Clinical trial NCT02903836
Conditions: Community-Acquired Bacterial Pneumonia (CABP)
Sponsor: Wockhardt
Start date: 2016-11-18; Completion date: 2017-07-08
Enrollment: 231 participants; Allocation: RANDOMIZED; Intervention model: FACTORIAL

Brief summary:
Study to Determine the Safety, Tolerability, Pharmacokinetics and Efficacy of Oral Nafithromycin Versus Oral Moxifloxacin in the Treatment of Community-Acquired Bacterial Pneumonia (CABP) in Adults

Detailed description:

Arms: arm 1: PO q24h for 3 days; subjects will receive matching placebo , to maintain the blind arm 2: PO q24h for 5 days; subjects will receive matching placebo, to maintain the blind arm 3: PO q24h for 7 days;subjects will also receive two nafithromycin placebo tablets PO q24h on Days 1 through Day 7 to maintain the blind
Interventions: intervention 1: Nafithromycin 800 mg 3 days intervention 2: Nafithromycin 800 mg 5 days intervention 3: Moxifloxacin 400 mg
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
Prot_SAP_000.pdf: 
Protocol W-4873-201 
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1.0 
TITLE PAGE 
Protocol Title 
A Phase II, Randomized, Double-Blind, Multicenter, Comparative 
Study to Determine the Safety, Tolerability, Pharmacokinetics and 
Efficacy of Oral Nafithromycin Versus Oral Moxifloxacin in the 
Treatment of Community-Acquired Bacterial Pneumonia (CABP) 
in Adults 
Short Title 
Phase II study of oral nafithromycin in CABP 
Protocol Number 
W-4873-201 
Study Drug 
Nafithromycin 
Original Protocol Date 
10 May 2016 
Sponsor 
Wockhardt Bio AG  
Grafenauweg 6  
Zug-6300, Switzerland  
Phone: +41-417275220 
Fax: +41-417275221 
CRO 
 
 
 
   
 
EU Legal Representative 
 
  
  
 
Sponsor Medical Monitor(s) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     
 
IND number 
 
 
 
Confidentiality Statement 
This document contains confidential information proprietary to Wockhardt Bio AG except, as otherwise 
agreed to in writing, by accepting or reviewing this document, you agree to hold this information in 
confidence and not copy or disclose it to others (except where required by applicable law) or use it for 
unauthorized purposes. In the event of any actual or suspected breach of this obligation, Wockhardt Bio 
AG must be promptly notified. 




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3.0 
 SYNOPSIS AND SCHEDULE OF ASSESSMENTS 
Study Number 
W-4873-201 
Title of Study 
A Phase II, Randomized, Double-Blind, Multicenter, Comparative Study to Determine the 
Safety, Tolerability, pharmacokinetics and Efficacy of Oral Nafithromycin Versus Oral 
Moxifloxacin in the Treatment of Community-Acquired Bacterial Pneumonia (CABP) in 
Adults 
Study Centers 
(Planned) 
Approximately 40 to 50 study centers in the US, Europe and South Africa 
Development Phase 
II 
Background and 
Rationale 
Lower respiratory tract infection, including CABP, remains the second largest cause of death 
and years of life lost worldwide; its associated age-standardized death rate was 41.7 per 
100,000 population in 2013. The global incidence of pneumonia is estimated to be between 1.5 
and 14.0 cases per 1000 person-years, varying by region, season, and patient characteristics. 
Short-term mortality (in-hospital and 30-day mortality) for hospitalized patients with CABP 
ranges from 4.0% to 18.0%. Costs related to CABP are high, and few approaches (such as 
reducing the length-of-stay, adequate use of antibiotics, and the introduction of vaccines) have 
reduced these costs to date. Streptococcus pneumoniae remains the most common pathogen of 
CABP worldwide, independent of age. Other frequent causes of CABP include Haemophilus 
influenzae, Moraxella catarrhalis, Staphylococcus aureus, and atypical bacteria (including 
Mycoplasma, Chlamydophila and Legionella spp.). 
A major therapeutic challenge impacting the treatment of CABP is the widespread resistance of 
S. pneumoniae to ß-lactam (especially penicillins and cephalosporins) and macrolide 
antibiotics. For example, the prevalence of S. pneumoniae macrolide resistance on a global 
scale is estimated to be 25% to 40%, varying by region. The prevalence of multidrug-resistant 
(MDR) S. pneumoniae is also worrisome. For example, in the US, a recent analysis of 1498 
clinical pneumococci strains collected between 2012 and 2013 found that 21.0% were MDR. 
Community-acquired MDR S. pneumoniae poses treatment challenges for outpatient 
CABP―most notably the lack of effective oral antibacterial options―because of resistance to 
the most commonly-used oral penicillins, cephalosporins, and/or macrolides. Failure of therapy 
due to resistance will continue to contribute to the morbidity and mortality of CABP, and 
treatment failures of mild disease will result in increased hospitalizations and contribute to 
increased healthcare costs. 
Nafithromycin (previously known as WCK 4873) is an intravenous (IV) and oral antibacterial 
agent of the ketolide class that is structurally related to the macrolide class. Diverse in vitro, in 
vivo, preclinical pharmacokinetic (PK) and safety studies have provided strong scientific 
evidence of the therapeutic potential of nafithromycin for difficult-to-treat respiratory tract 
infections caused by multidrug-resistant (MDR) pathogens, including CABP. Preclinical 
studies have shown that nafithromycin has potent activity against macrolide- and ketolide-
resistant strains of S. pneumoniae and Group A streptococci. Additionally, nafithromycin is 
active against other important CABP pathogens such as Haemophilus influenzae, Moraxella 
catarrhalis, and atypical pathogens.  
The ketolide class of antibiotics provides a convenient orally-administered and effective 
therapeutic option for pneumococci, streptococci, and multiple Gram-negative respiratory 
pathogens. Innovative structural modifications among newer ketolides provide them with 
several distinguishing features such as high-affinity binding to domain V and domain II of the 
23S ribosomal ribonucleic acid (rRNA) target, in contrast to macrolides that bind only to 
domain V. Such dual-target binding by ketolides overcomes multiple macrolide resistance 
mechanisms such as (1) erm gene-encoded methylases (macrolide, lincosamide and 
streptogramin B [MLSB]-type resistance, involving methylation of the 23 rRNA target), (2) 
point mutations within rRNA domain V and (3) diverse mutations in ribosomal proteins L-4 
and L-22. Additionally, newer ketolides such as nafithromycin are not susceptible to mef efflux 
pump-mediated resistance that impacts the activity of macrolides against S. pneumoniae and S. 
pyogenes. Thus, these newer ketolides possess several features that not only confer activity 


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against various resistotypes, irrespective of ß-lactam and macrolide susceptibility, but also 
minimize the risk of resistance emergence or induction of cross-resistance to other agents. A 
new ketolide antibiotic with improved coverage of MDR pathogens―especially respiratory 
pathogens that are resistant to the older macrolides ―would help address this unmet need. 
In all, nafithromycin is expected to have the following advantages over older, available 
macrolides based on data from in vivo, in vitro and preclinical studies conducted to date: 
1.
Mechanism-based activity potential against macrolide- and ketolide-resistant
pneumococci and Group A streptococci
2.
Excellent target-organ-tissue concentration leading to:
a.
Enabling potent activity vs. MDR pathogens in vivo
b.
Once-a-day dosing convenience
c.
Potential for shorter duration of therapy
3.
Minimal CYP inhibition leading to ease of co-administration of other drugs
4.
Favorable hepatic safety potential owing to favorable drug disposition resulting from
lower accumulation in liver
5.
Comprehensive coverage of all key CABP pathogens, including atypical pathogens
Objectives 
Primary Objectives: 

To assess the overall safety and tolerability of oral nafithromycin

To assess the clinical response in the Intent-to-Treat (ITT) population at Day 4
Secondary Objectives: 

To assess the clinical response in the Microbiological Intent-to-Treat (micro-ITT)
population at Day 4

To assess the clinical outcome in the ITT and Clinically Evaluable (CE) populations
at End-of-Treatment (EOT) and Test-of-Cure (TOC) (Day 15 ± 3 days)

To assess early improvement in clinical symptoms and normalization of vital signs in
the ITT population at Day 4

To assess clinical outcome in micro-ITT population at TOC

To assess by-subject and by-pathogen microbiological response in micro-ITT and
microbiologically evaluable (ME) populations at TOC

To assess readmission to the hospital (or admission to the hospital if not previously
hospitalized) for any reason prior to Follow-Up (FU)
Study Endpoints 
Primary efficacy endpoint: Clinical Response at Day 4 in the ITT population 

Clinical Response: Alive and programmatically-determined improvement of at least
1 level (e.g., severe to moderate, moderate to mild, mild to absent) in at least 2 CABP 
symptoms (dyspnea, cough, production of purulent sputum, and pleuritic chest pain)
compared to Screening, without worsening in any other symptom. Severity of
symptoms is based on a 4-point scale (absent, mild, moderate, or severe) (Appendix
III).

Clinical Non-Response: No programmatically-determined improvement of at least 1
level in at least 2 CABP symptoms compared to Screening; or worsening in any of
the 4 CABP symptoms compared to Screening; or requires alternative rescue
antibacterial therapy for CABP prior to Day 4; or death from any cause prior to Day
4.

Indeterminate: Study data are missing for evaluation of efficacy at Day 4 for any
reason, including lost to follow-up.
Secondary efficacy endpoints: 

Clinical Response at Day 4, as described above, in the micro-ITT population

Clinical Outcome at EOT (ITT and CE populations) and TOC (ITT, CE, and
micro-ITT populations):
o
Clinical Cure: Alive and CABP is sufficiently resolved such that further
antibacterial therapy is not needed. These subjects may have some residual


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findings related to infection (i.e., cough) requiring non-antibiotic ancillary 
treatment (e.g., expectorant). 
o
Clinical Failure: Requires alternative rescue antibacterial treatment for CABP
prior to the assessment (EOT or TOC) related to progression or worsening of
CABP symptoms, development of infectious complications of CABP (e.g.,
empyema, lung abscess), or development of a treatment-emergent adverse event
(TEAE) that required discontinuation of study therapy; or death from any cause
prior to the assessment.
o
Indeterminate: Study data are missing for evaluation of efficacy at the
assessment visit for any reason, including lost to follow-up.

Improvement in CABP Symptoms and Normalization in Vital Signs at Study  Day 4
(ITT population): Programmatically-determined improvement of at least 1 level in at
least 2 CABP symptoms (dyspnea, cough, production of purulent sputum, and
pleuritic chest pain) compared to Screening, without worsening in any other
symptom (Appendix III), plus normalization of vital signs (temperature, blood
pressure, heart rate, respiratory rate, and oxygen saturation within predefined normal
ranges [Section 13.2.3]), ability to maintain oral intake and normal mental status

By-subject and by-pathogen Microbiological Response at TOC (micro-ITT and ME 
populations):
o
Favorable Microbiological Response: Meet criteria for eradication or presumed
eradication (defined in Section 13.3)
o
Unfavorable Microbiological Response: Meets criteria for persistence or
presumed persistence (defined in Section 13.3)
o
Indeterminate: Post-baseline respiratory specimen culture or blood culture was
not available and the subject’s clinical response was assessed as indeterminate

Hospitalization Prior to FU (ITT population):  Hospital readmission for any reason
between Day 1 and FU Visit, if previously hospitalized and discharged, or initial
hospital admission for any reason between Day 2 and FU Visit, if not previously
hospitalized on Day 1 (Section 13.2.4)
Safety Endpoints: 
Safety evaluation is based on TEAEs, clinical laboratory evaluation, vital signs, physical 
examination findings and electrocardiograms (ECGs) collected during the study. 
Study Design 
This is a Phase II prospective, multicenter, multinational, randomized (1:1:1), double-blind, 
comparative efficacy, safety, tolerability, and PK study of oral nafithromycin versus oral 
moxifloxacin for treatment of male and female adults with CABP. Study drug is defined as oral 
nafithromycin or oral moxifloxacin. 
Subjects providing informed consent and meeting all study eligibility criteria will be enrolled 
in the study and randomized into the study in a 1:1:1 ratio to either of the following 3 treatment 
arms: 

Arm A: Nafithromycin 800 mg (two 400 mg tablets) PO q24h for 3 days;
subjects will receive matching placebo (two nafithromycin placebo tablets PO
q24h) on Days 4 through Day 7, and one moxifloxacin placebo capsule PO q24h 
on Days 1 through 7, to maintain the blind

Arm B: Nafithromycin 800 mg (two 400 mg tablets) PO q24h for 5 days;
subjects will receive matching placebo (two nafithromycin placebo tablets PO
q24h) on Day 6 and Day 7, and one moxifloxacin placebo capsule PO q24h on
Days 1 through 7, to maintain the blind

Arm C: Moxifloxacin 400 mg (one 400 mg capsule) PO q24h for 7 days;
subjects will also receive two nafithromycin placebo tablets PO q24h on Days 1
through Day 7 to maintain the blind
Baseline assessments for study eligibility will occur during the Screening visit, within 24 h 
prior to administration of the first dose of the study drug. Block randomization using an 


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interactive voice/web response system (IXRS), stratified by region (US vs. ex-US) and 
Pneumonia Outcomes Research Team (PORT) Risk Class (II vs. III/IV), will be used to assign 
subjects (1:1:1) to Arm A, Arm B, or Arm C. Enrolment of PORT Risk Class II will be capped 
at 50% and enrolment of subjects with allowed prior systemic antibiotic use will be capped 
initially at 25% (subject to change during study conduct). Study Day 1 is defined as the day 
that the study drug is first administered, and subsequent study days are defined by the number 
of consecutive calendar days thereafter. 
Subjects may be treated in the study as inpatients or outpatients based on their clinical 
condition, at the discretion of the Investigator; however, only oral study drug will be 
administered (i.e., parental moxifloxacin will not be administered). Subjects will be assessed 
daily by the Investigator between Day 1 and Day 5, whether being treated for CABP in the 
inpatient or outpatient setting. Investigators will assess for clinical outcome at Day 7 (EOT), 
and TOC (Day 15 ± 3 days). Vital signs, physical exam, assessment of CABP symptom 
severity, and other study procedures are detailed in Table 3-1. A FU visit will be conducted on 
Day 31 ±3 days from the start of treatment. The FU visit may be conducted via telephone 
contact or by another interactive technology for subjects who were considered to be clinical 
successes and had no AEs or clinically significant laboratory or ECG abnormalities noted at or 
after the TOC visit; otherwise, the visit must be conducted in person. 
Rationale for moxifloxacin as a comparator: 
Moxifloxacin is a member of the fluoroquinolone class of antibiotics. It is active against most 
CABP pathogens including macrolide- and penicillin-resistant S. pneumoniae, Gram-negative 
bacteria, and atypical pathogens. Empiric treatment of CABP with moxifloxacin, especially in 
subjects admitted to the hospital, is consistent with current US (Infectious Diseases Society of 
America [IDSA]/American Thoracic Society [ATS]) and European (The Task Force of the 
European Respiratory Society in collaboration with the European Society for Clinical 
Microbiology and Infectious Diseases [ESCMID]) therapeutic guidelines. The recommended 
dose (IDSA/ATS) is 400 mg once daily for 7-14 days, and in this study, a 7-day regimen will 
be used. 
Rationale for 800 mg of nafithromycin once daily: 
Preclinical PK conducted in rodent and non-rodent species and Phase I clinical studies have 
shown optimal PK profile commensurate to the once-a-day dosing potential of nafithromycin. 
Administration of multiple-ascending oral doses (600 mg, 800 mg, and 1000 mg) of 
nafithromycin to humans was well tolerated. No serious adverse events have been reported for 
any dose in clinical studies conducted to date. On average, steady state of plasma 
concentrations was achieved at Day 3-4 of multiple dosing. 
Rationale of therapeutic treatment duration with nafithromycin of 3 days and 5 days: 
Nafithromycin attained a geometric mean T½ of approximately 11 h in steady state at 800 
mg/day in healthy human subjects (steady state was achieved on average within 3-4 days over 
the 600 to 1000 mg/d dose range). In addition, significant accumulation of nafithromycin in 
polymorphonuclear cells (PMNs) was observed. 
Furthermore, superior tissue penetration observed in rodents ― particularly in the target organ 
(lung) ― is expected to drive superior pharmacodynamic (PD) activity, enabling a shorter 
duration of therapy of 3 to 5 days. 
A multiple dose study was conducted to compare plasma, epithelial lining fluid (ELF) and 
alveolar macrophage (AM) concentrations of nafithromycin (800 mg administered once daily 
for 3 days) in healthy adult subjects. Each subject underwent one standardized bronchoscopy 
with bronchoalveolar lavage (BAL) at 3, 6, 9, 12, 24 or 48 h after the third oral dose of 
nafithromycin. Concentrations of nafithromycin were significantly higher in ELF and AM than 
simultaneous plasma concentrations throughout the 48 h period after 3 days of once-daily 
dosing. The ratios of ELF to plasma concentrations and of AM to plasma concentrations based 
the mean AUC0-24 values were 13.8 and 527, respectively. 
Pharmacokinetic (PK) sampling: 
Blood samples for PK analysis will be collected from all subjects on Day 3 and Day 4 at sites 


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where PK sampling is possible. Time points for PK sample collection will be: 

Pre-dose: pre-dose PK sample will be collected within 10 minutes before dosing.

Post-dose at 2-4 h (Day 3) and 24-28 h (Day 4). Subjects who have been hospitalized are
also required to have a post-dose PK sample at 6-10 h (Day 3).
Inclusion Criteria 
Subjects are required to meet all of the following inclusion criteria: 
1.
Male or female ≥ 18 years of age
2.
Willing to participate in the study and provide written informed consent before any
protocol specific assessment is performed
3.
Meet the following clinical criteria for CABP:
a.
Have at least TWO of the following symptoms (new or worsening):

Dyspnea (shortness of breath)

Cough

Production of purulent sputum

Pleuritic chest pain
b.
Have at least TWO of the following vital sign abnormalities:

Fever or hypothermia documented by the Investigator (oral, rectal, or tympanic
temperature > 38.0°C [100.4°F] or < 36.0°C [95.5°F])

Hypotension, defined as systolic blood pressure < 90 mm Hg

Tachycardia, defined as heart rate > 90 beats per minute

Tachypnea, defined as respiratory rate > 20 breaths per minute
c.
Have at least ONE of the following laboratory abnormalities:

Hypoxemia defined as arterial oxygen saturation < 90% by pulse oximetry or
partial pressure of arterial oxygen (PaO2) < 60 mm Hg by arterial blood gas
(ABG)

Auscultatory findings on pulmonary examination consistent with bacterial
pneumonia or pulmonary consolidation (e.g., rales, dullness on percussion,
bronchial breath sounds, or egophony)

Elevated total white blood cell (WBC) count (> 10,000 cells/mm3) or leucopenia 
(WBC < 4,000 cells/mm3)

Elevated immature neutrophils (> 15% band forms), regardless of total
peripheral WBC count
d.
Radiographic evidence of CABP:

Radiographically-confirmed pneumonia, i.e., new or progressive pulmonary
infiltrate(s) on chest X-ray (CXR) or chest computed tomography (CT) scan
consistent with acute bacterial pneumonia within 48 h prior to randomization
e.
PORT score of 51 to 105 (PORT Risk Class of II, III or IV)
4.
All females must have a negative urine or serum pregnancy test (β-human chorionic
gonadotropin [β-HCG]) at Screening AND agree to the use of one of the following
acceptable methods of contraception from Screening through TOC: surgical sterilization
(defined as bilateral oophorectomy or bilateral salpingectomy, but excluding bilateral
tubal occlusion), post-menopausal  (defined by amenorrhea for at least 12 months
following cessation of all exogenous hormonal treatments), barrier contraception (e.g.,
condom, intrauterine device), levonorgestrel intrauterine system (e.g., Mirena®), regular
medroxyprogesterone injections (e.g., Depo-Provera®), sexual intercourse with only
vasectomised partners, or abstinence. Note that oral contraceptives should not be used as
the sole method of birth control because the effect of nafithromycin on the efficacy of oral
contraceptives has not yet been established; subjects who take oral contraceptives must
also use one of the acceptable forms of birth control (listed above) from Screening through 
TOC. Males must agree to use an acceptable barrier method of birth control (i.e., condom)
with female partner(s) and must not donate sperm from Screening through TOC.
5.
Ability to ingest oral study drug (e.g., able to swallow large capsules intact, and no
significant nausea, vomiting, diarrhea, or any other condition that might impair ingestion
or absorption of oral study drug)
Exclusion Criteria 
1.
Subjects with any of the following confirmed or suspected types of pneumonia:

Aspiration pneumonia


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
Hospital-acquired bacterial pneumonia (HABP), defined as pneumonia with onset of
clinical signs and symptoms after at least 48 h hospitalization in an acute inpatient
health care facility.

