe community-onset pneumonia in healthy 
adults caused by methicillin-resistant Staphylococcus aureus carrying the Panton-Valentine 
leukocidin genes. Clin Infect Dis. 2005; 40(1):100-107. 
 
Gillet et al., 2007. 
Gillet Y, Vanhems P, Lina G, et al. Factors predicting mortality in necrotizing community-
acquired pneumonia caused by Staphylococcus aureus containing Panton-Valentine 
leukocidin. Clin Infect Dis. 2007; 45(3):315-321. 
 
Hidron et al., 2009. 
Hidron AI, Low CE, Honig EG, Blumberg HM. Emergence of community-acquired 
meticillin-resistant Staphylococcus aureus strain USA300 as a cause of necrotising 
community-onset pneumonia. Lancet Infect Dis. 2009; 9(6):384-392. 
 
Kollef et al., 2005. 
Kollef MH, Shorr A, Tabak YP, Gupta V, Liu LZ, Johannes RS. Epidemiology and outcomes 
of health-care-associated pneumonia: results from a large US database of culture-positive 
pneumonia. Chest. 2005; 128(6):3854-3862. 
 
Lim et al., 2009. 
Lim WS, Baudouin SV, George RC, et al. The British Thoracic Society guidelines for the 
management of community acquired pneumonia in adults: update 2009. Thorax. 2009; 
64(Suppl 3):iii1-iii50. 
 


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Confidential Information 
Liu et al., 2014. 
Liu X, Jiang Y, Chen X, Li J, Shi D, Xin D. Drug resistance mechanisms of Mycoplasma 
pneumoniae to macrolide antibiotics. BioMed Research International, vol. 2014, Article ID 
320801, 7 pages, 2014. doi:10.1155/2014/320801. 
 
Mandell et al., 2007. 
Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of 
America/American Thoracic Society consensus guidelines on the management of 
community-acquired pneumonia in adults. Clin Infect Dis. 2007; 44(Suppl 2):S27-S72. 
 
Oldach et al., 2015.   
Oldach D, Barrera C, Mykietiuk A, Metev H, Nitu MF, Karimjee N, et al. SOLITAIRE-Oral: 
results of a global phase 3 trial comparing oral solithromycin versus oral moxifloxacin for 
treatment of community-acquired bacterial pneumonia (CABP) in adults.  Abstract (oral 
session) presented at: 25th ECCMID; 2015 Apr 25-28; Copenhagen, Denmark. LBOS0239c. 
 
Paukner et al., 2012. 
Paukner S, Ivezic-Schoenfeld Z, Tack KJ, Sahm D, Prince WT. Microbiological activity and 
outcome of the pleuromutilin BC-3781 in a clinical phase 2 trial in acute bacterial skin and 
skin structure infections (ABSSSI). Poster presented at: 52nd ICAAC; 2012 Sep 9-12; San 
Francisco, CA, USA. L-1660. 
 
Paukner et al., 2013. 
Paukner S, Sader HS, Ivezic-Schoenfeld Z, Jones RN. Antimicrobial activity of the 
pleuromutilin antibiotic BC-3781 against bacterial pathogens isolated in the SENTRY 
antimicrobial surveillance program in 2010. Antimicrob Agents Chemother. 2013; 
57(9):4489-4495. 
 
Pfaller et al., 2012. 
Pfaller MA, Farell DJ, Sader HS, Jones RN. AWARE Ceftaroline Surveillance Program 
(2008-2010): trends in resistance patterns among Streptococcus pneumoniae, Haemophilus 
influenzae, and Moraxella catarrhalis in the United States. Clin Infect Dis. 2012; 55 (Suppl 
3):S187-S193. 
 
Prince et al., 2010. 
Prince WT, Wicha WW, Strickmann DB, Moschetti V, Obermayr F, Novak R. Safety, 
tolerance and pharmacokinetics of single and repeat doses of BC-3781, a novel antimicrobial. 
Poster presented at: 20th ECCMID; 2010 Apr 10-12; Vienna, Austria. P906. 
 
Prince et al., 2013. 
Prince WT, Ivezic-Schoenfeld Z, Lell C, et al. Phase II clinical study of BC-3781, a 
pleuromutilin antibiotic, in treatment of patients with acute bacterial skin and skin structure 
infections. Antimicrob Agents Chemother. 2013; 57(5):2087-2094. 
 


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Rubino et al., 2015. 
Rubino CM, Xue B, Bhavnani SM, et al. Population pharmacokinetic analyses for BC-3781 
using phase 2 data from patients with acute bacterial skin and skin structure infections. 
Antimicrob Agents Chemother. 2015; 59(1):282-288. 
 
Sader et al., 2012. 
Sader HS, Paukner S, Ivezic-Schoenfeld Z, Biedenbach DJ, Schmitz FJ, Jones RN. 
Antimicrobial activity of the novel pleuromutilin antibiotic BC-3781 against organisms 
responsible for community-acquired respiratory tract infections (CARTIs). J Antimicrob 
Chemother. 2012; 67(5):1170-1175.  
 
Van Wart et al., 2009. 
Van Wart S, Andes DR, Ambrose PG, Bhavnani SM. Pharmacokinetic-pharmacodynamic 
modeling to support doripenem dose regimen optimization for critically ill patients. Diagn 
Microbiol Infect Dis. 2009; 63:409-414. 
 
Waites and Talkington, 2004. 
Waites KB, Talkington DF. Mycoplasma pneumoniae and its role as a human pathogen. Clin 
Microbiol Rev. 2004; 17(4):697-728. 
 
Wicha et al., 2010. 
Wicha WW, Lell C, Obermayr F, Logan DK, Prince WT. An age and gender study 
investigating the safety, tolerance and pharmacokinetics of BC-3781. Poster presented at: 
50th ICAAC; 2010 Sep 12-15; Boston, MA, USA. A1-019 
 
Wicha et al., 2013. 
Wicha WW, Lell C, Strickmann DB, Heilmayer W, Ivezic-Schoenfeld Z, Prince WT. Safety, 
tolerability and pharmacokinetics of orally administered BC 3781, a novel antimicrobial. 
Poster presented at: 53rd ICAAC; 2013 Sep 10-13; Denver, CO, USA. A-012. 
 
Zeitlinger et al., 2011. 
Zeitlinger M, Obermayr F, Burian A, et al. The pharmacokinetics of BC-3781 in muscle and 
adipose tissue in healthy subjects. Poster presented at: 51st ICAAC; 2011 Sep 17-20; 
Chicago, IL, USA. A1-1761a. 
 
Zeitlinger et al., 2016. 
Zeitlinger M, Schwameis R, Burian A, et al. Simultaneous assessment of the 
pharmacokinetics of a pleuromutilin, lefamulin, in plasma, soft tissues and pulmonary 
epithelial lining fluid. J Antimicrob Chemother. 2016; Jan 7. pii: dkv442. [Epub ahead of 
print] 
 
 
 


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20 APPENDICES 
 
Appendix 1 
Clinical Laboratory Tests (Safety) 
Appendix 2 
Short Acting Antibiotics 
Appendix 3 
Closely Monitored CYP3A4 Substrates and P-Glycoprotein Substrates 
(excluding strong CY3A inducers and inhibitors and excluding strong P-
glycoprotein inhibitors) 
Appendix 4 
Prohibited Strong P-Glycoprotein Inhibitors and Strong CYP3A Inducers 
and Inhibitors 
Appendix 5 
Drugs That Prolong QT 
 
 
 


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Appendix 1 
Clinical Laboratory Tests (Safety) 
Blood and urine samples for the following laboratory tests will be sent to a central 
laboratory for testing.    
 
Hematology 
Complete blood count (CBC) with RBC indices and WBC differential 
Platelet count 
Chemistry 
BUN 
Creatinine 
Glucose 
Sodium 
Potassium 
Chloride 
Calcium 
Magnesium 
Phosphorus 
AST 
ALT 
GGT 
Alkaline Phosphatase 
CPK 
Total Bilirubin 
Direct Bilirubin 
Uric Acid 
Albumin 
Total Protein 
Urinalysis 
Specific gravity 
pH, glucose, protein, blood, ketones, bilirubin and leukocyte esterase by dipstick 
Microscopic examination (all samples) 
Other tests 
Procalcitonin 
 
Testing at Screening Only 
Serum pregnancy test 
Urine pregnancy test (testing kit provided by central laboratory; test to be performed at 
the local site prior to randomization) 
 
 
 
 


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Appendix 2 
Short Acting versus Long Acting Antibiotics 
 
Short-acting 
Long-acting 
Cephalosporins 
Cefaclor, Cefadroxil, Cefdinir, Cefepime, 
Cefixime (200 mg), Cefotaxime, Cefpodoxime, 
Cefprozil, Ceftazadime, Ceftibuten, Cefditoren, 
Cefruoxime, Cephalexin, Loracarbef 
Cefixime (400 mg), Ceftriaxone 
Fluoroquinolones 
Ciprofloxacin, Norfloxacin 
Gatifloxacin, Gemifloxacin, Grepafloxacin, 
Levofloxacin, Moxifloxacin, Sparfloxacin 
Macrolides and Ketolides 
Clarithromycin, Erythromycin, Roxithromycin 
Azithromycin, Clarithromycin XL (extended 
release), Dirithromycin, Telithromycin 
Penicillins and Carbapenems 
Amoxicillin, Amoxicillin-Clavulanate, 
Amoxicillin-Sulbactam, Ampicillin, Ampicillin-
Sulbactam, Dicloxacillin, Imipenem, 
Meropenem, Nafcillin, Oxacillin, Penicillin-G, 
Penicillin-V, Piperacillin, Piperacillin-
Tazobactam, Ticaracillin-Clavulanate 
Ertapenem, Penicillin-G, Benzathine/Procaine 
Tetracyclines 
Doxycycline (100 mg), Minocycline, 
Tetracycline 
Doxycycline (200 mg), Minocycline Extended 
Release 
 
 
 
 


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Appendix 3 
Closely Monitored CYP3A4 Substrates and P-
Glycoprotein Substrates (excluding strong CY3A 
inducers and inhibitors and excluding strong P-
glycoprotein inhibitors) 
Closely Monitored CYP3A4 Substrates 
Alfentanyl 
Domperidone 
Pimozide 
Alprazolam 
Eplerenone 
Progesterone 
Amiodipine 
Estradiol 
Propranolol 
Aprepitant 
Fentanyl 
Quetiapine 
Aripiprazole 
Finasteride 
Quinine 
Astemizole 
Gleevec 
Reserpine 
Buspirone 
Haloperidol 
Salmeterol 
Cafergot 
Hydrocortisone 
Sildenafil 
Caffeine 
Lercanidipine 
Sirolimus 
Chlorpheniramine 
Lidocaine 
Terfenadine 
Cilostazol 
Methadone 
Testosterone 
Cocaine 
Midazolam 
Trazodone 
Codeine 
Nateglinide 
Triazolam 
Dapsone 
Nifedipine 
Zaleplon 
Dexamethasone 
Nisoldipine 
Ziprasidone 
Dextromethorphan 
Nitrendipine 
Zolpidem 
Docetaxel 
Ondansetron 
 
 
 


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Closely Monitored P-Glycoprotein Substrates 
Apixaban 
Fexofenadine 
Ranitidine 
Carvedilol 
Fosamprenavir 
Rivaroxaban 
Cimetidine 
Ivermectin 
Saxagliptin 
Colchicine 
Ledipasvir 
Silodosin 
Dabigatran 
Loperamide 
Sitagliptin 
Daclatasvir 
Losartan 
Sofosbuvir 
Dasabuvir 
Maraviroc 
Tetracycline  
Dexamethasone  
Methylprednisolone 
Tipranavir 
Digoxin  
Methotrexate  
Tolvaptan 
Domperidone 
Morphine 
Umeclidinium 
Edoxaban 
Ombitasvir 
Vecuronium  
Empagliflozin 
Paliperidone 
Vilanterol 
Estradiol 
Paritaprevir  
 
Ezetimibe 
Prazosin 
 
 
 
 


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Appendix 4 
Prohibited Strong P-Glycoprotein Inhibitors and Strong 
CYP3A Inducers and Inhibitors 
Prohibited Strong P-Glycoprotein Inhibitors 
Amiodarone  
Indinavir  
Ranolazine  
Atorvastatin  
Itraconazole  
Reserpine 
Boceprevir  
Ketoconazole  
Ritonavir  
Bromocriptine  
Linagliptin  
Saquinavir  
Captopril  
Lopinavir and ritonavir  
Simeprevir  
Carvedilol  
Lovastatin  
Simvastatin  
Cobicistat  
Meperidine  
Suvorexant  
Conivaptan  
Methadone 
Tacrolimus  
Cyclosporine  
Nelfinavir 
Tamoxifen  
Diltiazem  
Nicardipine  
Telaprevir  
Doxazosin  
Pentazocine  
Ticagrelor  
Dronedarone  
Progesterone 
Verapamil  
Felodipine  
Quercetin  
 
Fluvastatin  
Quinidine 
 
 
 
Prohibited Strong CYP3A Inhibitors 
Prohibited Strong CYP3A Inducers 
Indinavir 
Efavirenz 
Nelfinavir 
Nevirapine 
Ritonavir 
Phenobarbital 
Itraconazole 
Phenytoin 
Ketoconazole 
Pioglitazone 
Nefazodone 
Rifabutin 
Saquinavir 
Rifampin 
Suboxone 
St. John’s Wort 
Carbamazepine 
Troglitazone 
 


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Appendix 5 
Drugs That Prolong QT 
Anticonvulsants 
Fosphenytoin; Felbamate 
Antihistamines 
Azelastine, Clemastine 
Anti-infectives 
Amantadine, Clarithromycin, Chloroquine, Foscarnet, 
Erythromycin, Halofantrine, Mefloquine, Pentamidine, 
Sparfloxacin, Quinine, Trimethoprim-
Sulfamethoxazole, Ketoconazole 
Antineoplastics 
Tamoxifen 
Cardiovascular 
Antiarrhythmics 
Amiodarone, Bretylium, Disopyramide, Flecainide, 
Ibutilide, Procainamide, Quinidine, Sotalol, Dofetilide  
Calcium Channel Blockers 
Bepridil, Israpidine, Nicardipine 
Diuretics 
Indapamide, Moexipril/ hydrochlorothiazide 
Hormones 
Octreotide, Vasopressin 
Immunosuppressives 
Tacrolimus 
Migraine: Serotonin Receptor Agonists 
Zolmitriptan, Naratriptan, Sumatriptan 
Muscle Relaxants 
Tizanidine 
Narcotic Detoxification 
Levomethadyl 
Psycotherapeutics 
Antidepressants 
Amitriptyline, Desipramine, Fluoxetine, Imipramine, 
Venlafaxine 
Antipsychotics 
Chlorpromazine, Haloperidol, Pimozide, Quetiapine, 
Risperidone, Thioridazine 
Antianxiety 
Doxepin 
Antimanic 
Lithium 
Respiratory (Sympathomimetics) 
Salmeterol 
Sedative/Hypnotics 
Chloral hydrate 
Note: List not exhaustive 
 

SAP_000.pdf: 
Nabriva Therapeutics AG 
Statistical Analysis Plan – Protocol NAB-BC-3781-3102 
07May2018 
CONFIDENTIAL 
Page 1 of 64 
 
 
 
A Phase 3, Randomized, Double-Blind, Double-Dummy Study to Compare the 
Efficacy and Safety of Oral Lefamulin (BC-3781) Versus Oral Moxifloxacin in 
Adults with Community-Acquired Bacterial Pneumonia 
Protocol: NAB-BC-3781-3102 
 
 
FINAL 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
 
 
 
 
 
 


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07May2018 
CONFIDENTIAL 
Page 2 of 64 
STATISTICAL ANALYSIS PLAN APPROVAL 
Protocol: NAB-BC-3781-3102 
Version 1.0 
 
 
 
 
_________________________  
 
                    _____________ 
Anita F. Das, PhD                             
 
            
Date 
Project Statistician 
 
 
_________________________  
 
           
_____________ 
Leanne Gasink, MD 
 
 
 
 
 
Date 
Senior Director, Clinical Development and 
Medical Affairs 
Nabriva Therapeutics AG 
 
 
_________________________  
 
           
_____________ 
Lisa Goldberg 
 
 
 
 
 
 
Date 
Senior Director, Clinical Development 
Nabriva Therapeutics AG 
 


Nabriva Therapeutics AG 
Statistical Analysis Plan – Protocol NAB-BC-3781-3102 
07May2018 
CONFIDENTIAL 
Page 3 of 64 
TABLE OF CONTENTS 
TABLE OF CONTENTS ..............................................................................................................3 
LIST OF ABBREVIATIONS .......................................................................................................5 
1.0 
INTRODUCTION..............................................................................................................7 
2.0 
STUDY DESIGN ................................................................................................................7 
3.0 
STUDY OBJECTIVES ......................................................................................................8 
4.0 
PATHOGEN IDENTIFICATION ...................................................................................9 
4.1 
“Typical” Respiratory Pathogens .............................................................................9 
4.2 
“Atypical” Respiratory Pathogens .........................................................................11 
4.3 
Other Diagnostic Methods .....................................................................................13 
5.0 
ANALYSIS SETS.............................................................................................................14 
5.1 
Intent-to-Treat (ITT) Analysis Set .........................................................................14 
5.2 
Modified Intent-to-Treat (mITT) Analysis Set ......................................................14 
5.3 
Safety Analysis Set ................................................................................................14 
5.4 
Microbiological ITT (microITT) Analysis Set ......................................................14 
5.5 
Microbiological ITT-2 (microITT-2) Analysis Set ................................................14 
5.6 
Clinically Evaluable (CE) Analysis Sets ...............................................................14 
5.7 
Microbiologically Evaluable (ME) Analysis Sets .................................................17 
5.8 
Expanded Microbiological ITT (emicroITT) Analysis Set ...................................17 
5.9 
Pharmacokinetic (PK) Analysis Set .......................................................................18 
6.0 
DEFINITIONS OF OUTCOME MEASURES .............................................................19 
6.1 
Primary Efficacy Outcome: Early Clinical Response ............................................19 
6.2 
Secondary Efficacy Outcomes ...............................................................................21 
6.2.1 
Investigator’s Assessment of Clinical Response...................................21 
6.2.2 
Early Clinical Response in the microITT Analysis Set ........................24 
6.2.3 
By-Pathogen Microbiological Response ...............................................24 
6.2.4 
28-Day All-Cause Mortality .................................................................25 
6.3 
Additional Efficacy Outcomes ...............................................................................26 
6.3.1 
By-Subject Microbiological Response at the EOT, TOC and LFU 
Visits .....................................................................................................27 
6.3.2 
Early Clinical Response Plus Improvement in Vital Signs ...................28 
6.4 
Other Microbiological Outcomes ..........................................................................29 
6.5 
Pharmacokinetic Outcomes ...................................................................................30 
6.6 
Safety Outcomes ....................................................................................................30 
6.7 
Additional Exploratory Outcomes .........................................................................30 
7.0 
STATISTICAL METHODS ...........................................................................................30 


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7.1 
Sample Size ............................................................................................................30 
7.2 
Visit Windows .......................................................................................................31 
7.2.1 
Baseline .................................................................................................31 
7.2.2 
Post-Baseline .........................................................................................32 
7.2.3 
Unscheduled Assessments ....................................................................32 
7.3 
Randomization .......................................................................................................33 
7.4 
Interim Analysis .....................................................................................................33 
7.5 
Comments on the Statistical Analyses ...................................................................34 
7.6 
Handling of Missing Data ......................................................................................34 
8.0 
STATISTICAL ANALYSES ..........................................................................................36 
8.1 
Subject Disposition and Protocol Deviations ........................................................36 
8.2 
Demographics and Baseline Characteristics ..........................................................37 
8.3 
Baseline Microbiological Assessments..................................................................39 
8.4 
Extent of Exposure and Study Drug Treatment Compliance.................................42 
8.4.1 
Duration of Study Drug Therapy ..........................................................42 
8.4.2 
Prior and Concomitant Medications......................................................42 
8.4.3 
Study Drug Treatment Compliance ......................................................44 
8.5 
Efficacy Analyses ..................................................................................................44 
8.5.1 
Primary Efficacy Analysis ....................................................................44 
8.5.2 
Additional Analyses of the Primary Efficacy Outcome ........................45 
8.5.3 
Secondary Efficacy Analyses ................................................................46 
8.5.4 
Additional Efficacy Analyses ...............................................................48 
8.6 
Pharmacokinetic Analyses .....................................................................................50 
8.7 
Safety Analyses ......................................................................................................50 
8.7.1 
Adverse Events......................................................................................51 
8.7.2 
Clinical Laboratory Evaluations ...........................................................51 
8.7.3 
ECG Parameters ....................................................................................53 
8.7.4 
Vital Signs .............................................................................................53 
9.0 
CHANGES FROM THE PROTOCOL SPECIFIED ANALYSES ............................54 
10.0 
REFERENCES .................................................................................................................55 
APPENDIX A:  SCHEDULE OF ASSESSMENTS AND PROCEDURES ...........................57 
APPENDIX B:  CLINICAL LABORATORY POTENTIALLY CLINICALLY 
SIGNIFICANT VALUES ................................................................................................61 
APPENDIX C:  DIRECTIONALITY OF WORST LABORATORY PARAMETERS .......62 
APPENDIX D:  SAFETY ASSESSMENT WINDOWS ...........................................................63 
 
