Clinical trial NCT04160260
Conditions: Community-acquired Pneumonia
Sponsor: Paratek Pharmaceuticals Inc
Start date: 2019-11-28; Completion date: 2020-04-13
Enrollment: 18 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the pharmacokinetics of an oral omadacycline dosing regimen in the treatment of adults with CABP.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Omadacycline
Intervention descriptions: intervention 1: Omadacycline: PO Tablets

Protocol documents:
Prot_000.pdf: 
Clinical Trial Protocol:  PTK0796-CABPPO-19109
Study Title: 
A Phase 1 Multi-Center Study to Measure the Pharmacokinetics of 
Oral Omadacycline in Adult Subjects with Community-Acquired 
Bacterial Pneumonia (CABP) 
Study Number: 
PTK0796-CABPPO-19109 
Study Phase: 
1b 
Product Name: 
Omadacycline (PTK 0796) 
IND Number: 
75,928 
73,431 
Indication: 
Community Acquired Bacterial Pneumonia 
Investigators: 
Multicenter 
 
 
Sponsor: 
Paratek Pharma, LLC. 
A wholly-owned subsidiary of Paratek Pharmaceuticals, Inc. 
75 Park Plaza, 4th Floor  
Boston, MA 02116  
 
1000 First Ave  
Suite 200  
King of Prussia, PA 19406  
Sponsor 
Contact: 
Tel: +1 617-275-0040 
 
 
Global Medical 
Monitor: 
 
 
 
Original Protocol Version 1.1: 
26 August 2019 
Confidentiality Statement 
The concepts and information contained in this document or generated during the study are 
considered proprietary and may not be disclosed in whole or in part without the expressed, 
written consent of Paratek Pharma, LLC. 
The study was in accordance with the International Council on Harmonisation Harmonised 
Tripartite Guidelines for Good Clinical Practice. 


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SYNOPSIS 
Sponsor: 
Paratek Pharma, LLC.  
 
Name of Finished Product: 
Omadacycline oral tablet, 150 mg 
 
Name of Active Ingredient: 
Omadacycline  
 
Study Title:  
A Phase 1 Multi-Center Study to Measure the Pharmacokinetics of Oral Omadacycline in 
Adult Subjects with Community-Acquired Bacterial Pneumonia (CABP) 
 
Study Number: 
PTK0796-CABPPO-19109 
 
Study Phase:  1b 
 
Study Rationale: 
Omadacycline is an aminomethylcycline, a tetracycline class antibiotic, for intravenous 
(IV) or oral administration.  NUZYRA® (omadacycline) has been approved by the United 
States (US) Food and Drug Administration (FDA) for the treatment of adult patients with 
community-acquired bacterial pneumonia (CABP) caused by susceptible microorganisms.   
This study is intended to evaluate the pharmacokinetics (PK) of an oral dosing regimen on 
Days 1 and 2 in adults with CABP.  
 
Primary Objective:  
To evaluate the PK of per oral (po) only omadacycline in adults with CABP. 
 
Secondary Objectives: 
 To evaluate the safety of omadacycline in the treatment of adults with CABP.  
Exploratory Objectives: 
 To evaluate the efficacy of oral only omadacycline in the treatment of adults with 
CABP.  
Study Design: 
This is an open-label Phase 1b study evaluating oral omadacycline in the treatment of 
adults with CABP.   