Healthcare-associated bacterial pneumonia (HCAP), defined as pneumonia acquired
in a long-term care or subacute healthcare facility (e.g., nursing home) or pneumonia
with onset after recent hospital discharge (within 90 days of current admission and
previously hospitalized for ≥ 48 h)

Ventilator-associated bacterial pneumonia (VABP), defined as pneumonia with onset
of clinical signs and symptoms after at least 48 h endotracheal intubation

Pneumonia that may be caused by pathogen(s) resistant to either study drug
(nafithromycin or moxifloxacin), including viral, mycobacterial, or fungal
pneumonia (e.g., Pneumocystis jiroveci pneumonia, active pulmonary tuberculosis)

Post-obstructive pneumonia

Pneumonia associated with cystic fibrosis
2.
Suspected or confirmed pleural empyema (a parapneumonic pleural effusion is not an
exclusion criterion) or lung abscess
3.
Suspected or confirmed non-infectious causes of pulmonary infiltrates (e.g., pulmonary
embolism, hypersensitivity pneumonia, congestive heart failure)
4.
Receipt of 1 or more dose(s) of a potentially effective systemic antibacterial treatment for
treatment of the current CABP within 72 h prior to randomization with the exception of:

Receipt of a single dose of a short-acting antibacterial agent within 72 h of
randomization (Appendix I) OR

Failure (worsening of symptoms) of at least 48 h of treatment for the current episode
of CABP with an antibacterial agent other than a ketolide or fluoroquinolone
5.
Subjects requiring concomitant adjunctive or additional potentially-effective systemic
antibacterial treatment for management of CABP
6.
Evidence of significant immunologic disease determined by any of the following:

Current or anticipated neutropenia defined as < 500 neutrophils/mm3

Known infection with human immunodeficiency virus (HIV) (prior to Screening) and 
a cluster of differentiation 4 (CD4) count that is unknown or documented to be < 200
cells/mm3 within the last year, or an Acquired Immune Deficiency Syndrome
(AIDS)-defining illness; note that neither HIV nor CD4 testing is required at
Screening

History of heart, lung, or kidney transplant

The receipt of cancer chemotherapy, radiotherapy, or potent, non-corticosteroid
immunosuppressant drugs (e.g., cyclosporine, azathioprine, tacrolimus, immune-
modulating monoclonal antibody therapy) within the past 3 months, or the receipt of
corticosteroids equivalent to or greater than 40 mg of prednisone per day for more
than 14 days in the 30 days prior to randomization
7.
Known or suspected primary or metastatic neoplastic lung disease, bronchiectasis,
bronchial obstruction, chronic neurological disorder preventing clearance of pulmonary
secretions, or severe chronic obstructive pulmonary disease (COPD) (severe COPD is
defined as known [prior to Screening] forced expiratory volume in one second/forced vital
capacity ratio [FEV1/FVC] < 0.70 and FEV1 < 50% normal); note that pulmonary function
tests are not required at Screening
8.
Compromised hepatic or renal function, including but not limited to: clinical evidence of
end-stage liver disease (e.g., ascites, hepatic encephalopathy), screening serum total
bilirubin > 2 times the upper limit of normal (ULN) (unless associated with an elevated
indirect bilirubin typical of Gilbert syndrome), aspartate aminotransferase (AST) or
alanine aminotransferase (ALT) > 3 times ULN, serum creatinine > 2.0 mg/dl and/or
blood urea nitrogen (BUN) > 30 mg/dl. Other clinically-significant abnormal laboratory
findings should be discussed with the Medical Monitor prior to the subject's entry.
9.
History of Clostridium difficile-associated disease within 6 months prior to enrolment
10. History of hypersensitivity, known contraindication (e.g. lactose intolerance, lactase
deficiency and glucose-galactose malabsorption etc. ) or allergic reaction (e.g.,
anaphylaxis, urticaria, other significant reaction) to any ketolide,any fluoroquinolone


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antibiotic medicinal products or any of their excipients. 
11. Current second- or third-degree atrioventricular block or sick sinus syndrome,
uncontrolled atrial fibrillation, severe or unstable angina, congestive heart failure,
myocardial infarction within 3 months of the Screening visit, clinically significant ECG
abnormalities including QT interval corrected for heart rate using Fridericia’s formula
(QTcF) > 450 msec (males) or > 470 msec (females), or requirement for medications
known to cause QT prolongation
12. Prior (within 14 days prior to randomization) or concomitant use of cytochrome P450
liver enzyme inducers (e.g., phenobarbital, carbamazepine, griseofulvin, sulfonylureas,
phenytoin, or rifampin)
13. History of tendon rupture
14. Current peripheral neuropathy or myasthenia gravis
15. Known or suspected seizure disorder or other central nervous system (CNS) disorders that
may predispose the subject to seizures or lower the seizure threshold
16. Nursing mother or pregnant female
17. Subjects who received any experimental drug within 30 days prior to enrolment
18. Require admission to in intensive care unit for any reason, life expectancy of less than 2
months, or any concomitant condition that, in the opinion of the Investigator, is likely to
interfere with evaluation of the response of the infection under study, determination of
AEs, or completion of the expected course of treatment
Study Visits 
(Calendar Days) 

Screening Visit (within 24 h prior to randomization)

Day 1: Randomization and 1st dose of study drug

Day 2

Day 3: Includes PK sampling

Day 4: Includes PK sampling

Day 5

Day 6

Day 7 (EOT is on Day 7 or within 2 days following Day 7)

TOC: Day 15 ±3 days (inclusive)

FU: Day 31 ±3 days (may be conducted via telephone contact or by another
interactive technology for subjects who were considered to be clinical successes and
had no AEs or clinically significant laboratory or ECG abnormalities noted at or after
the TOC visit; otherwise, the visit must be conducted in person)
Investigational 
Medicinal Product 
(IMP): Test Product 
and Matching 
Placebo 
Nafithromycin: 

Strength and pharmaceutical dosage form: 400 mg tablet

Dose: 800 mg once daily (2 tablets of 400 mg each) for 3 days (Arm A) or for 5 days
(Arm B)

Route of administration: Oral
Placebo to match Nafithromycin: 

Pharmaceutical dosage form: Tablet

Dose: 2 tablets daily for 4 days following active nafithromycin (Arm A), for 2 days
following active nafithromycin (Arm B), or for 7 days (Arm C)

Route of administration: Oral
IMP: Reference 
Therapy and 
Matching Placebo 
Moxifloxacin: 

Strength and pharmaceutical dosage form: 400 mg capsule (i.e. over-encapsulated
tablet)

Dose: 400 mg once daily for 7 days (Arm C)

Route of administration: Oral (parenteral moxifloxacin is not allowed)
Placebo to match Moxifloxacin: 

Pharmaceutical dosage form: Capsule

Dose: 1 capsule daily for 7 days (Arm A and Arm B)

Route of administration: Oral
Study Duration 
Each subject will remain in the study for approximately one month. This will include a 
Screening visit (within 24 h of randomization), a 7-day oral treatment period, and post 


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treatment assessments at TOC (Day 12 to Day 18) and FU (Day 28 to Day 34). 
Sample Size 
Approximately 225 adult subjects (75 subjects per arm) diagnosed with CABP. Subjects with a 
PORT Risk Class of II (PORT score 51-70; see Appendix II) will be capped at 50% of the 
subjects randomized. Prior antibiotic use will be restricted to a single dose of a short-acting 
antibacterial drug within 72 h of enrolment (Appendix I), and this prior antibiotic use will be 
capped at 25%. 
Statistical Methods 
Efficacy  
Efficacy will be analyzed in the following populations according to the random treatment 
assignment: 

ITT population: All subjects who were randomized

micro-ITT population: All ITT subjects who have at least one baseline Gram-positive 
or atypical bacterial pathogen known to cause CABP, including bacterial pathogens
identified by respiratory specimen culture, blood culture, urinary antigen test (S.
pneumoniae, L. pneumophila), or atypical bacterial serologic response (M.
pneumoniae, C. pneumoniae, L. pneumophila). Subjects with sole baseline Gram-
negative bacterial infection will be excluded from this population.

Clinically evaluable (CE) population: ITT population that follows important
components of the trial (criteria provided in Section 16.1.4)

ME population: Micro-ITT population that follows important components of the trial
(criteria provided in Section 16.1.5)
This study is not powered for inferential statistical analyses. All data will be summarized 
separately by study drug (nafithromycin for 3 days, nafithromycin for 5 days, and 
moxifloxacin). Descriptive statistics (mean, standard deviation, median, minimum, and 
maximum) will be presented for continuous variables.  Frequency distributions (counts and 
percentages) will be presented for categorical variables. All summaries will be presented within 
each treatment group. The 95% confidence intervals, obtained using the Clopper-Pearson 
method, for the proportions of subjects with a favorable response in each treatment group will 
be presented.  
Safety: Safety data will be summarized for the Safety population, which includes all 
randomized subjects who received any amount of study drug, analyzed according to the 
treatment received.  The subject incidence of serious adverse events (SAEs), including deaths 
and discontinuations due to adverse events (AEs) will be presented by system organ class and 
preferred term according to the Medical Dictionary of Regulatory Activities (MedDRA®), 
relationship to study drug, and severity.   
PK: The PK data acquisition and analysis strategy entails the use of a sparse PK sampling 
schedule. Efforts will be made to obtain PK samples from all subjects at sites where PK 
sampling is possible. Plasma concentrations of nafithromycin will be listed for each subject in 
the PK Population. Nafithromycin plasma concentration data, along with other information 
including demographic data, will be combined with appropriate data from other clinical studies 
and analyzed using a population PK approach and reported separately.  


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Table 3–1. 
Schedule of Assessments and Procedures. 
Visits 
Screening 
Visit (Day -1)
a
Day 1b 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
EOT (Day 
7 (+2 
days)c
TOC 
(Day 15 
±3 days d 
FU Day 
31 ±3 
days e 
Informed Consentf 
 
Medical history & demography 
 
Physical exam, incl. CABP symptom 
severityg  
 
 
 
 
 
 
 
 
Vital signs, incl. oximetryh 
 
 
 
 
 
 
 
 
12 Lead ECGi 
 
 
 
 
 
i 
i 
CXR or chest CT scanj 
 
PORT score calculationk 
 
Inclusion/exclusion criteria 
 
 
Randomization 
 
Laboratory Assessments: 
Hematology, coagulation, serum 
chemistryl 
 
 
 
 
  
Atypical pathogen serologym 
 
 
Urine testsn 
 
Urinary antigen testingo 
 
Pregnancy testp 
 
 
Respiratory specimen Gram 
stain/cultureq 
 
As clinically indicated 
Blood culturer 
 
Repeat the blood cultures as necessary until negative blood cultures are obtained 
Blood for PK samplings 
 
 
Study drug administration and 
accountabilityt 
 
 
 
 
 
 
 
Adverse Eventsu 
 
 
 
 
 
 
 
 
 
 
Prior and concomitant medicationsv 
 
 
 
 
 
 
 
 
 
 
Clinical outcome assessment 
 
 
Abbreviations: CABP = Community-acquired bacterial pneumonia; CT = Computed tomography; CXR = chest x-ray; ECG = electrocardiogram; EOT = End-of-Therapy; FU = Follow-up; 
PK = Pharmacokinetic; PORT = Pneumonia Outcomes Research Team; TOC = Test-of-Cure. 
a Following the signing of the informed consent form, all Screening evaluations should be completed within 24 h prior to randomization.  
b Day 1 is the first day of study drug administration. Subsequent study days are consecutive calendar days. If feasible, Screening and randomization procedures 
(Screening Visit and Day 1) can be performed on same day. Standard of care data from within 24 h (laboratory) and 48 h prior (radiology) to randomization can be used 
as Screening Visit procedures.   
cEOT is to be conducted on the day of, or within 2 days following, Day 7. EOT should also be conducted for any premature withdrawal from study or study drug. 


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d TOC is to be conducted on Day 15 ±3 days. 
e FU is to be conducted on Day 31 ±3 days. The FU assessment may be conducted via telephone contact or by another interactive technology for subjects who were 
considered to be Clinical Cures (Section 13.2.2) and had no AEs or clinically significant laboratory or ECG abnormalities noted at or after the TOC visit; otherwise, the 
visit must be conducted in person. 
f Written and signed informed consent must be obtained before any protocol assessment is performed. 
g Complete physical exam―consisting of general appearance, skin, eyes, ears, nose, throat, lungs, heart, abdomen, back, extremities, lymph nodes, vascular, and 
neurological exams―will be conducted at Screening and daily between Day 1 and Day 5 (whether inpatient or outpatient), EOT, and TOC. As part of the complete 
physical exam, the Investigator should assess the severity of the subject’s CABP symptoms of dyspnea, cough, production of purulent sputum, and pleuritic chest pain, based 
upon the CABP Symptom Severity Guidance for Investigator Assessment in Appendix III. 
h Vital signs―including body temperature (oral, rectal, or tympanic), blood pressure, heart rate, respiratory rate, and pulse oximetry―will be collected at Screening and daily 
between Day 1 and Day 5 (whether inpatient or outpatient), EOT, and TOC. Height, weight, and creatinine clearance (CrCl) will also be collected at the Screening Visit. 
i A 12-lead ECG will be performed at Screening, Day 1, Day 3, Day 5, and EOT. A 12-lead ECG will be performed at TOC or FU if prior ECG(s) showed any clinically-
significant abnormality (Sections 11.9 and 11.10).   
j Subjects must have a confirmatory CXR or chest CT scan consistent with acute bacterial pneumonia within 48 h prior to randomization. 
k Subjects with a PORT score of 51 to 105 (PORT Risk Class of II, III or IV) are eligible for enrolment (Appendix II). 
l At Screening, local laboratory evaluations required for assessing subject eligibility include serum transaminase (ALT and AST) and total bilirubin levels, serum 
creatinine and BUN (or urea), peripheral WBC count, absolute neutrophil count, coagulation, and immature neutrophil percentage. Blood will be collected for central 
laboratory testing at the Screening, Day 5, EOT and TOC visits (including serum β-HCG in females; full list of central laboratory tests available in Appendix IV); blood will 
also be collected for central laboratory testing at FU in subjects with clinically significant laboratory abnormalities noted at or after the TOC visit. 
m Collect blood for acute (Screening) and convalescent (TOC) atypical pathogen serology, including Mycoplasma pneumoniae, Chlamydophila pneumoniae, and 
Legionella pneumophila, for central laboratory testing. 
n At Screening, a urine dipstick will be performed locally; if results are abnormal and deemed clinically significant by the Investigator, a urinalysis will be sent to the central 
laboratory. 
o At Screening, urine will be tested locally for Streptococcus pneumoniae and Legionella pneumophila using provided rapid antigen test kits. 
p At Screening, local laboratory urine or serum pregnancy test (females only) is required to confirm study eligibility. In addition, blood will be collected from all female 
subjects for serum β-HCG pregnancy test by the central laboratory at the Screening and TOC visits.   
q At Screening, collection of expectorated sputum or other deep respiratory sample should be attempted in all subjects. Gram stain will be performed on all sputum 
specimens and quality assessed. Culture will be performed on all adequate sputum samples or deep respiratory specimens. Post-baseline respiratory specimens should be 
collected as clinically indicated and from subjects who are clinical failures and require alternative antibacterial treatment for CABP (Section 12.6).  
rTwo sets of blood cultures (each set consists of 1 aerobic and 1 anaerobic blood culture bottle) will also be collected at Screening. Repeat post-baseline blood cultures 
should be collected on the day that the positive blood culture is detected. If subsequent blood cultures are also positive, repeat the blood cultures as necessary until 
negative blood cultures are obtained (Section 12.6).   
s Blood samples for PK analysis will be collected from all subjects at sites where PK sampling is possible on Day 3, including within 10 minutes before study drug 
administration, and post-dose at 2-4 h and 24-28 h. Subjects who have been hospitalized are also required to have a post-dose PK sample at 6-10 h (Day 3). 
t Study drug should be administered q24h (±4 h) between Day 1 and Day 7, with the exception of Day 2 in which an additional window of 4h may be utilized, depending 
on the randomization time on day 1.    
u AEs and SAEs will be recorded and reported from signing of the informed consent to the FU visit. 
v Prior medications that have been administered within 14 days prior to the date of signing the informed consent or during the Screening phase will be recorded in the 
electronic Case Report Form (eCRF).  All medications administered after the first dose of study drug must be recorded in the eCRF. 


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4.0 
TABLE OF CONTENTS 
4.1 
OVERALL TABLE OF CONTENTS 
1.0 
TITLE PAGE .................................................................................................................................... 1 
2.0 
PROTOCOL APPROVAL PAGE .................................................................................................... 2 
3.0 
SYNOPSIS AND SCHEDULE OF ASSESSMENTS ...................................................................... 3 
4.0 
Table of Contents ............................................................................................................................ 13 
4.1 
Overall Table of Contents ................................................................................................. 13 
5.0 
LIST OF ABBREVIATIONS ......................................................................................................... 16 
6.0 
BACKGROUND AND RATIONALE ........................................................................................... 18 
6.1 
Community-Acquired Bacterial Pneumonia and Unmet Medical Need ........................... 18 
6.2 
Nafithromycin ................................................................................................................... 19 
6.3 
Clinical Experience ........................................................................................................... 20 
6.4 
Study Drug Dose Rationale .............................................................................................. 22 
6.4.1 
Nafithromycin .................................................................................................... 22 
6.4.2 
Moxifloxacin ...................................................................................................... 24 
7.0 
STUDY OBJECTIVES ................................................................................................................... 25 
7.1 
Primary Objectives ........................................................................................................... 25 
7.2 
Secondary Objectives ....................................................................................................... 25 
7.3 
Exploratory Objectives ..................................................................................................... 25 
8.0 
STUDY DESIGN ............................................................................................................................ 26 
8.1 
Type of Study ................................................................................................................... 26 
8.2 
Randomization .................................................................................................................. 27 
8.3 
Number of Subjects .......................................................................................................... 27 
8.4 
Expected Duration of Subject Participation ...................................................................... 27 
9.0 
SELECTION, DISCONTINUATION, AND WITHDRAWAL OF SUBJECTS ........................... 28 
9.1 
Study Population ............................................................................................................... 28 
9.2 
Inclusion Criteria .............................................................................................................. 28 
9.3 
Exclusion Criteria ............................................................................................................. 29 
9.4 
Criteria for Premature Discontinuation of Study Drug or Subject Withdrawal From 
Study ................................................................................................................................. 31 
9.4.1 
Premature Discontinuation from Study Drug Administration ............................ 31 
9.4.2 
Withdrawal from Study ...................................................................................... 33 
9.5 
Replacement of Subjects ................................................................................................... 33 
9.6 
Study Termination by Sponsor and Termination Criteria ................................................. 33 
9.7 
Guidance to Investigators on When to End Study Drug Therapy ..................................... 34 
10.0 
TREATMENT OF SUBJECTS ...................................................................................................... 35 
10.1 
Study Drug ........................................................................................................................ 35 
10.1.1 
Oral Nafithromycin & Matching Placebo ........................................................... 35 
10.1.2 
Oral Moxifloxacin & Matching Placebo ............................................................ 35 
10.2 
Treatment Compliance ...................................................................................................... 36 
10.3 
Prior and Concomitant Medications ................................................................................. 36 
10.4 
Accountability Procedures ................................................................................................ 36 
10.5 
Study Drug Handling and Disposal .................................................................................. 37 
10.6 
Blinding and Unblinding Procedures ................................................................................ 37 