 


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07May2018 
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LIST OF ABBREVIATIONS 
ACM 
All-cause mortality 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
ATS 
American Thoracic Society 
BAL 
Bronchoalveolar lavage 
BUN 
Blood urea nitrogen 
C 
Celsius 
CABP 
Community-acquired bacterial pneumonia 
CE 
Clinically evaluable 
CE-EOT 
Clinically Evaluable at End of Treatment 
CE-LFU 
Clinically Evaluable at Late Follow Up 
CE-TOC 
Clinically Evaluable at Test-of-Cure 
CI 
Confidence interval 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
ECR 
Early Clinical Response 
eCRF 
Electronic case report form 
EMA 
European Medicines Agency 
emicroITT 
Expanded Microbiological Intent-to-Treat 
EOT 
End of Treatment 
EU 
European Union 
F 
Fahrenheit 
FDA 
US Food and Drug Administration 
GGT 
Gamma-glutamyl-transferase 
IAC 
Interim Analysis Committee 
IACR 
Investigator's Assessment of Clinical Response 
IRT 
Interactive response technology 
ITT 
Intent-to-Treat 
IV 
Intravenous 
LFU 
Late follow-up 
LLN 
Lower limit of normal 
LPF 
Low power field 
ME 
Microbiologically evaluable 
MedDRA 
Medical Dictionary for Regulatory Activities 
ME-EOT 
Microbiologically Evaluable at End of Treatment 


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07May2018 
CONFIDENTIAL 
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ME-LFU 
Microbiologically Evaluable at Late Follow Up 
ME-TOC 
Microbiologically Evaluable at Test-of-Cure 
Mg 
Milligram 
MIC 
Minimum inhibitory concentration 
microITT 
Microbiological Intent-to-Treat 
microITT-2 
Microbiological Intent-to-Treat-2 
mITT 
Modified Intent-to-Treat 
mmHg 
Millimeter of mercury 
MRSA 
Methicillin resistant Staphylococcus aureus 
MSSA 
Methicillin susceptible Staphylococcus aureus 
NA 
Not applicable 
NI 
Non-inferiority 
PCS 
Potentially clinically significant 
PISP 
Penicillin intermediate Streptococcus pneumoniae 
PMNs 
Polymorphonuclear neutrophils 
PO 
By mouth (oral) 
PORT 
Pneumonia Outcomes Research Team 
PRO 
Patient Reported Outcome 
PRSP 
Penicillin resistant Streptococcus pneumoniae 
PSSP 
Penicillin susceptible Streptococcus pneumoniae 
PVL 
Panton-Valentine Leukocidin 
q12h 
Every 12 hours  
q24h 
Every 24 hours  
QTcF 
QT interval corrected by the Fridericia formula 
RQ-PCR 
Real-time quantitative Polymerase chain reaction 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SEC 
Squamous epithelial cells 
SIRS 
Systemic Inflammatory Response Syndrome 
Spp 
Species 
TEAE 
Treatment-emergent adverse event 
TOC 
Test of Cure 
UAT 
Urinary antigen test 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell 
WHO 
World Health Organization 


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1.0 
INTRODUCTION 
This statistical analysis plan (SAP) provides the framework for the summarization and analysis 
of the clinical data from the study, “A Phase 3, Randomized, Double-Blind, Double-Dummy 
Study to Compare the Efficacy and Safety of Oral Lefamulin (BC-3781) Versus Oral 
Moxifloxacin in Adults With Community-Acquired Bacterial Pneumonia”.  Changes made to 
this SAP after it has been signed but prior to database lock will be documented in an amendment.  
Any important changes made to the analysis after database lock will be described in the clinical 
study report.  Pharmacokinetic analyses (except for the description of plasma concentrations) and 
health utilization and patient-reported outcome analyses will not be included in this SAP.  A 
separate analysis plan will be written for the health utilization and patient-reported outcome 
analyses. 
Study NAB-BC-3781-3102 has been designed to address both the United States (US) Food and 
Drug Administration (FDA) and European Medicines Agency (EMA) regulatory requirements.  
While the EMA supports the assessment of clinical response by the Investigator at a Test of Cure 
(TOC) Visit (which is scheduled to occur 5-10 days after the last dose of study drug) as the 
primary endpoint, the FDA is using an earlier primary endpoint (3-5 days after the first dose of 
study drug) based on improvement in pneumonia symptoms.  
This SAP addresses the primary efficacy outcome and analyses for the FDA. A SAP Addendum 
will be developed to address the different primary efficacy outcome and analyses for the EMA.  
2.0 
STUDY DESIGN 
This is a Phase 3, multicenter, multinational, randomized, double-blind, double-dummy 
comparative efficacy and safety study of oral lefamulin (600 mg every 12 hours [q12h]) and oral 
moxifloxacin (400 mg every 24 hours [q24h]) in the treatment of adult subjects with community-
acquired bacterial pneumonia (CABP).  The duration of blinded study drug administration is 7 
days. Subjects randomized to lefamulin will receive oral lefamulin 600 mg q12h for 5 days 
(10 doses) and oral moxifloxacin placebo q24h for 7 days (7 doses).  Subjects randomized to 
moxifloxacin will receive oral moxifloxacin 400 mg q24h for 7 days (7 doses) and oral lefamulin 
placebo q12h for 5 days (10 doses).   
A total of 738 subjects with CABP (Pneumonia Outcomes Research Team [PORT] Risk Class II, 
III, or IV) will be randomized 1:1 to study treatment (369 to each treatment arm) using 
interactive response technology (IRT).  Randomization will be stratified by geographic region 
(US vs ex-US), prior single dose treatment with a short acting antibiotic vs. none, and by PORT 
risk class: (PORT II vs. III/IV).  Enrollment of subjects receiving prior single dose treatment 
with a short acting antibiotic will be capped at 25%. A minimum of 50% of the total number of 
subjects randomized will have a PORT Risk Class of III or IV.    
After informed consent is obtained, all potential study participants undergo screening 
evaluations, which includes a medical history, clinical assessments, and laboratory assessments.  
An assessment of Early Clinical Response (ECR) will occur 96 ± 24 hours after the first dose of 
study drug.  An Investigator’s Assessment of Clinical Response (IACR) will be evaluated at the 
End of Treatment (EOT) Visit (within 1 day after the last dose of study drug or if not logistically 


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feasible [eg, visit would need to be conducted over a weekend], then conducting the visit within 
2 days is acceptable), at the TOC Visit (5 to 10 days after the last dose of study drug), and at a 
Late Follow-up (LFU) Visit conducted on Day 30 (±3 days). 
The schedule of assessments and procedures is provided in Appendix A.  
3.0 
STUDY OBJECTIVES 
Primary: 
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  
Secondary: 
 Demonstrate the NI of lefamulin versus comparator with respect to the Investigator’s 
Assessment of Clinical Response at TOC (ie, 5-10 days after the last dose of study drug) 
in the modified-ITT (mITT) and Clinically Evaluable at TOC (CE-TOC) Analysis Sets.  
NOTE: This is the primary efficacy endpoint for the EMA.  
 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 
 Evalute the By-Pathogen Microbiologic Response at TOC in the microITT and ME-TOC 
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 
Additional: 
 
Evaluate the Early Clinical Response by baseline pathogen in the microITT Analysis Set 
 
Evaluate the Investigator’s Assessment of Clinical Response at EOT (ie, within 2 days 
after the last dose of study drug) and at LFU in the mITT and Clinically Evaluable (CE) 
Analysis Sets (CE-EOT for IACR at EOT and CE-LFU for IACR at LFU). 
 
Evaluate the Investigator’s Assessment of Clinical Response by baseline pathogen at 
TOC and LFU in the microITT and Microbiologically Evaluable (ME) Analysis Sets 
(ME-TOC for IACR at TOC and ME-LFU for IACR at LFU). 
 
Evaluate the By-Subject Microbiologic Response at TOC in the microITT and ME-TOC 
Analysis Sets 
 Evaluate the Early Clinical Response PLUS improvement in vital signs in the ITT 
Analysis Set 


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 
Evaluate the plasma pharmacokinetics of lefamulin and its main metabolite, BC-8041, in 
the Pharmacokinetic Analysis Set 
 Explore a variety of health utilization variables and an investigational patient reported 
outcome measure in subjects receiving lefamulin compared with subjects receiving 
comparator. 
4.0 
PATHOGEN IDENTIFICATION 
All microbiology data will be reviewed by the Sponsor for pathogen identification.  A pathogen 
is defined as bacteria implicated as causative in a subject’s CABP and will be determined 
separately for each subject.  Baseline pathogens and post-baseline pathogens will be identified. 
Additional details regarding the pathogen review process and determination are included in the 
Evaluability Review Plan. 
Baseline for microbiologic specimens is defined as the 24-hour period prior to the administration 
of the first dose of study drug and the 24 hours after the first dose of study drug. A pathogen 
identified from a respiratory (pleural fluid, bronchoalveolar lavage (BAL), sputum), blood for 
culture, urine, nasopharyngeal or oropharyngeal specimen collected at baseline is considered a 
baseline pathogen.  An atypical pathogen identified by serology is considered a baseline 
pathogen if the baseline sample is collected in the 24-hour period prior to the administration of 
the first dose of study drug or the 24 hours after the first dose of study. A Gram stain from a 
specimen collected at baseline is considered a baseline Gram stain.  
If more than 1 specimen is taken during the baseline period, all specimens will be reviewed for 
pathogen identification.  If the same pathogen (based on genus and species) is identified from 
more than 1 specimen, the pathogen with the highest minimum inhibitory concentration (MIC) to 
study drug received will be considered the baseline pathogen. If the pathogens have the same 
MIC to study drug received, the one with the highest accession number will be considered the 
baseline pathogen. 
Post-baseline is defined as the period starting 24 hours after the first dose of study drug.  A 
pathogen identified from a specimen collected post-baseline is considered a post-baseline 
pathogen.  Only pathogens identified by culture of the sputum, BAL, pleural fluid or blood are 
considered post-baseline pathogens. 
4.1 
“Typical” Respiratory Pathogens 
Sputum samples will undergo a microscopic examination. Microscopic examination of Gram-
stained sputum specimens will be performed by the local/regional laboratory. Gram's stain slides 
will be sent to the central laboratory for a confirmatory reading.  The stained slide read by the 
local/regional laboratory as well as an unstained slide will be sent to the central laboratory. The 
best Gram stain reading from the central read of a central laboratory Gram stained respiratory 
specimen and the central read of the local/regional laboratory Gram stained respiratory specimen 
will be used to determine the adequacy of the specimen for pathogen determination.  If the Gram 
stain reading from the central read of a central laboratory Gram stained respiratory specimen and 
the central read of the local/regional laboratory Gram stained respiratory specimen have the same 


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ranking, the central read of a central laboratory Gram stained respiratory specimen will be 
considered the best Gram stain.  The central reads of polymorphonuclear neutrophils 
(PMNs)/low power field (LPF) and squamous epithelial cells (SECs)/LPF ranked best to worst 
are as follows: 
1. >25 PMNs/LPF    and <10 SECs/LPF 
2. 10-25 PMNs/LPF and <10 SECs/LPF 
3. <10 PMNs/LPF    and <10 SECs/LPF 
4. >25 PMNs/LPF    and 10-25 SECs/LPF 
5. 10-25 PMNs/LPF and 10-25 SECs/LPF 
6. <10 PMNs/LPF    and 10-25 SECs/LPF 
7. >25 PMNs/LPF    and >25 SECs/LPF 
8. 10-25 PMNs/LPF and >25 SECs/LPF 
9. <10 PMNs/LPF    and >25 SECs/LPF 
If neither of the central reads is available, the local/regional read of the local/regional laboratory 
Gram stained respiratory specimen will be used.   
In general, the central lab identification of genus and species will be used.  If the local laboratory 
grows an isolate but the central laboratory is not able to grow the isolate, if isolates were lost 
during transportation or storage, or there are major discrepancies between the local and central 
laboratory in the identification of species, the central laboratory will request the local laboratory 
to resend the isolate.  If the central laboratory identification remains unavailable for an isolate 
after the lab has requested the isolate be resent, the local laboratory identification will be used. 
For any discrepancies in genus and/or species identification between the central and local 
laboratory, the central laboratory identification will be used as the default identification.  Thus, it 
is possible for subjects to have different isolates from both central and local laboratories as a 
result.   
Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus and Moraxella 
catarrhalis will always be considered a CABP pathogen in the presence of the following criteria:  
Streptococcus pneumoniae 
 Positive BAL, pleural fluid or blood culture; or  
 Positive sputum culture in the presence of a Gram stain with >25 PMNs/LPF and 
<10 SECs/LPF (NOTE: ≥10 PMNs/LPF and <10 SECs/LPF in the expanded 
Microbiological ITT (emicroITT) Analysis Set); or 
 Positive urinary antigen test; or 
 Positive real-time quantitative Polymerase chain reaction (RQ-PCR) of nasopharyngeal 
swab or sputum (see Table 1 for cutoff values); or 
 Positive nasopharyngeal specimen culture 
 
 


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Haemophilus influenzae  
 Positive BAL, pleural fluid or blood culture; or  
 Positive sputum culture in the presence of a Gram stain with >25 PMNs/LPF and 
<10 SECs/LPF (NOTE: ≥10 PMNs/LPF and <10 SECs/LPF in the emicroITT 
Analysis Set); or 
 Positive RQ-PCRof sputum (see Table 1 for cutoff value); or 
Staphylococcus aureus 
 Positive BAL, pleural fluid or blood culture; or 
 Positive sputum culture in the presence of a Gram stain with >25 PMNs/LPF and 
<10 SECs/LPF (NOTE: ≥10 PMNs/LPF and <10 SECs/LPF in the emicroITT 
Analysis Set); or 
 Positive RQ-PCR of sputum (see Table 1 for cutoff value) 
Moraxella catarrhalis 
 Positive BAL, pleural fluid or blood culture; or  
 Positive sputum culture in the presence of a Gram stain with >25 PMNs/LPF and 
<10 SECs/LPF (NOTE: ≥10 PMNs/LPF and <10 SECs/LPF in the emicroITT 
Analysis Set); or 
 Positive RQ-PCR of sputum (see Table 1 for cutoff value) 
The following isolates are considered as contaminants from respiratory specimens rather than 
primary pathogens of CABP: fungi, Enterococcus spp., viridans streptococci, coagulase-negative 
staphylococci, Micrococcus spp., Neisseria spp. other than N. meningitidis, Corynebacterium 
spp. and other coryneforms, Lactobacillus spp., Vibrio spp., Capnocytophaga spp., 
Cardiobacterium spp., Flavobacterium spp. 
Other isolates identified from culture of blood and respiratory specimens will be reviewed in a 
blinded manner by the Sponsor on a case-by-case basis for determination of whether the 
organism is a pathogen for CABP.   
4.2 
“Atypical” Respiratory Pathogens 
Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydophila pneumoniae will always 
be considered a CABP pathogen in the presence of the following criteria: 
Legionella pneumophila 
 Positive BAL, plueral fluid or blood culture; or 
 Positive sputum culture, regardless of Gram stain findings; or 
 Positive urinary antigen test; or 


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 Between baseline and convalescent (LFU Visit) specimens, a 4-fold or greater increase in 
L. pneumophila antibody titer to ≥1:128; or  
 Positive RQ-PCR of sputum  
Mycoplasma pneumoniae 
 Between baseline and convalescent (LFU Visit) specimens, a 4-fold or greater increase in 
M. pneumoniae IgG serum antibody titer to ≥1:160; or 
 Positive oropharyngeal specimen culture; or 
 Positive BAL, pleural fluid or blood culture; or  
 Positive sputum culture in the presence of a Gram stain with >25 PMNs/LPF and 
<10 SECs/LPF (NOTE: ≥10 PMNs/LPF and <10 SECs/LPF in the emicroITT 
Analysis Set); or 
 Positive RQ-PCR of oropharyngeal swab or sputum (see Table 1 for cutoff values) 
Chlamydophila pneumoniae 
 Between baseline and convalescent (LFU Visit) specimens, a 4-fold or greater increase in 
C. pneumoniae IgG serum antibody titer; or   
 Positive RQ-PCR of sputum  


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4.3 
Other Diagnostic Methods 
Real-time quantitative Polymerase chain reaction based methods will also be used to determine 
the etiology of CABP at baseline.  
 Frozen sputum samples will be analyzed by RQ-PCR using specific and conserved 
primers for the target genes based on current published studies (see Table 1). Single-plex 
RQ-PCR will be set up, validated and sputum samples will be analyzed by a specialized 
Good Laboratory Practices-certified bioanalytical laboratory (Accelero Bioanalytics 
GmbH, Germany). 
 Oropharyngeal specimens will be analyzed by a specialized laboratory (K. Waites, 
Diagnostic Mycoplasma Laboratory, UAB, AL, USA) using RQ- PCR for Mycoplasma 
pneumoniae (repMp1) and for detection of macrolide-resistance (23S rDNA).  
 Nasopharyngeal specimens will be analyzed by a specialized laboratory (J. Vidal, Emory 
University, GA, USA) using RQ-PCR for detection of S. pneumoniae (lytA). 
Amplified genes and cut-off values for the definition of a pathogen from the oropharyngeal and 
nasopharyngeal swabs are presented in Table 1.  
Table 1. 
Amplified Genes and Cut-off Values for RQ-PCR 
Specimen / 
Organism 
PCR 
Proposed 
Amplified gene a 
Cut-off values for consideration of the organism as 
definite etiological significant for CABP 
Cut-off values 
Reference 
Sputum 
S. pneumoniae 
RQ-PCR 
lytA 
DNA corresponding to 
≥104 CFU/mL 
Albrich et al, 2014 
H. influenzae 
RQ-PCR 
frdB 
DNA corresponding to 
≥106 CFU/mL  
Johansson et al, 2010;  
Kais et al, 2006 
M. catarrhalis 
RQ-PCR 
copB 
DNA corresponding to 
≥106 CFU/mL  
Johansson et al, 2010;  
Kais et al, 2006 
S. aureus 
RQ-PCR 
nuc 
DNA corresponding to 
≥6 x 105 CFU/mL 
Huang et al, 2015 
M. pneumoniae 
RQ-PCR 
CARDS TX gene 
Positive 
Thurman et al, 2011;  
Waites et al, 2012 
L. pneumophila 
RQ-PCR 
ssrA 
Positive 
Thurman et al, 2011 
C. pneumoniae 
RQ-PCR 
argR 
Positive 
Thurman et al, 2011 
Oropharyngeal swabs 
M. pneumoniae 
RQ-PCR 
repMp1  
Positive 
Thurman et al, 2011;  
Waites et al, 2012 
Nasopharyngeal swabs 
S. pneumoniae 
RQ-PCR 
lytA 
≥1 x 103 CFU/mL 
Chochua et al, 2015 
a RQ-PCR will amplify the proposed genes provided that the validation is successful. If the RQ-PCR for the proposed target gene 
cannot be validated, another gene target will be used. 