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Subjects will initiate treatment with an oral loading dose of 300 mg BID on Day 1 
followed by 300 mg QD on subsequent days.  
Following a screening period of up to 24 hours, eligible subjects will be assigned to 
receive 7 to 10 days of po treatment. Subjects with baseline bacteremia (ie, confirmed 
from local blood culture drawn at screening) can receive up to 14 days of omadacycline 
treatment after consultation with the medical monitor. 
Subjects may receive oral treatment in either inpatient or outpatient settings, provided that 
all assessments can be completed at the timepoints required by protocol.     
Eligible subjects will be assigned to the following treatment group.   
Test Article 
Study Day 
Study Day 
Study Days 
1 
2 
3-10 
Omadacycline 
300 mg po BID 
300 mg po QD 
300 mg po QD 
po = per oral, a dosing day is a 24-hour day not a calendar day 
a The total duration of treatment is 7 to 10 days. Treatment duration can be extended to up to 14 days for 
subjects with bacteremia that, in the opinion of the investigator, requires more than 10 days of treatment.  
Refer to the Schedule of Events (Appendix 1) for the summary of subject visits and 
assessments through end of treatment (EOT).  
Subjects will return to the study site for a Post Therapy Evaluation (PTE) 5 to 10 days 
after the last dose of omadacycline.  A Final Follow-up visit (FFU) will be conducted 
within 30 to 37 days following the first dose of omadacycline.  The FFU assessment may 
be conducted via telephone contact or by another interactive technology for subjects who 
had an outcome of Clinical Success in the opinion of the investigator at EOT and PTE and 
had no adverse events (AEs) or clinically significant laboratory or electrocardiogram 
(ECG) abnormalities noted at or after the PTE visit.  Otherwise, this assessment must be 
performed with an in-person study visit.  
The planned length of subject participation in the study is up to 37 days.  
 
Rationale for Omadacycline Dose Regimen Selection: 
The dosing regimen of omadacycline selected for this study is based on the nonclinical and 
clinical experience to date, including in vitro antibacterial activity, PK characteristics, 
clinical efficacy in prior studies, the overall safety and tolerability profile, and the FDA 
approved dosing regimen for CABP.   
A regimen of 200 mg omadacycline administered by IV infusion OR 100 mg 
omadacycline administered by IV infusion every 12 hours (q12h) on Day 1 followed by 
100 mg of omadacycline administered by IV infusion once daily OR 300 mg of 
omadacycline administered orally once daily has been approved by US FDA for the 
treatment of adult patients with CABP and acute bacterial skin and skin structure infections 
(ABSSSI) caused by susceptible microorganisms.  In addition, an oral only regimen of 450 
mg for Days 1 and 2, followed by 300 mg has been approved by US FDA for ABSSSI.  


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The total approved treatment duration is 7 to 14 days.  The oral-only regimen is also being 
studied for the treatment of uncomplicated urinary tract infections (UTI). 
The duration for the po only regimen in this study will be 7 to 10 days.  The shorter 
regimen is supported by the efficacy observed in the previously completed CABP Phase 3 
study which included Pneumonia Outcomes Research Team (PORT) Risk Classification II, 
III, and IV subjects, PTK0796-CABP-1200, where by Day 7 of treatment, > 80% of 
patients in the omadacycline treatment group had symptom improvement (as defined by 
the Early Clinical Response endpoint) and had reached clinical stability.  The current study 
will be limited to PORT Risk Class II and III subjects only. 
Approximate Number of Subjects/Sites:  
Up to 30 subjects will be enrolled at approximately 5 sites in the US to ensure that at least 
20 subjects complete all PK sample collections.  The number may be adjusted as needed to 
meet this requirement. 
Approximate Duration of the Study: 
The study is expected to be complete in approximately 6 months.    