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11.0 
STUDY PROCEDURES ................................................................................................................ 38 
11.1 
Screening Visit.................................................................................................................. 38 
11.2 
Study Day 1 ...................................................................................................................... 42 
11.3 
Study Day 2 ...................................................................................................................... 42 
11.4 
Study Day 3 ...................................................................................................................... 43 
11.5 
Study Day 4 ...................................................................................................................... 43 
11.6 
Study Day 5 ...................................................................................................................... 44 
11.7 
Study Day 6 ...................................................................................................................... 45 
11.8 
Study Day 7 (End-of-Therapy [EOT]) .............................................................................. 45 
11.9 
Test-of-Cure (TOC) .......................................................................................................... 46 
11.10 
Follow-Up (FU) ................................................................................................................ 47 
12.0 
MICROBIOLOGICAL ASSESSMENTS ....................................................................................... 48 
12.1 
Screening Respiratory Specimens ..................................................................................... 48 
12.2 
Screening Blood Cultures ................................................................................................. 49 
12.3 
Screening Urinary Antigen Tests ...................................................................................... 50 
12.4 
Serology for Atypical Bacterial Titers .............................................................................. 50 
12.5 
Post-Baseline Microbiological Assessments .................................................................... 50 
12.6 
Central Laboratory Procedures ......................................................................................... 50 
13.0 
EFFICACY EVALUATION .......................................................................................................... 51 
13.1 
Primary and Secondary Efficacy Variables ...................................................................... 51 
13.2 
Clinical Outcome Assessments ......................................................................................... 51 
13.2.1 
Clinical Response at Day 4 ................................................................................. 51 
13.2.2 
Clinical Outcome at EOT or TOC ...................................................................... 52 
13.2.3 
Improvement in CABP Symptoms and Normalization of Vital signs at 
Study Day 4 ........................................................................................................ 52 
13.2.4 
Hospitalization Prior to the Follow-Up Visit ...................................................... 53 
13.3 
Microbiological Outcomes ............................................................................................... 54 
13.3.1 
Microbiological Outcomes at TOC .................................................................... 54 
14.0 
SAFETY EVALUATION ............................................................................................................... 56 
14.1 
Adverse Events ................................................................................................................. 56 
14.1.1 
Adverse Event Definition ................................................................................... 56 
14.1.2 
Relatedness to Study Drug ................................................................................. 57 
14.1.3 
Severity Assessment ........................................................................................... 58 
14.1.4 
Serious Adverse Events ...................................................................................... 58 
14.1.5 
Recording and Reporting Adverse Events .......................................................... 60 
14.1.6 
Reporting of Pregnancies Occurring During the Study ...................................... 60 
14.2 
Clinical Assessments ........................................................................................................ 61 
14.3 
Laboratory Assessments ................................................................................................... 61 
14.4 
Data Monitoring Committee ............................................................................................. 61 
15.0 
PHARMACOKINETIC EVALUATION ....................................................................................... 62 
15.1 
Pharmacokinetic Blood Sample Collection ...................................................................... 62 
15.2 
Pharmacokinetic Analyses ................................................................................................ 62 
16.0 
STATISTICAL METHODS ........................................................................................................... 63 
16.1 
Study Populations ............................................................................................................. 63 
16.1.1 
Safety Population ............................................................................................... 63 
16.1.2 
Intent-to-Treat Population (ITT) ........................................................................ 63 
16.1.3 
Microbiological Intent-to-Treat Population (micro-ITT) ................................... 63 
16.1.4 
Clinically-Evaluable Population (CE) ................................................................ 63 
16.1.5 
Microbiologically-Evaluable Population (ME) .................................................. 64 
16.1.6 
Pharmacokinetic Population ............................................................................... 64 
16.2 
Methods of Analysis ......................................................................................................... 64 


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16.2.1 
Determination of Sample Size ............................................................................ 64 
16.2.2 
Analysis of Disposition and Subject Characteristics .......................................... 64 
16.2.3 
Efficacy Analyses ............................................................................................... 65 
16.2.4 
Safety Analyses .................................................................................................. 66 
16.2.5 
Pharmacokinetic Analyses .................................................................................. 66 
16.3 
Interim Analysis ................................................................................................................ 66 
16.4 
Handling of Dropouts and Missing Data .......................................................................... 67 
17.0 
INVESTIGATOR REQUIREMENTS ............................................................................................ 68 
17.1 
Protocol Adherence .......................................................................................................... 68 
17.2 
Electronic Case Report Forms and Data Capture System ................................................. 68 
17.3 
Source Document Maintenance ........................................................................................ 68 
17.4 
Study Monitoring Requirements ....................................................................................... 69 
17.5 
Study Completion ............................................................................................................. 69 
18.0 
PROTECTION OF HUMAN SUBJECTS AND GENERAL STUDY ADMINISTRATION ....... 70 
18.1 
Statement of Compliance .................................................................................................. 70 
18.2 
Subject Confidentiality ..................................................................................................... 70 
18.3 
Informed Consent ............................................................................................................. 70 
18.4 
Ethics Committee Approval .............................................................................................. 71 
19.0 
DATA HANDLING AND RECORD KEEPING ........................................................................... 72 
19.1 
Study Drug Accountability ............................................................................................... 72 
19.2 
Retention and Review of Records ..................................................................................... 72 
19.3 
Declaration of the End of Study and Clinical Study Report ............................................. 73 
20.0 
FINANCING AND INSURANCE ................................................................................................. 74 
21.0 
PUBLICATION POLICY ............................................................................................................... 75 
22.0 
REFERENCES ............................................................................................................................... 76 
23.0 
APPENDICES ................................................................................................................................ 78 
Appendix I 
Allowed and Disallowed Prior Antibiotics ......................................................... 79 
Appendix II 
PORT Score Calculation .................................................................................... 80 
Appendix III 
CABP Symptom Severity Guidance for Investigator Assessment ..................... 82 
Appendix IV 
Safety Laboratory Tests Conducted by the Central Laboratory ......................... 83 
Appendix V 
Oral Moxifloxacin Summary of Product Characteristics .................................... 84 
Appendix VI 
Investigator Signature Page ................................................................................ 85 


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5.0 
LIST OF ABBREVIATIONS 
ABG 
arterial blood gas 
AE 
adverse event 
AIDS 
acquired immunodeficiency syndrome 
ALT 
alanine aminotransferase  
AM 
alveolar macrophage 
AST 
aspartate aminotransferase  
ATS 
American Thoracic Society 
AUC0-24 
area under the plasma concentration versus time curve over 24 hours 
BAL 
bronchoalveolar lavage 
β-HCG 
β–human chorionic gonadotropin 
BUN 
blood urea nitrogen 
CABP 
community-acquired bacterial pneumonia 
CBC 
complete blood count 
CD4 
cluster of differentiation 4 
CNS 
central nervous system 
COPD 
chronic obstructive pulmonary disease 
CrCl 
creatinine clearance 
CT 
computed tomography 
CXR 
chest x-ray 
eCRF 
electronic case report form 
ECG 
electrocardiogram 
EDC 
electronic data capture 
ELF 
epithelial lining fluid 
EOT 
End-of-Therapy 
ESCMID 
European Society for Clinical Microbiology and Infectious Diseases 
fAUC/MIC 
free drug area under the plasma concentration versus time curve/minimum 
inhibitory concentration 
FEV1 
forced expiratory volume in one second 
FU 
Follow-Up 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
h 
Hours 
HABP 
hospital-acquired bacterial pneumonia 
HCAP 
healthcare-associated pneumonia 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IDSA 
Infectious Diseases Society of America 
IMP 
Investigational Medicinal Product 


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IMPD 
Investigational Medicinal Product Dossier 
ITT 
Intent-to-Treat 
IV 
intravenous(ly) 
IXRS 
interactive voice/web response system 
LPF 
low power field 
MDR 
multidrug-resistant 
ME 
Microbiologically Evaluable 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIC 
minimum inhibitory concentration 
micro-ITT 
Microbiological Intent-to-Treat population 
MLSB 
macrolide, lincosamide and streptogramin B 
PaO2 
partial pressure of arterial oxygen 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PMN 
polymorphonuclear cell 
PO 
per os (by mouth) 
PORT 
Pneumonia Outcomes Research Team 
QT 
time from electrocardiogram Q wave to the end of the T wave 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
rRNA 
ribosomal ribonucleic acid 
SAE 
serious adverse event 
SI 
Système International d'Unités 
T½
half-life 
TEAE 
treatment-emergent adverse event 
Tmax
time at which drug is present at maximum concentration in serum 
TOC 
Test-of-Cure 
ULN 
upper limit of normal 
US 
United States 
VABP 
ventilator-associated bacterial pneumonia 
WBC 
white blood cell 


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6.0 
BACKGROUND AND RATIONALE 
6.1 
COMMUNITY-ACQUIRED BACTERIAL PNEUMONIA AND 
UNMET MEDICAL NEED 
Lower respiratory tract infection, including community-acquired bacterial pneumonia 
(CABP), remains the second largest cause of death and years of life lost worldwide; its 
associated age-standardized death rate was 41.7 per 100,000 population in 2013 (GBD, 
2015). The global incidence of pneumonia is estimated to be between 1.5 and 14.0 cases 
per 1000 person-years, varying by region, season, and patient characteristics (File, 2010b; 
Millett, 2013). Short-term mortality (in-hospital and 30-day mortality) for hospitalized 
patients with CABP ranges from 4.0% to 18.0% (Arnold, 2013; File, 2010b). Costs 
related to community-acquired pneumonia are high, and few approaches (such as 
reducing the length-of-stay, adequate use of antibiotics, and the introduction of vaccines) 
have reduced these costs to date (Prina, 2015). Streptococcus pneumoniae remains the 
most common pathogen of CABP worldwide, independent of age. Other frequent causes 
of CABP include Haemophilus influenzae, Moraxella catarrhalis, and atypical bacteria 
(including Mycoplasma, Chlamydophila, and Legionella spp.). 
A major therapeutic challenge impacting the treatment of CABP is the widespread 
resistance of S. pneumoniae to ß-lactams (especially penicillins and 1st and 2nd-generation
cephalosporins) and macrolide antibiotics. For example, the prevalence of S. pneumoniae 
macrolide resistance on a global scale is estimated to be 25% to 40%, varying by region 
(Farrell, 2008; Reinert, 2009). The prevalence of multidrug-resistant (MDR) S. 
pneumoniae, defined by penicillin nonsusceptibility plus resistance to two additional non-
β-lactam antibiotic classes, is also worrisome. For example, in the US, an analysis of 
1498 clinical pneumococci strains collected between 2012 and 2013 found that 21.0% 
were MDR (Richter, 2014). Community-acquired MDR S. pneumoniae poses treatment 
challenges for outpatient CABP―most notably the lack of effective oral antibacterial 
options―because of resistance to the most commonly-used oral penicillins, 
cephalosporins, and/or macrolides. Failure of therapy due to resistance will continue to 
contribute to the morbidity and mortality of CABP, and treatment failures of mild disease 
will result in increased hospitalizations and contribute to increased healthcare costs.   
The development of oral nafithromycin (described below in Section 6.2), which has 
activity against MDR S. pneumoniae, Streptococcus pyogenes, respiratory Gram-negative 
pathogens, and atypical pathogens, would provide clinicians with a new treatment option 
for CABP caused by the most common etiologies of CABP, including MDR S. 
pneumoniae, while maintaining an acceptable safety profile. 


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6.2 
NAFITHROMYCIN 
Nafithromycin (previously known as WCK 4873) is an IV and oral antibacterial agent of 
the ketolide class that is structurally related to the macrolide class. Diverse in vitro, in 
vivo, preclinical pharmacokinetic (PK) and safety studies have provided strong scientific 
evidence of the therapeutic potential of nafithromycin for difficult to treat respiratory 
tract infections caused by MDR pathogens. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Refer to the current nafithromycin Investigator's Brochure (IB) for additional information 
regarding relevant nonclinical, microbiology, pharmacology and clinical studies. 
6.3 
CLINICAL EXPERIENCE 
 
 
 
 
 


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Additional details for each study are available in the IB. 
6.4 
STUDY DRUG DOSE RATIONALE 
In this study, study drug is defined as oral nafithromycin tablet or oral moxifloxacin 
capsule (i.e., over-encapsulated tablet). Relevant matching placebo formulations (tablets 
and capsules) are used to maintain the blind. 
6.4.1 
Nafithromycin 
Rationale for 800 mg of nafithromycin once daily for 3 – 5 days: 
 
 
 
 
 
 
 
 
 
 


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6.4.2 
Moxifloxacin 
Moxifloxacin was selected as the optimal comparator for this Phase II CABP study, given 
its long history of efficacy and tolerability in this infection. The proposed dose regimen 
and treatment scheme (400 mg once daily for 7 days) has been selected for consistency 
purposes worldwide as this study is planned to be conducted in different regions, such as 
Europe, US and South Africa.  
 Moxifloxacin has a similar spectrum of activity to that of nafithromycin, with coverage 
against the most common typical and atypical causes of CABP (e.g., S. pneumoniae 
[including penicillin-resistant and macrolide-resistant isolates], H. influenzae, 
Mycoplasma pneumoniae, Chlamydophila pneumoniae, and Legionella pneumophila). 
This broad spectrum of activity along with its once-daily dosage allows for the double-
blind monotherapy design of this trial, obviating the need for combination therapy in 
either treatment arm. The use of moxifloxacin for CABP is consistent with the current 
treatment guidelines by IDSA/ATS and ESCMID (Mandell, 2007; Woodhead, 2005). In 
conclusion, the 7-day oral treatment duration of moxifloxacin, allowed in this study was 
selected to be generally consistent with clinical guideline recommendations as well as the 
duration of therapy recommended in the package inserts for the oral switch agent 
(moxifloxacin package inserts) from different regions, and can thus be considered a 
globally appropriate treatment duration from both efficacy and safety standpoints. 


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7.0 
STUDY OBJECTIVES 
7.1 
PRIMARY OBJECTIVES 
The primary objectives of this study are: 

To assess the overall safety and tolerability of oral nafithromycin

To assess the clinical response in the ITT population at Day 4
7.2 
SECONDARY OBJECTIVES 
The secondary objectives of this study are: 

To assess the clinical response in the micro-ITT population at Day 4

To assess the clinical outcome in the ITT and CE populations at EOT and TOC

To assess early improvement in clinical symptoms and normalization of vital
signs in the ITT population at Day 4

To assess clinical outcome in micro-ITT population at TOC

To assess by-subject and by-pathogen microbiological response in micro-ITT and
ME populations at TOC

To assess readmission to the hospital (or admission to the hospital if not
previously hospitalized) for any reason prior to FU
7.3 
EXPLORATORY OBJECTIVES 
Additional exploratory and subgroup analyses may be conducted, as described in the 
Statistical Analysis Plan. 


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8.0 
STUDY DESIGN 
8.1 
TYPE OF STUDY 
This is a Phase II prospective, multicenter, multinational, randomized (1:1:1), double-
blind, comparative study to determine the efficacy, safety, tolerability, and PK of oral 
nafithromycin versus oral moxifloxacin for treatment of adults with CABP. Study drug is 
defined as oral nafithromycin tablets or oral moxifloxacin capsules. Relevant matching 
placebo formulations (tablets and capsules) are used to maintain the blind. 
Subjects providing informed consent and meeting all study eligibility criteria will be 
randomized into the study in a 1:1:1 ratio to either of the following 3 treatment arms: 

Arm A: Nafithromycin 800 mg (two 400 mg tablets) PO q24h for 3 days; subjects
will receive matching placebo (two nafithromycin placebo tablets PO q24h) on
Days 4 through Day 7, and one moxifloxacin placebo capsule PO q24h on Days 1
through 7, to maintain the blind

Arm B: Nafithromycin 800 mg (two 400 mg tablets) PO q24h for 5 days; subjects
will receive matching placebo (two nafithromycin placebo tablets PO q24h) on
Day 6 and Day 7, and one moxifloxacin placebo capsule PO q24h on Days 1
through 7, to maintain the blind

Arm C: Moxifloxacin 400 mg (one 400 mg over-encapsulated tablet) PO q24h for
7 days; subjects will also receive two nafithromycin placebo tablets PO q24h on
Days 1 through Day 7, to maintain the blind
Baseline assessments for study eligibility will occur within 24 h prior to randomization 
using IXRS, stratified by region (US vs. ex-US) and PORT Risk Class (II vs. III/IV), will 
be used to assign subjects (1:1:1) to Arm A, Arm B or Arm C. Study Day 1 is defined as 
the day that the study drug is first administered, and subsequent study days are defined by 
the number of consecutive calendar days thereafter. 
Subjects may be treated in the study as inpatients or outpatients based on their clinical 
condition, at the discretion of the Investigator; however, only oral study drug will be 
administered (i.e., parental moxifloxacin will not be administered). Subjects will be 
assessed daily by the Investigator between Day 1 and Day 5, whether being treated for 
CABP in the inpatient or outpatient setting. Investigators will assess for clinical outcome 
on EOT (Day 7) and TOC (Day 15 ± 3 days). Vital signs, physical exam, assessment of 
CABP symptom severity, and other study procedures are detailed in Table 3-1. A FU 
visit will be conducted on Day 31 ±3 days from the start of treatment. The FU visit may 
be conducted via telephone contact or by another interactive technology for subjects who 
were considered to be clinical successes and had no AEs or clinically significant 
laboratory or ECG abnormalities noted at or after the TOC visit; otherwise, the visit must 
be conducted in person. 


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8.2 
RANDOMIZATION 
Block randomization using an IXRS, stratified by region (US vs. ex-US) and PORT Risk 
Class (II vs. III/IV), will be used to assign subjects (1:1:1) to Arm A, Arm B or Arm C. 
After informed consent has been obtained and study eligibility established, a study 
pharmacist or designee will obtain the study drug assignment from the IXRS. Subjects 
are considered randomized when the pharmacist or designee receives the IXRS-generated 
treatment assignment. 
8.3 
NUMBER OF SUBJECTS 
Approximately 225 adult subjects (75 subjects per arm) diagnosed with CABP will be 
enrolled in this study.  
Enrolment of PORT Risk Class II (PORT score 51 to 70; Appendix II) will be capped at 
50% and enrolment of subjects with allowed prior systemic antibiotic use (Appendix I) 
will be capped initially at 25% (subject to change during study conduct). 
8.4 
EXPECTED DURATION OF SUBJECT PARTICIPATION 
Each subject will remain in the study for approximately one month. This will include a 
Screening visit (within 24 h of randomization), a 7-day oral treatment period, and post 
treatment assessments at TOC (Day 12 to Day 18) and FU (Day 28 to Day 34).  