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5.0 
ANALYSIS SETS 
5.1 
Intent-to-Treat (ITT) Analysis Set  
The ITT Analysis Set will consist of all randomized subjects regardless of whether or not the 
subject received study drug.  A subject is considered randomized when an IRT-generated 
randomization number has been assigned. 
5.2 
Modified Intent-to-Treat (mITT) Analysis Set  
The mITT Analysis Set will consist of all randomized subjects who receive any amount of study 
drug. Subjects are analyzed based on the randomized (ie, assigned) treatment group. 
5.3 
Safety Analysis Set 
The Safety Analysis Set will consist of all randomized subjects who receive any amount of study 
drug.  Subjects are analyzed based on the study drug actually received. All safety analyses will 
be conducted in this population.   
5.4 
Microbiological ITT (microITT) Analysis Set  
The microITT Analysis Set will consist of all subjects in the ITT Analysis Set who have at least 
1 baseline bacterial pathogen known to cause CABP as defined in Sections 4.1 and 4.2.  
Additional isolates not a priori defined as pathogens in this SAP will be evaluated on a case by 
case basis by the Evaluability Review Team. 
5.5 
Microbiological ITT-2 (microITT-2) Analysis Set 
The microITT-2 Analysis Set will consist of all subjects in the ITT Analysis Set who have at 
least 1 baseline bacterial pathogen known to cause CABP as defined in Sections 4.1 and 4.2 from 
a diagnostic method other than PCR.  Thus, the following will not be considered pathogens for 
the microITT-2 Analysis Set: 
 Streptococcus pneumoniae from RQ-PCR of nasopharyngeal swab 
 Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, or 
Moraxella catarrhalis from RQ-PCR of sputum 
 Legionella pneumophila, Mycoplasma pneumoniae, or Chlamydophila pneumoniae from 
RQ-PCR of sputum 
 Mycoplasma pneumoniae from RQ-PCR of oropharyngeal swab 
5.6 
Clinically Evaluable (CE) Analysis Sets 
Three CE Analysis Sets will be defined, the CE-EOT, CE-TOC and CE-LFU Analysis Sets.  The 
CE Analysis Sets will consist of all subjects in the ITT Analysis Set who also meet the criteria 
listed below.  These criteria will be programmed from the electronic case report form (CRF) data 
and/or reviewed manually by the Sponsor in a blinded manner prior to database lock to confirm 


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each subject’s inclusion in or exclusion from the CE Analysis Sets. Details regarding the 
programming and review of eCRF data are included in the Evaluability Review Plan. 
1. Subjects must meet all of the inclusion criteria below to be included in the CE-EOT, 
CE-TOC and CE-LFU Analysis Sets. 
Inclusion criterion 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 
Inclusion criterion 4: Have at least 2 of the following vital sign abnormalities:  
 Fever (body temperature >38.0ºC [100.4ºF] measured orally or equivalent 
temperature from alternate body site) or hypothermia (body temperature <35.0ºC 
[95.0ºF] 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)  
Inclusion criterion 5: Have at least 1 other clinical sign or laboratory finding of CABP: 
 Hypoxemia (ie, 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 (eg, 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 
Inclusion criterion 6: Have radiographically-documented pneumonia within 48 hours 
before enrollment (ie, infiltrates in a lobar or multilobar distribution or diffuse opacities 
on chest x-ray or chest computed tomography scan consistent with acute bacterial 
pneumonia per the radiologists interpretation ). NOTE: If the imaging study is done more 
than 48 hours before enrollment but in the timeframe consistent with onset of the 
subject's symptoms, the subject will be included in the CE Analysis Sets as long as the 
imaging study shows an infiltrate or diffuse opacities consistent with CABP. 
Inclusion criterion 7: Have a 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. 


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2. Completed the visit within the protocol mandated window: 
 For the CE-EOT Analysis Set: 
o Completed the EOT Visit on the day of last dose of study drug or within 2 days 
after the last dose of study drug.  
 For the CE-TOC Analysis Set: 
o Completed the TOC Visit 5-10 days after the last dose of study drug, unless the 
subject was considered a failure at the EOT Visit based on the IACR.  
 For the CE-LFU Analysis Set: 
o Completed the LFU Visit Day 30 (±3 days) unless the subject was considered a 
failure at either the EOT or TOC Visit based on the IACR.  
3. Must not have had a clinical response of indeterminate based on the IACR at EOT 
(CE-EOT Analysis Set), TOC (CE-TOC Analysis Set) or LFU (CE-LFU Analysis Set).  
4. Duration of study drug was at least 48 hours, unless the subject died prior to 48 hours.  
5. Did not receive another systemic antibacterial from the first dose of study drug through 
EOT (CE-EOT), through TOC (CE-TOC) or through LFU (CE-LFU) with likely or 
documented activity against confirmed or potential CABP pathogens, unless the 
antibacterial was administered due to clinical failure (or relapse at LFU) or the subject 
had been classified as clinical failure by the Investigator prior to receipt of the 
antibacterial.  Subjects who do not have a pathogen isolated at baseline and receive a 
concomitant antibiotic with activity against any potential CABP pathogen will be 
excluded from the relevant CE-EOT, CE-TOC and CE-LFU Analysis Set(s), unless the 
antibacterial was administered due to clinical failure (or relapse at LFU) or the subject 
had been classified as clinical failure by the Investigator prior to receipt of the 
antibacterial.  
6. Received the correct study drug, based on randomization assignment, for all active doses 
taken.  
7. Study personnel involved in the assessment of efficacy, or monitoring of the efficacy 
data, remained blinded to the subject treatment assignment through EOT (CE-EOT), 
TOC (CE-TOC) or LFU (CE-LFU) Visits. Subjects whose treatment assignments were 
unblinded to study personnel due to an adverse event (AE) will be included in the 
CE Analysis Sets. 
8. Subjects who meet any of the following exclusion criteria at baseline as indicated on the 
Inclusion Exclusion eCRF will be excluded from the CE Analysis Sets: 
Exclusion criterion 1: Have received more than a single dose of a short-acting oral or IV 
antibacterial for CABP within 72 hours before randomization. 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 (ie, 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 
to fluoroquinolones. 


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Exclusion criterion 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. 
Exclusion criterion 4: Have confirmed or suspected CABP caused by a pathogen known to 
be resistant to any of the study drugs (eg, MRSA, Pseudomonas aeruginosa, any pathogen 
of the Enterobacteriaceae Family) or attributable to etiologies other than 
community-acquired bacterial pathogens (eg, ventilator-associated pneumonia, 
hospital-acquired bacterial pneumonia, bacterial aspiration pneumonia, Pneumocystis 
jiroveci pneumonia or other fungal pneumonia, viral or mycobacterial infection of the 
lung). 
Exclusion criterion 5: Have a noninfectious cause of pulmonary infiltrates (eg, pulmonary 
embolism, chemical pneumonitis from aspiration, hypersensitivity pneumonia, congestive 
heart failure, bronchial obstruction, lung cancer, cystic fibrosis). 
Exclusion criterion 6: Have confirmed or suspected pleural empyema (does not include 
sterile parapneumonic effusions). 
Exclusion criterion 16: Have been previously treated with lefamulin or previously 
enrolled in this study. 
9. Subjects who have pneumonia attributable to etiologies other than community-acquired 
pneumonia, a noninfectious cause of pulmonary infiltrates or confirmed pleural empyema 
at Screening but discovered post-baseline will be excluded from the CE Analysis Sets.  
10. Any additional factor that may confound the assessment of efficacy as determined by the 
Sponsor during blinded review for evaluability. If a subject is excluded from the CE 
Analysis Sets due to an additional factor, the reason for exclusion will be documented in 
the appropriate analysis database and the Evaluability Review Plan. 
5.7 
Microbiologically Evaluable (ME) Analysis Sets 
The ME Analysis Sets (ME-EOT, ME-TOC and ME-LFU) will consist of all subjects who meet 
criteria for inclusion in both the microITT and the CE-EOT (ME-EOT) Analysis Set, the 
CE-TOC (ME-TOC) Analysis Set or the CE-LFU (ME-LFU) Analysis Set. Subjects who have 
CABP caused only by a pathogen(s) resistant to moxifloxacin or lefamulin will be excluded from 
the ME Analysis Sets.  Resistance is defined as: 1) a pathogen resistant to moxifloxacin or non-
susceptible to lefamulin based on susceptibility results from the central laboratory, or 2) a 
pathogen in the Enterobacteriacea family or a non-fermenting Gram-negative pathogen (with the 
exception of Legionella pneumophila and Moraxella catarrhalis), unless susceptibility data from 
the central laboratory is available and indicates the pathogen is susceptible to both moxifloxacin 
(Table 9) and lefamulin (Table 10). 
5.8 
Expanded Microbiological ITT (emicroITT) Analysis Set  
The emicroITT Analysis Set will consist of all subjects in the ITT Analysis Set who have at least 
1 baseline bacterial pathogen known to cause CABP as defined in Sections 4.1 and 4.2, except a 


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baseline pathogen from a sputum culture is defined using the presence of a Gram stain with 
≥10 PMNs/LPF and <10 SECs/LPF rather than >25 PMNs/LPF and <10 SECs/LPF.  
5.9 
Pharmacokinetic (PK) Analysis Set 
The PK Analysis Set will consist of all subjects in the mITT Analysis Set who have 
concentration results from at least one pharmacokinetic sample. 


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6.0 
DEFINITIONS OF OUTCOME MEASURES 
Efficacy will be assessed, either programmatically or by the Investigator (as outlined below), at 
the following time points:  
 96 ± 24 hours (as described in Section 6.1) after the first dose of study drug (ECR only).  
 EOT – within 2 days after the last dose of study drug. 
 TOC – 5 to 10 days after last dose of study drug.  
 LFU – Day 30 (±3 days) . 
For the EOT, TOC and LFU assessments, subjects will be assigned an IACR (success, failure, or 
indeterminate at EOT and TOC, sustained success, relapse, prior failure or indeterminate at 
LFU).  Early Clinical Response will be determined programmatically based on recorded 
symptom assessments that compare the assessments at Baseline and at 96 ± 24 hours after the 
first dose of study drug as defined in Section 6.1.  The Investigator will not make a determination 
of Early Clinical Response and will make treatment decisions based on the subject's overall 
response to therapy. Microbiologic responses will be determined at EOT, TOC and LFU.   
6.1 
Primary Efficacy Outcome: Early Clinical Response 
The primary efficacy outcome is the percentage of subjects with an ECR of responder at 
96 ± 24 hours after the first dose of study drug in the ITT Analysis Set.  Symptom definitions for 
the assessment are shown in Table 2. Subjects will be programmatically defined as a responder 
if the following 4 criteria are met: 
 Alive; 
 Improvement in at least 2 of the 3 or 4 cardinal symptoms of CABP 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 by at least 1 level of severity for any symptom;  
 Did not receive a concomitant antibiotic for the treatment of CABP up through the 
assessment of the cardinal symptoms of CABP. 


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Table 2. 
Symptom Assessment for Early Clinical Response Assessment 
Symptom 
Absent (0) 
Mild (1) 
Moderate (2) 
Severe (3) 
Dyspnea 
Resolution (to pre-
CABP baseline) or 
absence of dyspnea 
Dyspnea on exertion 
(eg, climbing stairs) 
Dyspnea with 
normal/routine 
activities (eg, walking) 
Dyspnea at rest or 
requiring oxygen 
therapy 
Cough 
Resolution (to pre-
CABP baseline) or 
absence of cough 
Transient, does not 
interfere with normal 
activity 
Frequent, interferes 
with normal activity or 
sleep 
Constant, interferes 
with most or all 
activity or sleep 
Production of purulent 
sputum 
Resolution (to pre-
CABP baseline) or 
absence of sputum 
production 
Sputum production 
rarely causes difficulty 
or distress 
Sputum production 
often causes difficulty 
or distress 
Constant difficulty 
with sputum 
production 
Chest pain 
Resolution or absence 
of chest pain related to 
CABP 
Transient, does not 
interfere with normal 
activity 
Frequent, interferes 
with normal activity or 
sleep 
Constant, interferes 
with most or all 
activity or sleep 
Subjects will be programmatically defined as a non-responder if any of the following are met: 
 Did not show an improvement in at least 2 of the 3 or 4 cardinal symptoms of CABP the 
subject presented with at baseline.  Improvement is defined as a decrease by at least 
1 level of severity; or 
 Worsening of any of the 4 cardinal symptoms of CABP. Worsening is defined as an 
increase by at least 1 level of severity for any symptom; or 
 Received a concomitant antibiotic for the treatment of CABP up through the assessment 
of the cardinal symptoms of CABP, or if no assessment was completed, up to 120 hours 
after the first dose of study drug (or randomization if the subject did not receive study 
drug); or 
 Died from any cause up through the assessment of the cardinal symptoms of CABP, or if 
no assessment was completed, up through Study Day 5. 
If more than 1 assessment of symptoms is obtained in the 96 ± 24 hour window, the following 
rules apply: 
 Use the latest assessment of symptoms conducted in person occurring in the 96 ± 24 hour 
window 
 If no assessment was conducted in person, use the latest assessment of symptoms 
conducted via a telephone call occurring in the 96 ± 24 hour window 
If no assessment of symptoms (either in person or by telephone) was conducted in the 
96 ± 24 hour window, the following rules apply: 
 Use the latest assessment of symptoms conducted in person occurring 60 to <72 hours 
after the first dose of study drug 
 If no assessment was conducted in person in the 60 to <72 hour window, use the latest 
assessment of symptoms conducted via a telephone call occurring 60 to <72 hours after 
the first dose of study drug 


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Subjects with missing data such that a response cannot be determined will be considered an 
indeterminate response.  Subjects who are randomized and not treated or did not have at least 2 
symptoms of CABP at baseline will also be considered to have an indeterminate response.  Since 
the analysis of the primary outcome is based on the ITT Analysis Set, subjects with an 
indeterminate response are essentially considered non-responders.  For the ITT Analysis Set, the 
percentage of ITT subjects considered responders for ECR is defined using the following 
formula (where the denominator is comprised of the total number of subjects in the ITT Analysis 
Set): 
 
Number of subjects who are a responder 
x 100% 
(Number of subjects who are a responder + Number of subjects who are a 
non-responder + Number of indeterminate subjects) 
 
6.2 
Secondary Efficacy Outcomes 
Secondary efficacy outcomes include: 
 Percentage of subjects with IACR of success at the TOC Visit in the mITT and CE-TOC 
Analysis Sets 
 Percentage of subjects with ECR of responder in the microITT Analysis Set 
 Percentage of subjects with IACR of success at the TOC Visit in the microITT and 
ME-TOC Analysis Sets 
 Proportion of subjects with a by-pathogen microbiologic response of success at the TOC 
Visit in the microITT and ME-TOC Analysis Sets 
 All-cause mortality (ACM) through Day 28 in the ITT Analysis Set 
6.2.1 
Investigator’s Assessment of Clinical Response  
Clinical response will be assessed by the Investigator at the EOT, TOC and LFU Visits. The 
IACR at EOT and TOC will be classified as success, failure, or indeterminate according to the 
definitions in Table 3.  Subjects who are deemed to have an IACR of failure at the EOT Visit 
will not have an IACR performed at the TOC Visit and will be considered to have an IACR of 
failure at the TOC Visit.  


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Table 3. 
Investigator’s Assessment of Clinical Response at EOT and TOC 
Outcome 
EOT and TOC 
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 the 
treatment of the current episode of CABP. 
 Bacteremia has worsened or failed to improve resulting in administration of non-study 
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. 
For subjects who do not have an IACR of failure at the TOC Visit, a determination of clinical 
response (sustained success, relapse, prior failure or indeterminate) will be made at the LFU 
Visit as outlined in Table 4. Subjects who are deemed to have an IACR of failure at the TOC 
Visit will not have an IACR performed at the LFU Visit and will be considered to have an IACR 
of prior failure at the LFU Visit.  
Table 4. 
Investigator’s Assessment of Clinical Response at LFU 
Outcome 
LFU 
Sustained Success 
The subject's clinical signs and symptoms remain resolved or further improved such that no 
additional antibacterial therapy has been administered for the treatment of the current episode 
of CABP. 
Relapse 
The subject was a clinical success at TOC, however, any of the following are met: 
 Clinical signs and symptoms of CABP have recurred such that additional 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 recurred such 
that additional non-study antibacterial therapy is administered for the treatment of the 
current episode of CABP. 
 Recurrent bacteremia resulting in administration of non-study antibacterial therapy. 
 Death from any cause. 
Prior Failure 
The subject had an IACR of failure at the TOC Visit. 
Indeterminate 
Insufficient information is available to determine sustained success or relapse, specifically 
lost to follow-up. 


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The secondary efficacy analysis of IACR at the TOC Visit will be conducted in the mITT, 
CE-TOC, microITT, and ME-TOC Analysis Sets.  An additional analysis will be conducted in 
the microITT-2 and emicroITT Analysis Sets (see Section 6.3).  Analyses of IACR at the EOT 
Visit will be conducted in the mITT, microITT, CE-EOT and ME-EOT Analysis Sets, and 
analyses at the LFU Visit will be conducted in the mITT, microITT, CE-LFU and ME-LFU 
Analysis Sets (see Section 6.3).  For the analysis of IACR at the EOT and TOC Visits in the 
mITT, microITT, microITT-2 and emicroITT Analysis Sets, the success rate will be calculated as 
follows: 
 
Number of subjects who are a success 
x 100% 
(Number of subjects who are a success + Number of subjects who are a 
failure + Number of subjects with an indeterminate IACR) 
For the analysis of IACR at the LFU Visit in the mITT and microITT Analysis Sets, the 
sustained success rate will be calculated as follows: 
 
Number of subjects who are a sustained success 
x 100% 
(Number of subjects who are a sustained success + Number of subjects who 
are a relapse + Number of subjects who are a prior failure (carried forward 
from TOC) + Number of subjects with an indeterminate IACR) 
Subjects with an indeterminate IACR at the EOT, TOC and LFU Visits will be excluded from 
the analysis of IACR at the EOT, TOC and LFU Visits, respectively, in the CE and ME Analysis 
Sets. For the analysis of IACR at the EOT and TOC Visits in the CE and ME Analysis Sets, the 
success rate will be calculated as follows: 
 
Number of subjects who are a success 
x 100% 
(Number of subjects who are a success + Number of subjects who are a failure) 
 
For the analysis of IACR at the LFU Visit in the CE-LFU and ME-LFU Analysis Sets, the 
sustained success rate will be calculated as follows: 
 
Number of subjects who are a sustained success 
x 100% 
(Number of subjects who are a sustained success + Number of subjects who are a 
relapse + Number of subjects who are a prior failure (carried forward from TOC)) 
 


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6.2.2 
Early Clinical Response in the microITT Analysis Set 
The secondary efficacy analysis of ECR will be conducted in the microITT Analysis Set.  An 
additional analysis will be conducted in microITT-2 and emicroITT Analysis Sets (see 
Section 6.3).  For the microITT and microITT-2 Analysis Sets, the percentage of subjects 
considered responders for ECR is defined using the following formula (where the denominator is 
comprised of the total number of subjects in the microITT and microITT-2 Analysis Sets): 
 
Number of subjects who are a responder 
x 100% 
(Number of subjects who are a responder + Number of subjects who are a 
non-responder + Number of indeterminate subjects) 
6.2.3 
By-Pathogen Microbiological Response 
By-pathogen microbiological responses are eradication, presumed eradication, persistence, 
presumed persistence and indeterminate, as defined in Table 5.  Microbiological responses of 
eradication and persistence are based on comparing the baseline pathogen(s) to post-baseline 
pathogens, where post-baseline organisms are identified from post-baseline cultures and 
considered pathogens based on the criteria in Section 4.0.  If a pathogen is persistent at the EOT 
Visit, the persistence is carried forward to the TOC and LFU Visits.  If a pathogen is presumed 
persistent at the EOT Visit, the presumed persistence is carried forward to the TOC and LFU 
Visits, unless a repeat culture is obtained between the EOT and TOC or EOT and LFU Visits, 
respectively, which shows persistence.  Baseline pathogens identified by a modality other than 
culture of a blood or respiratory sample (ie, pathogen from serology, urine antigen or PCR) can 
only have a presumed or indeterminate microbiological response.  
Table 5. 
By-Pathogen Microbiological Response at EOT, TOC and LFU 
Outcome 
EOT 
TOC and LFU 
Success 
Eradication 
The baseline causative pathogen was absent from 
repeat culture(s) obtained at EOT (ie, the post-
baseline culture showed no growth or the post-
baseline culture did not grow the same pathogen 
as isolated at baseline, or the same organism(s) 
was present but did not meet the definition of 
pathogen as defined in Section 4.0).  
The baseline causative pathogen was absent from 
repeat culture(s) obtained between EOT and TOC or 
EOT and LFU, respectively (ie, the post-baseline 
culture showed no growth or the post-baseline 
culture did not grow the same pathogen as isolated 
at baseline, or the same organism(s) was present but 
did not meet the definition of pathogen as defined in 
Section 4.0). 
Presumed 
eradication 
The IACR was success and culture was not 
repeated at EOT. 
The IACR was success (TOC) or sustained success 
(LFU) and culture was not repeated (at TOC and 
LFU, respectively). 
Failure 
Persistence 
The baseline causative pathogen was isolated in 
repeat culture(s) obtained at EOT.  
Persistence at EOT is carried forward or a culture 
obtained after EOT and up to and including TOC 
grew the same pathogen identified at baseline 
(TOC).  Persistence at TOC is carried forward or a 
culture obtained after TOC and up to an including 
LFU grew the same pathogen identified at baseline 
(LFU).  