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9.0 
SELECTION, DISCONTINUATION, AND WITHDRAWAL OF 
SUBJECTS 
9.1 
STUDY POPULATION 
Adult subjects (≥ 18 years) with CABP will be enrolled in this study. Based on recent 
Phase III CABP study experience, subjects of at least 65 years of age will constitute 
approximately 48% of randomized subjects (File, 2010a). 
9.2 
INCLUSION CRITERIA 
Subjects are required to meet all of the following inclusion criteria: 
1. Male or female ≥ 18 years of age
2. Willing to participate in the study and provide written informed consent before
any protocol specific assessment is performed
3. Meet the following clinical criteria for CABP:
a. Have at least TWO of the following symptoms (new or worsening):
•
Dyspnea (shortness of breath)
•
Cough
•
Production of purulent sputum
•
Pleuritic chest pain
b.
Have at least TWO of the following vital sign abnormalities:
•
Fever or hypothermia documented by the Investigator (oral, rectal, or
tympanic temperature > 38.0°C [100.4°F] or < 36.0°C [95.5°F])
•
Hypotension, defined as systolic blood pressure < 90 mm Hg
•
Tachycardia, defined as heart rate > 90 beats per minute
•
Tachypnea, defined as respiratory rate > 20 breaths per minute
c.
Have at least ONE of the following laboratory abnormalities:
•
Hypoxemia defined as arterial oxygen saturation < 90% by pulse oximetry
or PaO2 < 60 mm Hg by ABG
•
Auscultatory findings on pulmonary examination consistent with bacterial
pneumonia or pulmonary consolidation (e.g., rales, dullness on percussion,
bronchial breath sounds, or egophony)
•
Elevated total WBC count (> 10,000 cells/mm3) or leucopenia (WBC
<4,000 cells/mm3)
•
Elevated immature neutrophils (> 15% band forms), regardless of total
peripheral WBC count
d.
Radiographic evidence of CABP:


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•
Radiographically-confirmed pneumonia, i.e., new or progressive
pulmonary infiltrate(s) on CXR or CT scan consistent with acute bacterial
pneumonia within 48 h prior to randomization
e.
PORT score of 51 to 105 (PORT Risk Class of II, III or IV) (Appendix II)
4. All females must have a negative urine or serum pregnancy test (β-HCG) at
Screening AND agree to the use of one of the following acceptable methods of
contraception from Screening through TOC: surgical sterilization (defined as
bilateral oophorectomy or bilateral salpingectomy, but excluding bilateral tubal
occlusion), post-menopausal  (defined by amenorrhea for at least 12 months
following cessation of all exogenous hormonal treatments), barrier contraception
(e.g., condom, intrauterine device), levonorgestrel intrauterine system (e.g.,
Mirena®), regular medroxyprogesterone injections (e.g., Depo-Provera®), sexual
intercourse with only vasectomised partners, or abstinence. Note that oral
contraceptives should not be used as the sole method of birth control because the
effect of nafithromycin on the efficacy of oral contraceptives has not yet been
established; subjects who take oral contraceptives must also use one of the
acceptable forms of birth control (listed above) from Screening through TOC.
Males must agree to use an acceptable barrier method of birth control (i.e.,
condom) with female partner(s) and must not donate sperm from Screening
through TOC.
5. Ability to ingest oral study drug (e.g., able to swallow large capsules intact, and
no significant nausea, vomiting, diarrhea, or any other condition that might impair
ingestion or absorption of oral study drug)
9.3 
EXCLUSION CRITERIA 
1. Subjects with any of the following confirmed or suspected types of pneumonia:
•
Aspiration pneumonia
•
HABP, defined as pneumonia with onset of clinical signs and symptoms
after at least 48 h hospitalization in an acute in-subject health care facility.
•
HCAP, defined as pneumonia acquired in a long-term care or subacute
healthcare facility (e.g., nursing home) or pneumonia with onset after
recent hospital discharge (within 90 days of current admission and
previously hospitalized for ≥ 48 h)
•
VABP, defined as pneumonia with onset of clinical signs and symptoms
after at least 48 h endotracheal intubation
•
Pneumonia that may be caused by pathogen(s) resistant to either study
drug (nafithromycin or moxifloxacin), including viral, mycobacterial, or
fungal pneumonia (e.g., Pneumocystis jiroveci pneumonia, active
pulmonary tuberculosis)
•
Post-obstructive pneumonia
•
Pneumonia associated with cystic fibrosis


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2. Suspected or confirmed pleural empyema (a parapneumonic pleural effusion is 
not an exclusion criterion) or lung abscess 
3. Suspected or confirmed non-infectious causes of pulmonary infiltrates (e.g., 
pulmonary embolism, hypersensitivity pneumonia, congestive heart failure) 
4. Receipt of 1 or more dose(s) of a potentially-effective systemic antibacterial 
treatment for treatment of the current CABP within 72 h prior to randomization 
with the exception of: 
• 
Receipt of a single dose of a short-acting antibacterial agent within 72 h of 
randomization (Appendix I), OR 
• 
Failure (worsening of symptoms) of at least 48 h of treatment for the 
current episode of CABP with an antibacterial agent other than a ketolide 
or fluoroquinolone 
5. Subjects requiring concomitant adjunctive or additional potentially effective 
systemic antibacterial treatment for management of CABP 
6. Evidence of significant immunologic disease determined by any of the following: 
• 
Current or anticipated neutropenia defined as < 500 neutrophils/mm3 
• 
Known infection with HIV (prior to Screening) and a CD4 count that is 
unknown or documented to be < 200 cells/mm3 within the last year, or an 
AIDS-defining illness; note that neither HIV nor CD4 testing is required at 
Screening 
• 
History of heart, lung, or kidney transplant 
• 
The receipt of cancer chemotherapy, radiotherapy, or potent, non-
corticosteroid immunosuppressant drugs (e.g., cyclosporine, azathioprine, 
tacrolimus, immune-modulating monoclonal antibody therapy) within the 
past 3 months, or the receipt of corticosteroids equivalent to or greater 
than 40 mg of prednisone per day for more than 14 days in the 30 days 
prior to randomization 
7. Known or suspected primary or metastatic neoplastic lung disease, bronchiectasis, 
bronchial obstruction, chronic neurological disorder preventing clearance of 
pulmonary secretions, or severe COPD (severe COPD is defined as known [prior 
to Screening] FEV1/FVC < 0.70 and FEV1 < 50% normal); note that pulmonary 
function tests are not required at Screening  
8. Compromised hepatic or renal function, including but not limited to: clinical 
evidence of end-stage liver disease (e.g., ascites, hepatic encephalopathy), 
screening serum total bilirubin > 2 times ULN (unless associated with an elevated 
indirect bilirubin typical of Gilbert syndrome), AST or ALT > 3 times ULN, 
serum creatinine > 2.0 mg/dl and/or BUN > 30 mg/dl. Other clinically-significant 
abnormal laboratory findings should be discussed with the Medical Monitor prior 
to the subject's entry. 
9. History of Clostridium difficile-associated disease within 6 months prior to 
enrolment 


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10. History of hypersensitivity, known contraindication (e.g. lactose intolerance, 
lactase deficiency and glucose-galactose malabsorption etc. ) or allergic reaction 
(e.g., anaphylaxis, urticaria, other significant reaction) to any ketolide,any 
fluoroquinolone  antibiotic medicinal products or any of their excipients. 
11. Current second- or third- degree atrioventricular block or sick sinus syndrome, 
uncontrolled atrial fibrillation, severe or unstable angina, congestive heart failure, 
myocardial infarction within 3 months of the Screening visit, clinically significant 
ECG abnormalities including QTcF > 450 msec (males) or > 470 msec (females), 
or requirement for medications known to cause QT prolongation  
12. Prior (within 14 days prior to randomization) or concomitant use of cytochrome 
P450 liver enzyme inducers (e.g., phenobarbital, carbamazepine, griseofulvin, 
sulfonylureas, phenytoin, or rifampin) 
13. History of tendon rupture 
14. Current peripheral neuropathy or myasthenia gravis 
15. Known or suspected seizure disorder or other CNS disorders that may predispose 
the subject to seizures or lower the seizure threshold  
16. Nursing mother or pregnant female 
17. Subjects who received any experimental drug within 30 days prior to enrolment  
18. Require admission to in intensive care unit for any reason, life expectancy of less 
than 2 months, or any concomitant condition that, in the opinion of the 
Investigator, is likely to interfere with evaluation of the response of the infection 
under study, determination of AEs, or completion of the expected course of 
treatment 
9.4 
CRITERIA FOR PREMATURE DISCONTINUATION OF STUDY 
DRUG OR SUBJECT WITHDRAWAL FROM STUDY 
Subjects should be encouraged to complete all study assessments. However, subjects may 
discontinue study drug or withdraw consent to participate in this study at any time 
without penalty or loss of benefits to which the subject is otherwise entitled. 
9.4.1 
Premature Discontinuation from Study Drug Administration 
9.4.1.1 
Discontinuations Due to Safety 
Possible reasons for premature discontinuation from study drug administration due to 
safety include, but are not limited to, the following: 
 Occurrence of an AE that, in the opinion of the Investigator, warrants the 
subject’s permanent discontinuation from study drug administration.  
 Meets Hy’s law criteria, defined by at least 3-fold elevations of ALT or AST 
above the ULN, elevation of serum total bilirubin to > 2 times ULN without 
elevated serum alkaline phosphatase, and no other disease or condition can be 
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 Known pregnancy or breastfeeding during the study drug administration period. 
Female subjects whose pregnancy test is positive post-baseline must be followed 
through the immediate postnatal period or until termination of the pregnancy. 
Study center personnel must report every pregnancy as soon as possible (within 
24 h of learning of the pregnancy, as described in Section 14.1.6). 
Assessments and Procedures: Subjects who are prematurely discontinued from study 
drug administration (i.e., before the anticipated full course of study drug required for 
effective treatment of the CABP) for safety reasons should continue to undergo study 
assessments at every study visit (Section 11.0). If a subject is discontinued from study 
drug on Day 3 or Day 4, an attempt should be made to collect any remaining PK blood 
samples scheduled for that day. 
Clinical Outcome Assessment: Subjects prematurely discontinued from any study drug 
for safety reasons and for whom further antibacterial therapy is not required for treatment 
of the primary infection (i.e., the CABP has resolved completely or improved to the point 
where no further antibacterial therapy is necessary), may be assessed as a clinical cure at 
the EOT and TOC visits. 
Subjects prematurely discontinued from any study drug for safety reasons and who 
require further antibacterial therapy for the CABP should be assessed as a clinical failure 
on the day of discontinuation and automatically assigned an outcome of clinical failure at 
the next outcome evaluation time point. 
9.4.1.2 
Discontinuations Due to Insufficient Therapeutic Effect 
Possible reasons for discontinuation from study drug due to insufficient therapeutic effect 
include, but are not limited to, the following: 
 Clinical worsening: Subjects who show systemic or local signs of clinical 
worsening may be prematurely discontinued from study drug administration at 
any time. If the Investigator deems the benefit-to-risk ratio of study drug 
continuance acceptable, study drug administration of at least 48 h is encouraged 
before discontinuation from study drug therapy. 
 Lack of clinical progress: For subjects who are stable, yet do not show signs of 
improvement, the Investigator is encouraged to continue study drug therapy for at 
least 48 h before such subjects are considered clinical failures and prematurely 
discontinued from study drug therapy. 
Assessments and Procedures: Subjects who are prematurely discontinued from study 
drug due to insufficient therapeutic effect should have EOT assessments conducted 
(Section 11.8) on the day of discontinuation and undergo safety assessments at TOC 
(Section 11.9). Prematurely discontinued subjects should also be encouraged to attend the 
FU visit. If a subject is discontinued from study drug on Day 3 or Day 4, an attempt 
should be made to collect any remaining PK blood samples scheduled for that day. If a 
subject is discontinued from study drug administration due to insufficient therapeutic 
effect and is switched to an alternative antibiotic, that therapy should be documented. 


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Clinical Outcome Assessment: Subjects who are prematurely discontinued from study 
drug administration due to insufficient therapeutic effect should be assessed as clinical 
failure on the day of discontinuation. Subjects prematurely discontinued from study drug 
administration due to insufficient therapeutic effect will be automatically assigned an 
outcome of clinical failure at the next outcome evaluation time point. 
9.4.2 
Withdrawal from Study 
Reasons: Possible reasons for withdrawal from study include, but are not limited to, the 
following: 
 Withdrawal of consent 
 Significant subject noncompliance, defined as refusal or inability to adhere to the 
prescribed dosing and follow-up regimen 
 Investigator determines that it is in the best interest of the subject to withdraw 
from the study protocol, due to reasons other than an AE 
Assessments and Procedures: Subjects may withdraw from the study or be withdrawn at 
the request of the Investigator or Sponsor at any time. Subjects who wish to withdraw 
completely from this clinical study during the treatment period should be encouraged to 
undergo safety assessments at the time of withdrawal. Additionally, if a subject is 
withdrawn on Day 3 or Day 4, an attempt should be made to collect any remaining PK 
blood samples scheduled for that day. Subjects withdrawn from the study need not 
undergo TOC or FU assessments. 
Clinical Outcome Assessment: Subjects who withdraw from the study and are not 
assessed as clinical failures should be assessed as indeterminate for all remaining 
scheduled clinical assessments. 
9.5 
REPLACEMENT OF SUBJECTS 
Randomized subjects who are withdrawn from the study will not be replaced. 
9.6 
STUDY TERMINATION BY SPONSOR AND TERMINATION 
CRITERIA 
The Sponsor reserves the right to terminate an investigational site or this clinical study at 
any time. Reasons for termination may include, but are not limited to, the following: 
 The incidence or severity of AEs in this or other studies of nafithromycin or 
moxifloxacin indicate a potential health hazard to subjects 
 Serious or persistent noncompliance by the Investigators with the protocol, 
clinical research agreement, Form FDA 1572, or applicable regulatory guidelines 
in conducting the study 
 Relevant ethics committee(s) or regulatory agency(ies) decision to terminate or 
suspend approval for the Investigator or clinical conduct at site 


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 Investigator request to withdraw from participation 
 Subject enrolment is unsatisfactory 
9.7 
GUIDANCE TO INVESTIGATORS ON WHEN TO END STUDY 
DRUG THERAPY 
The duration of study drug in this study is a fixed 7-day course in all three Treatment 
Arms; therefore, subjects who are improving clinically will receive no less or no more 
than 7 days of the study treatment regimen. At Day 7 (EOT), an assessment of clinical 
outcome will be performed by the Investigator. A subject will be determined as a clinical 
cure at EOT if the subject is alive and the infection is sufficiently resolved such that 
further antibacterial therapy is not needed (Section 13.2.2).  Note that subjects with 
CABP may have some residual findings related to infection (i.e., cough) requiring non-
antibiotic ancillary treatment (e.g., expectorant) at EOT and still meet criteria for clinical 
cure.  
If additional antibacterial therapy is required for the index CABP (e.g., progressively 
worsening CABP between Day 1 and Day 7, or gradually improving CABP that requires 
additional antibacterial therapy beyond 7 days), study drug should be discontinued, the 
subject will be deemed a clinical failure on the day of study drug discontinuation, and 
open-label antibacterial therapy will be started at the discretion of the Investigator. 
Administration of blinded study drug will not be allowed beyond Day 7. In cases of 
premature discontinuation of study drug, subjects should not be discontinued from the 
study itself; subjects should remain in the study and undergo all scheduled assessments at 
EOT, TOC and FU (Section 11.0). 
The Investigator may use culture and susceptibility results from the local microbiology 
laboratory to help guide therapy; however, decisions to continue or discontinue study 
drug should be based on clinical response rather than susceptibility results (as 
nafithromycin susceptibility testing is not available at the local site). If the index CABP is 
caused by a microorganism that is not susceptible to fluoroquinolones, macrolides, or 
ketolides in vitro, the decision to continue or discontinue study treatment should be based 
on the subject's clinical course and the Investigator’s clinical judgment. These cases 
should be discussed with the Medical Monitor prior to prematurely discontinuing study 
drug, and the rationale for this decision should be recorded in the source documents. 


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10.0 
TREATMENT OF SUBJECTS 
Subjects will be randomized 1:1:1 to receive either oral nafithromycin tablets or oral 
moxifloxacin capsules (over-encapsulated tablets). The duration of therapy is 7 days (3 or 
5 days of active oral nafithromycin followed by placebo to complete 7 days of therapy 
[Arms A and B, respectively] or 7 days of active oral moxifloxacin [Arm C]). Relevant 
matching placebo formulations (tablets and capsules) are used to maintain the blind. 
10.1 
STUDY DRUG 
10.1.1 
Oral Nafithromycin & Matching Placebo 
Each subject randomized to receive nafithromycin (Arm A or Arm B) will receive oral 
nafithromycin administered as two 400 mg tablets ― for a total of 800 mg ― once daily.  
Nafithromycin is a novel IV and oral antibacterial agent of ketolide class (molecular 
weight 859 Daltons), which is structurally related to macrolide class. The chemical 
nomenclature is: (11S, 21R)-3-Decladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11-
{oxycarbonyl-[E-N-[1-(5-pyridin-2-yl-1,3,4-thiadiazol-2-yl)-(S)-ethoxy]-
carboxamidino]methylene}-erythromycin-A. 
The nafithromycin and matching placebo tablets have been manufactured under GMP 
conditions and have undergone stability studies in compliance with regulatory norms. 
Oral nafithromycin 400 mg tablets and corresponding clinical placebo tablets are of white 
color, oval shaped, biconvex film coated, scored on both sides and debossed with W and 
755 on either side of the score on one side (IB).  
Storage and dispensing of nafithromycin tablets can be undertaken at room temperature 
(below 25°C) in its packaging (while protected from moisture). Detailed instructions 
regarding storage are presented in the Investigational Medicinal Product Dossier (IMPD). 
The blinded products will be packaged in subject-specific blister wallets. Tablets are to 
be swallowed with water in an upright position. 
10.1.2 
Oral Moxifloxacin & Matching Placebo 
Each subject randomized to receive moxifloxacin (Arm C) will receive oral moxifloxacin 
administered as a single 400 mg capsule (i.e., over-encapsulated tablet) once daily.  
All other subjects, randomized to receive nafithromycin (Arms A and B), will receive 
moxifloxacin matching placebo.  
The blinded products will be packaged in subject-specific blister wallets. Capsules are to 
be swallowed with water in an upright position. 
Consult the summary of products characteristics or prescribing information (Appendix V) 
or other local dosing guidelines regarding preparation, storage, administration, maximum 
doses, contraindications, warnings, precautions, and AEs reported with the use of 
moxifloxacin.  


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10.2 
TREATMENT COMPLIANCE 
Treatment compliance will be documented in the eCRF by recording the date, time, and 
whether or not each oral dose of study drug was administered. 
10.3 
PRIOR AND CONCOMITANT MEDICATIONS 
All prior systemic or inhaled antimicrobial agents (administered within 14 days prior to 
randomization) and all systemic or inhaled concomitant antimicrobial agents 
(administered during the study) will be documented.  
A subject who received more than a single dose of any potentially-effective, short-acting, 
systemic antibacterial therapy for the current episode of CABP within 72 h before 
randomization will be excluded from the study (Section 9.3), unless there is unequivocal 
clinical evidence of treatment failure of the current episode of CABP (e.g., worsening 
signs and symptoms) after administration of an antibacterial agent other than a ketolide or 
fluoroquinolone.  
Concomitant use of potentially effective systemic antibacterials or potentially effective 
inhaled antibacterials is not permitted. 
Nafithromycin is a weak inhibitor of human cytochrome P450 (CYP) isoforms such as 
CYP3A4; specifically, nafithromycin is a 2-5x and 14-60x less potent inhibitor of 
CYP3A4 than telithromycin and solithromycin, respectively (details in IB). 
Nafithromycin is not an inhibitor of CYP2D6. In addition, nafithromycin does not induce 
enzyme activity or mRNA levels of CYP1A2, CYP2B6, or CYP3A4. Concomitant 
medications that induce P450 enzymes are contraindicated in this study. Specifically, 
prior (within 14 days prior to randomization) or concomitant use of cytochrome P450 
liver enzyme inducers (e.g., phenobarbital, carbamazepine, griseofulvin, sulfonylureas, 
phenytoin, or rifampin) are excluded. 
All other concomitant medications and nutrients necessary for the health and well-being 
of the subject are permitted.  
10.4 
ACCOUNTABILITY PROCEDURES 
It is the responsibility of the Investigator or designee to ensure that current records of 
study drug inventory and accountability are maintained. Records must be readily 
available for inspection by the Sponsor or Sponsor’s Representative and are open to 
inspection at any time by applicable regulatory authorities. 
Upon receipt of study therapy drugs, the Investigator or designee must acknowledge 
receipt, visually inspect the shipment, verify the number of tablets or capsules shipped 
are received, and document the condition of the drugs received.  


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10.5 
STUDY DRUG HANDLING AND DISPOSAL 
All study drugs provided by the Sponsor should be retained at the investigational site 
until otherwise instructed in writing by the Sponsor. Upon completion of the study or 
termination of the investigational site, all unused and partially used study drugs supplied 
by the Sponsor will be either disposed of at the site level or shipped to a site designated 
by the Sponsor as per local regulatory requirement. For additional information, please 
refer to current version of the Pharmacy manual.  
10.6 
BLINDING AND UNBLINDING PROCEDURES 
This study will be double-blinded with regard to study drug treatment. After written 
informed consent has been obtained and eligibility established, the study center’s 
pharmacist/designee will obtain the randomization code using IXRS. The IXRS system 
will also confirm the study drug assignment including the unique identification number(s) 
of the kits to be prepared for the subject’s oral therapy. The pharmacist/designee will be 
responsible for maintaining accountability and  dispensing the oral study drug according 
to the handling instructions. Study center personnel will remain blinded to the identity of 
study drug until the database has been locked and the study has been unblinded. In the 
case of a medical emergency requiring the Investigator to know the identity of the oral 
study drug, the Investigator will follow the procedures outlined below. 
Individual treatment codes, indicating the treatment for each randomized subject, will be 
available to the Investigators or pharmacists from IXRS. Interactive voice/web response 
system procedures will be described in the IXRS user manual that will be provided to 
each center. To maintain investigator blinding, the treatment code should not be broken 
except in medical emergencies when the appropriate management of the subject requires 
knowledge of the treatment randomization. In such a case, the subject should receive all 
appropriate medical care. Prior to any unblinding, the Investigator should contact the 
Sponsor Medical Monitor to discuss options. The unblinding procedure will be done 
through the IXRS system. As soon as possible and without revealing the subject’s study 
drug assignment (unless important to the safety of subjects remaining in the study), the 
Investigator must notify the Sponsor if the blind is broken for any reason and the 
Investigator was unable to contact the Sponsor prior to unblinding. The Investigator will 
record in the source documentation the date and reason for revealing the blinded 
treatment assignment for that subject; the treatment assignment itself should not be 
entered into source documentation. The Sponsor may break the code for SAEs that are 
unexpected and are believed to be causally related to study drug and that potentially 
require expedited reporting to regulatory authorities. In such cases, the minimum number 
of Sponsor personnel will be unblinded. Treatment codes will not be broken for the 
planned analyses of data until all decisions on the evaluability of the data from each 
individual subject have been made and documented and databases have been locked. 


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11.0 
STUDY PROCEDURES 
The Schedule of Assessments and Procedures is located in Table 3–1.  
11.1 
SCREENING VISIT 
Screening visit procedures must be completed within 24 h prior to randomization, in 
order to determine study eligibility. Potential subjects who do not meet entrance criteria 
may, as appropriate, be rescreened and undergo repeat the baseline assessments within 72 
h of initial screening for possible enrolment into the study. 
Local or regional laboratory results will be used to determine subject eligibility for study 
enrolment. Any protocol-required eligibility laboratory or radiological evaluations 
already performed as part of the subject’s regular medical care or site’s standards of care 
within 24 h (laboratory) and 48 h (radiology) before randomization do not have to be 
repeated to determine subject eligibility. In addition, laboratory assessments (Table 3-1) 
must be sent to the central laboratory as part of baseline safety assessments. If local or 
regional laboratory results are not confirmed by central laboratory results, the subject 
should not be automatically withdrawn from the study or study drug. The subject should 
be assessed for safety and the Medical Monitor must be contacted to confirm subject 
eligibility to remain on study. 
Written and signed informed consent must be obtained before any protocol assessment is 
performed. 
Clinical Assessments: 
 Verify inclusion and exclusion criteria 
 Obtain a complete medical and surgical history, including all active conditions 
and all conditions diagnosed within the previous 5 years 
 Record all prior medications that have been administered within 14 days prior to 
the date of signing the informed consent 
 Record height and weight, and estimate creatinine clearance (CrCl) using the 
following Cockcroft-Gault formula (use actual body weight): 
 
For serum creatinine in mg/dL: 
Males: 
CrCl = 
(140 - age in years) × weight (kg)  
 
72 × serum creatinine (mg/dL) 
Females: CrCl =  
(140 - age in years) × weight (kg)  
 × 0.85  
72 × serum creatinine (mg/dL) 


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If the serum creatinine value reported is in Système International d'Unités (SI) 
units (i.e., μmol/L), convert to conventional units (mg/dL) using the following 
formula: 
Conventional units (mg/dL) = 
SI units (μmol/L) 
88.4 
 
 Record vital signs of body temperature (oral, rectal, or tympanic), blood pressure, 
heart rate, respiratory rate, and pulse oximetry; the highest daily temperature 
should be recorded, and attempts should be made to measure temperatures using 
the same methodology throughout the study 
 Perform a complete physical examination, including general appearance, skin, 
eyes, ears, nose, throat, lungs, heart, abdomen, back, extremities, lymph nodes, 
vascular, and neurological exams 
 Assess CABP symptom severity (Appendix III) 
 Obtain a 12-lead ECG 
 Identify, assess and record any AEs (since the time of informed consent) 
Radiographic Evaluation 
 Obtain a CXR or chest CT scan for all subjects at Screening. If a CXR is 
performed, anteroposterior and lateral views are preferred, and confirmation of 
new or progressive pulmonary infiltrates consistent with CABP may occur with 
either (or both) CXR view; however, posteroanterior (i.e., portable) views are also 
acceptable. Chest radiography may be obtained as part of routine, non-study 
evaluation of a subject presenting with signs and symptoms of CABP and 
therefore may be performed in some circumstances before informed consent is 
obtained for participation in this study; radiological evaluations already 
performed as part of the subject’s regular medical care or site’s standards of care 
within 48 h before randomization do not have to be repeated to determine subject 
eligibility. Radiologic evaluation(s) will be performed locally and interpreted by 
appropriately qualified personnel who are certified or licensed to interpret chest 
radiographs according to applicable regional requirements, and the evaluations 
will be reviewed by the Investigator or qualified personnel during the Screening 
Visit; the conclusions of the Investigator’s review will be the basis for subject 
inclusion. The written radiography report (i.e., formal interpretation of the 
radiographic image or film) should be included in the source documents; 
however, the radiography images or films are not needed in the source documents. 


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Local or Regional Laboratory Assessments for Study Eligibility: 
○ Obtain serum transaminase (ALT, AST) and total bilirubin levels, coagulation 
profile, serum creatinine and blood urea nitrogen (or urea), peripheral WBC 
count, absolute neutrophil count, and immature neutrophil percentage to 
determine eligibility. ABG is recommended, but not required, to measure blood 
pH and partial pressure of oxygen (PaO2) for the PORT score calculation.  
○ Obtain serum or urine sample for pregnancy test (β-HCG) in all females and 
ensure that the test is negative before randomization. 
○ Obtain a urine dipstick test; a standard urine dipstick includes detection of 
specific gravity, pH, leukocytes, blood (hemoglobin), nitrite, ketones, bilirubin, 
urobilinogen, protein, and glucose. If any results is abnormal (e.g., not negative) 
and deemed clinically significant by the Investigator, a urinalysis will be sent to 
the central lab. 
PORT Score 
 Calculate the PORT score using local laboratory and radiographic results 
(Appendix II). As part of the Inclusion Criteria to this study, subjects must have a 
PORT score between 51 and 105 (PORT Risk Class of II, III, or IV) at 
randomization. For subjects without an optional ABG at Screening, no points will 
be added for pH or PaO2; however, oxygen saturation results can be used in place 
of PaO2 (Appendix II). 
Central Laboratory Assessments: 
 Obtain complete blood count (CBC), chemistry panel, urinalysis (only if local 
urine dipstick results are abnormal and deemed clinically significant by the 
Investigator), and serum β-HCG test (Appendix IV)  
 Collect blood to test serology for Legionella pneumophila, Mycoplasma 
pneumoniae and Chlamydophila pneumoniae by the central laboratory 
Local or Regional Microbiological Assessments: 


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 Attempt to collect an adequate quality expectorated or induced sputum or other 
respiratory specimen reflecting fluid from the lower respiratory tract from every 
subject (e.g., respiratory fluid obtained by bronchoalveolar lavage or 
bronchoscopy; pleural fluid obtained by thoracentesis; or expectorated or induced 
sputum meeting adequacy criteria) and submit the specimen to the local 
microbiology laboratory for Gram stain and culture (see Section 12.0 for 
additional details). A Gram stain slide and an unstained slide should be submitted 
to the central laboratory for the confirmation of white cell and epithelial cell 
counts. Attempts should be made to collect quality respiratory specimens prior to 
the first dose of study drug. Respiratory specimens might be obtained as part of 
routine, non-study evaluation of a subject being evaluated for CABP and therefore 
could be obtained prior to obtaining informed consent. An adequate quality 
sputum specimen will be defined as having the following 2 findings as reported 
by the local laboratory: 
o < 10 squamous epithelial cells/low power field (LPF) (i.e., 100×) 
o > 25 PMNs/LPF  
Processing: Sputum and tracheal samples will be rejected if they contain ≥10 
squamous epithelial cells/LPF and should NOT be processed. All sputum and 
tracheal samples with < 10 SECs will be processed, irrespective of the PMN 
count.  
Resubmission: sputum /tracheal aspirate samples should be resubmitted (if 
possible): 
o If both criteria i.e., < 10 squamous epithelial cells/LPF and > 25 
PMNs/LPF are not met  
o If specimen meets the first criterion, i.e., < 10 squamous epithelial 
cells/LPF, but not the second i.e., > 25 PMNs/LPF 
 Obtain blood (1 aerobic bottle and 1 anaerobic bottle from 2 separate 
venipuncture sites, for a total of 4 bottles) 
 Collect a urine specimen to test for the presence of Legionella pneumophila and 
Streptococcus pneumoniae antigens. Testing will be performed at the local 
laboratory using kits supplied by the Sponsor. 
 
Randomize the subject using IXRS after verifying that the subject meets all study 
inclusion criteria (Section 9.2) and no exclusion criteria (Section 9.3).  


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11.2 
STUDY DAY 1 
Day 1 is the first calendar day of study drug administration. Subsequent study days are 
consecutive calendar days. If feasible, Screening and randomization procedures 
(Screening Visit and Day 1) can be performed on the same day. Standard of care 
laboratory and radiological data from within 24 h (laboratory) and 48 h (radiology) prior 
to randomization can be used as Screening Visit procedures. If the Screening Visit and 
Day 1 occur on different calendar days or on the same day, verify all Inclusion Criteria 
and Exclusion Criteria prior to randomization. All Day 1 procedures described below and 
in Table 3–1 are to be conducted after the first administration but before the second 
administration of study drug. 
Administer study drug per the schedule in Section 10.1. 
Clinical Assessments: 
 Record one set of vital signs, including body temperature (highest daily oral, 
rectal, or tympanic temperature), blood pressure, heart rate, respiratory rate, and 
pulse oximetry 
 Perform a complete physical examination 
 Assess CABP symptom severity (Appendix III) 
 Obtain a 12-lead ECG 
 Identify, assess and record any AEs  
 Record any concomitant medications  
11.3 
STUDY DAY 2 
Administer study drug per the schedule in Section 10.1. 
Clinical Assessments: 
 Record one set of vital signs, including body temperature (highest daily oral, 
rectal, or tympanic temperature), blood pressure, heart rate, respiratory rate, and 
pulse oximetry 
 Perform a complete physical examination 
 Assess CABP symptom severity (Appendix III) 
 Identify, assess and record any AEs  
 Record any concomitant medications  


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Microbiological Assessments: 
 If prior blood cultures are positive, repeated post-baseline blood cultures should 
be collected on the day that the positive blood culture is detected 
 Repeated respiratory specimens should be obtained only if clinically indicated 
11.4 
STUDY DAY 3 
Administer study drug per the schedule in Section 10.1. 
Clinical Assessments: 
 Record one set of vital signs, including body temperature (highest daily oral, 
rectal, or tympanic temperature), blood pressure, heart rate, respiratory rate, and 
pulse oximetry 
 Perform a complete physical examination 
 Assess CABP symptom severity (Appendix III) 
 Obtain a 12-lead ECG 
 Identify, assess and record any AEs  
 Record any concomitant medications 
Microbiological Assessments: 
 If prior blood cultures are positive, repeated post-baseline blood cultures should 
be collected on the day that the positive blood culture is detected 
 Repeated respiratory specimens should be obtained only if clinically indicated 
PK Assessments: 
 Blood samples for PK analyses will be taken from all subjects at sites where 
PK sampling is possible on Day 3 at the following times:  
o Within 10 minutes before study drug administration 
o 2-4 h after study drug administration 
o subjects who have been hospitalized are also required to have a post-
dose PK sample at 6-10 h (Day 3) 
11.5 
STUDY DAY 4 
Administer study drug per the schedule in Section 10.1. 


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Clinical Assessments: 
 Record one set of vital signs, including body temperature (highest daily oral, 
rectal, or tympanic temperature), blood pressure, heart rate, respiratory rate, and 
pulse oximetry 
 Perform a complete physical examination 
 Assess CABP symptom severity (Appendix III). CABP symptom severity 
information entered into the eCRF will be used to programmatically determine 
clinical response at Day 4 (Section 13.2.1); note this is not an Investigator-
determined clinical outcome. 
 Identify, assess and record any AEs  
 Record any concomitant medications 
Microbiological Assessments: 
 If prior blood cultures are positive, repeated post-baseline blood cultures should 
be collected on the day that the positive blood culture is detected 
 Repeated respiratory specimens should be obtained only if clinically indicated 
PK Assessments: 
 A single blood sample for PK analyses will be taken from all subjects at sites 
where PK sampling is possible on Day 4 at 24-28 h following study drug 
administration on Day 3 
11.6 
STUDY DAY 5 
Administer study drug per the schedule in Section 10.1. 
Clinical Assessments: 
 Record one set of vital signs, including body temperature (highest daily oral, 
rectal, or tympanic temperature), blood pressure, heart rate, respiratory rate, and 
pulse oximetry 
 Perform a complete physical examination 
 Assess CABP symptom severity (Appendix III) 
 Obtain a 12-lead ECG 
 Identify, assess and record any AEs  
 Record any concomitant medications 


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Central Laboratory Assessments: 
 Obtain  hematology, coagulation and chemistry panel (Appendix IV) 
Microbiological Assessments: 
 If prior blood cultures are positive, repeated post-baseline blood cultures should 
be collected on the day that the positive blood culture is detected 
 Repeated respiratory specimens should be obtained only if clinically indicated 
11.7 
STUDY DAY 6 
Administer study drug per the schedule in Section 10.1. 
Clinical Assessments: 
 Identify, assess and record any AEs  
 Record any concomitant medications 
Microbiological Assessments: 
 If prior blood cultures are positive, repeated post-baseline blood cultures should 
be collected on the day that the positive blood culture is detected 
 Repeated respiratory specimens should be obtained only if clinically indicated 
11.8 
STUDY DAY 7 (END-OF-THERAPY [EOT]) 
Perform EOT assessments at any time during Day 7 after the final dose of study drug, or 
within 2 days following Day 7. Additional guidance on when to end study drug therapy is 
provided in Section 9.7. 
Administer study drug per the schedule in Section 10.1. 
Clinical Assessments: 
 Record one set of vital signs, including body temperature (highest daily oral, 
rectal, or tympanic temperature), blood pressure, heart rate, respiratory rate, and 
pulse oximetry 
 Perform a complete physical examination 
 Assess CABP symptom severity (Appendix III) 
 Obtain a 12-lead ECG 
 Identify, assess and record any AEs  


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 Record any concomitant medications 
 Conduct clinical outcome assessment (Section 13.2.2) 
Central Laboratory Assessments: 
 Obtain CBC, coagulation and chemistry panel (Appendix IV) 
Microbiological Assessments: 
 If prior blood cultures are positive, repeated post-baseline blood cultures should 
be collected on the day that the positive blood culture is detected 
 Repeated respiratory specimens should be obtained only if clinically indicated 
11.9 
TEST-OF-CURE (TOC) 
Perform TOC assessments on Day 15 ±3 days.  
Clinical Assessments: 
 Record one set of vital signs, including body temperature (highest daily oral, 
rectal, or tympanic temperature), blood pressure, heart rate, respiratory rate, and 
pulse oximetry 
 Perform a complete physical examination 
 Assess CABP symptom severity (Appendix III) 
 Obtain a 12-lead ECG only if prior study ECG(s) showed any clinically-
significant abnormality 
 Identify, assess and record any AEs  
 Record any concomitant medications 
 Conduct clinical outcome assessment (Section 13.2.2) 
Central Laboratory Assessments: 
 Obtain CBC, coagulation, chemistry panel, and serum β-HCG test (Appendix IV) 
 Collect blood to test serology for Legionella pneumophila, Mycoplasma 
pneumoniae and Chlamydophila pneumoniae by the central laboratory 
Microbiological Assessments: 
 If prior blood cultures are positive, repeated post-baseline blood cultures should 
be collected on the day that the positive blood culture is detected 


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 Repeated respiratory specimens should be obtained only if clinically indicated 
11.10 
FOLLOW-UP (FU) 
FU is to be conducted on Day 31 ±3 days. The FU assessment may be conducted via 
telephone contact or by another interactive technology for subjects who were considered 
to be Clinical Successes and had no AEs or clinically significant laboratory or ECG 
abnormalities noted at or after the TOC visit; otherwise, the visit must be conducted in 
person. 
Clinical Assessments: 
 Assess for clinical relapse or recurrence of CABP, including new hospitalization 
for any reason within 30 days from initiation of treatment (a secondary endpoint, 
see Section 13.2.4) 
 Obtain a 12-lead ECG only if prior ECG(s) showed any clinically-significant 
abnormality 
 Identify, assess and record any AEs  
Central Laboratory Assessments: 
 Obtain CBC, coagulation, and/or chemistry panel only if prior study laboratory 
results showed any clinically-significant abnormality (Appendix IV); previously-
normal (or abnormal but not clinically-significant) laboratory tests do not need to 
be repeated. 
Microbiological Assessments: 
 If prior blood cultures are positive, repeated post-baseline blood cultures should 
be collected on the day that the positive blood culture is detected 
 Repeated respiratory specimens should be obtained only if clinically indicated, 
e.g., if clinical relapse or recurrence of CABP 


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12.0 
MICROBIOLOGICAL ASSESSMENTS  
Microbiology specimens will be collected by sites. All microbiological assessments will 
be initiated at the local or regional laboratory, including Gram stain, organisms 
identification, local susceptibility testing, and shipment of isolates and Gram stain slides 
to Central Microbiology Laboratory. Additional details with regard to handling and 
processing of microbiological specimens at the local laboratory vs. central laboratory are 
provided in the Microbiology Laboratory Manual. 
12.1 
SCREENING RESPIRATORY SPECIMENS 
An attempt should be made to collect an adequate-quality expectorated or induced 
sputum or other deep respiratory specimen reflecting fluid from the lower respiratory 
tract from every subject (e.g., respiratory fluid obtained by bronchoalveolar lavage or 
bronchoscopy; pleural fluid obtained by thoracentesis; or expectorated or induced sputum 
meeting adequacy criteria) at Screening. The respiratory specimen should be submitted to 
the local microbiology laboratory for Gram stain and culture. A Gram stain slide and an 
unstained slide should be submitted to the central laboratory for the confirmation of white 
cell and epithelial cell counts. Attempts should be made to collect quality respiratory 
specimens prior to the first dose of study drug. Respiratory specimens might be obtained 
as part of routine, non-study evaluation of a subject being evaluated for CABP and 
therefore could be obtained prior to obtaining informed consent.  
An adequate quality sputum specimen will be defined as meeting the following 2 criteria, 
as reported by the local laboratory: 
1. < 10 squamous epithelial cells/ LPF (magnification, x100) 
2. > 25 PMNs/LPF 
In the event that a sputum specimen is determined to be inadequate, or cannot be obtained 
prior to the first dose of study drug, repeated collection of a specimen should be 
attempted as early as possible, not later than 24 h after the first dose of study drug.   
If pleural fluid is collected for culture, collect the pleural fluid sample in 1 aerobic blood 
culture bottle and 1 anaerobic blood culture bottle for a total of 2 bottles (if limited 
pleural fluid is available, collect the fluid in the aerobic bottle at a minimum). Pleural 
fluid can be collected in sterile caps for Gram stain and culture. Pleural fluid cultures 
must be obtained during thoracentesis or initial chest tube placement; cultures are not 
acceptable if obtained from an indwelling chest tube.  
Respiratory specimens should be processed (i.e., Gram's stain and initiation of overnight 
cultures) within 2 hours of sampling at ambient temperature. Refrigerated samples should 
be processed within 12 hours. Refer to the Microbiology Laboratory Manual for details. 
Culture results are to include identification of  organisms to the level of genus and 
species. Susceptibility testing for nafithromycin will not be available to the local 
laboratory. Nafithromycin minimum inhibitory concentrations (MICs) will be assessed at 
the central laboratory; however, these MIC results will not be available to the Investigator 
during real-time management of the subjects, and MICs will not be associated with 


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formal breakpoints for susceptibility vs. resistance. Therefore, decisions related to subject 
care (e.g., study drug discontinuation) will be based on the evolution of the clinical signs 
and symptoms of CABP, rather than specific nafithromycin MIC data (see Section 9.7 for 
additional guidance). Susceptibility testing for moxifloxacin (or other fluoroquinolones) 
may be performed locally using local laboratory methods usually employed by the 
laboratory. Results of this testing can be used by Investigators along with clinical 
findings to help guide therapy. 
With the exception of respiratory “contaminants” listed below, all isolates identified by 
the local laboratory from expectorated or induced sputum specimens and/or that are 
isolated from respiratory specimens or blood or pleural fluid and are potential pathogens 
as defined in the local/regional Microbiology Laboratory Manual, will be submitted to 
the central laboratory for verification of genus and species and for standardized MIC 
testing performed for nafithromycin, moxifloxacin, and a panel of currently approved 
antibiotics.  In the event that local laboratory genus and species identification are not 
consistent with central laboratory results, a back-up isolate should be sent to the central 
laboratory. All isolates submitted to the central laboratory must also be retained by the 
local/regional laboratory. 
For the purposes of this study, the following respiratory specimen isolates are considered 
“contaminants” and should not to be sent to the central laboratory: 
 Normal respiratory microflora, mixed respiratory microflora, or equivalent 
(including, but not limited to viridans group streptococci, coagulase-negative 
staphylococci, Corynebacterium spp.) 
 Fungal spp. (e.g., Candida spp., molds) 
Refer to the study-specific Microbiology Laboratory Manual for further detail, including 
specific procedures pertaining to the collection, processing, storage, and shipment of 
microbiological samples. 
12.2 
SCREENING BLOOD CULTURES 
At Screening, one aerobic blood culture bottle and one anaerobic blood culture bottle 
from two separate sites for a total of four bottles must be collected for culture (i.e., 1 
aerobic and 1 anaerobic bottle from 2 separate venipuncture sites, for a total of 4 bottles).  
Either an automated or a manual system can be used for blood and pleural fluid culture 
methods according to the preference of the local microbiological laboratory performing 
the testing. Refer to the Microbiology Laboratory Manual for details. 
Culture results are to include identification of pathogens to the level of genus and species. 
Susceptibility testing for nafithromycin will not be available to the local laboratory; MICs 
will be assessed at the central laboratory. Therefore, decisions related to subject care 
(e.g., study drug discontinuation) will be based on the evolution of the clinical signs and 
symptoms of CABP. 