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Presumed 
persistence 
The IACR was failure and culture was not 
repeated at EOT. 
The IACR was failure (TOC) or prior failure/relapse 
(LFU) and culture was not repeated (at TOC and 
LFU, respectively) and no cultures demonstrated 
persistence (between EOT and TOC and EOT and 
LFU, respectively).  
Indeterminate 
The IACR was indeterminate and culture was not 
repeated at EOT. 
The IACR was indeterminate and culture was not 
repeated (at TOC and LFU, respectively) and no 
cultures demonstrated persistence (between EOT 
and TOC and EOT and LFU, respectively).  
The by-pathogen microbiological response success rate at the EOT, TOC and LFU Visits in the 
microITT and microITT-2 (TOC Visit only; see Section 6.3) Analysis Sets is calculated as 
follows: 
Number of subjects who are a success for the specific pathogen 
(Number of subjects who are a success for the specific pathogen + Number of subjects who are 
a failure for the specific pathogen + Number of subjects who are indeterminate for the 
specific pathogen) 
Subjects with an indeterminate microbiological response at the EOT, TOC and LFU Visits will 
be excluded from the ME Analysis Sets. Thus, the by–pathogen microbiological response 
success rate is calculated as follows:   
Number of subjects who are a success for the specific pathogen 
(Number of subjects who are a success for the specific pathogen + Number of subjects who are 
a failure for the specific pathogen) 
Subjects who have the same pathogen isolated at baseline from more than 1 specimen type are 
counted only once in the determination of by-pathogen microbiological response.  If a subject 
has the same baseline pathogen identified by culture of blood or respiratory sample and another 
modality and a repeat culture is obtained, microbiological response is based on the post-baseline 
culture results.  If a subject has the same baseline pathogen identified from culture of blood and a 
respiratory sample, eradication requires the baseline pathogen to be absent from respiratory 
sample culture without evidence of ongoing bacteremia.  Persistence requires the baseline 
pathogen to be present from either the blood or respiratory sample culture. 
6.2.4 
28-Day All-Cause Mortality 
The outcome measure of all-cause mortality (ACM) is defined as deceased on or before Study 
Day 28.  
Subjects with an LFU visit on Study Day 27 will be considered alive on Study Day 28 unless 
known to have died on Study Day 28.  Other subjects who are not known to be alive or deceased 
as of Study Day 28 will be defined as deceased and included in the numerator and denominator 
for the calculation of the ACM rate.  The 28-day ACM rate is defined by the following formula: 
 
Number of subjects deceased 
x 100% 
(Number of subjects alive at Day 28 + Number of subjects deceased) 


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6.3 
Additional Efficacy Outcomes 
Additional efficacy outcomes specified in the protocol include: 
 Proportion of subjects with an ECR of responder by baseline pathogen in the microITT 
Analysis Set 
 Percentage of subjects with an IACR of success at the EOT Visit in the mITT and 
CE-EOT Analysis Sets, and at the LFU Visit (sustained success) in the mITT and 
CE-LFU Analysis Sets 
 Proportion of subjects with an IACR of success by baseline pathogen at the TOC Visit in 
the microITT and ME-TOC Analysis Sets, and at the LFU Visit (sustained success) in the 
microITT and ME-LFU Analysis Sets 
 Number and percentage of subjects with a by-subject microbiologic response of success 
at the TOC Visit in the microITT and ME-TOC Analysis Sets 
 Proportion of subjects with an ECR of responder PLUS improvement in vital signs in the 
ITT Analysis Set 
Other additional efficacy outcomes specified in this SAP include: 
 Percentabe of subjects with an ECR of responder in the microITT-2 and emicroITT 
Analysis Sets 
 Proportion of subjects with an ECR of responder by baseline pathogen in the microITT-2 
Analysis Set 
 Proportion of subjects with an ECR of responder by baseline pathogen and MIC to study 
drug received in the microITT Analysis Set 
 Proportion of subjects with an ECR of responder by baseline pathogen and disk diffusion 
zone diameter to study drug received in the microITT Analysis Set 
 Proportion of subjects with an ECR of responder by baseline pathogens identified from 
blood specimens in the microITT Analysis Set 
 Percentage of subjects with an IACR of success at the TOC Visit in the microITT-2 and 
emicroITT Analysis Sets, at the EOT Visit in the microITT and ME-EOT Analysis Sets, 
and at the LFU Visit (sustained success) in the microITT and ME-LFU Analysis Sets 
 Proportion of subjects with an IACR of success by baseline pathogen at the TOC Visit in 
the microITT-2 Analysis Set, and at the EOT Visit in the microITT and ME-EOT 
Analysis Sets 
 Proportion of subjects with an IACR of success at the TOC Visit by baseline pathogen 
and MIC to study drug received in the microITT and ME-TOC Analysis Sets 
 Proportion of subjects with an IACR of success at the TOC Visit by baseline pathogen 
and disk diffusion zone diameter to study drug received in the microITT and ME-TOC 
Analysis Sets 


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 Proportion of subjects with an IACR of success at the TOC Visit by baseline pathogens 
identified from blood specimens in the microITT Analysis Set 
 Proportion of subjects with a by-pathogen microbiologic response of success at the TOC 
Visit in the microITT-2 Analysis Set, at the EOT Visit in the microITT and ME-EOT 
Analysis Sets, and at the LFU Visit in the microITT and ME-LFU Analysis Sets 
 Proportion of subjects with a microbiologic response of success at the TOC Visit by 
baseline pathogen and MIC to study drug received in the microITT and ME-TOC 
Analysis Sets 
 Proportion of subjects with a microbiologic response of success at the TOC Visit by 
baseline pathogen and disk diffusion zone diameter to study drug received in the 
microITT and ME-TOC Analysis Sets 
 Number and percentage of subjects with a by-subject microbiologic response of success at 
the TOC Visit in the microITT-2 Analysis Set, at the EOT Visit in the microITT and 
ME-EOT Analysis Sets, and at the LFU Visit in the microITT and ME-LFU Analysis Sets 
6.3.1 
By-Subject Microbiological Response at the EOT, TOC and LFU Visits 
By-subject microbiological response is determined from the by-pathogen microbiological 
responses as defined in  
Table 6. 
Table 6. 
By-Subject Microbiological Response at EOT, TOC and LFU  
 Outcome 
Definition  
Success 
Eradication 
or Presumed 
eradication 
All baseline pathogens have a by-pathogen microbiological response of eradication or 
presumed eradication at the specified visit. 
Failure 
Persistence or 
Presumed 
persistence 
At least 1 baseline pathogen has a by-pathogen microbiological response of persistence or 
presumed persistence at the specified visit. 
Indeterminate 
At least 1 baseline pathogen has a by-pathogen microbiological response of indeterminate 
and none have a by-pathogen microbiological response of persistence or presumed 
persistence. 
The by-subject microbiological response success rate at the EOT, TOC and LFU Visits in the 
microITT and microITT-2 (TOC Visit only) Analysis Sets is calculated as follows: 
 
Number of subjects who are a success 
x 100% 
(Number of subjects who are a success + Number of subjects who are a 
failure + Number of subjects who are indeterminate) 


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Subjects with an indeterminate microbiological response at the EOT, TOC and LFU Visits will 
be excluded from the ME Analysis Sets. Thus, the by–subject microbiological response success 
rate is calculated as follows:   
 
Number of subjects who are a success 
x 100% 
(Number of subjects who are a success + Number of subjects who are a failure) 
6.3.2 
Early Clinical Response Plus Improvement in Vital Signs 
Subjects will be programmatically defined as a responder if the following 5 criteria are met: 
 Alive; 
 Improvement in at least 2 of the 3 or 4 cardinal symptoms of CABP 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 by at least 1 level of severity for any symptom;  
 Improvement in all vital signs (ie, body temperature, blood pressure, heart rate, 
respiratory rate) that were abnormal at baseline.  Improvement is defined as returning to 
normal.  If a vital sign was normal at baseline (ie, not abnormal as per the definitions 
below), it cannot have worsened. Abnormal vital signs are defined as: 
o Fever: defined as body temperature >38.0°C (100.4°F) measured orally, >38.5°C 
(101.3°F) measured tympanically,  >39.0°C (102.2°F) measured rectally, or >37.5°C 
(99.5°F) by axillary measurement 
o Hypothermia: defined as body temperature <35.0°C (95.0°F) measured orally, 
<35.5°C (95.9°F) measured tympanically, <36.0°C (96.8°F) measured rectally, or 
<34.5°C (94.1°F) by axillary measurement 
o Hypotension: defined as systolic blood pressure <90 mmHg  
o Tachycardia: defined as heart rate >100 beats/min 
o Tachypnea: defined as respiratory rate >20 breaths/min 
 Did not receive a concomitant antibiotic for the treatment of CABP up through the 
assessment of the cardinal symptoms of CABP. 
Subjects will be programmatically defined as a non-responder if any of the following are met: 
 Did not show an improvement in at least 2 of the 3 or 4 cardinal symptoms of CABP the 
subject presented with at baseline.  Improvement is defined as a decrease by at least 1 
level of severity; or 
 Worsening of any of the 4 cardinal symptoms of CABP.  Worsening is defined as an 
increase by at least 1 level of severity for any symptom; or 
 Did not show an improvement in all vital signs that was abnormal at baseline.  
Improvement is defined as the following:  


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o Body temperature 35.0 to 38.0°C (95.0 to 100.4°F) measured orally, 35.5 to 38.5°C 
(95.9 to 101.3°F), measured tympanically, or 36.0 to 39.0°C (96.8 to 102.2°F) 
measured rectally or 34.5 to 37.5°C (94.1 to 99.5°F) by axillary measurement 
o Systolic blood pressure ≥90 mmHg  
o Heart rate >50 to  ≤100 beats/min 
o Respiratory rate  ≤20 breaths/min; or 
 Received a concomitant antibiotic for the treatment of CABP up through the assessment 
of the cardinal symptoms of CABP, or if no assessment was completed, up to 120 hours 
after the first dose of study drug (or randomization if the subject did not receive study 
drug); or 
 Died from any cause up through the assessment of the cardinal symptoms of CABP, or if 
no assessment was completed, up through Study Day 5. 
Section 6.1 describes rules for determining the outcome if more than 1 assessment of symptoms 
is obtained in the 96 ± 24 hour window or if no assessment of symptoms is obtained in the 96 ± 
24 hour window.  Subjects with missing data such that a response cannot be determined will be 
considered to have an indeterminate response.  Subjects who did not have at least 2 symptoms of 
CABP at baseline or who did not have an assessment of vital signs at baseline will also be 
considered to have an indeterminate response.  Since the analysis of ECR plus improvement in 
vital signs is based on the ITT Analysis Set, subjects with an indeterminate response are 
essentially considered non-responders.  For the ITT Analysis Set, the percentage of ITT subjects 
determined to be responders for ECR plus improvement in vital signs is defined using the 
following formula (where the denominator is comprised of the total number of subjects in the 
ITT Analysis Set): 
 
Number of subjects who are a responder 
x 100% 
(Number of subjects who are a responder + Number of subjects who are a 
non-responder + Number of indeterminate subjects) 
 
6.4 
Other Microbiological Outcomes 
Superinfections are defined as new pathogens (ie, pathogen(s) not present at baseline) identified 
in post-baseline cultures through the TOC Visit with persistent signs and symptoms of CABP (ie, 
IACR of failure at the TOC Visit), such that additional antibacterial therapy is necessary for 
current episode of CABP. 
Colonization is defined as new pathogens (ie, pathogen(s) not present at baseline) identified in at 
least 2 post-baseline cultures through the TOC Visit but signs and symptoms of CABP have 
resolved (ie, IACR of success at the TOC Visit), such that no additional antibacterial therapy is 
necessary for the current episode of CABP. 


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Development of decreasing susceptibility is defined as a ≥4x increase from baseline in MIC to 
the study drug received or a ≥6 mm decrease from baseline in disk inhibition zone diameter to 
the study drug received for a baseline pathogen subsequently isolated from culture of a post-
baseline blood or respiratory sample (ie, for a post-baseline pathogen).   
6.5 
Pharmacokinetic Outcomes 
Measured plasma concentrations of BC-3781 and BC-8041 will be summarized for subjects in 
the lefamulin group. 
6.6 
Safety Outcomes 
Safety will be assessed by analysis of AEs and changes in laboratory parameters (chemistry and 
hematology), electrocardiogram (ECG) parameters, and vital signs. Laboratory abnormalities are 
not considered AEs unless they are associated with clinical signs and symptoms or require 
medical intervention.  Clinically significant abnormal clinical laboratory findings or other 
abnormal assessments that are associated with the disease being studied, unless judged by the 
Investigator as more severe than expected for the subject's condition, or that are present or 
detected at the start of the study and do not worsen, will not be reported as AEs or SAEs. 
6.7 
Additional Exploratory Outcomes 
Exploratory evaluation of a variety of health utilization variables (eg, length of hospital stay, 
discharge status and discharge destination) and a patient-reported outcome instrument (SF-12) 
will be performed. Details of this exploratory analysis will be presented in a separate SAP and 
results will be presented in a separate report. 
7.0 
STATISTICAL METHODS 
7.1 
Sample Size  
A total of 738 subjects will be randomized in a ratio of 1:1 (lefamulin:moxifloxacin) resulting in 
369 subjects in the lefamulin arm and 369 in the moxifloxacin arm in this study.  The total 
number of subjects included in this study is sufficient to achieve the primary and secondary 
study objectives based on statistical considerations. 
Retrospective analyses of clinical study data for patients with CABP of varying severity as well 
as 2 recent clinical trials in CABP indicate the point estimates for an ECR responder at Days 3-5 
range from 72% to 81% (FDA, 2011; Barrera et al., 2016; Cempra, 2015; Oldach et al., 2015).  
Thus, it is reasonable to assume that in a prospective study of subjects with CABP, the 
proportion of subjects who are responders for ECR at 96 ± 24 hours post first dose of study drug 
will be approximately 79%.   
The primary efficacy analysis variables used for NI analyses for the Marketing Authorization 
Application (MAA) to the EMA will be the proportion of subjects with an IACR of Success at 
TOC in the mITT and CE-TOC Analysis Sets.  In recent clinical studies, IACR success rates at 
the TOC Visit in the CE Analysis Set ranged from 77% to 93% (Cempra, 2015) and in the ITT 


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Analysis Set ranged from 85% to 89% depending on the antibiotics under study and the severity 
of the CABP.  Based on these data, an 85% IACR success rate in the CE-TOC Analysis Set was 
chosen for determination of the sample size.  The success rate is expected to be about 5% lower 
in the mITT Analysis Set. It is expected that <1% of subjects will be excluded from the mITT 
Analysis Set and thus, the sample size determination assumes the same number of subjects in the 
ITT and mITT Analysis Sets. 
Utilizing an anticipated ECR responder rate of 79% in the ITT Analysis Set, a 1:1 randomization 
ratio, a one-sided alpha of 0.025, and a continuity corrected Z-test with unpooled variance, a 
sample size of 738 subjects (369 subjects in the lefamulin group and 369 in the moxifloxacin 
group) provides 90% power to establish the NI of lefamulin to moxifloxacin for ECR using a NI 
margin of 10.0%.  Assuming an IACR success of 80% and 85% in the mITT and CE-TOC 
Analysis Sets, respectively, and a clinical evaluability rate of 80%, there is 91% power for 
demonstration of NI for IACR at the TOC Visit using a 10% NI margin. 
The calculated power in each analysis set for the primary and secondary outcomes is provided in 
Table 7. 
Table 7. 
Power Calculations for the Primary and Secondary Efficacy 
Outcomes 
 
Primary Outcome (FDA) 
(ECR 96 ± 24 hours After the First 
Dose of Study Drug) 
Secondary Outcome  
(Investigator’s Assessment of Clinical Response at 
TOC- Primary for EMA) 
Analysis Set 
ITT 
mITT 
CE-TOC 
NI Margin 
10% 
10% 
10% 
N 
738 (369:369) 
738 
590 
Outcome Rate 
79% 
80% 
85% 
Evaluability Rate 
NA 
NA 
80% 
Power 
90% 
91 % 
91% 
CE = clinically evaluable; ITT = intent to treat; mITT = modified ITT; TOC = test of cure 
7.2 
Visit Windows 
7.2.1 
Baseline 
Unless otherwise stated below, baseline is defined as the last measurement prior to the first dose 
of study drug.   
 For microbiological pathogen determination, baseline is defined as the 24-hour period 
prior to the administration of the first dose of study drug and the 24 hours after the first 
dose of study drug. A pathogen identified from a respiratory (pleural fluid, 
bronchoalveolar lavage (BAL), sputum), blood for culture, urine, nasopharyngeal or 
oropharyngeal specimen collected at baseline is considered a baseline pathogen.  An 
atypical pathogen identified by serology is considered a baseline pathogen if the baseline 


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sample is collected in the 24-hour period prior to or the 24 hours after the administration 
of the first dose of study drug. 
 For vital signs, baseline is defined as the Screening assessment (since time of assessment 
is not captured) as long as the date of collection is on or before the date of first dose of 
study drug.  
 For ECGs, baseline is defined as the mean of the triplicates (or duplicate or single, if a 
triplicate is not obtained) from the last assessment prior to the first dose of study drug, 
including scheduled and unscheduled visits. 
 If no study drug is received, baseline is defined as the measurement taken at the 
Screening Visit (ie, prior to the randomization date/time) 
Study Day 1 is defined as the first calendar day of study drug administration (or the date of 
randomization if no study drug was received). The calendar day prior to the first dose of study 
drug (or randomization day if no study drug is received) is Study Day -1; there is no Study Day 
0. 
For all clinical assessments and procedures performed prior to the date of the first study drug 
administration, study day will be calculated as the date of the assessment minus the date of the 
first dose of study drug. For all clinical assessments and procedures performed on or after the 
date of the first dose of study drug, study day will be calculated as the date of the assessment 
minus the date of the first dose of study drug, plus 1.  
7.2.2 
Post-Baseline 
The visit window for ECR is defined in Section 6.1. Clinical efficacy and safety analyses will 
utilize the data obtained on the scheduled visit (ie, nominal visit will be utilized).  When a 
nominal visit assessment is unavailable, an unscheduled assessment may be utilized as described 
in Appendix D.    
See Appendix A for a complete description on the timing of the safety assessments. See 
Appendix D for a summary of visit window definitions for the safety assessments. 
7.2.3 
Unscheduled Assessments 
If no scheduled visit was done, but an unscheduled safety assessment was done in the window of 
the scheduled assessment (for the specific safety parameter), the unscheduled assessment should 
be used as described in Appendix D. If more than 1 measurement is taken during the visit 
window (a scheduled visit and an unscheduled visit), the value taken on the scheduled visit will 
be utilized.  If more than one unscheduled assessment is completed in the visit window of the 
scheduled assessment (and no scheduled assessment), the earliest should be used. All 
unscheduled visits not satisfying the analysis visit condition as described in Appendix D will be 
referred to as “Unscheduled” as their analysis visit designation. For overall worst post-baseline 
analyses (i.e. minimum, maximum, highest, lowest, any post-baseline, and PCS), all assessments 
including those obtained on unscheduled (i,e. analysis visit “Unscheduled”) and scheduled visits 
(e.g., analysis visits “Baseline”, “Day 1”, “Day 4”, “TOC”, “EOT” and “LFU”) will be included. 
See Section 8.7.2 for a discussion of when to use central and local safety laboratory values. 


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7.3 
Randomization  
Subjects will be assigned to receive lefamulin or moxifloxacin in a 1:1 ratio with stratification by 
geographic region (US vs. ex-US), receipt of prior single dose short-acting antibiotic therapy for 
CABP vs. none, and PORT risk class (II vs. III/IV) using blocked randomization via the IRT.  
The randomization schedule will be generated by the Sponsor (or designee).  Subjects 
randomized into the study will be assigned the treatment corresponding to the next available 
number in the respective stratum of the computer-generated randomization schedule.   The 
subject will only be randomized after the inclusion and exclusion criteria are verified. 
The Sponsor designee (ie, IRT vendor) will maintain the randomization codes in accordance with 
standard operating procedures to ensure the blind is properly maintained, and that only Sponsor 
personnel who require knowledge of treatment assignments will be unblinded (eg, staff involved 
in maintaining the clinical supplies or SAE reporting).  After the database is locked and the SAP 
is final, the study blind codes will be broken. 
7.4 
Interim Analysis 
No interim analyses of efficacy will be conducted. 
An independent Data Monitoring Committee (DMC) will be constituted for this study to monitor 
important aspects of study conduct, including safety results on an ongoing basis.  The DMC will 
receive masked data (treatment “A” vs. treatment “B”) at pre-specified time points for their 
review of safety data throughout the conduct of the trial. DMC meeting frequency and conduct 
will be outlined in a separate DMC Charter. An independent, unblinded statistician will provide 
the committee with masked data for review, but will not be a member of the committee.  In 
addition, a clinical representative from the Sponsor will be available during an open session of 
each meeting to help answer questions or relay additional information to the DMC as needed, but 
this individual will not be a voting member of the committee. All members of the DMC will treat 
study data, reports, meeting discussions, and conclusions as confidential.  