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12.3 
SCREENING URINARY ANTIGEN TESTS 
At the Screening visit, urine will be collected to test for Legionella pneumophila and 
Streptococcus pneumoniae antigens.  Testing will be performed at the local laboratory 
using kits supplied by the Sponsor and the results will be recorded on the eCRF. 
12.4 
SEROLOGY FOR ATYPICAL BACTERIAL TITERS 
At the Screening Visit and at TOC, blood samples will be collected to conduct acute and 
convalescent serology, respectively, for Legionella pneumophila, Mycoplasma 
pneumoniae and Chlamydophila pneumoniae by the central laboratory. 
12.5 
POST-BASELINE MICROBIOLOGICAL ASSESSMENTS 
At any time after the Screening Visit, respiratory specimen and blood cultures should be 
obtained as clinically indicated. As CABP responds to therapy, obtaining repeated 
specimens for culture or examination may not be clinically appropriate and/or there may 
be no material for culture.  
If study drug is prematurely discontinued due to insufficient effect of study drug (e.g., 
failure at EOT or TOC, or clinical relapse at any time), an appropriate respiratory 
specimen and blood should be obtained for culture on the day of discontinuation; if new 
antibacterial therapy is administered to treat the current CABP after premature 
discontinuation of study drug, it is preferred that respiratory specimens and blood be 
collected for culture after stopping the study drug but before new treatment is started. 
Blood cultures should be repeated upon knowledge of a positive result from any previous 
collection until sterilization is confirmed (Table 3-1).  
Repeat, post-baseline urinary antigen tests for L. pneumophila or S. pneumoniae should 
not be performed. 
12.6 
CENTRAL LABORATORY PROCEDURES 
With the exception of “contaminants” defined above (Section 12.1), all cultured bacterial 
isolates collected at each visit will be forwarded to the designated central laboratory for 
each study site. Central laboratory services will perform the following procedures: 
1. Re-identify all bacterial isolates to the genus and species level  
2. Test all bacterial isolates for nafithromycin and moxifloxacin MICs using 
standardized testing methodologies  
3. Test Screening and TOC blood samples for atypical acute and convalescent 
serology, respectively, for Legionella pneumophila, Mycoplasma pneumoniae and 
Chlamydophila pneumoniae (Section 12.4) 
Any questions regarding microbiological procedures, interpretation of results, or storage 
of isolates should be discussed with the Sponsor or designee. Additional detail is 
available in the Microbiology Laboratory Manual. 


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13.0 
EFFICACY EVALUATION 
13.1 
PRIMARY AND SECONDARY EFFICACY VARIABLES 
Primary efficacy variable: 
 
Clinical response at Day 4 (ITT population) 
Secondary efficacy variables: 
 Clinical response at Day 4 (micro-ITT population) 
 Clinical outcome at EOT and TOC (ITT and CE populations) 
 Improvement in CABP symptoms and normalization of vital signs at Day 4 (ITT 
population) 
 Clinical outcome at TOC (micro-ITT population) 
 By-subject and by-pathogen microbiological response at TOC (micro-ITT and 
ME populations)  
 Hospitalization prior to FU (ITT population) 
13.2 
CLINICAL OUTCOME ASSESSMENTS  
13.2.1 
Clinical Response at Day 4 
The primary efficacy endpoint is clinical response (response, non-response, or 
indeterminate) at Day 4, tested in the ITT Population. Clinical response (response, non-
response, or indeterminate) at Day 4 will also be tested in the micro-ITT Population as a 
secondary efficacy endpoint. Clinical response is determined programmatically using the 
Investigator’s determination of CABP symptoms entered into the eCRF (Table 13.2.1-1). 
The Investigator is not responsible for categorizing subjects as clinical response, non-
response, or indeterminate at Day 4. The severity of the subject CABP symptoms of 
dyspnea (shortness of breath), cough, production of purulent sputum, and pleuritic chest 
pain will be evaluated on a 4-point scale (absent, mild, moderate, or severe) based upon 
the CABP Symptom Severity Guidance in Appendix III.  
Table 13.2.1.-1. 
Clinical Outcome Assessment at Day 4. 
Outcome 
Definition 
Clinical 
Response 
Alive and programmatically-determined improvement of at least 1 level (e.g., severe to 
moderate, moderate to mild, mild to absent) in at least 2 CABP symptoms (dyspnea, 
cough, production of purulent sputum, and pleuritic chest pain) compared to Screening, 
without worsening in any other symptom. Severity of symptoms is based on a 4-point 
scale (absent, mild, moderate, or severe) (Appendix III). 
Clinical Non-
Response 
Meets any of the following criteria: 
 
No programmatically-determined improvement of at least 1 level in at least 2 
CABP symptoms compared to Screening 


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Table 13.2.1.-1. 
Clinical Outcome Assessment at Day 4. 
Outcome 
Definition 
 
Worsening in any of the 4 CABP symptoms compared to Screening 
 
Requires alternative rescue antibacterial therapy for CABP prior to Day 4 
 
Death from any cause prior to Day 4 
Indeterminate 
Study data are missing for evaluation of efficacy at Day 4 for any reason, including lost 
to follow-up. 
Abbreviations: CABP = community-acquired bacterial pneumonia. 
13.2.2 
Clinical Outcome at EOT or TOC 
An assessment of clinical outcome (cure, failure, or indeterminate) will be made by the 
Investigator at EOT (conducted on the day of, or within 2 days following, Day 7) or TOC 
(Day 15 ±3 days). Clinical outcome at EOT and TOC will be analyzed as secondary 
endpoints in the ITT and CE populations, and at TOC in the micro-ITT population. 
Clinical success and clinical failure are defined in Table 13.2.2-1. Clinical failure 
determined at any visit prior to TOC will be carried forward to subsequent assessment 
visits. 
Table 13.2.2-1. 
Clinical Outcome Assessments at EOT and TOC. 
Outcome 
Definition 
Clinical Cure 
Alive and CABP is sufficiently resolved such that further antibacterial therapy is not 
needed. These subjects may have some residual findings related to infection (i.e., 
cough) requiring non-antibiotic ancillary treatment (e.g., expectorant). Criteria for 
clinical failure or indeterminate (below) should not be met. 
Clinical Failure 
Meets any of the following criteria: 
 
Requires alternative rescue antibacterial treatment for CABP prior to the 
assessment (EOT or TOC) related to progression or worsening of CABP 
symptoms, development of infectious complications of CABP (e.g., empyema, 
lung abscess), or development of a TEAE that required discontinuation of study 
therapy 
 
Death from any cause prior to the assessment (EOT or TOC) 
Indeterminate 
Study data are missing for evaluation of efficacy at the assessment visit (EOT or TOC) 
for any reason, including lost to follow-up 
Abbreviations: CABP = community-acquired bacterial pneumonia; EOT = End-of-Therapy; TEAE = treatment-
emergent adverse event; TOC = Test-of-Cure. 
13.2.3 
Improvement in CABP Symptoms and Normalization of Vital signs at 
Study Day 4 
An assessment of improvement in CABP symptoms and normalization in vital signs at 
Study Day 4 will be made programmatically on Day 4. Improvement in CABP symptoms 
and normalization in vital signs is defined in Table 13.2.3-1. 
 


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Table 13.2.3-1    Improvement in CABP Symptoms and Normalization of Vital signs at 
Study Day 4. 
Outcome 
Definition 
Improvement in CABP 
Symptoms and Normalization 
of Vital signs at Study Day 4 
Meets all of the following criteria: 
 
Programmatically-determined improvement of at least 1 level in at 
least 2 CABP symptoms (dyspnea, cough, production of purulent 
sputum, and pleuritic chest pain) compared to Screening, without 
worsening in any other symptom (Appendix III) 
 
Normalization of all vital signs:  
o 
Temperature (oral, rectal, or tympanic) between 35.0°C and 
38.0°C 
o 
SBP between 90 and 140 mm Hg, or return to baseline SBP ± 5 
mm Hg  
o 
Heart rate less than 100 beats per minute  
o 
Respiratory rate less than 20 breaths per minute 
o 
Oxygen saturation ≥ 90% by pulse oximetry at room air 
 
Ability to maintain oral intake 
 
Normal mental status 
No Improvement in CABP 
Symptoms and Normalization 
of Vital signs at Study Day 4 
Does not meet all criteria for improvement in CABP symptoms and 
normalization in vital signs as defined above 
Indeterminate 
Study data are missing for evaluation of efficacy at Day 4 for any reason, 
including lost to follow-up. 
Abbreviations: CABP = community-acquired bacterial pneumonia; SBP = systolic blood pressure. 
13.2.4 
Hospitalization Prior to the Follow-Up Visit 
An assessment of hospitalization (defined as readmission to the hospital if previously 
hospitalized on or after study drug initiation [Day 1], or initial hospital admission (if not 
previously hospitalized) for any reason between the initiation of study drug (Day 1) and 
FU will be made programmatically based on information collected in the eCRF.  
For the purposes of this secondary efficacy assessment, “hospital admission” is defined 
as inpatient admission for at least 24 h in an acute care facility (including inpatient 
hospital ward or emergency room); in contrast, admission to nursing homes, assisted 
living facilities, rehabilitation units, or acute care facilities (hospital wards or emergency 
rooms) for less than 24 h is not considered a formal hospital admission. The assessment 
of hospitalization within 30 days of study drug initiation is defined in Table 13.2.4-1. 
Of note, adverse events that lead to readmission or new admission to the hospital will 
meet SAE criteria, as defined in Section 14.1.4. 
Table 13.2.4-1    Hospitalization Prior to the Follow-Up Visit 
Outcome 
Definition 
Hospitalization Prior to FU 
Meets any of the following criteria: 
 
Hospital readmission for any reason between Day 1 and FU Visit, 
if previously hospitalized and discharged  
 
Initial hospital admission for any reason between Day 2 and FU 
Visit, if not previously hospitalized on Day 1  


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Table 13.2.4-1    Hospitalization Prior to the Follow-Up Visit 
Outcome 
Definition 
No Hospitalization Prior to 
FU 
Does not meet the criteria for hospitalization within 30 days of study drug 
initiation as defined above, or till FU whichever is earlier. 
Indeterminate 
Study data are missing for evaluation of efficacy at FU Visit for any 
reason, including lost to follow-up. 
Abbreviations: FU = Follow-Up 
13.3 
MICROBIOLOGICAL OUTCOMES  
13.3.1 
Microbiological Outcomes at TOC 
An assessment of by-subject and by-pathogen microbiological response (favorable, 
unfavorable, or indeterminate) will be made at TOC (Day 15 ±3 days) in the micro-ITT 
and ME populations. Microbiological outcome categories at TOC are defined in 
Table 13.3.1–1. Favorable microbiological outcomes include eradication or presumed 
eradication.  
The by-subject microbiological outcome at TOC will be determined based on individual 
outcomes for each baseline pathogen; specifically, for a subject to have a favorable 
microbiological outcome, the outcome for each baseline pathogen must be favorable 
(eradicated or presumed eradicated). If the outcome for any pathogen is unfavorable 
(persistence or presumed persistence), the subject will be considered to have an 
unfavorable microbiological outcome. 
As CABP responds to therapy, obtaining repeated specimens for culture or examination 
may not be clinically appropriate and/or there may be no respiratory material for culture. 
However, if study drug is prematurely discontinued due to insufficient effect of study 
drug (e.g., failure at EOT or TOC, or clinical relapse at any time), an appropriate 
respiratory specimen and blood should be obtained for culture on the day of 
discontinuation (Section 12.6). 
Table 13.3.1–1. 
Microbiological Outcome Categories at TOC 
Outcome 
Definition 
Eradication 
Post-baseline respiratory specimen (e.g., respiratory fluid obtained by 
bronchoalveolar lavage or bronchoscopy; pleural fluid obtained by 
thoracentesis; or expectorated or induced sputum meeting adequacy 
criteria) culture or blood culture demonstrates absence of the original 
baseline pathogen 
Presumed eradication 
Post-baseline respiratory specimen culture or blood culture was not 
available and the subject was assessed as a clinical cure at TOC 
Persistence 
Post-baseline respiratory specimen culture or blood culture demonstrates 
continued presence of the original baseline pathogen. Note that post-
baseline urinary antigen tests for L. pneumophila or S. pneumoniae should 
not be performed (Section 12.3), and positive post-baseline urinary 
antigen tests (if performed) will not be considered as persistence. 
Presumed persistence 
Post-baseline respiratory specimen culture or blood culture was not 


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available and the subject was assessed as a clinical failure at EOT or TOC 
Indeterminate 
Post-baseline respiratory specimen culture or blood culture was not 
available and the subject’s clinical response was assessed as indeterminate 
Abbreviations: EOT = End-of-Therapy; TOC = Test-of-Cure. 
CABP caused by pathogens first appearing after Screening (emergent infections) will be 
categorized as either superinfections or new infections as defined in Table 13.3.1-2. 
Emergent infections will not be considered in the by-subject or by-pathogen 
microbiological response analyses described above. 
Table 13.3.1-2 Emergent Infections 
Category 
Definition 
Superinfection 
Isolation of a new pathogen(s) (other than the original CABP pathogen[s]) 
from an appropriate post-baseline respiratory specimen (e.g., respiratory 
fluid obtained by bronchoalveolar lavage or bronchoscopy; pleural fluid 
obtained by thoracentesis; or expectorated or induced sputum meeting 
adequacy criteria) culture or blood culture, which is accompanied by signs 
and symptoms of infection requiring alternative systemic antimicrobial 
therapy during the period up to and including EOT 
New infection 
Isolation of a new pathogen(s) (other than the original CABP pathogen[s]) 
from an appropriate post-baseline respiratory specimen culture or blood 
culture, which is accompanied by signs and symptoms of infection 
requiring alternative systemic antimicrobial therapy in the time period after 
EOT (e.g., TOC) 
Abbreviations: CABP = community-acquired pneumonia; EOT = End of Treatment; TOC = Test-of-Cure. 


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14.0 
SAFETY EVALUATION 
Subjects must be evaluated by a physician or an appropriately trained healthcare 
professional at every study visit, and the evaluation must be documented. The procedures 
discussed below will be completed at the designated visits as outlined in Section 11.0.  
14.1 
ADVERSE EVENTS 
14.1.1 
Adverse Event Definition 
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. An AE can, therefore, be any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product (ICH-E2A guideline). 
Adverse events may also include post-treatment complications that occur as a result of 
protocol-mandated procedures (e.g. invasive procedures such as venipuncture and 
biopsy). Pre-existing events that increase in severity or change in nature during, or as a 
consequence of, use of a medicinal product in a human clinical study will also be 
considered AEs. 
Any preexisting medical condition or diagnosis associated with a clinically significant 
laboratory abnormality should be documented in the CRF. 
 
An AE does not include the following: 
 Medical or surgical procedures (e.g. surgery, endoscopy, tooth extraction, 
transfusion); the condition that necessitates the procedure is an AE. Any pre-
existing medical condition that necessitates a procedure during the study should 
not be captured as an AE, and the condition should be listed in the medical 
history. 
 Any pre-existing disease or condition or laboratory abnormality present or 
detected prior to the start of the study treatment regimen that does not worsen  
 Laboratory abnormalities without clinical manifestations, which do not require 
medical intervention, or that do not result in termination or delay of study drug 
administration   
 Situations where an untoward medical occurrence has not occurred (e.g. 
hospitalization for elective surgery, social and/or convenience admissions) 
 Overdose of any study treatment or concomitant medication without any signs or 
symptoms, unless the subject is hospitalized for observation 
 Progression of the index CABP or insufficient therapeutic effect of study drug, 
which is captured as an efficacy outcome (i.e., clinical failure at EOT or TOC) 


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 Progression of disease or insufficient therapeutic effect which causes new 
hospitalization (in subjects not previously hospitalized for the index CABP), 
rehospitalization (in subjects that were previously hospitalized for the index 
CABP and discharged); however, if this leads to death, it should be recorded as a 
serious adverse event (SAE) (Section 14.1.3). 
A TEAE is defined as an AE or SAE that occurs during or after the first administration of 
study drug and up through the FU visit. 
A life-threatening AE is an AE that, in the view of either the Investigator or Sponsor, 
places the subject at immediate risk of death.  It does not include an AE that, had it 
occurred in a more severe form, might have caused death. 
An AE is considered “unexpected” if it is not listed in the IB or is not listed at the 
specificity or severity that has been observed; or, if an IB is not available, is not 
consistent with the risk information described in the general investigational plan. For 
example, under this definition, hepatic necrosis would be unexpected (by virtue of greater 
severity) if the IB referred only to elevated hepatic enzymes or hepatitis. Similarly, 
cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of 
greater specificity) if the IB listed only cerebral vascular accidents. "Unexpected," as 
used in this definition, also refers to AEs that are mentioned in the IB as occurring with a 
class of drugs or as anticipated from the pharmacological properties of the drug, but are 
not specifically mentioned as occurring with the particular drug under investigation. 
Progressive worsening of the index CABP or insufficient therapeutic effect of study drug 
that leads to hospitalization or death (i.e., SAE criteria, Section 14.1.4) is considered 
expected―as part of potential disease progression―and not unexpected. 
Some AEs are listed in the IB as occurring with the same class of drugs, or as anticipated 
from the pharmacological properties of the drug, even though they have not been 
observed with the drug under investigation. Such events would be considered unexpected 
until they have been observed with the drug under investigation. 
The list of AEs included in the current version of the Investigator’s Brochure will be used 
as reference safety information. 
14.1.2 
Relatedness to Study Drug 
For each reported AE, the Investigator must make an assessment of the relationship of the 
event to the study drug using the following scale: 
 Unrelated: The event is definitely not associated with administration of the study 
treatment, and is judged clearly due to causes other than the study treatment. 
Clinical failure of CABP due to insufficient therapeutic effect of study drug is 
also considered “unrelated” to study drug. 
 Related: The event is possibly or probably associated with administration of study 
treatment. Possibly-related events follow a reasonable temporal sequence from 
administration of study treatment, but may be due to another cause and could also 
be reasonably explained by the subject's clinical state or other modes of therapy 


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administered to the subject. Probably-related events follow a reasonable temporal 
sequence from administration of the study treatment, but are not easily explained 
by another cause such as known characteristics of the subject’s clinical state or 
other treatment, and are confirmed by improvement after stopping the study 
treatment.  
These criteria, in addition to good clinical judgment, should be used as a guide for 
determining the causal assessment.  If the event is believed to be unrelated to the study 
treatment, then an alternative explanation should be provided. 
14.1.3 
Severity Assessment 
The Investigator will be asked to provide an assessment of the severity of the AE using 
the following categories: mild, moderate, or severe (Table 14.1.3-1).  This assessment is 
subjective and the Investigator should use medical judgment to compare the reported AE 
to similar types of events observed in clinical practice.  Severity, which is a description of 
the intensity of manifestation of the AE, is distinct from seriousness, for which specific 
SAE criteria are met (Section 14.1.4).   
 
Table 14.1.3-1:  Severity Assessments of Adverse Events. 
Mild 
Symptom(s) barely noticeable to the subject or does not make the subject 
uncomfortable.  The AE does not influence performance or functioning.  
Prescription drugs are not ordinarily needed for relief of symptom(s). 
Moderate 
Symptom(s) of a sufficient severity to make the subject uncomfortable.  
Performance of daily activities is influenced. Treatment of symptom(s) may be 
needed.  
Severe 
Symptom(s) of a sufficient severity to cause the subject severe discomfort.  
Severity may cause cessation of treatment with the drug.  Treatment for 
symptom(s) needed. 
 Abbreviation: AE = Adverse event. 
14.1.4 
Serious Adverse Events 
An SAE is any adverse experience that occurs from the signing of the informed consent 
to the FU visit and that results in any of the following outcomes: 
 Death  
 Life-threatening situation (subject is at immediate risk of death) 
 Inpatient hospitalization or prolongation of existing hospitalization  
 Persistent or significant disability/incapacity 
 Congenital anomaly/birth defect in the offspring of a subject who received study 
treatment 
 Events that jeopardize the subject sufficiently that medical or surgical intervention 
may be required to prevent one of the above outcomes.  Examples may include, 
but are not limited, to: 


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o Intensive treatment in an emergency room for allergic bronchospasm 
o Blood dyscrasias that do not result in hospitalization 
o Seizures that do not result in hospitalization 
Progression of disease or insufficient therapeutic effect which causes new 
hospitalization (in subjects not previously hospitalized for the index 
CABP), rehospitalization (in subjects that were previously hospitalized for 
the index CABP and discharged) is not a SAE; however, if this leads to 
death, it should be recorded as a serious adverse event (SAE) (Section 
14.1.3) 
The Sponsor is required to inform worldwide regulatory authorities of SAEs that meet 
specific criteria. Therefore, the Sponsor must be notified immediately regarding any SAE 
that occurs after informed consent is obtained. All SAEs and follow-up information must 
be reported within 1 business day, or 24 h as required by local regulations, by faxing a 
completed SAE Report Form to the fax number below (Table 14.1.4-1) or emailing a 
completed SAE Report Form to the 
 at
.  
Table 14.1.4-1:  Toll-free Safety Line Numbers for SAE Reporting*. 
Country 
Toll-free Safety Line Numbers 
Bulgaria 
 
Georgia 
 
Latvia 
 
Republic of South Africa 
 
Romania 
 
 
Russia 
 
 
 
USA 
 
 
 
*Any fax sent to these lines will be routed to 
 
. 
 
Supplemental information for each SAE should be submitted as soon as available and 
may include laboratory results, radiology reports, progress notes, hospital admission and 
emergency room notes, holding and observation notes, discharge summaries, autopsy 
reports, and death certificates. 


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The Investigator is expected to take all therapeutic measures necessary for resolution of 
the SAE. Any medications or procedures necessary for treatment of the SAE must be 
recorded in the eCRF. All SAEs are to be followed until resolution or until the SAE is 
deemed stable. The Sponsor may contact the study center to solicit additional information 
or follow up on the event. 
14.1.5 
Recording and Reporting Adverse Events 
All AEs and SAEs will be recorded and reported from the signing of the informed 
consent form (ICF) to the time of the FU Visit. The Investigator must instruct the subject 
to report AEs and SAEs during this time period. Reports of death within 30 days after the 
last contact with the subject will be reported to the Sponsor and additional information 
relative to the cause of death will be sought and documented.   
All AEs and SAEs must be recorded on source documents. All AEs and SAEs for 
subjects who receive a treatment assignment will be recorded in the eCRF. 
The Investigator must follow-up as medically necessary on all AEs and SAEs until the 
events have subsided, the condition has returned to baseline, or in case of permanent 
impairment, until the condition stabilizes. 
AEs should be based on the signs or symptoms detected during the physical examination 
and on clinical evaluation of the subject.  In addition to the information obtained from 
those sources, the subject should be asked the following nonspecific question: "How have 
you been feeling since your last visit?"  Signs and symptoms should be recorded using 
standard medical terminology. 
Any unanticipated risks to the subjects must be reported promptly to the relevant ethics 
committee(s) and regulatory agency(ies). 
14.1.6 
Reporting of Pregnancies Occurring During the Study 
Study center personnel must report every pregnancy from the time the subject signs the 
ICF through the FU Visit. Within 24 h of learning of the pregnancy, the study center 
personnel must report the event on the Clinical Trial Pregnancy Form and fax or email it 
to the SAE/Pregnancy fax number or email provided in Section 14.1.4, even if no AE has 
occurred. Pregnancies in female partners of male subjects occurring during the time 
frame described above must also be reported. 
The pregnancy must be followed to term and the outcome reported by completing the 
Clinical Trial Pregnancy Form. If the pregnancy is associated with an SAE (e.g., if the 
mother is hospitalized for hemorrhage), a separate SAE Form for Clinical Trials must be 
filed as described in Section 14.1.4 with the appropriate serious criterion (e.g., 
hospitalization) indicated, in addition to the Clinical Trial Pregnancy Form. 


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14.2 
CLINICAL ASSESSMENTS 
Safety parameters will be monitored according to standard medical practice and 
guidelines for oral administration of study drug. Vital sign assessments (temperature, 
blood pressure, pulse, respiratory rate, and oxygen saturation), medical history, prior and 
concomitant medications, height, weight, and physical examination findings will be 
conducted at the specified time points outlined in the Schedule of Assessments and 
Procedures (Table 3–1) and Section 11.0. 
14.3 
LABORATORY ASSESSMENTS 
Blood samples for clinical laboratory tests and blood/urine samples for pregnancy tests 
will be collected at baseline and throughout the study according to the Schedule of 
Assessments and Procedures (Table 3–1) and Section 11.0.  
Unscheduled clinically-indicated laboratory tests (emergency or unscheduled tests) 
should be conducted at the local or regional laboratory on an as-needed basis. 
14.4 
DATA MONITORING COMMITTEE 
An internal, blinded Data Monitoring Committee (DMC) will be utilized in this study. 
The DMC will perform periodic reviews of blinded data from the study to evaluate 
subject safety, compliance with the study protocol, and the quality of data. Safety of 
study drug will be monitored by reviewing AEs, SAEs, and the safety laboratory 
assessments on a regular basis. If specific issues are identified that warrant more 
extensive review, the DMC will recommend that experts external to the company review 
the data and provide a formal opinion of their significance and recommend any necessary 
interventions. 


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15.0 
PHARMACOKINETIC EVALUATION 
The PK data acquisition and analysis strategy entails the use of a sparse PK sampling 
schedule. Pharmacokinetic samples will be obtained from all subjects at sites where PK 
sampling is possible (for which a study center has been identified by the Sponsor as 
ineligible to perform PK assessments). 
Pharmacokinetic sample handling and shipping procedures are described in the PK 
Sample Handling and Shipping Manual. 
15.1 
PHARMACOKINETIC BLOOD SAMPLE COLLECTION 
Efforts will be made to obtain PK samples from all subjects on Day 3 and Day 4 at sites 
where PK sampling is possible, as described below. Blood samples for PK analyses will 
be collected at the following times: 
 Day 3: Pre-dose sample will be collected within 10 minutes before administration 
of study drug  
 Day 3: Post-dose at 2-4 h; subjects who have been hospitalized are also required 
to have a post-dose PK sample at 6-10 h 
 Day 4: 24-28 h after the Day 3 dose.  
Refer to the PK Manual for additional details regarding PK sample collection times and 
handling instructions. 
15.2 
PHARMACOKINETIC ANALYSES 
Plasma samples from nafithromycin-treated subjects will be analyzed to determine 
concentrations of nafithromycin using a validated assay. 
The PK Population in this study will include all subjects in the Safety Population who 
received at least 1 dose of oral nafithromycin and had at least 1 analyzable plasma PK 
sample (Section 16.1.6).  


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16.0 
STATISTICAL METHODS 
16.1 
STUDY POPULATIONS 
16.1.1 
Safety Population 
The safety population will include all randomized subjects who receive any amount of 
study drug (nafithromycin or moxifloxacin). Subjects will be analyzed according to the 
treatment actually received.   
16.1.2 
Intent-to-Treat Population (ITT) 
The ITT population will include all subjects who were randomized. 
16.1.3 
Microbiological Intent-to-Treat Population (micro-ITT) 
The micro-ITT population will include all ITT subjects who have a at least one baseline 
Gram-positive or atypical bacterial pathogen known to cause CABP, including bacterial 
pathogens identified by respiratory specimen culture (e.g., respiratory fluid obtained by 
bronchoalveolar lavage or bronchoscopy; pleural fluid obtained by thoracentesis; or 
expectorated or induced sputum meeting adequacy criteria), blood culture, urinary 
antigen test (S. pneumoniae, L. pneumophila), or atypical bacterial serologic response (M. 
pneumoniae, C. pneumoniae, L. pneumophila). Subjects with sole baseline Gram-
negative bacterial infection will be excluded from this population.   
16.1.4 
Clinically-Evaluable Population (CE) 
The CE population will include all ITT subjects who follow important components of the 
trial. Sufficient information regarding the clinical course of CABP must be available to 
determine the subject’s clinical outcome at TOC, and the subject must not have 
confounding factors that interfere with the assessment of that outcome.  
In order to be included in the CE population, subjects must meet all of the following 
criteria: 
 Meet the clinical disease criteria for CABP as described in Inclusion Criterion #3 
(Inclusion Criteria 3a–3e; Section 9.2)  
 Receive at least 1 dose of study drug 
 Do not receive non-study, potentially-effective, systemic antibacterial therapy 
between Day 1 and TOC (except in cases of treatment failure)  
 Have an Investigator-determined clinical response of clinical cure or clinical 
failure at TOC (unless determined to be a prior clinical failure at EOT)  
 Receive at least 80% of the intended doses of study drug therapy 


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 Receive at least 48 h of study drug therapy in order to be considered an evaluable 
clinical failure and at least 72 h of study drug therapy in order to be considered an 
evaluable clinical success 
16.1.5 
Microbiologically-Evaluable Population (ME) 
The ME population will include all subjects who meet both micro-ITT population 
(Section 16.1.3) and CE population (Section 16.1.4) criteria. 
16.1.6 
Pharmacokinetic Population 
The PK Population includes all subjects in the Safety Population who received at least 1 
dose of oral nafithromycin and had at least 1 analyzable plasma PK sample. 
16.2 
METHODS OF ANALYSIS 
This is an exploratory study and, therefore, is not powered for inferential statistical 
analyses and no formal comparisons between the treatment groups will be conducted.  
All data will be summarized separately by study drug (nafithromycin for 3 days, 
nafithromycin for 5 days, and moxifloxacin). Descriptive statistics (mean, standard 
deviation, median, minimum, and maximum) will be presented for continuous variables 
for each study drug. Frequency distributions (counts and percentages) will be presented 
for categorical variables.  
A comprehensive Statistical Analysis Plan will be prepared and finalized prior to 
database lock. 
16.2.1 
Determination of Sample Size 
Approximately 225 adult subjects with CABP will be enrolled in this study. 
Randomization will have a 1:1:1 (Arm A: Arm B: Arm C) allocation ratio; therefore, 
approximately 150 subjects will be randomized to receive active oral nafithromycin. The 
objectives of this Phase 2 study are to collect initial efficacy data and to evaluate the 
safety and PK of oral nafithromycin in subjects with CABP. The sample size chosen for 
this study is considered to be adequate to achieve the study objectives and provide 
sufficient data to inform the design of future definitive studies, including Phase 3 studies, 
of nafithromycin. Assuming a 78% clinical response rate at Day 4 in the oral 
nafithromycin treatment arms, the sample size of 75 subjects per treatment arm will yield 
a 95% confidence interval around the response rate of 66.9% to 86.7%. 
16.2.2 
Analysis of Disposition and Subject Characteristics 
Subject disposition (enrolment, discontinuations from the study), study drug 
administered, premature discontinuations from study medication, withdrawals from the 
study, and major protocol deviations will be summarized by treatment group in the ITT 
Population.  


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Demographics and baseline characteristics such as age, sex, race, weight, and medical 
history will be summarized by treatment group in the ITT using means, standard 
deviations, medians, minima and maxima for continuous variables, and counts and 
percentages for categorical variables.  
16.2.3 
Efficacy Analyses 
16.2.3.1 
Primary Efficacy Analysis  
The primary efficacy evaluation will be the by-subject clinical response at Day 4 in the 
ITT population. Each subject will be classified programmatically as a responder, non-
responder, or indeterminate based on CABP symptom data entered in the e-CRF (Section 
13.2.1).   
The number and percentage of subjects in each treatment group classified 
programmatically as a responder, non-responder and indeterminate will be reported.  
Exact 95% confidence intervals around the percentage of subjects classified as 
responders will be calculated for each treatment group using the Clopper-Pearson 
Method.  The treatment difference will also be determined and a 95% confidence for the 
difference will be calculated using the method of Miettinen-Nurminen. Individual subject 
data will also be displayed as a listing.  
16.2.3.2 
Secondary Efficacy Analyses  
The secondary analysis variables are listed in Section 13.1. 
For analyses of the variables above that measure clinical success on a per-subject basis 
(i.e., clinical cure, improvement in CABP symptoms and normalization in vital signs at 
Day 4, lack of readmission or new admission to the hospital), the number and percentage 
of subjects in each treatment group in the specified population(s) classified as clinical 
success, clinical failure, and indeterminate (as applicable to each secondary analysis; 
Section 13.2) at the specified time point(s) will be tabulated. The difference between 
treatment groups in clinical success and 2-sided 95% CI for the difference also will be 
included in the tabulation. 
The per-pathogen and per-subject microbiological efficacy analyses will be conducted in 
the micro-ITT and ME Populations at TOC. Per-subject responses will be based on per-
pathogen outcomes (Section 13.3). These responses include eradication, presumed 
eradication, persistence, and presumed persistence. Of these responses, eradication and 
presumed eradication will be regarded as a favorable outcome. Persistence and presumed 
persistence will be regarded as an unfavorable outcome. To have an overall favorable 
microbiologic response, the outcome for each baseline pathogen must be favorable. 
Microbiological outcomes in the ME Population, by definition, will not include subjects 
with indeterminate responses.  


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The number and percentage of subjects in each treatment group recorded as having a 
favorable and unfavorable microbiologic response will be tabulated. Since this is an 
exploratory study, no statistical comparison between treatment groups is planned. In 
addition, a table summarizing the number and percent of all responses for each treatment 
group will be displayed. Individual subject data will also be displayed as a listing. 
Emergent infections (i.e., superinfection, new infection) will not be considered in the by-
subject or by-pathogen microbiological response and will be provided in separate listings 
(Section 13.3.1; Table 13.3.1-2). 
16.2.4 
Safety Analyses 
Evaluation of the safety and tolerability of oral nafithromycin for 3 or 5 days in the 
treatment of CABP is an important primary objective for this Phase II study. Safety will 
be analyzed in the Safety Population (Section 16.1.1). Subjects in the Safety Population 
will be analyzed according to the treatment actually received.  
Safety will be evaluated by presenting summaries of AEs, physical examinations, vital 
signs, laboratory evaluations (hematology evaluation, chemistry panel, UA, and ECG 
parameters). For each safety parameter, the last assessment made prior to the first 
administration of study drug will be used as the baseline value for all analyses. 
The incidence of TEAEs (defined in Section 14.1.1) will be presented by system organ 
class and preferred term according to MedDRA®, by relationship to the administration of 
study drug, and by severity. In addition, the incidence of SAEs and AEs leading to 
discontinuation of study drug will be presented by system organ class, preferred term, 
and relationship to study drug.  If the incidence of SAEs and AEs leading to 
discontinuation of study drug is low, only a listing will be provided.  
Descriptive statistics of vital signs at each time point measured, as well as the change 
from baseline and PCS changes, will be presented. Descriptive statistics for ECGs and 
physical examinations will also be presented for each time point measured. The number 
and percentage of subjects with a normal physical exam result at baseline and an 
abnormal physical examination result at a follow-up assessment will be provided for each 
time point. Descriptive statistics for clinical laboratory tests and vital signs and for the 
change from baseline will be presented by study visit. Potentially clinically significant 
clinical laboratory results will be determined based on normal limits and percent change 
from baseline. 
16.2.5 
Pharmacokinetic Analyses 
See Section 15.0. 
16.3 
INTERIM ANALYSIS 
No interim analysis is planned for this study. 


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16.4 
HANDLING OF DROPOUTS AND MISSING DATA 
Every effort will be made to collect all data at specified times. A detailed description of 
the handling of dropouts and missing data for all efficacy and safety evaluations will be 
provided in the SAP. 


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17.0 
INVESTIGATOR REQUIREMENTS 
17.1 
PROTOCOL ADHERENCE 
Each Investigator must adhere to the protocol as detailed in this document and agree that 
the Sponsor or Sponsor representative must approve any change to the protocol before 
seeking approval from the relevant ethics committee(s) and regulatory agency(ies). Each 
Investigator will be responsible for enrolling only those subjects who have met the 
protocol inclusion and exclusion criteria. 
17.2 
ELECTRONIC CASE REPORT FORMS AND DATA CAPTURE 
SYSTEM 
Data collection will involve the use of an Electronic Data Capture (EDC) system, to 
which only authorized personnel will have access. Electronic case report forms will be 
used to capture study data in an EDC system. Entering of eCRFs should be handled in 
accordance with instructions from the Sponsor or Sponsor representative. All eCRFs 
must be completed by qualified study center personnel. Each Investigator is responsible 
for ensuring that accurate data are entered into the EDC system in a timely manner. 
Before the first subject is dosed at the investigational site, the Sponsor or Sponsor 
representative will meet with the Investigator and the study center’s personnel to train 
them on recording the data on the eCRFs using the EDC system. The Investigator or 
designee will be responsible for reviewing eCRFs, resolving data queries generated by 
the Sponsor via the system, providing missing or corrected data, approving all changes 
performed on the subject data, and endorsing these data within the EDC system. This 
approval method will include applying an electronic signature, a uniquely assigned user 
name, and a password that together will represent a traditional handwritten signature. 
Queries may be issued electronically to the clinical study center and answered 
electronically by that study center’s personnel. The identifying information (assigned 
user name, date, and time) for both the originator of the query and the originator of the 
data change (if applicable) will be collected. 
All data collected in the context of this study will be stored and evaluated per regulatory 
requirements and applicable guidance for electronic records. 
17.3 
SOURCE DOCUMENT MAINTENANCE 
Source documents may include, but are not limited to, study progress notes, study- or 
subject-specific e-mail correspondence, computer printouts, laboratory data, and recorded 
data from automated instruments, study drug accountability records. The original signed 
ICF for each participating subject shall be filed with records kept by the Investigator. All 
documents produced in this study will be maintained by the Investigator and made 
available for inspection by the Sponsor or Sponsor representative and applicable 
regulatory authorities.  


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17.4 
STUDY MONITORING REQUIREMENTS 
The Sponsor or Sponsor representative will conduct center visits to inspect study data, 
subjects’ medical records, and eCRFs in accordance with current ICH E6 Good Clinical 
Practice (GCP) guideline, and the respective US, EU and local regulations and 
guidelines, as applicable. The Sponsor or Sponsor representative will also be able to 
review query status remotely, which may warrant additional communication with the 
Investigator and the study center’s personnel. The Investigator will make available to the 
Sponsor, or Sponsor representative, source documents, signed ICFs, and all other study-
related documents. 
The Investigator will allow the Sponsor or Sponsor representative and applicable 
regulatory authorities to inspect facilities and records relevant to this study. 
17.5 
STUDY COMPLETION 
The Sponsor requires the following data and materials before the study can be considered 
complete or terminated: 
 Clinical and laboratory results from Screening through TOC 
 eCRFs properly completed by appropriate study personnel and signed and dated 
by the Investigator within the EDC system. This approval method will include 
applying an electronic signature, a uniquely assigned user name, and a password 
that together will represent a traditional handwritten signature 
 Copies of complete study drug accountability records (e.g., study drug inventory 
logs and shipment and return records) 
 Copies of all relevant ethics committee(s) and regulatory agency(ies) approvals 
and acknowledgements 
 A summary of the study prepared by the Investigator (an ethics committee or 
regulatory agency summary letter is acceptable) 


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18.0 
PROTECTION OF HUMAN SUBJECTS AND GENERAL STUDY 
ADMINISTRATION 
18.1 
STATEMENT OF COMPLIANCE 
This study will be conducted in compliance with the current ICH E6 GCP guideline, the 
ethical principles of the Declaration of Helsinki, current FDA, European Union clinical 
trials related guidelines, and any additional relevant ethics committee or regulatory 
agency-required procedures, whichever represents the greater protection for the 
individual. 
Investigators will apply due diligence to avoid protocol deviations. No authorized 
deviations or protocol waivers will be permitted. All significant protocol deviations will 
be recorded and reported in the clinical study report. 
18.2 
SUBJECT CONFIDENTIALITY 
The Sponsor, its designee, the Investigator and all parties involved will comply with 
applicable subject data privacy regulations/guidance as per international and local 
requirements. The Investigator must assure that the privacy of the subjects, including 
their identity and all personal medical information, will be maintained at all times. In 
eCRFs and other documents or image material submitted to the Sponsor, subjects will be 
identified not by their names, but by an identification code (e.g., initials and identification 
number). 
Personal medical information may be reviewed for the purpose of subject safety and/or 
verifying data in the source and transcribed onto the eCRF. This review may be 
conducted by the study monitor, properly authorized persons on behalf of the Sponsor, 
the quality assurance unit, and/or regulatory authorities. Personal medical information 
will always be treated as confidential. 
18.3 
INFORMED CONSENT 
This study will be conducted in compliance with the current ICH E6 GCP guideline 
pertaining to informed consent, the current US CFR (Title 21, Parts 50 Subparts B and D, 
56 and 312) as well as relevant European and local guidelines. Subjects will give written 
consent to participate in the study at the first visit, before initiation of any study-related 
procedures, after having been informed about the nature and purpose of the study, 
participation and termination conditions, risks, and benefits. If a subject is unable to 
provide written informed consent, the subject’s legally acceptable representative(s) may 
provide written consent, as approved according to institution specific guidelines. The ICF 
must be signed and dated by the subject, or the subject’s legally authorized 
representative(s), before study participation. An original copy of the signed ICF must be 
provided to the subject or legally acceptable representative(s). If applicable, the ICF will 
be provided in certified translation (native language) for non-English-speaking subjects. 
Signed ICFs must remain in the subjects’ study files and be available for verification by 
the Sponsor or Sponsor representative at any time. 