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7.5 
Comments on the Statistical Analyses 
 All clinical data will be provided in by-subject listings. 
 Continuous variables will be summarized using number (N), mean, standard deviation 
(SD), median, minimum, and maximum.   
 Frequency counts and percentages will be reported for all categorical data.  
 If a laboratory result (other than an MIC value) is reported relative to a lower/upper range 
of detection for an assay, for example, “<10”,  the numeric portion of the result (10) will 
be used for statistical analyses and the full result, including any symbols, will be provided 
in the subject listings. 
 For AEs with onset on or after the first dose of study drug, onset day will be calculated as 
the date of onset of the AE minus the date of the first dose of study drug, plus 1. For AEs 
with onset prior to the first dose of study drug, onset day will be calculated as the date of 
onset of the AE minus the date of the first dose of study drug. 
 For prior medications, start day will be calculated as the start date of the medication 
minus the date of the first dose of study drug (or date of randomization if no study drug 
was received). For concomitant medications and prior medications taken on the same day 
as the first dose of study drug (or date of randomization if no study drug was received), 
start day will be calculated as the start date of the medication minus the date of the first 
dose of study drug (or date of randomization if no study drug was received), plus 1.  
 Version 9.2 (or higher) of SAS statistical software package will be used to provide all 
summaries, listings, figures and statistical analyses. 
7.6 
Handling of Missing Data 
For ECR, missing data will be handled as follows: 
 If any component of ECR is missing in the time frame detailed in Section 6.1 (unless the 
subject dies or is deemed a failure prior to this time point), or if the subject does not have 
at least 2 symptoms of CABP at baseline, ECR will be defined as an indeterminate.  
 If the time of a post-baseline assessment of CABP symptoms obtained in the window for 
determination of ECR is missing but the date of the ECR assessment is known, the time 
will be imputed to noon on the date of the CABP symptom assessment.  If the time of 
assessment of CABP symptoms obtained on or prior to the date of the first dose of study 
drug is missing, the time will be imputed to 00:00. 
 Missing start and stop times of antibiotics will be set to 00:00 on the start and stop date of 
the antibiotic. 
 For the analysis of ECR in the ITT Analysis Set, where ECR may be missing 
(indeterminate), all subjects in the ITT Analysis Set will be included in the denominator. 
Thus, subjects with an indeterminate response are essentially considered as a failure. 


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For IACR, missing data will be handled as follows: 
 A missing IACR at the EOT Visit will be considered indeterminate at the EOT Visit. 
 A missing IACR at the TOC Visit will be considered indeterminate unless the IACR at 
the EOT Visit is failure. An IACR of failure at the EOT Visit will be carried forward to 
the TOC Visit.  
 A missing IACR at the LFU Visit will be considered indeterminate unless the IACR at 
the TOC Visit is failure. An IACR of failure at the TOC Visit will be carried forward to 
the LFU Visit. 
 For the analysis of IACR at the EOT, TOC and LFU Visits in the mITT, microITT, 
microITT-2 and emicroITT Analysis Sets, where Clinical Response may be missing 
(indeterminate), all subjects who meet the analysis set criteria will be included in the 
denominator.  
 For the analysis of IACR at the EOT, TOC and LFU Visits in the CE and ME Analysis 
Sets, subjects with a missing (indeterminate) IACR will not be included in the analyses, 
since by definition, subjects in the CE or ME Analysis Sets cannot have a missing IACR. 
For microbiological response, missing data will be handled as follows: 
 If a followup specimen for culture was not obtained, microbiological response at the EOT 
Visit will be determined based on the IACR at the EOT Visit.  
 A by-pathogen microbiological response of persistence and a by-subject microbiological 
response of failure at the EOT Visit will be carried forward to the TOC Visit. If a 
followup specimen for culture was not obtained and the pathogen/subject was not a 
microbiologic persistence/failure at EOT, microbiological response at the TOC Visit will 
be determined based on IACR at the TOC Visit. If the IACR at the TOC Visit is 
indeterminate, the microbiological response at the TOC Visit will be indeterminate, 
unless a followup specimen for culture was obtained.  
 A by-pathogen microbiological response of persistence and a by-subject microbiological 
response of failure at the TOC Visit will be carried forward to the LFU Visit. If a 
followup specimen for culture was not obtained and the pathogen/subject was not a 
microbiologic persistence/failure at TOC, microbiological response at theLFU Visit will 
be determined based on IACR at the LFU Visit. If the IACR at the LFU Visit is 
indeterminate, the microbiological response at the LFU Visit will be indeterminate, 
unless a followup specimen for culture was obtained.  
 For the analysis of microbiological response at the EOT, TOC and LFU Visits in the 
microITT and microITT-2 Analysis Sets, where microbiological response may be 
missing (indeterminate), all subjects who meet the analysis set criteria will be included in 
the denominator.  
 For the analysis of microbiological response at the EOT, TOC and LFU Visits in the ME 
Analysis Sets, subjects with a missing (indeterminate) microbiological response will not 
be included in the analysis, since by definition, subjects in the ME Analysis Sets cannot 
have a missing microbiological response. 


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For all other outcome measures, missing data are handled as follows: 
 Missing values for individual data points will remain as missing. Missing values will not 
be imputed and only observed values will be used in data analyses and presentations.  
 When individual data points are missing, categorical data will be summarized based on 
reduced denominators (ie, only subjects with available data will be included in the 
denominators). 
8.0 
STATISTICAL ANALYSES 
8.1 
Subject Disposition and Protocol Deviations 
The number of subjects randomized by region, country and center will be presented by treatment 
group in the ITT Analysis Set.  The number of subjects included in each of the study analysis 
sets (ITT, mITT, Safety, emicroITT, microITT, microITT-2, CE-EOT, CE-TOC, CE-LFU, ME-
EOT, ME-TOC and ME-LFU) will be summarized overall and by geographic region, for each 
treatment group and across treatment groups.  Regions are defined as follows:  North America 
(United States), Latin America (Argentina, Brazil, Chile, Mexico, Peru), Eastern Europe 
(Bulgaria, Georgia, Latvia, Russia, Serbia, Ukraine), Western Europe (Hungary, Poland, Spain) 
and Rest of World (Philippines, South Korea, Taiwan, South Africa).  The reasons for exclusion 
from the mITT, Safety, emicroITT, microITT, microITT-2, CE and ME Analysis Sets will be 
tabulated.  A by-subject listing will be provided that will include the reason(s) for exclusion from 
each of the study analysis sets.   
A listing will provide the date of informed consent for all randomized subjects, whether or not 
the subject met all inclusion/exclusion criteria and if not, which criteria were not met.  The 
number of subjects completing the study (ie, completing the LFU Visit), completing the EOT 
assessment, completing the TOC assessment, prematurely withdrawing from the study, 
completing study drug, prematurely discontinuing study drug, and the reasons for premature 
withdrawal and premature discontinuation will be summarized by treatment group and overall 
for all subjects in the ITT Analysis Set.  The percentages of subjects discontinued from study 
drug and prematurely withdrawn from the study will be compared between treatment groups 
using Fisher’s exact test.  A listing of study completion/premature withdrawal and study drug 
completion/premature discontinuation for all subjects will be provided and will display subject 
ID, treatment, the primary reason for premature withdrawal or discontinuation, date and study 
day of last study visit, and vital status at Day 28. 
The number and percentage of subjects in the ITT Analysis Set with at least 1 significant 
protocol deviation will be summarized by treatment group and overall.  A significant protocol 
deviation is one that has the potential to affect efficacy assessments, placement into analysis 
populations, the safety or ability to monitor the safety of a subject, or the scientific value of the 
trial.   The number and percentage of subjects with at least 1 significant deviation that excludes a 
subject from the CE Analysis Sets and the number and percentage of subjects with at least 1 
other significant deviation will also be summarized by treatment group and overall, and by 
deviation subtype. 


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A by-subject listing of all significant protocol deviations will also be provided.  
8.2 
Demographics and Baseline Characteristics 
Descriptive statistics for continuous variables (age, height, weight, and body mass index), and 
frequency counts and percentages for categorical variables (age group, race, ethnicity, gender 
and renal status [severe impairment [<30 mL/min], moderate impairment [30-<60 mL/min], mild 
impairment [60-<90 mL/min] and normal function [≥90 mL/min]) will be summarized by 
treatment group and overall for the ITT, mITT and CE-TOC Analysis Sets.  Body mass index 
will be calculated by dividing weight (kg) by height (m2).  Creatinine clearance based on the 
central lab determination will be used.  In those cases where creatinine clearance is not available 
from the central lab, it will be calculated using the local lab serum creatinine based on the 
Cockcroft-Gault equation: 
(140-age[yrs]) * weight [kg] * (Z) 
Z = 1.0, if Male 
Z = 0.85, if Female 
Cr [mg/dL] * 72 
A table will provide the frequency counts and percentages by treatment group and overall for 
PORT Risk Class (both as per IRT [II, III/IV] as well as calculated from components reported in 
the eCRF [II, III/IV]), subjects meeting minor and modified American Thoracic Society (ATS) 
severity criteria, subjects meeting the Systemic Inflammatory Response Syndrome (SIRS), 
CURB-65 category and subjects with bacteremia for the ITT, mITT and CE-TOC Analysis Sets.  
PORT score and CURB-65 Score will also be summarized as a continuous variable.  CURB-65 
is derived from the eCRF data and ranges from 0-5 where 1 point is given for each of the 
following at baseline:  
 Confusion (defined as altered mental status as recorded on the PORT Risk Assessment 
eCRF) 
 blood urea nitrogen (BUN) >19 mg/dL (>6.8 mmol/L) 
 respiratory rate ≥30 breaths/min, 
 systolic blood pressure <90 mmHg or diastolic blood pressure ≤60 mmHg 
 age ≥65 years.   
ATS severity and SIRS criteria are derived from the eCRF data and baseline PMNs reported in 
the central safety laboratory data. The minor ATS severity criteria is defined as presence of ≥3 of 
the following 9 criteria at baseline:  
 respiratory rate ≥30 breaths/min 
 O2 saturation <90% or PaO2 <60 mmHg 
 BUN ≥20 mg/dL 
 WBC <4000 cells/mm3 
 confusion 
 multilobar infiltrates (defined as infiltrates present in any two locations, except lingula 
and left upper loabe is not multilobar.  Lingula and other location is multilobar) 
 
platelets <100,000 cells/mm3 
 temperature <36C 
 systolic blood pressure <90 mmHg.   


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Modified ATS severity criteria is defined as presence of ≥3 of the following 6 criteria at 
baseline: 
 respiratory rate ≥30 breaths/min 
 SpO2/FiO2 <274 where SpO2/FiO2 = 64+0.84 (PaO2/Fi O2) 
 BUN ≥20 mg/dL 
 Confusion 
 Age ≥ 65 years 
 multilobar infiltrates.  
SIRS criteria is defined as ≥2 of the following 4 symptoms at baseline:  
 temperature <36C or >38C  
 heart rate >90 beats/min 
 respiratory rate >20 breaths/min 
 WBC <4000 cells/mm3, or WBC >12,000 cells/mm3, or immature PMNs >10%.   
Baseline assessments of clinical signs and symptoms of CABP, including fever (defined as body 
temperature >38.0C (100.4F) oral, tympanic >38.5C (101.3F), rectal/core >39.0C 
(102.2F), or axillary >37.5C (99.5F)), hypothermia (defined as body temperature <35.0C 
(95.0F) oral, tympanic <35.5C (95.9F), or rectal/core <36.0C (96.8F)), hypotension 
(systolic blood pressure <90 mmHg), tachycardia (heart rate >100 beats/min), tachypnea 
(respiratory rate >20 breaths/min), dyspnea, cough, production of purulent sputum and chest pain 
will be summarized by treatment group and overall for the ITT, mITT and CE-TOC Analysis 
Sets.  
Medical history (including diseases/conditions and surgical procedures) will be summarized by 
treatment group and overall for subjects in the ITT Analysis Set.  For the summary of medical 
history, subjects with more than 1 abnormality within the same preferred term will be counted 
only once for that preferred term.  Subjects are counted only once in a system organ class.   
CABP risk factors, including tobacco history (current and previous use of cigarettes, cigars, 
chewing tobacco and other), history of pneumococcal vaccination, evidence of influenza during 
the current illness and history of influenza vaccination, will be summarized by treatment group 
and overall for subjects in the ITT, mITT and CE-TOC Analysis Sets.   
Readings of baseline chest radiographs by the radiologist, including the type of assessment (chest 
X-ray or CT scan), radiographic evidence of CABP (ie, a pulmonary infiltrate or diffuse 
opacity), presence of pleural effusion, whether the pleural effusion is unilateral or bilateral, 
presence of pulmonary infiltrate, whether the pulmonary infiltrate was uni- or multi-lobar, the 
location of the pulmonary infiltrate(s), presence of diffuse opacities and the location of the 
diffuse opacities will be summarized by treatment group and overall for all subjects in the ITT, 
mITT and CE-TOC Analysis Sets.  
Descriptive statistics of baseline procalcitonin and number and percentage of subjects in the 
categories <0.1 mcg/L, 0.1 mcg/L to 0.25 mcg/L and >0.25 mcg/L will be presented by treatment 
group and overall for the ITT, mITT and CE-TOC Analysis Sets. 


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8.3 
Baseline Microbiological Assessments 
Baseline pathogens will be summarized by genus and species, treatment group and overall for 
the microITT, microITT-2, emicroITT, and ME-TOC Analysis Sets. Selected pathogens will also 
be summarized by phenotypic susceptibility profile. In addition, for Staphylococcus aureus 
isolated at baseline, the PVL and MecA status (positive or negative) will be summarized. Table 8 
provides the definition for each pathogen susceptibility profile. 


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Table 8. 
Definitions for Pathogen Susceptibility Profile 
Pathogen 
Susceptibility Profile 
Definition 
Staphylococcus aureus 
MSSA 
Susceptible to cefoxitin 
 
MRSA 
Resistant to cefoxitin 
Streptococcus pneumoniae 
PSSP 
Susceptible to penicillin 
 
PISP 
Intermediate susceptibility to penicillin 
 
PRSP 
Resistant to penicillin 
 
Macrolide resistant 
Resistant to azithromycin or 
erythromycin 
 
Quinolone resistant 
Resistant to moxifloxacin 
 
Multidrug resistant 
Resistant to 2 or more of the following 
classes of drugs: 
 
Penicillins – oral penicillin 
 
Fluoroquinolones – moxifloxacin 
 
Cephalosporins – ceftriaxone 
 
Lincosamides – clindamycin 
 
Macrolides – azithromycin or 
erythromycin  
 
Tetracyclines – doxycycline  
 
Folate Pathway Inhibitors – 
trimethoprim/sulfamethoxazole  
Haemophilus influenzae 
B-lactamase positive 
Zone diameter for ampicillin ≤18 mm 
 
B-lactamase negative 
Zone diameter for ampicillin >18 
Mycoplasma pneumoniae 
Macrolide susceptible 
Susceptible to azithromycin and 
erythromycin 
 
Macrolide resistant 
Resistant to azithromycin or 
erythromycin 
 
Quinolone resistant 
Resistant to moxifloxacin 
Findings from the baseline Gram-stained respiratory specimens (ie, the best Gram stain reading) 
will be tabulated by treatment group and overall for subjects in the microITT, microITT-2, 
emicroITT and ME-TOC Analysis Sets. The number and percentage of subjects with a Gram-
stained respiratory specimen that shows >25 PMNs and <10 SECs per LPF and ≥10 PMNs and 
<10 SECs per LPF will be presented.  In addition, summaries of PMNs and SECs and bacterial 
morphology for all Gram-stained respiratory specimens will be provided.  Baseline for Gram 
stains is defined as the 24-hour period prior to the first dose of study drug and the 24-hour period 
after the first dose of study drug. 
Baseline pathogens will be summarized by treatment group and overall, by genus and species, 
and diagnostic modality for the microITT, microITT-2, and ME-TOC Analysis Sets.  The 
number and percentage of subjects with specimens tested, by testing modality, and the number 
and percentage of subjects with specimens positive for a pathogen and the specific pathogen 
(genus and species) will be presented.  The number and percentage of subjects with 
monomicrobial or polymicrobial gram-positive or gram-negative pathogen infections, only 
atypical pathogens, a mixture of gram-positive and gram-negative pathogens, a mixture of gram-
positive and atypical pathogens, a mixture of gram-negative and atypical pathogens or a mixture 
of gram-positive, gram-negative and atypical pathogens will be summarized by treatment group 
and overall for the microITT, microITT-2 and ME-TOC Analysis Sets.   


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The MIC distribution detailing the number and percentage of pathogens at the respective MIC 
values and the cumulative distribution will be presented for lefamulin and moxifloxacin by 
baseline pathogen, phenotype and study drug for both treatment groups combined and by 
treatment group for subjects in the microITT and ME-TOC Analysis Sets.  Disk diffusion zone 
diameters for lefamulin and moxifloxacin will be summarized by baseline pathogen, phenotype, 
and study drug for both treatment groups combined and by treatment group for subjects in the 
microITT and ME-TOC Analysis Sets. Scatter plots of the MIC to lefamulin versus the disk 
diffusion zone diameter will be provided for Streptococcus pneumoniae, Haemophilus 
influenzae, Staphylococcus aureus, and Moraxella catarrhalis, as long as there are at least 10 
pathogens in the lefamulin group. 
The minimum inhibitory concentration 50 (MIC50), 90 (MIC90), and range of lefamulin and 
moxifloxacin for baseline pathogens and susceptibility (susceptible and resistant, based on MIC 
and zone diameter) of pathogens to lefamulin and moxifloxacin will be summarized by baseline 
pathogen for both treatment groups combined and by treatment group for subjects in the 
microITT and ME-TOC Analysis Sets. MIC50 and MIC90 will be provided only where there are 
at least 10 pathogens of a particular species; range will be provided for all pathogens.   
Baseline pathogens are considered susceptible (S), intermediate (I), or resistant (R) to 
moxifloxacin and S or non-susceptible (NS) to lefamulin according to the criteria in Table 9 and 
Table 10.  
Table 9. 
Interpretive Criteria for Moxifloxacin for CABP Pathogens 
According to CLSI Guidelines  
Pathogen 
Moxifloxacin 
MIC breakpoint a 
[µg/mL] 
Moxifloxacin 
Disk Diffusion Zone Diameter a 
[mm] 
S 
I 
R 
S 
I 
R 
Streptococcus pneumoniae 
≤ 1  
2  
≥ 4  
≥ 18  
15-17  
≤ 14  
Staphylococcus spp. 
≤ 0.5  
1  
≥ 2  
≥ 24  
21-23  
≤ 20  
Haemophilus influenzae 
≤ 1  
-  
-  
≥ 18  
- 
-  
Moraxella catarrhalis 
-  
-  
-  
-  
-  
-  
Legionella pneumophila 
-  
-  
-  
-  
-  
-  
Mycoplasma pneumoniae b 
≤ 0.25  
- 
≥ 0.5  
-  
-  
-  
S=susceptible, I=intermediate, R=resistant 
a According to CLSI M100-S25 (2015)  
b Breakpoints according to CLSI M43-A (2011) 


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Table 10. 
Proposed Tentative Susceptibility Interpretive Criteria for 
Lefamulin for CABP Pathogens Based on In Vitro Data 
Determined According to CLSI Guidelines  
Pathogen 
Lefamulin 
MIC breakpoint a 
[µg/mL] 
Lefamulin 
Disk Diffusion Zone Diameter a 
[mm] 
S 
NS 
 
S 
NS 
 
Streptococcus pneumoniae 
≤ 1 
> 1 
 
≥ 19 
< 19 
 
Staphylococcus spp. 
≤ 1 
> 1 
 
≥ 20 
< 20 
 
Haemophilus influenzae 
≤ 2 
> 2 
 
≥ 20 
< 20 
 
Moraxella catarrhalis 
≤ 1 
> 1 
 
≥ 20 
< 20 
 
Legionella pneumophila 
≤ 1 
> 1 
 
- b 
- b 
 
Mycoplasma pneumoniae 
≤ 1 
> 1 
 
- b 
- b 
 
S=susceptible, NS=non-susceptible 
a The current absence of data on resistant isolates except for S. aureus precludes defining any category other than 
“susceptible.”  
b No disk diffusion zone diameter criteria have been established for M. pneumoniae and L. pneumophila. 
By-subject listings of pathogen MICs, susceptibilities, and disk diffusion zone diameters will 
also be provided.  
8.4 
Extent of Exposure and Study Drug Treatment Compliance 
8.4.1 
Duration of Study Drug Therapy 
Duration of study drug treatment (placebo and/or active, as well as active only) will be 
summarized for the Safety and mITT Analysis Sets.  Duration of study drug treatment is defined 
as the date of last dose – the date of first dose + 1.  The number and percentage of subjects who 
received study drug for 1-2 days, ≥3-5 days, and 6-8 days as well as descriptive statistics of the 
number of days on study drug (n, mean, standard deviation, minimum, median, and maximum) 
will be presented by treatment group.   
The proportion of subjects receiving all doses of study drug as inpatients, receiving all doses of 
study drug as outpatients and receiving doses of study drug as both inpatients and outpatients 
will be presented for the mITT Analysis Set. 
8.4.2 
Prior and Concomitant Medications 
The World Health Organization (WHO) drug dictionary will be used to classify prior and 
concomitant medications, including antibacterial medications, by therapeutic class.  A prior 
medication is defined as any medication taken prior to the date and time of the first dose of study 
drug (or date of randomization if no study drug was received).  For non-antibacterials (for which 
only start and stop dates [not times] are collected), any medication taken on or after the date of 
first dose of study drug (or date of randomization if no study drug was received) will be 
considered concomitant; medications stop dates occurring prior to the date of first dose of study 
drug (or date of randomization if no study drug was received) will be considered prior 
medications. A concomitant medication is defined as any medication taken on or after the date 
and time of the first dose of study drug (or date of randomization if no study drug was received). 


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If the start date of a medication is missing, the medication will be assumed to be both prior and 
concomitant, unless the end date of the medication clearly indicates the medication was stopped 
prior to the first dose of study drug (or date of randomization if no study drug was received). If 
the start date is a partial date such that it cannot be determined if the medication is prior or 
concomitant, the medication will be assumed to be both prior and concomitant, unless the end 
date of the medication clearly indicates the medication stopped prior to the first dose of study 
drug (or date of randomization if no study drug was received). 
For antibacterials, missing start and stop times will be set to 00:00 on the start and stop date of 
the antibiotic.  
Prior systemic antibacterial medications and concomitant systemic antibacterial medications will 
be summarized by Anatomical Therapeutic Chemical (ATC) level 4  (or the next available level 
if level 4 is not available) and preferred term separately by treatment group for the ITT, mITT 
and CE-TOC Analysis Sets. Subjects receiving the same medication more than once will be 
counted only once for a particular ATC level and preferred term.  Prior systemic antibacterial 
medications will be summarized based on receipt within 72 hours prior to randomization and 
receipt more than 72 hours prior to randomization.  
Additional tables (ITT, mITT and CE-TOC Analysis Sets) will summarize the percent of 
subjects receiving any prior systemic antibacterial medication, the percent of subjects receiving 
an antibacterial medication in the 72 hours prior to randomization, the percent receiving the 
antibacterial for the current episode of CABP, the percent receiving a single dose of a short-
acting oral or IV antibacterial for CABP (per the eCRF), the percent receiving more than 1 dose 
of a short-acting antibacterial for CABP or ≥1 dose of a long-acting antibacterial for CABP, the 
percentage of subjects receiving >48 hours of prior systemic antibacterial therapy for the current 
episode of CABP enrolled as a treatment failure (ie, the exception to exclusion criterion 1), the 
percentage of subjects receiving a prior systemic antibacterial for an infection not related to 
CABP and the percentage of subjects receiving a prior systemic antibacterial for an “other” 
reason.  
Prior and concomitant non-antibacterial medications will be presented in a by-subject listing and 
concomitant non-antibacterial medications will be summarized by ATC level 4 (or the next 
available level if level 4 is not available), preferred term and treatment group for the ITT 
Analysis Set.  Subjects receiving the same medication more than once will be counted only once 
for a particular ATC level and preferred term.  
The reasons for receipt of concomitant systemic antibacterial medications will be summarized by 
treatment group for the ITT, mITT and CE-TOC Analysis Sets.  For concomitant systemic 
antibacterial medications, the number and percentage of subjects excluded from the CE Analysis 
Sets due to receipt of an antibacterial and not excluded from the CE Analysis Sets will be 
summarized.  The reasons for receipt of the antibacterial will be provided for each category 
(excluded and not excluded from the CE Analysis Sets) and include current CABP prior to 
randomization, infection prior to randomization not related to CABP, concomitant infection 
unrelated to CABP, insufficient therapeutic effect of study drug (only for not excluded from the 
CE Analysis Sets), treatment-limiting AE resulting in study drug discontinuation (only for not 
excluded from the CE Analysis Sets), and “other.” 


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8.4.3 
Study Drug Treatment Compliance 
Each subject’s compliance with study drug treatment will be calculated based on the number of 
doses the subject would have been expected to receive based on the number of treatment days 
(ie, the date of the first and last dose of study drug). Treatment compliance is defined as the 
number of doses actually received divided by the number of doses expected for the time period 
between the dates of the first and last doses of study drug (× 100). Subjects are expected to 
receive 7 days of study drug (5 days of active lefamulin plus 2 days of placebo) or moxifloxacin 
(7 days of active moxifloxacin).  Descriptive statistics (number of subjects, mean, standard 
deviation, minimum, median, and maximum) will be presented for the ITT, microITT, CE-EOT 
and CE-TOC Analysis Sets. 
8.5 
Efficacy Analyses 
For all efficacy analyses, subjects will be analyzed in the group to which they were randomized.  
By definition, subjects who receive the wrong study drug are not included in the CE and ME 
Analysis Sets.  Unless otherwise stated, subjects who are randomized to the wrong geographic 
region, prior antibiotic, or PORT risk class stratum will be analyzed in the stratum to which they 
were randomized. 
8.5.1 
Primary Efficacy Analysis 
The primary efficacy outcome is the percentage of subjects with an ECR of responder at 96 ± 24 
hours after the first dose of study drug in the ITT Analysis Set. Each subject will be 
programmatically categorized as a responder, non-responder, or indeterminate based on data on 
the eCRF.  Subjects with missing data or who are lost to follow up are defined as indeterminate 
for the primary analysis and are included in the denominator for the calculation of the response 
rate. Thus, subjects with an indeterminate outcome are considered non-responders for the 
primary analysis. The number and percentage of subjects in each treatment group in each 
response category (and combined non-responder/indeterminate) will be reported.  
The null and alternative hypotheses are: 
H0: P1-P2 ≤- ∆ 
H1: P1-P2 >- ∆ 
Where P1 = the primary efficacy outcome rate in the lefamulin group 
P2 = the primary efficacy outcome rate in the moxifloxacin group 
∆ = the non-inferiority margin 
The NI hypothesis test is a 1-sided hypothesis test performed at the 2.5% level of significance. 
This is based on the lower limit of the 2-sided 95% confidence interval (CI) for the observed 
difference in the early clinical response rate (lefamulin group minus the moxifloxacin group). 
The CI will be calculated using an unadjusted continuity corrected Z-test. If the lower limit of 
the 95% CI for the difference in responder rates in the ITT Analysis Set is greater than -10%, the 
null hypothesis will be rejected and the NI of lefamulin to moxifloxacin will be concluded.  
The reasons for an ECR of non-responder and indeterminate will be summarized by treatment 
group for all subjects who are a non-responder or indeterminate at 96 ± 24 hours after the first 


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dose of study drug.  Reasons for non-responder are: did not show improvement in at least 2 of 
the cardinal symptoms of CABP, worsening of at least 1 symptom of CABP, received a 
concomitant antibacterial and died from any cause. Reasons for indeterminate are: no assessment 
of symptoms and did not have at least 2 cardinal symptoms at baseline. 
8.5.2 
Additional Analyses of the Primary Efficacy Outcome 
Early Clinical Response will be assessed separately across the randomization stratification 
factors (from the IRT) of geographic regions (US vs. ex-US), prior antibiotic use vs. none, and 
PORT risk class (II vs. III/IV). For each geographic region, prior antibiotic use, and PORT risk 
class stratum a 2-sided 95% CI for the observed difference in ECR responder rates will be 
calculated for the ITT Analysis Set.  
Sensitivity analyses of early clinical response include: 
 An analysis adjusted for the stratification factors of geographic region, prior antibiotic 
use and PORT risk class stratum (based on the randomization stratum the subject was 
actually randomized to).  A 95% CI using the method proposed with stratification by 
Miettinen and Nurminen will be computed for the difference in the ECR responder rates 
between lefamulin and moxifloxacin.  Cochran-Mantel-Haenszel weights will be used for 
the stratum weights in the calculation of the CI. 
 An analysis adjusted for the stratification factors of geographic region, prior antibiotic 
use, and PORT risk class stratum based on the randomization stratum the subject 
correctly belongs to.  A 95% CI using the method proposed with stratification by 
Miettinen and Nurminen will be computed for the difference in the ECR responder rates 
between lefamulin and moxifloxacin.  Cochran-Mantel-Haenszel weights will be used for 
the stratum weights in the calculation of the CI. 
 All subjects with missing data at 96 ± 24 hours after the first dose of study drug or with 
less than 2 symptoms at baseline (ie, indeterminates) as ECR responders (these subjects 
are considered ECR non-responders in the primary analysis).  An unadjusted 95% CI will 
be computed using a continuity corrected Z-test for the difference in the ECR responder 
rates between lefamulin and moxifloxacin. 
 Subjects who are non-responders and receive less than 48 hours total duration of study 
drug will be reclassified as indeterminates and the number and percentage of subjects in 
each treatment group in each response category will be reported. Subjects who died prior 
to receipt of at least 48 hours total duration of study drug will remain classified as a non-
responder. An unadjusted 95% CI will be computed using a continuity corrected Z-test 
for the difference in the ECR responder rates between lefamulin and moxifloxacin. 
Subgroup analyses of the primary efficacy outcome, including treatment differences and 95% 
CIs (computed using a continuity corrected Z-test), will also be conducted for descriptive 
purposes.  These include but are not limited to PORT Risk Class per the eCRF (II, III, IV), prior 
antibiotic use in the 72 hours before randomization per the eCRF (use, no use), SIRS (yes, no), 
ATS (yes, no), CURB-65, gender, age group (<65, 65-74, ≥75 years), renal impairment category 
and bacteremic subjects.  Exploratory analyses in other subgroups may also be conducted. A 


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Forest plot of the treatment difference in ECR responder rate and CI by the stratification factors 
and subgroups will also be provided. 
8.5.3 
Secondary Efficacy Analyses 
8.5.3.1 
Investigator’s Assessment of Clinical Response at the TOC Visit in the 
mITT and CE-TOC Analysis Sets 
The number and percentage of subjects in each treatment group determined to have an IACR of 
success, failure, or indeterminate (and combined failure and indeterminate) at the TOC Visit will 
be presented for the mITT and CE-TOC Analysis Sets (indeterminates are excluded from the 
CE-TOC Analysis Set).  Two-sided unadjusted 95% CIs for the difference in success rate will be 
calculated using a continuity corrected Z-test.  
The reasons for IACR of failure at the TOC Visit will be summarized by treatment group for all 
subjects in the mITT and CE-TOC Analysis Sets. The reasons for IACR of indeterminate 
(subject lost to follow-up, missed visit, withdrew from the study or did not have CABP) will also 
be summarized by treatment group for all subjects at the TOC Visit for the mITT Analysis Set.   


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8.5.3.2 
Early Clinical Response in the Microbiologic Intent-to-Treat Analysis 
Sets 
The number and percentage of subjects categorized as responder, non-responder and 
indeterminate (and combined non-responder and indeterminate) for the outcome of ECR will be 
presented for the microITT, microITT-2 and emicroITT Analysis Sets and a 2-sided unadjusted 
95% CI for the difference in responder rate will be calculated using a continuity corrected Z-test.   
The reasons for an ECR of non-responder and indeterminate at 96 ± 24 hours after the first dose 
of study drug will be summarized by treatment group for all subjects in the microITT and 
microITT-2 Analysis Sets.  
8.5.3.3 
Investigator’s Assessment of Clinical Response at the TOC Visit in the 
microITT and ME-TOC Analysis Sets 
The number and percentage of subjects in each treatment group determined to have an IACR of 
success, failure, or indeterminate (and combined failure and indeterminate) at the TOC Visit will 
be presented for the microITT and ME-TOC Analysis Sets (indeterminates are excluded from the 
ME-TOC Analysis Set).  Two-sided unadjusted 95% CIs for the difference in success rate will be 
calculated using a continuity corrected Z-test.  
The reasons for IACR of failure at the TOC Visit will be summarized by treatment group for all 
subjects in the microITT and ME-TOC Analysis Sets. The reasons for IACR of indeterminate at 
the TOC Visit will also be summarized by treatment group for all subjects in the microITT 
Analysis Set.   
8.5.3.4 
By-Pathogen Microbiological Response at the TOC Visit in the microITT 
and ME-TOC Analysis Sets 
The proportion of subjects with a microbiological response of success by baseline pathogen (and 
where relevant, the susceptibility phenotype) at the TOC Visit will be tabulated separately by 
treatment group for subjects in the microITT and ME-TOC Analysis Sets.  Distinct pathogens 
are based on genus and species and where relevant, the susceptibility phenotype as defined in 
Table 8.   
For all by-pathogen analyses, subjects with a pathogen of the same genus and species with more 
than 1 phenotype, for example both MRSA and MSSA, will be counted once for each phenotype 
and once for the overall tabulation of the pathogen, for example, Staphylococcus aureus. 
8.5.3.5 
28-Day All-Cause Mortality in the ITT Analysis Set 
All-cause mortality through Study Day 28 will be summarized by treatment group in the ITT 
Analysis Set.  Subjects who are lost to follow-up will be considered deceased for analysis and 
will be summarized separately on the table.  A 2-sided unadjusted 95% CI will be calculated for 
the treatment difference in survival rates at Study Day 28 using a continuity corrected Z-test.  


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8.5.4 
Additional Efficacy Analyses 
Additional efficacy analyses will be conducted to support the efficacy findings for the primary 
and secondary efficacy outcomes.  Confidence intervals for proportions will be determined for 
descriptive purposes, as indicated below, but no conclusions of NI will be made. 
8.5.4.1 
Clinical Outcome Measures  
The proportion of subjects in each treatment group with an ECR of responder at 96 ± 24 hours 
after the first dose of study drug will be determined by baseline pathogen (and where relevant, 
the susceptibility phenotype) in the microITT and microITT-2 Analysis Sets.  
The number and percentage of subjects in each treatment group determined to have an IACR of 
success, failure, or indeterminate (and combined failure and indeterminate) at the TOC Visit in 
the microITT-2 and emicroITT Analysis Sets will be presented.  A 2-sided unadjusted 95% CI 
for the difference in IACR success rate will be calculated using a continuity corrected Z-test. 
The number and percentage of subjects in each treatment group determined to have an IACR of 
success, failure, or indeterminate (and combined failure and indeterminate) at the EOT Visit in 
the mITT, microITT, CE-EOT and ME-EOT Analysis Sets will be presented.  A 2-sided 
unadjusted 95% CI for the difference in IACR success rates will be calculated using a continuity 
corrected Z-test. 
The number and percentage of subjects in each treatment group determined to have an IACR of 
sustained success, relapse, prior failure or indeterminate (and combined relapse, prior failure and 
indeterminate) at the LFU Visit in the mITT, microITT, CE-LFU and ME-LFU Analysis Sets 
will be presented. Prior failure is defined as a subject who had an IACR of failure at the TOC 
Visit. A 2-sided unadjusted 95% CI for the difference in IACR sustained success rates will be 
calculated using a continuity corrected Z-test. 
The proportion of subjects with an IACR of success will be presented by baseline pathogen (and 
where relevant, the susceptibility phenotype) at the TOC Visit in the microITT, microITT-2, and 
ME-TOC Analysis Sets. The proportion of subjects with an IACR of sustained success will be 
presented by baseline pathogen (and where relevant, the susceptibility phenotype) at the LFU 
Visit in the microITT and ME-LFU Analysis Sets. The proportion of subjects with an IACR of 
success will be presented by baseline pathogen (and where relevant, the susceptibility 
phenotype) at the EOT Visit in the microITT and ME-EOT Analysis Sets. 
The proportion of subjects with an ECR of responder will be presented by baseline pathogens 
(and where relevant, the susceptibility phenotype) identified from blood specimens in the 
microITT Analysis Set.  The proportion of subjects with an IACR of success will be presented 
by baseline pathogens (and where relevant, the susceptibility phenotype) identified from blood 
specimens at the TOC Visit in the microITT Analysis Set. 
A summary (number and percentage of subjects) of the assessment of clinical signs and 
symptoms of CABP at each time point throughout the study will be presented by treatment group 
as a shift table compared to baseline in the ITT Analysis Set.  If the EOT Visit and the last day of 
study drug are on the same day and only 1 assessment is performed, the assessment will be 


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summarized both at the study day and the EOT Visit. The proportion of subjects with resolution 
of all baseline signs and symptoms will also be provided by study visit (CAPB signs and 
symptoms were collected at baseline, daily while on study drug, at EOT, TOC and LFU).  
Analyses of signs and symptoms will only be assessed in subjects with non-missing assessments 
of all baseline signs and symptoms at the specified visit. 
A summary of subjects who met the criteria for ECR responder will be provided by study visit. 
For each study visit, ECR will be determined for (ie, the denominator will consist of) those 
subjects who have died up through the relevant assessment, those subjects who have received an 
antibiotic for the treatment of CABP up through the relevant visit and those subjects with non-
missing assessments of all baseline cardinal CABP symptoms at the relevant visit.  If the EOT 
Visit and the last day of study drug are on the same day and only 1 assessment was performed, 
the assessment will be summarized both at the study day and the EOT Visit. 
The number and percentage of subjects categorized as responder, non-responder and 
indeterminate (and combined non-responder and indeterminate) for the outcome of ECR plus 
improvement in vital signs, will be presented for the ITT Analysis Set and a 2-sided unadjusted 
95% CI for the difference in responder rate will be calculated using a continuity corrected Z-test.  
The reasons for an ECR plus improvement in vital signs of non-responder and indeterminate at 
96 ± 24 hours after the first dose of study drug will be summarized by treatment group for all 
subjects in the ITT Analysis Set. Reasons for non-response include those for ECR (Section 8.5.1) 
as well as did not show an improvement in body temperature, hypotension, tachycardia and 
tachypnea.  Reasons for indeterminate include no assessment of symptoms, did not have at least 
2 cardinal symptoms of CABP at baseline and had no assessment of vital signs. 
The proportion of subjects with an ECR of responder at 96 ± 24 hours after the first dose of 
study drug by baseline pathogen (and where relevant, the susceptibility phenotype) and MIC to 
study drug received and by baseline pathogen (and where relevant, the susceptibility phenotype) 
and disk diffusion zone diameter will be determined for each pathogen isolated at baseline in the 
microITT Analysis Set. 
The proportion of subjects with an IACR of success at the TOC Visit by baseline pathogen (and 
where relevant, the susceptibility phenotype) and MIC to study drug received and by baseline 
pathogen (and where relevant, the susceptibility phenotype) and disk diffusion zone diameter will 
be determined for each pathogen isolated at baseline in the microITT and ME-TOC Analysis Sets.   
A concordance analysis of ECR and IACR at the TOC Visit by treatment group will be provided 
in the ITT Analysis Set.  
8.5.4.2 
Microbiological Response Measures 
The number and percentage of subjects determined to have a by-subject microbiological 
response of success (eradication or presumed eradication), failure (persistence or presumed 
persistence) or indeterminate at the EOT, TOC and LFU Visits will be tabulated by treatment 
group for subjects in the microITT, microITT-2 (TOC Visit only) and ME-EOT (EOT Visit), 
ME-TOC (TOC Visit) and ME-LFU (LFU Visit) Analysis Sets. A 2-sided unadjusted 95% CI 


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for the difference in by-subject microbiological response success rates between the lefamulin and 
moxifloxacin treatment groups will be provided.   
The proportion of subjects with a microbiological response of success by baseline pathogen (and 
where relevant, the susceptibility phenotype) at the TOC Visit will be tabulated separately by 
treatment group for subjects in the microITT-2 Analysis Set. The proportion of subjects with a 
microbiological response of success by baseline pathogen (and where relevant, the susceptibility 
phenotype) at the EOT Visit will be tabulated separately by treatment group for subjects in the 
microITT and ME-EOT Analysis Sets. The proportion of subjects with a microbiological 
response of sustained success by baseline pathogen (and where relevant, the susceptibility 
phenotype) at the LFU Visit will be tabulated separately by treatment group for subjects in the 
microITT and ME-LFU Analysis Sets.   
A by-subject listing will present the by-pathogen and by-subject microbiological response at the 
EOT, TOC and LFU Visits in the ITT Analysis Set.  A second by-subject listing will present the 
by-pathogen and by-subject microbiological response at the EOT, TOC and LFU Visits for non-
responders, clinical failures, or subjects with persistence. 
The proportion of subjects with a microbiological response of success at the TOC Visit by 
baseline pathogen (and where relevant, the susceptibility phenotype) and MIC to study drug 
received and by baseline pathogen (and where relevant, the susceptibility phenotype) and disk 
diffusion zone diameter will be determined for each pathogen isolated at baseline in the 
microITT and ME-TOC Analysis Sets. 
A by-subject listing of subjects in the ITT Analysis Set with a superinfection or colonization will 
be provided. The listing will include subject ID, treatment group, baseline and post-baseline 
pathogen genus and species, study day of post-baseline pathogen, and whether the emergent 
pathogen is a superinfection or a colonization. 
A by-subject listing of subjects in the ITT Analysis Set showing at least 1 pathogen with 
decreasing susceptibility will be presented in a listing providing the subject ID, treatment group, 
collection date/time and study day, type of specimen, pathogen (baseline and post-baseline), 
MIC values, disk diffusion zone diameters, and susceptibility to study drug received.  
8.6 
Pharmacokinetic Analyses 
Measured plasma concentrations of BC-3781 and BC-8041 will be summarized descriptively for 
the lefamulin group and nominal time point of collection. Summary statistics in the tabulation 
will include n, mean, standard deviation, CV [%], median, minimum and maximum. 
8.7 
Safety Analyses 
All safety analyses will be conducted in the Safety Analysis Set. Subjects who receive the wrong 
study drug for their entire course of treatment will be analyzed in the group based on the drug 
received.  Subjects who receive the wrong study drug less than the entire course of treatment will 
be analyzed in the as randomized treatment group. 