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18.4 
ETHICS COMMITTEE APPROVAL 
The relevant ethics committee(s) and regulatory agency(ies) must approve the protocol or 
amended protocol (if applicable) and the corresponding ICF before the study may be 
initiated as per local requirements; any recruiting materials before use; and subsequent 
amended protocols and corresponding ICFs, before instituting amendment-specified 
changes to the study, unless required for subject safety following the local legislation.  
The Investigator is responsible for informing the relevant ethics committees and 
regulatory authorities of any changes made to the protocol, and to advise the relevant 
ethics committees and regulatory authorities , at least once a year, about the progress of 
the study. The Investigator (or Sponsor, if applicable) is also responsible for notifying the 
relevant ethics committees and regulatory authorities of any significant AEs that occur 
during the study according to local ethics committee requirements. 


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19.0 
DATA HANDLING AND RECORD KEEPING 
Training sessions, regular monitoring of the investigative center by the Sponsor or 
Sponsor representative, instruction manuals, and data verification, crosschecking, and 
auditing will be provided or performed to ensure quality of all study data. One or more 
Investigator meetings will be held to prepare the Investigator and other study personnel 
for appropriate collection of study data. 
The Sponsor or Sponsor representative will review and validate study data as defined in 
the monitoring plan. 
It will be the responsibility of the Investigator to ensure that the essential documents are 
available in the Investigator’s files or at the institutional center. Any or all of these 
documents should be available for monitoring by the Sponsor or Sponsor representative 
and inspection by the regulatory authorities as defined in the monitoring plan. 
19.1 
STUDY DRUG ACCOUNTABILITY 
It is the responsibility of the Investigator or designee to ensure that current records of 
study drug inventory and accountability are maintained. Records must be readily 
available for inspection by the Sponsor or Sponsor’s Representative and open to 
inspection at any time by applicable regulatory authorities. 
19.2 
RETENTION AND REVIEW OF RECORDS 
Records and documents pertaining to the conduct of this study in all formats (including, 
but not limited to, written, electronic, magnetic, and optical records and scans/X-rays) 
must be retained by the Investigator for a period of at least 15 years after study 
completion unless local regulations or institutional policies require a longer retention 
period or otherwise notified in writing by the Sponsor. These records include CRFs, 
source documents, ICFs, regulatory documents, clinical reports and laboratory results 
(including, but not limited to, all local and central laboratory and microbiology results), 
and medication inventory records.  
No study records shall be destroyed without notifying the Sponsor and providing the 
Sponsor the opportunity to arrange long-term storage for such study records or 
authorizing in writing the destruction of these records after the required retention period. 
The Investigator must permit access to any documentation relating to the study upon 
request of the Sponsor or Sponsor representative, the corresponding relevant ethics 
committee(s) or regulatory agency(ies). If the Investigator for the study retires, relocates, 
or for other reasons withdraws from the responsibility of keeping study records, custody 
must be transferred to a suitable alternate custodian employee of the institution or to a 
suitably qualified and responsible third party. The Sponsor must be notified in writing of 
the name and address of the new custodian in advance of the transfer. 


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The Investigator agrees by his or her participation that the results of this study may be 
used for submission to national or international registration. If required, these authorities 
will be provided with the name of the Investigator and his or her address, qualifications, 
and extent of involvement. 
Data generated by this study must be available for inspection by applicable regulatory 
authorities, the Sponsor or Sponsor representative, and the relevant ethics committee(s) 
and regulatory agency(ies) as appropriate. At the request of a subject’s parent(s) or 
legally acceptable representative(s), medical information may be given to the subject’s 
personal physician or other appropriate medical personnel responsible for the subject’s 
welfare. 
19.3 
DECLARATION OF THE END OF STUDY AND CLINICAL 
STUDY REPORT 
For clinical investigational centers located in the EU, a declaration of the end of the 
clinical study will be made according to the procedures outlined in Directive 
2001/20/ED, Article 10(c); for other countries, local regulations will be followed. 
Last subject last visit is defined as completion of the FU visit for the final subject 
enrolled in the study. This will be considered the end of the trial for global clinical trial 
submission. 
Whether the study is completed or prematurely terminated, the Sponsor will ensure that 
the clinical study reports are prepared and provided to the regulatory authority(ies) as 
required by the applicable regulatory requirement(s). The Sponsor will also ensure that 
the clinical study reports in marketing applications meet the standards of the ICH 
Harmonised Tripartite Guideline E3: Structure and Content of Clinical Study Reports. 
Where required by applicable regulatory requirements, an Investigator signatory will be 
identified for the approval of the clinical study report. Upon completion of the clinical 
study report, the Sponsor will provide the Investigators with the full summary of the 
study results. The study results summary will also be made publicly available according 
to applicable FDA/EU requirements. 
 


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20.0 
FINANCING AND INSURANCE 
The financing and insurance for this study are outlined in the Clinical Trial Agreement. 


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21.0 
PUBLICATION POLICY 
The data generated in this clinical study are the exclusive property of the Sponsor and are 
confidential. The Sponsor will make all reasonable efforts to publish the results of the 
study in an appropriate peer-reviewed journal. Authorship on the primary publication of 
the results from this study will be based on contributions to study design, enrolment, data 
analysis, and interpretation of results. 


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22.0 
REFERENCES 
Arnold FW, Wiemken TL, Peyrani P, Ramirez JA, Brock GN, for the CAPO authors. 
Mortality diff erences among hospitalized patients with community-acquired pneumonia 
in three world regions: results from the Community-Acquired Pneumonia Organization 
(CAPO) International Cohort Study. Respir Med 2013;107:1101-11. 
Bader JC, Lakota EA, Rubino CM, Patel MV, Bhagwat SS, Ambrose PG, Bhavnani SM. 
Pharmacokinetic-pharmacodynamic (PK-PD) target attainment (TA) analyses to support 
WCK 4873 dose selection for the treatment of community-acquired bacterial pneumonia 
(CABP) [Abstract]. ASM Microbe 2016, Boston MA. 
Farrell DJ, Couturier C, Hryniewicz W. Distribution and antibacterial susceptibility of 
macrolide resistance genotypes in Streptococcus pneumoniae: PROTEKT Year 5 (2003–
2004). Int J Antimicrob Agents 2008;31:245-249. 
File TM, Low DE, Eckburg PB, Talbot GH, Friedland HD, Lee J, Llorens L, Critchley I, 
Thye D. Integrated analysis of FOCUS 1 and FOCUS 2: randomized, doubled-blinded, 
multicenter phase 3 trials of the efficacy and safety of ceftaroline fosamil versus 
ceftriaxone in patients with community-acquired pneumonia. Clin Infect Dis 2010a; 
51(12):1395-1405. 
File TM Jr, Marrie TJ. Burden of community-acquired pneumonia in North American 
adults. Postgrad Med 2010b;122:130-41. 
Fine MJ, Auble TE, Yealy DM, Hanusa BH, Weissfeld LA, Singer DE, Coley CM, 
Marrie TJ, Kapoor WN. A prediction rule to identify low-risk patients with community-
acquired pneumonia. N Engl J Med 1997;336:243-250. 
GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national 
age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–
2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 
2015;385:117-71. 
Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, Dowell 
SF, File TM, Musher DM, Niederman MS, Torres A, Whitney CG. Infectious Diseases 
Society of America/American Thoracic Society Consensus Guidelines on the 
Management of Community-Acquired Pneumonia in Adults. Clin Infect Dis 
2007;44:S27-S72 
Millett ER, Quint JK, Smeeth L, Daniel RM, Thomas SL. Incidence of community-
acquired lower respiratory tract infections and pneumonia among older adults in the 
United Kingdom: a population-based study. PLoS One 2013;8:e75131. 
Prina E, Ranzani OT, Torres A. Community-acquired pneumonia. Lancet Infect Dis 
2015;386:1097-1108. 


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Reinert RR. The antimicrobial resistance profile of Streptococcus pneumoniae. Clin 
Microbiol Infect 2009;15(Suppl 3):7-11. 
Richter SS, Diekema DJ, Heilmann KP, Dohrn CL, Riahi F, Doern GV. Changes in 
pneumococcal serotypes and antimicrobial resistance after introduction of the 13-valent 
conjugate vaccine in the United States. Antimicrob Agents Chemother 2014;58:6484-89. 
Woodhead M, Blasi F, Ewig S, Huchon G, Ieven M, Ortqviste A, Schaberg T, Torres A, 
van der Heijden G,Verheij TGM. Guidelines for the management of adult lower 
respiratory tract infections. Eur Respir J 2005;26:1138-1180. 


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23.0 
APPENDICES 
 


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APPENDIX I 
ALLOWED AND DISALLOWED PRIOR ANTIBIOTICS 
Allowed Antibiotics 
(One dose within 72 h prior to randomization*) 
Disallowed Antibiotics 
Penicillins 
Amoxicillin 
Nafcillin 
Benzathine/Penicillin-G Procaine 
Amoxicillin-Clavulanate 
Oxacillin 
 
Amoxicillin-Sulbactam 
Penicillin-G or -V 
 
Ampicillin 
Piperacillin 
 
Ampicillin-Sulbactam 
Piperacillin-Tazobactam 
 
Dicloxacillin 
Ticarcillin-Clavulanate 
 
Cephalosporins 
Cefaclor 
Cefpodoxime  
Cefixime (400 mg) 
Cefadroxil 
Cefprozil  
Ceftriaxone 
Cefazolin 
Ceftaroline  
Cefdinir 
Ceftazidime 
Cefepime 
Ceftibuten 
Cefixime (200 mg) 
Cefuroxime 
Cefditoren  
Cephalexin 
Cefotaxime  
Loracarbef 
Carbapenems 
Doripenem 
Imipenem 
Meropenem 
Ertapenem 
Glycopeptides 
Televancin 
Dalbavancin 
Vancomycin 
Oritavancin 
Fluoroquinolones 
Ciprofloxacin 
Levofloxacin 
Moxifloxacin 
Macrolides 
Clarithromycin 
Erythromycin 
Azithromycin 
Clarithromycin XL  
Tetracyclines 
Doxycycline (100 mg) 
Minocycline 
Doxycycline (200 mg) 
Minocycline Extended Release 
Tigecycline 
Oxazolidinones 
Linezolid 
Tedizolid 
Miscellaneous 
Clindamycin 
Metronidazole 
Trimethoprim-sulfamethoxazole/Co-trimoxazole 
 
*Prior (within 72 h prior to randomization) administration of potentially effective systemic antibacterial therapy is an 
Exclusion Criterion (Section 9.3); however, subjects may be eligible for the study despite prior antimicrobial therapy if 
they received a single dose of a single short-acting systemic antibiotic within 72 h prior to randomization.  For the 
purposes of this protocol, short-acting is defined as having a dosage frequency of more than once a day.  If a subject 
received a prior short-acting systemic antibiotic that is not listed here, the Investigator must contact the Medical 
Monitor to ensure subject eligibility. 


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APPENDIX II 
PORT SCORE CALCULATION 
Subject Characteristic 
Point Assignment 
Age 
Male 
Age (years) 
Female 
Age (years) -10 
Nursing home resident1 
+10 
Coexisting illnesses 
Neoplastic disease2 
+30 
Liver disease3 
+20 
Congestive heart failure4 
+10 
Cerebrovascular disease5 
+10 
Renal disease6 
+10 
Physical-examination findings 
Altered mental status7 
+20 
Respiratory rate ≥ 30/minute 
+20 
Systolic blood pressure < 90 mm Hg 
+20 
Temperature < 35°C (95°F) or ≥ 40°C (104°F) 
+15 
Pulse ≥ 125/minute 
+10 
Laboratory and radiographic findings 
Arterial pH < 7.35 8 
+30  
Blood urea nitrogen ≥ 30 mg/dL (11 mmol/L)6  
+20 
Sodium < 130 mmol/L 
+20 
Glucose ≥ 250 mg/dL (14 mmol/L)  
+10 
Hematocrit < 30% 
+10 
Partial pressure of arterial oxygen < 60 mm Hg or 
oxygen saturation < 90% (by pulse oximetry)8 
+10 
Pleural effusion 
+10 
PORT Score 
Sum of numbers above 
 
 
PORT Risk Class 
PORT Score 
I (ineligible for study) 
0-50 
II (eligible) 
51-70 
III (eligible) 
71-90 
IV (score of 91-105 eligible and 106-130 ineligible) 
91-130 
V (ineligible for study) 
≥ 131 
 
1. Subjects that reside in a nursing home are excluded from the study and should not be enrolled per 
Exclusion Criterion #1. 
2. Neoplastic disease is defined as any cancer, except basal or squamous cell cancer of the skin that was 
active at the time of presentation or diagnosed within one year of presentation.  Subjects with 
neoplastic lung disease are excluded from the study and should not be enrolled per Exclusion Criterion 
#7. 
3. Liver disease is defined as a clinical or histologic diagnosis of cirrhosis or another form of chronic 
liver disease, such as chronic active hepatitis.  Subjects with liver test abnormalities or evidence of 
end-stage liver disease as defined in Exclusion Criterion #8 should not be enrolled. 
4. Congestive heart failure is defined as systolic or diastolic ventricular dysfunction documented by 
history, physical examination, and chest radiograph, echocardiogram, multiple gated acquisition scan, 


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or left ventriculogram.  Subjects with acute congestive heart failure are excluded from the study and 
should not be enrolled per Exclusion Criterion #11. 
5. Cerebrovascular disease is defined as a clinical diagnosis of stroke or transient ischemic attack or 
stroke documented by magnetic resonance imaging or CT.   
6. Renal disease is defined as a history of chronic renal disease or abnormal blood urea nitrogen and 
creatinine concentrations documented in the medical record.  Subjects with compromised renal 
function are excluded from the study and should not be enrolled per Exclusion Criterion #8. 
7. Altered mental status is defined as disorientation with respect to person, place, or time that is not 
known to be chronic, stupor, or coma. 
8. For subjects without an optional ABG at Screening, no points will be added for pH or PaO2; however, 
oxygen saturation results should be used in place of PaO2.   
 
Reference: Fine, 1997. 
 


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APPENDIX III  
CABP SYMPTOM SEVERITY GUIDANCE FOR 
INVESTIGATOR ASSESSMENT 
CABP 
Symptom 
Absent 
Mild 
Moderate 
Severe 
Dyspnea 
(Shortness 
of Breath 
[SOB]) 
No CABP-
associated SOB; 
or return to pre-
CABP baseline 
SOB 
SOB with only 
strenuous activity but 
it does not interfere 
with subject’s usual 
daily activities; or 
mild SOB above pre-
CABP baseline 
SOB with usual 
activities and it does 
interfere with some of 
the subject’s usual 
daily activities; or 
moderate SOB above 
pre-CABP baseline  
SOB with minimal 
exertion or at rest 
and it limits most of 
the subject’s usual 
daily activities; or 
severe SOB above 
pre-CABP baseline 
Cough 
Resolution of 
cough; or return 
to pre-CABP 
baseline cough 
Cough present, 
infrequent, and it does 
not interfere with 
subject’s usual daily 
activities; or mild 
cough above pre-
CABP baseline 
Cough present, 
frequent, and it does 
interfere with some of 
the subject’s usual 
daily activities; or 
mild cough above pre-
CABP baseline 
Cough is present 
throughout the day 
and night; it limits 
most of the subjects’ 
usual daily activities 
and sleep patterns; 
or mild cough above 
pre-CABP baseline 
Production 
of Purulent 
Sputum 
No production of 
purulent sputum; 
or return to pre-
CABP baseline 
productive cough  
Production of small 
amount of purulent 
sputum; or minimal 
amount of sputum 
production above pre-
CABP baseline 
Production of 
moderate amount of 
purulent sputum; or 
moderate amount of 
sputum production 
above pre-CABP 
baseline 
Production of large 
amount of purulent 
sputum; or large 
amount of sputum 
production above 
pre-CABP baseline 
Pleuritic 
Chest Pain 
No CABP-
associated 
pleuritic chest 
pain 
CABP-associated 
pleuritic chest pain 
present occasionally 
with deep breathing 
but it does not 
interfere with 
subject’s usual daily 
activities 
CABP-associated 
pleuritic chest pain is 
present with normal 
breaths, and it does 
interfere with the 
subject’s usual daily 
activities 
CABP-associated 
pleuritic chest pain 
is present at rest 
and/or with shallow 
breathing, and it 
limits most of the 
subject’s usual daily 
activities 


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APPENDIX IV 
SAFETY LABORATORY TESTS CONDUCTED BY THE 
CENTRAL LABORATORY 
Hematology: 
 
Hemoglobin 
 
Hematocrit 
 
Erythrocyte count  
 
Mean red blood cell volume 
 
Mean red blood cell hemoglobin  
 
Mean red blood cell hemoglobin 
concentration  
 
Leukocyte count (WBC) 
 
Neutrophils (including immature 
neutrophils [bands] and absolute neutrophil 
count) 
 
Lymphocytes 
 
Monocytes 
 
Eosinophils 
 
Basophils 
 
Platelets 
 
Reticulocytes 
 
Coagulation: 
 
Prothrombin time/International normalized 
ratio (PT/INR) 
 
Partial thromboplastin time 
 
Urinalysis (only if local urine dipstick test 
abnormal and deemed clinically significant by 
the Investigator; see Section 11.1): 
 
Specific gravity 
 
pH 
 
Protein 
 
Glucose 
 
Ketones 
 
Bilirubin  
 
Occult blood 
 
Nitrites 
 
Urobilinogen 
 
Leukocyte esterase 
Chemistry (Serum Concentrations): 
 
Glucose 
 
Calcium  
 
Albumin  
 
Total protein  
 
Sodium  
 
Potassium  
 
Carbon dioxide 
 
Chloride  
 
Blood urea nitrogen (BUN) 
 
Creatinine  
 
Alkaline phosphatase  
 
Alanine aminotransferase (ALT) 
 
Aspartate aminotransferase (AST) 
 
Total and direct bilirubin 
 
Magnesium 
 
Lactate dehydrogenase (LDH) 
 
Phosphorus 
 
Uric acid 
 
Creatine kinase 
 
Gamma-glutamyl transferase (GGT) 
 
β-Human chorionic gonadotropin (β-HCG) 
for females 


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APPENDIX V  
ORAL MOXIFLOXACIN SUMMARY OF PRODUCT 
CHARACTERISTICS 
Insert SPC from Bayer plc, updated 26-August-2015, 
http://www.medicines.org.uk/emc/print-document?documentId=11841 
 
NDA 021085 AVELOX FDA Approved 8 May 2015 - Merck 
https://www.merck.com/product/usa/pi_circulars/a/avelox/avelox_pi.pdf 
 


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APPENDIX VI 
INVESTIGATOR SIGNATURE PAGE 
I have read and understand the protocol. I agree to the following: 
1. To conduct the study in compliance with Good Clinical Practice, with applicable 
regulatory requirement(s), and with the protocol agreed to by the Sponsor and 
given approval/favorable opinion by the Institutional Review Board, Independent 
Ethics Committee, or Competent Authority  
2. To comply with procedures for data recording and reporting 
3. To permit monitoring, auditing, and inspection by the Sponsor, its designated 
representatives, and regulatory authorities 
4. To retain the essential documents in the Investigator/Institution files until the 
Sponsor informs the Investigator or Institution that these documents are no longer 
needed 
_________________________________________ 
_______________________ 
Investigator Signature 
Date (DD Mmm YYYY) 
_________________________________________ 
Investigator Name (printed) 
_________________________________________ 
Site Name 
_________________________________________ 
Street Address 
_________________________________________ 
City, State/Province, Country, and Zip/Postal Code