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For each safety parameter with the exception of ECGs which are measured in triplicate at each 
time point and vital signs which uses the last assessment prior to Day 1, the last assessment made 
prior to the first dose of study drug will be used as the baseline for all analyses. 
8.7.1 
Adverse Events 
Adverse events will be monitored throughout the study from the time a subject is consented 
through the TOC Visit; SAEs are to be collected from the time of consent through the LFU Visit.  
Adverse events will be coded using Version 18.0 or higher of MedDRA. A treatment-emergent 
AE (TEAE) is defined as an AE that starts or worsens at or during the time of or after the first 
study drug administration. If the AE start date is unknown or is a partial date such that it cannot 
be determined if the AE started on or after the first study drug administration, it will be 
categorized as a TEAE. 
An overall summary of AEs will include the number and percentage of subjects who experienced 
at least 1 AE of the following categories: any AE, any TEAE, any serious TEAE, any treatment-
related TEAE, any treatment-related serious TEAE, any TEAE leading to premature 
discontinuation of study drug, any TEAE leading to premature discontinuation from the study, 
and any TEAE leading to death. 
The number and percentage of subjects reporting a TEAE and the number and percentage of 
subjects reporting a treatment-related TEAE (related defined as possibly, probably or definitely 
related to study drug) in each treatment group will be tabulated by system organ class, preferred 
term, and severity (mild, moderate, and severe).  A summary of TEAEs and treatment-related 
TEAEs sorted by decreasing frequency of preferred term in lefamulin subjects will also be 
provided.  Likewise, the number and percentage of subjects reporting a serious TEAE and the 
number and percentage of subjects reporting a TEAE leading to premature discontinuation of 
study drug in each treatment group will be tabulated separately by system organ class and 
preferred term.  For all analyses of TEAEs, if the same AE (based on preferred term) is reported 
for the same subject more than once, the AE is counted only once for that preferred term and at 
the highest severity and strongest relationship to study drug.  
A listing of TEAEs leading to discontinuation of study drug will be provided and will include 
subject ID, subject age, sex and race, onset day of the AE, duration of AE in days, duration of 
study drug (days), preferred term, verbatim term, severity, relationship to study drug, outcome, 
therapy given (Y/N) and seriousness (Y/N).  A listing of all serious TEAEs will also be provided 
and will include subject ID, subject age, sex and race, onset day of the AE, duration of AE in 
days, preferred term, verbatim term, severity, relationship to study drug, outcome, therapy given 
(Y/N) and drug withdrawn (Y/N). If the outcome of the SAE is death, the date and study day of 
the death and whether it was prior to EOT or after EOT will be presented. 
8.7.2 
Clinical Laboratory Evaluations  
Central laboratory data will be utilized for all analyses.  For the purposes of summarizing post-
baseline maximum alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), and total bilirubin and for the purposes of identifying cases of potential 
Hy’s law, both central and local laboratory data will be used.  In addition, local laboratory data 


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will be utilized in the assessment of any Potentially Clinically Significant (PCS) labs as defined 
in Appendix B.  Local laboratory data are collected on the eCRF: 1) if the subject did not meet 
the laboratory inclusion/exclusion criteria based on the central laboratory results, 2) potential 
Hy’s law is reported based on local laboratory results, and 3) the Principal Investigator chooses 
to report local laboratory results obtained in the clinical management of the patient. 
Laboratory values will be defined as potentially clinically significant (PCS) according to the 
table in Appendix B. To be considered PCS, the laboratory value must meet both the lower limit 
and the percent decrease from baseline or both the upper limit and the percent increase from 
baseline. The proportion of subjects in the Safety Analysis Set with at least 1 PCS laboratory 
value will be summarized by treatment group and PCS laboratory values will be summarized by 
treatment group, laboratory parameter, visit and for the overall worst post-baseline value 
(minimum and maximum value, where appropriate defined in Appendix C). Percentages for each 
laboratory test will be based on the number of subjects with a baseline and post-baseline 
evaluation at the visit for the specific laboratory test.  By-subject listings of all laboratory values 
for a subject with any PCS post-baseline laboratory value will also be provided. 
Shift tables will be presented to show the number and percentage of subjects with a laboratory 
value below the lower limit of normal (LLN), within normal limits, above the upper limit of 
normal (ULN) and missing at baseline versus the value at each visit and the worst post-baseline 
value. Percentages for each laboratory test will be based on the number of subjects in the Safety 
Analysis Set.   
A listing of subjects who have the laboratory criteria for potentially meeting Hy’s Law will also 
be provided.  The laboratory criteria for potentially meeting Hy’s Law is defined as ALT or AST 
>3 x ULN, ALP ≤2.0 x ULN and total bilirubin >2 x ULN.  The proportion of subjects with any 
post-baseline AST >3 x ULN, >5 x ULN and >10 x ULN, any post-baseline ALT >3 x ULN, >5 
x ULN and >10 x ULN, any post-baseline total bilirubin >1.5 x ULN and >2 x ULN, any post-
baseline ALP >2 x ULN, and any post-baseline ALT or AST value >3 x ULN and any post-
baseline total bilirubin value >2 x ULN with an ALP ≤2 x ULN and with an ALP >2 x ULN will 
be presented by treatment group. 
Descriptive statistics for chemistry and hematology parameter values and the change from 
baseline at Day 4, EOT, and TOC will be summarized by treatment group for the Safety Analysis 
Set.  Change from baseline will be calculated for each subject at the specified visit as the value at 
the specified visit minus the baseline value. The change from baseline to the minimum and 
maximum post-baseline values for chemistry and hematology parameters will also be 
summarized by treatment group. Change from baseline will be calculated for each subject as the 
minimum or maximum post-baseline value minus the baseline value. Baseline is defined as the 
last assessment prior to the first dose of study drug.  Box-plots, which provide the median, mean, 
inter-quartile range, 5th and 95th percentile, and outliers will also be provided for ALP, AST, 
ALT, BUN, calcium, creatinine, phosphate, sodium, total bilirubin, absolute neutrophil count, 
hemoglobin, platelets, and WBC by scheduled study visit and treatment group. 
Urinalysis data will be provided in a listing. 


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8.7.3 
ECG Parameters 
ECG data are being read centrally. The mean of the triplicates (or if triplicates not available, the 
duplicates or single ECG, whichever is available) will be used for all analyses, even if not 
performed within a 5-minute interval. Descriptive statistics for heart rate, PR interval, QRS 
interval, QT interval, and QT interval corrected by the Fridericia formula (QTcF) and the change 
from baseline at Day 1 (1-3 hours after the first dose of study drug), Day 4 (inpatients)/96±24h 
after the first dose of study drug (outpatients) (prior to the first dose of study drug) and Day 4 (1-
3 hours after the first dose of study drug) will be summarized by treatment group for subjects in 
the Safety Analysis Set.  In addition, Day 4 post-active dose will be summarized.  Change from 
baseline will be calculated for each subject at Day 1 (1-3 hours after the first dose of study drug) 
and Day 4 (inpatients)/96±24h after the first dose of study drug (outpatients) (prior to and 1-3 
hours after the first dose of study drug) as the value at the specified visit and time point minus 
the baseline value. The change from baseline to the minimum and maximum post-baseline values 
will also be summarized by treatment group, where these post-baseline values include 
unscheduled visits. Change from baseline will be calculated for each subject as the minimum or 
maximum post-baseline value minus the baseline value.  Baseline is defined as the mean of the 
triplicates from the last assessment prior to the first dose of study drug. ECG parameters for each 
of the triplicates (including the change in QTcF value from pre-dose to post-dose) and the overall 
interpretation of the ECG will be presented on a listing. 
The number and percentage of subjects with any post-baseline increase in QTcF and any post-
baseline increase of >30 msec or >60 msec in QTcF will be summarized by treatment group. The 
number and percentage of subjects with a post-baseline QTcF of >480 msec or >500 msec will 
also be summarized by treatment group. The number and percentage of subjects with a post-
baseline increase in QTcF of >30 msec resulting in a post-baseline QTcF of >480 msec or 
>500 msec as well as QTcF of >60 msec resulting in a post-baseline QTcF of >480 msec or >500 
msec will also be summarized by treatment group.  The distribution of QTcF values (≤450 msec, 
>450 - ≤480 msec, >480 - ≤500 msec, and >500 msec) at each time point and the distribution of 
change from baseline in QTcF values at each time point (0 or less (no increase), 1-<30 msec, 30-
60 msec, and >60 msec) will be summarized by treatment group for subjects in the Safety 
Analysis Set.  These analyses will also be provided by study visit. 
A listing will be provided of findings identified on the ECG. 
8.7.4 
Vital Signs 
Descriptive statistics for temperature, respiratory rate, heart rate, diastolic blood pressure, 
systolic blood pressure, and the change from baseline at each post-baseline visit will be 
summarized by treatment group for all subjects in the Safety Analysis Set. Change from baseline 
will be calculated for each subject at the specified visit as the value at the specified visit minus 
the baseline value. The change from baseline to the minimum and maximum post-baseline values 
will also be summarized by treatment group.  Change from baseline will be calculated for each 
subject as the minimum or maximum post-baseline value minus the baseline value.  Baseline is 
defined as the last assessment prior to Day 1.  


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Post-baseline vital signs will be defined as high or low if the criterion value listed in Table 11 is 
met.  All vital signs will be presented in a listing with a flag for high and low indicating the 
criterion value was met. PCS is defined as meeting both the criterion value and the change from 
baseline criterion listed in Table 11.  The number and percentage of subjects with any post-
baseline PCS vital sign will be presented by treatment group. The overall post-baseline incidence 
of PCS values, which includes values from unscheduled post-baseline visits, will be summarized 
by treatment group for the Safety Analysis Set, and all PCS vital sign values will be listed and 
flagged in by subject listings. 
Table 11. 
Criteria for Treatment Emergent Potentially Clinically Significant 
Vital Signs 
Vital Sign Parameter 
Flag 
Criterion Value 
Change from Baseline 
Systolic Blood Pressure 
(mmHg) 
High (CH) 
 180 
Increase of  20 mmHg 
Low (CL) 
<90 
Decrease of  20 mmHg 
Diastolic Blood 
Pressure (mmHg) 
High (CH) 
 105 
Increase of  15 mmHg 
Low (CL) 
 50 
Decrease of  15 mmHg 
Heart Rate (beats/min) 
High (CH) 
 120 
Increase of  15 beats/min 
Low (CL) 
 50 
Decrease of  15 beats/min 
9.0 
CHANGES FROM THE PROTOCOL SPECIFIED ANALYSES 
Two additional microbiologic Analysis Sets (microITT-2 and emicroITT) were included.  The 
microITT-2 Analysis Set will consist of all subjects in the ITT Analysis Set who have at least 
1 baseline bacterial pathogen known to cause CABP as defined in Sections 4.1 and 4.2 from a 
diagnostic method other than PCR.  The emicroITT Analysis Set will consist of all subjects in 
the ITT Analysis Set who have at least 1 baseline bacterial pathogen known to cause CABP as 
defined in Sections 4.1 and 4.2, except a baseline pathogen from a sputum culture is defined 
using the presence of a Gram stain with ≥10 PMNs/LPF and <10 SECs/LPF rather than 
>25 PMNs/LPF and <10 SECs/LPF. Additional analyses performed in these Analysis Sets 
include summaries of the following:  ECR (microITT-2 and emicroITT), ECR by baseline 
pathogen (microITT-2), IACR at TOC (microITT-2 and emicroITT), IACR at TOC by baseline 
pathogen (microITT-2), by-subject microbiologic response at TOC (microITT-2), and 
by-pathogen microbiologic response at TOC (microITT-2). 
Other additional efficacy analyses specified in this SAP include summaries of the following:  
ECR by baseline pathogen and MIC or disk diffusion zone diameter to study drug received 
(microITT), ECR by baseline pathogen identified from blood (microITT), IACR at EOT and 
LFU (microITT and relevant ME Analysis Sets), IACR at EOT by baseline pathogen (microITT 
and ME-EOT), IACR at TOC by baseline pathogen and MIC or disk diffusion zone diameter to 
study drug received (microITT and ME-TOC), IACR at TOC by baseline pathogen identified 
from blood (microITT), by-subject and by-pathogen microbiologic response at EOT and LFU 
(microITT and relevant ME Analysis Sets), and by-pathogen microbiologic response at TOC by 
MIC or disk diffusion zone diameter to study drug received (microITT and ME-TOC). 


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10.0 REFERENCES 
Albrich WC, Madhi SA, Adrian PV, Telles JN, Paranhos-Baccala G, Klugman KP. Genomic 
load from sputum samples and nasopharyngeal swabs for diagnosis of pneumococcal pneumonia 
in HIV-infected adults. J Clin Microbiol. 2014; 52(12):4224-9. 
Barrera CM, Mykietiuk A, Metev H, et al. Efficacy and safety of oral solithromycin versus oral 
moxifloxacin for treatment of community-acquired bacterial pneumonia: a global, double-blind, 
multicentre, randomised, active-controlled, non-inferiority trial (SOLITAIREORAL). Lancet 
Infect Dis. 2016; Feb 4. pii: S1473-3099(16)00017-7. doi: 10.1016/S1473-3099(16)00017-7. 
[Epub ahead of print] 
Cempra, Inc. 16-Jan-2015. Cempra announces positive topline phase 3 clinical results for 
intravenous solithromycin in the treatment of community-acquired bacterial pneumonia [Press 
release]. Retrieved from http://investor.cempra.com/releasedetail.cfm?releaseid=936994 
Chochua S, Sheets A, Keedy K, et al. Detection of pneumococcal pneumonia in a phase 3 trial 
comparing oral solithromycin versus oral moxifloxacin for treatment of community-acquired 
bacterial pneumonia in adults. Poster presented at IDWeek 2015 Oct 7-11; San Diego, CA, USA. 
894.  
CLSI. Methods for antimicrobial susceptibility testing for human mycoplasmas. Approved 
Guideline. CLSI document M43-A. Wayne, PA: Clinical and Laboratory Standards Institute; 2011. 
CLSI. Performance standards for antimicrobial susceptibility testing. Twenty-fifth Informational 
Supplement. CLSI document M-100-S25. Wayne, PA: Clinical and Laboratory Standards 
Institute; 2015. 
FDA Anti-infective Drugs Advisory Committee (03-Nov-2011). Endpoints and clinical trial 
issues in community-acquired bacterial pneumonia. Recommendations to FDA for interim 
endpoints for clinical trials in community-acquired bacterial pneumonia (document dated, 
26-Aug-2011).  Prepared by: Foundation for the National Institutes of Health Biomarkers 
Consortium Project Team. CABP Docket ID:  FDA-2009-D-0136. Available at: 
http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/anti-
infectivedrugsadvisorycommittee/ucm275823.pdf.  
Huang ZG, Zheng XZ, Guan J, Xiao SN, Zhuo C. Direct detection of methicillin-resistant 
Staphylococcus aureus in sputum specimens from patients with hospital-associated pneumonia 
using a novel multilocus PCR assay. Pathogens. 2015; 4(2):199-209. 
Johansson N, Kalin M, Tiveljung-Lindell A, Giske CG, Hedlund J. Etiology of community-
acquired pneumonia: increased microbiological yield with new diagnostic methods. Clin Infect 
Dis. 2010; 50(2):202-9. 
Kais M, Spindler C, Kalin M, Ortqvist A, Giske CG. Quantitative detection of Streptococcus 
pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in lower respiratory tract 
samples by real-time PCR. Diagn Microbiol Infect Dis. 2006; 55(3):169-78. 


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Statistical Analysis Plan – Protocol NAB-BC-3781-3102 
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Oldach D, Barrera C, Mykietiuk A, et al. SOLITAIRE-Oral: results of a global phase 3 trial 
comparing oral solithromycin versus oral moxifloxacin for treatment of community-acquired 
bacterial pneumonia (CABP) in adults. Abstract (oral session) presented at: 25th ECCMID; 2015 
Apr 25-28; Copenhagen, Denmark. LBOS0239c. 
Thurman KA, Warner AK, Cowart KC, Benitez AJ, Winchell JM. Detection of Mycoplasma 
pneumoniae, Chlamydia pneumoniae, and Legionella spp. in clinical specimens using a single-
tube multiplex real-time PCR assay. Diagn Microbiol Infect Dis. 2011; 70(1):1-9. 
Waites KB, Xiao L, Paralanov V, Viscardi RM, Glass JI. Molecular methods for the detection of 
Mycoplasma and ureaplasma infections in humans: a paper from the 2011 William Beaumont 
Hospital Symposium on molecular pathology. J Mol Diagn. 2012; 14(5):437-50. 
 


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APPENDIX A:  SCHEDULE OF ASSESSMENTS AND PROCEDURES 
Assessment or Procedure 
Screening/ 
Baseline a 
Study Drug Administration 
    EOT d 
Visit 
Follow-up Visits 
Day 1b 
Day 2 
Day 3 
Days 4 to 7 c 
TOC e 
LFU f 
Informed consent form completed g 
X 
 
 
 
 
 
 
 
Verify inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
Medical and surgical history 
X 
 
 
 
 
 
 
 
Determine PORT Risk Class 
X 
 
 
 
 
 
 
 
Height and weight 
X 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
Prior and concomitant medications 
X 
X 
X 
X 
Daily 
X 
X 
X 
Vital signs including oxygen saturation and supplemental oxygen i 
X 
X 
X 
X 
Daily 
X 
X 
 
CABP signs and symptoms j 
X 
X 
X 
X 
Daily j 
X 
X 
X 
AEs and SAEs k 
X 
X 
X 
X 
Daily 
X 
X 
X 
12-lead ECG l 
X 
X 
 
 
Day 4 m 
 
 
 
Physical examination n 
X 
 
 
 
Day 4 o 
X 
X 
 
Hematology, clinical chemistry, urinalysis, procalcitonin (Central Lab) p 
X h 
 
 
Day 4 q 
X 
X 
 
Urine and serum pregnancy tests r 
X 
X 
 
 
 
 
 
 
CXR or CT scan 
X 
 
 
 
 
 
 
 
Arterial blood gases (PaO2, PaCO2) and pH [optional; record data if available] 
if clinically indicated 
Calculate CrCl (Cockcroft-Gault formula) 
X 
if clinically indicated 
Urine sample for L. pneumophila and S. pneumoniae antigen tests 
X h 
 
 
 
 
 
 
Blood sample for serologic tests for M. pneumoniae, C. pneumoniae, and L. pneumophila s 
X h 
 
 
 
 
 
X 
Blood sample for culture t 
X h 
if clinically indicated 
Respiratory sample for Gram’s stain and culture u 
X h 
if clinically indicated 
Pleural fluid and/or bronchoalveolar lavage (BAL) sample for Gram’s stain and culture v 
if clinically indicated 
Oropharyngeal and nasopharyngeal samples w 
X h 
 
 
 
 
 
 
Administer SF-12 health status questionnaire  
X h 
 
 
 
 
X 
 
Study drug administration x 
 
X 
X 
X 
Daily 
 
 
 
Blood samples for PK analyses 
 
Day 1y 
 
 
Day 4 y 
 
 
 


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Assessment or Procedure 
Screening/ 
Baseline a 
Study Drug Administration 
    EOT d 
Visit 
Follow-up Visits 
Day 1b 
Day 2 
Day 3 
Days 4 to 7 c 
TOC e 
LFU f 
Investigator’s Assessment of Clinical Response (IACR) z 
 
 
 
 
 
X 
X 
X 
NOTE:  Hospitalization is not a requirement for this study.  However, all subjects, including Outpatients, must be evaluated at the investigational site by study personnel at the following 
time points/visits:  Screening/Baseline; Day 1; Day 4 / 96 ± 24 hours after the first dose of study drug; EOT; TOC; and LFU. 
a: 
Perform Screening/Baseline assessments within 24 hours before the first dose of study drug.  Administration of study drug should begin as soon as possible after the diagnosis of 
CABP.  See Footnote x.  Assessments performed as part of routine standard of care prior to consent (e.g., chest X-ray, blood culture) may be used to satisfy study screening 
requirements; however, no study specific procedures may be performed prior to informed consent. 
b: 
Day 1 is the first day of study drug administration; subsequent study days are consecutive calendar days.  Assessments/ procedures on Day 1 should be performed prior to first dose. 
c: 
INPATIENTS will be assessed daily while hospitalized; thus, data required for ECR Assessment (96 ± 24 hours after the first dose of study drug) will be collected.  
 
OUTPATIENTS must have a visit at the study site that is 96 ± 24 hours after the first dose of study drug to assess CABP signs and symptoms for calculation of ECR.  Study 
personnel will inform subjects as to the timing of this visit during the course of daily telephone contact.  In addition to the assessment of CABP signs/symptoms, subjects will also have 
the following procedures/assessments performed at that study site visit:  ECGs, physical examination, AE monitoring, review of concomitant medications, vital signs, oxygen 
saturation, and blood sampling for PK analysis and safety laboratory evaluations.  Importantly, study personnel will advise OUTPATIENTS not to take their first dose of study drug at 
home that day, rather to bring their blister packs (used and unused) to the study site where they will take their dose while supervised; thus, specific assessments can be performed both 
prior to and after taking the dose (i.e., ECGs and PK).  See Footnotes i, k, l, m, o, p, and y below for details. 
d: 
Perform End of Treatment (EOT) assessments at the study site within 1 day (up to 2 days permitted) after the last dose of study drug or at the time of premature discontinuation of study 
drug or early withdrawal from study.  EOT assessments resulting from premature discontinuation of study drug should be done in place of the regular study visit on Days 1 to 7. 
e: 
Perform Test of Cure (TOC) assessments at the study site 5–10 days after the last dose of study drug.  All subjects will have a TOC Visit irrespective of early clinical failure or receipt 
of an alternative antibiotic.   
f: 
Perform Late Follow Up (LFU) assessments at the study site on Day 30 ± 3 days.  All subjects will have a LFU Visit irrespective of early clinical failure or receipt of an alternative 
antibiotic.   
g: 
Obtain informed consent before initiating any study-specific assessments or procedures. 
h: 
Assessment or procedure may occur at either Screening OR prior to the first dose of study drug on Day 1 once eligibility has been determined. 
i: 
All subjects will have vital signs and O2 saturation evaluated at Screening/Baseline and Day 1.  If screening/baseline and Day 1 occur on the same calendar day, vital signs and O2 
saturation do not need to be repeated. All subjects will also have assessments at EOT and TOC; at LFU, vital signs should be performed if medically indicated.  If EOT and the last day 
of study drug are the same day, vital signs do not need to be repeated, they may be recorded once on that day (i.e., as part of the EOT assessment).  Record the vital signs associated 
with the highest temperature after the first dose of study drug. 
 
INPATIENTS:  Vital signs, O2 saturation, and supplemental O2 usage will be measured daily.  If multiple vital signs are taken on a study day, the highest temperature and the vital signs 
associated with that high temperature will be recorded.   
OUTPATIENTS: In addition to the above time points, vital signs, O2 saturation and, if applicable, supplemental O2 usage will be measured at the study visit scheduled 96 ± 24 hours 
after the first dose of study drug.   
j: 
Study personnel will evaluate signs and symptoms of CABP at Baseline, daily while on study therapy, and at EOT, TOC, and LFU Visits. NOTE:  If Screening and Day 1 are the same 
day, signs and symptoms of CABP do not need to be repeated on Day 1.  If EOT and the last day of study drug are the same day, signs and symptoms of CABP should be done only 
once on that day (i.e., as part of the EOT assessment).  Signs and symptoms are not obtained at TOC or LFU if the subject was previously deemed to have an IACR of Failure. 
 
OUTPATIENTS:  Study personnel will contact subjects daily by telephone to track signs and symptoms of CABP; however, subjects must report to the study site for the 
assessment of CABP signs/symptoms 96 ± 24 hours after the first dose of study drug.  See Footnote c.   


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k: 
Record AEs from the signing of the ICF through TOC and SAEs from signing of the ICF through LFU.  Study personnel will follow unresolved AEs and SAEs present at LFU until 
resolution or stabilization.  In addition, study personnel will monitor AEs for OUTPATIENTS in conjunction with daily telephone contacts for CABP signs/symptoms and at the study 
site visit 96 ± 24 hours after the first dose of study drug.  See Footnote c. 
l: 
At each required time point, ECGs should be recorded in triplicate within a 5-minute interval.  The subject should be stabilized in a supine position for 5 min before recording the 
ECG.  If Screening and Day 1 are on the same day, the Screening ECG can serve as the Day 1 ECG prior to the first dose of study drug; an additional ECG must be performed 1-3 hours 
after administration of first dose.  See Footnote m.   
m:  INPATIENTS:  The Day 4 ECG in triplicate is required prior to the first dose of study drug and again within 1-3 hours after the first dose of study drug. 
 
OUTPATIENTS:  The Day 4 ECG can be performed at the required study site visit 96 ± 24 hours after the first dose.  See Footnote c.  The Day 4 ECG in triplicate is required prior to 
the first dose of study drug and again within 1-3 hours after the first dose of study drug.   
n: 
A complete physical examination is performed at Baseline and directed physical examinations are performed thereafter.  
o: 
INPATIENTS:  On Day 4, a directed physical examination will be performed.. 
OUTPATIENTS:  A directed physical examination will be performed at the study site visit scheduled 96 ± 24 hours after the first dose.  See Footnote c.    
p: 
Blood samples sent to the local laboratory for the purposes of determining study eligibility must be repeated and sent to the central laboratory following enrollment. Collect blood 
and/or urine at LFU only if subject had an abnormal (high/low flag) result at TOC.   
q: 
INPATIENTS:  On Day 4, blood and urine samples will be collected for safety laboratory evaluations. 
OUTPATIENTS: Blood and urine samples will be collected for safety laboratory evaluations at the study site visit scheduled 96 ± 24 hours after the first dose.  See Footnote c.   
r: 
A urine pregnancy test will be performed at the site on all females unless surgically sterile or at least 2 years post-menopausal.  A negative urine pregnancy test is required prior to 
randomization.  Serum must be collected on Day 1 prior to 1st dose and sent to the central lab for confirmatory testing. 
s: 
Blood to be collected and sent to central laboratory for serologic tests for M. pneumoniae, C. pneumoniae and L. pneumophila.   
t: 
Collect blood samples (2 sets via peripheral venipuncture) for microbiologic culture and susceptibility testing at the local/regional lab at Baseline and as clinically indicated during the 
study.  Repeat blood cultures after a positive result until sterilization is documented.  If possible, subjects who are discontinued from study drug due to confirmed MRSA or MSSA 
bacteremia should have blood samples collected for microbiologic culture prior to switching to alternate appropriate therapy.  All organisms isolated from blood cultures which are not 
considered contaminants will be sent to the central laboratory for confirmatory identification and susceptibility testing. 
u: 
All lower respiratory tract and expectorated sputum samples should be sent to the local/regional laboratory for Gram’s stain, culture and susceptibility testing.  A sputum sample will be 
taken at Screening for Gram’s staining, culture and susceptibility testing at the local/regional laboratory.  If a subject is unable to produce an adequate (> 25 polymorphonuclear [PMN] 
cells AND < 10 squamous epithelial cells per LPF) sputum sample at Screening, a specimen should be obtained, if possible, within 24 hours after the first dose of study drug. Gram’s 
stain and culture results from the local/regional laboratory will be recorded in the eCRF. Slides (stained and unstained) will also be sent to the central laboratory for a confirmatory 
reading of the Gram’s stain.  If possible, subjects who are discontinued from study drug due to clinical failure should have repeat cultures collected for microbiologic culture prior to 
switching to alternate appropriate therapy.  All organisms isolated from sputum samples, which are not considered contaminants, will be sent to the central laboratory for confirmatory 
identification and susceptibility testing.  In addition, a portion of all Baseline sputum samples must be frozen until sent to the central laboratory for quantitative PCR.  Subjects with a 
urinary antigen positive for Legionella spp. will also have a portion of their sputum sample sent frozen to the central laboratory for isolation of L. pneumophila. 
v: 
Collect pleural fluid samples and/or BAL only if medically indicated.  Gram’s stain samples, culture, and test the isolated pathogens for susceptibility.  Pathogens isolated from pleural 
fluid and/or BAL samples will be sent to the central laboratory for confirmatory identification and susceptibility testing.  If possible, pleural fluid samples should be incubated in blood 
culture bottles for optimal pathogen recovery. 
w: An oropharyngeal specimen (2 swabs) and a nasopharyngeal specimen (1 swab) will be collected and frozen until sent to the central laboratory.  The oropharyngeal specimen will be 
used for culture of M. pneumoniae and identification by PCR.  The nasopharyngeal specimen will be used for culture and identification by PCR of S. pneumoniae, and potentially, H. 
influenzae.   
x: 
Study personnel will administer the first dose of study drug at the study site, as soon as possible after the diagnosis of CABP and completion of all required pre-dose Day 1 procedures. 
On Day 1, if q12h dosing is not feasible, the 1st and 2nd doses may be administered as close as 8 hours apart, in order to allow 2 doses to be given on Day 1.  In this circumstance, the 
subject’s dosing schedule should be adjusted on Day 2 to a regular q12h morning and evening schedule.  Subsequently, every effort should be made to maintain a q12h dosing schedule.  
When this is not possible, it is acceptable to administer doses within 4 hours of the scheduled dosing time (i.e., a minimum of 8 hours between doses).  For Outpatients, or in the event a 
subject is discharged from the hospital during the study drug administration period, an adequate supply of study drug will be dispensed for self-administration at home.  Subjects will be 
provided instructions regarding the dosing schedule.  Subjects may self-administer oral study drug at home with the following exception:  Study personnel will advise subjects who are 


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Outpatients that they must return to the study site to assess CABP signs and symptoms at 96 ± 24 hours after the first dose of study drug.  See Footnote c.  Administration of study drug 
may occur on the same calendar day as EOT, and if so will be completed before EOT assessments begin. 
y: 
Collect blood samples for PK analysis relative to the first dose of study drug.  Blood will be collected within 1 h pre-dose, 1-2 h post dose, and 3-4 h post dose, and 8-9 h post dose.  
INPATIENTS:  PK sampling should occur on Day 4 but, if not feasible, it can be done relative to the first dose on Day 5; the 8-9 h post dose is required.  OUTPATIENTS:  PK 
sampling will be done during the 96 ± 24 hours post 1st dose visit. The 8-9 h post dose sample is optional; however, it should be obtained if logistically feasible.   
z: 
Investigator to determine IACR - Success, Failure or Indeterminate (i.e., subject lost to follow up) at EOT and TOC and Sustained Success, Relapse or Indeterminate at LFU.  The 
Investigator will not determine Clinical Response at TOC or LFU if the subject was previously deemed to have an IACR of Failure. 


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APPENDIX B:  CLINICAL LABORATORY POTENTIALLY CLINICALLY 
SIGNIFICANT VALUES 
Parameter 
Lower Limit 
% Decrease 
from Baseline 
Upper Limit 
% Increase 
from Baseline 
HEMATOLOGY 
 
 
 
 
Hemoglobin 
<0.8 x LLN 
>20% 
>1.3 x ULN 
>30% 
WBC 
<0.65 x LLN 
>60% 
>1.6 x ULN 
>100% 
Neutrophils 
<0.65 x LLN 
>75% 
>1.6 x ULN 
>100% 
Lymphocytes 
<0.65 x LLN 
>75% 
>1.6 x ULN 
>100% 
Platelets 
<0.65 x LLN 
>50% 
>1.5 x ULN 
>100% 
CHEMISTRY 
 
 
 
 
Sodium 
<0.85 x LLN 
>10% 
>1.1x ULN 
>10% 
Potassium 
<0.8 x LLN 
>20% 
>1.2xULN 
>20% 
Creatinine 
NA 
NA 
>2.0 x ULN 
>100% 
Urea nitrogen 
(BUN) 
NA 
NA 
>3.0 x ULN 
>200% 
Calcium 
<0.7 x LLN 
>30% 
>1.3 x ULN 
>30% 
Magnesium 
<0.5 x LLN 
>50% 
NA 
NA 
Phosphorus 
<0.5 x LLN 
>50% 
>3.0 x ULN 
>200% 
Alkaline 
phosphatase 
<0.5 x LLN 
>80% 
>2.0 x ULN  
>100% 
ALT 
NA 
NA 
>3.0 x ULN 
>200% 
AST 
NA 
NA 
>3.0 x ULN 
>200% 
GGT 
NA 
NA 
>3.0 x ULN 
>200% 
Total bilirubin 
NA 
NA 
>=2.0 x ULN 
>150% 
Albumin 
<0.5 x LLN 
>50% 
>1.5 x ULN 
>50% 
Glucose 
<0.6 x LLN 
>40% 
>3.0 x ULN 
>200% 
 


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APPENDIX C:  DIRECTIONALITY OF WORST LABORATORY PARAMETERS 
Laboratory 
Test 
Parameter 
Worst Value 
Hematology 
Hematocrit 
Lowest value 
 
Red blood cell count 
Lowest value 
 
Mean cell hemoglobin 
Lowest value 
 
Mean cell hemoglobin concentration 
Lowest value 
 
Hemoglobin 
Lowest value 
 
Mean cell volume 
Lowest value 
 
White blood cell count 
Lowest value 
 
Platelets 
Lowest value 
 
Neutrophils 
Lowest value 
 
Lymphocytes 
Lowest value 
 
Monocytes 
Lowest value 
 
Eosinophils 
Highest value 
 
Basophils 
Lowest value 
Chemistry 
Albumin 
Lowest value 
 
Alkaline phosphatase 
Highest value 
 
Alanine aminotransferase (ALT/SGPT) 
Highest value 
 
Aspartate aminotransferase (AST/SGOT) 
Highest value 
 
Blood urea nitrogen (BUN) 
Highest value 
 
Calcium 
Both highest value and lowest value 
 
Chloride 
Both highest value and lowest value 
 
Creatinine 
Highest value 
 
Creatine kinase (CK) 
Highest value 
 
Direct bilirubin 
Highest value 
 
Gamma-glutamyl transferase (GGT) 
Highest value 
 
Glucose 
Both highest value and lowest value 
 
Magnesium 
Both highest value and lowest value 
 
Phosphorus 
Both highest value and lowest value 
 
Potassium 
Both highest value and lowest value 
 
Sodium 
Both highest value and lowest value 
 
Total bilirubin 
Highest value 
 
Total protein 
Lowest value 
 
Uric acid 
Highest value 
Other Tests 
Procalcitonin 
Highest value 


Nabriva Therapeutics AG 
Statistical Analysis Plan – Protocol NAB-BC-3781-3101 
07May2018 
CONFIDENTIAL 
Page 63 of 64 
APPENDIX D:  SAFETY ASSESSMENT WINDOWS 
Vital Signs: 
Analysis Visit 
Study Visit 
Target 
Day 
If scheduled study visit assessment not available: 
Consider 
Unscheduled 
assessment for 
Analysis Visit? 
Study Days acceptable for Analysis 
Visit1 
Baseline 
Screening2  
- 
No 
- 
Day 1 
Day 1 
1 
Yes 
1 
Day 2 
Day 2 
2 
Yes 
2 
Day 3 
Day 3 
3 
Yes 
3 
Day 4 
Day 4 
4 
Yes 
4 
Day 5 
Day 5 
5 
Yes 
5 
Day 6 
Day 6 
6 
Yes 
6 
Day 7 
Day 7 
7 
Yes 
7 
EOT 
EOT 
- 
Yes 
within 2 days after the last dose of 
study drug (i.e., last day of study drug 
through 2 subsequent calendar days) 
TOC 
TOC 
- 
Yes 
5-10 days after last dose of study drug 
Unscheduled3 
- 
- 
Yes 
 
Notes: EOT: End of Treatment; TOC: Test of Cure; N/A: Not applicable. 
1  Except for Baseline, if more than 1 measurement is taken during the visit window (and no scheduled is 
taken) the earliest value will be analyzed.. 
2  Provided the date of collection is on or before the date of first dose 
3 Any unscheduled assessments not meeting the criteria for an analysis visit.    
ECG: 
Analysis Visit and 
Timepoint 
Timepoint 
Target 
Day 
 
Consider Unscheduled 
assessment for Analysis 
Visit? 
Study Days acceptable for 
Analysis Visit 
Baseline 
Screening or 
Day 1 pre-
dose or 
Unscheduled1 
 
Yes 
-4 to 1 (pre-dose) 
Day 1 post dose 
Day 1 post-
dose 
1  
No 
- 
Day 4 pre dose 
Day 42  pre-
dose 
4 
No 
- 
Day 4 post dose4 
Day 42 post- 
dose 
4 
No 
- 
Unscheduled3 
Unscheduled 
- 
- 
- 
Notes: N/A: Not applicable. 
1  Baseline is the mean of the triplicates (or duplicates or single if a triplicate is not obtained) from the last 
assessment prior to the first dose of study drug.  
2The timepoint identified as the Day 4 or 96 +/- 24 hour timepoint regardless of visit. 
3 Any unscheduled assessments (i.e., timepoint=’Unscheduled’) not meeting the criteria for an analysis 
visit.    
4 In addition, Day 4 post-active dose will be summarized. 
 
 


Nabriva Therapeutics AG 
Statistical Analysis Plan – Protocol NAB-BC-3781-3101 
07May2018 
CONFIDENTIAL 
Page 64 of 64 
 
Safety Laboratory: 
Analysis Visit 
Study Visit 
Target 
Day 
If scheduled study visit assessment not available: 
Consider Unscheduled 
central assessment for 
Analysis Visit? 1 
Consider Local lab 
assessments for 
Analysis Visit? 
Study Days 
acceptable for 
Analysis Visit 
Baseline 
Screening2 
- 
Yes 
No 
-4 to 12 
Day 4 
Day 43 
4 
Yes 
No4 
3 to 6 
EOT5 
EOT 
- 
Yes 
No4 
within 2 days after 
the last dose of 
study drug (i.e., 
last day of study 
drug through 2 
subsequent 
calendar days) 
TOC 
TOC 
- 
Yes 
No4 
5-10 days after 
last dose of study 
drug 
LFU 
LFU 
30 
Yes 
No4 
27 to 33 
Unscheduled6 
- 
- 
Yes 
Yes4 
- 
Notes: EOT: End of Treatment; TOC: Test of Cure; LFU: Late Follow-up; N/A: Not applicable. 
1 Except for Baseline, if more than 1 central measurement is taken during the visit window (and no 
scheduled is taken) the earliest value will be analyzed.  
2 Provided the date and time of collection is on or before the date and time of first dose  
3 The visit identified as the 96 +/- 24 hour visit (i.e., study visit Day 4, Day 5, or Day 6). 
4 Local labs assessment are to be included in the identification of worst post-baseline values (i.e. 
minimum, maximum, highest, lowest, any post-baseline, and PCS). See section 8.7.2. 
5 If an EOT assessment is done within the day 4 visit window, and no assessment was done at the study 
day 4 visit, the assessment will be reported at both the Day 4 and EOT analysis visits.  
6 Any unscheduled assessments not meeting the criteria for an analysis visit.