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Main Criteria for Inclusion: 
1. Written and signed informed consent must be obtained before any protocol specific 
assessment is performed.   
2. Male or female, age 18 years or older. 
3. Has at least 3 of the following symptoms: 
 Cough 
 Production of purulent sputum 
 Dyspnea (shortness of breath) 
 Pleuritic chest pain 
4. Has at least TWO of the following abnormal vital signs: 
 Fever or hypothermia documented by the investigator (temperature > 38.0°C 
[100.4°F] or < 36.0°C [95.5°F]) 
 Hypotension with systolic blood pressure (SBP) < 90 mm Hg 
 Heart rate > 90 beats per minute (bpm) 
 Respiratory rate (RR) > 20 breaths/minute 
5. Has at least 1 clinical sign or laboratory finding associated with CABP: 
 Hypoxemia (partial pressure of arterial oxygen [PaO2] < 60 mm Hg by arterial 
blood gas [ABG] or oxygen saturation < 90% by pulse oximetry) 
 Physical examination findings of pulmonary consolidation (eg, dullness on 
percussion, bronchial breath sounds, or egophony) 
 An elevated total white blood cell (WBC) count (> 12,000 cells/mm3) or 
leucopenia (WBC < 4,000 cells/mm3) or elevated immature neutrophils (> 15% 
band forms), see % bands calculation in Appendix 2 (regardless of total peripheral 
WBC count) 
6. Has disease categorized as being PORT Risk Class II or III at Screening where 
initiation of antibiotics with oral therapy is appropriate in the opinion of the 
investigator, whether inpatient or outpatient setting (see PORT Risk Class calculation 
in Appendix 4). 
7. Radiographically-confirmed pneumonia, ie, new or progressive pulmonary infiltrate(s) 
on chest X-ray (CXR) or chest computed tomography (CT) scan consistent with acute 
bacterial pneumonia within 48 hours prior to the first dose of test article.   
8. Ability to swallow up to 3 tablets in succession. 
9. Females must have a negative urine pregnancy test at Screening and agree to comply 
with using an acceptable method of birth control as per your local requirements (eg, 
abstinence, oral contraceptive, intrauterine device [IUD], barrier contraception 
[condom], tubal ligation, hysterectomy, bilateral oophorectomy, postmenopausal, or 
vasectomized partner) from Screening through PTE.  Males must agree to use an 
acceptable method of birth control with female partner(s) and must not donate sperm 
from Screening through PTE. 
Main Criteria for Exclusion: 
1. Has received more than 24 hours (ie, a single dose of a daily therapy or the 
recommended daily frequency of a short acting therapy) of a potentially effective 


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systemic antibacterial treatment within the 72 hours prior to the first dose of test article. 
A subject will be considered to have received a potentially effective systemic 
antibacterial treatment if the pathogen identified as causing infection is shown to be 
susceptible to the antibacterial given or, in the circumstance where a pathogen is not 
identified, if the antibacterial agent is approved for treatment of pneumonia or is 
known to have activity against any of the leading causes of CABP (eg, Streptococcus 
pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, 
Legionella pneumophila).   
2. Is known or suspected to have CABP caused by a pathogen that may be resistant to test
article (eg, Pseudomonas aeruginosa, Proteus spp., Morganella morganii,
Providencia spp., Pneumocystis jiroveci, obligate anaerobes, mycobacteria, fungal
pathogens).
3. Suspected or confirmed empyema (a parapneumonic pleural effusion is not an
exclusion criterion) or lung abscess.
4. Subjects who reside in a long-term care or subacute/intermediate healthcare facility
(eg, nursing home) or a subject diagnosed with pneumonia following a recent
hospitalization (overnight admission within 90 days prior to current admission).
5. Has a known history of having experienced unstable cardiac disease (eg, unstable
angina, myocardial infarction, acute congestive heart failure, unstable cardiac
arrhythmia) within the 3 months prior to Screening or presents with a tachyarrhythmia
(excluding sinus tachycardia).
6. Has any of the following at Screening:

alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 3 × upper
limit of normal (ULN)

total bilirubin > 1.5 × ULN

suspected or confirmed clinical evidence of end-stage liver disease (eg, ascites,
hepatic encephalopathy)
7. Requires any form of dialysis (eg, hemodialysis, peritoneal dialysis), has a history or
evidence of severe renal disease, or has a calculated creatinine clearance (CrCl)
of < 30 mL/minute, using the Cockcroft-Gault equation (see calculation in Appendix
2). 
8. Significant immunological compromise determined by any of the following:

Current or anticipated neutropenia defined as < 500 neutrophils/mm3

Known infection with Human Immunodeficiency Virus (HIV) 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

The receipt of cancer chemotherapy, radiotherapy, or potent, non-corticosteroid 
immunosuppressant drugs (eg, cyclosporine, azathioprine, tacrolimus,
immune-modulating monoclonal antibody therapy, etc.) within the past 3 months, 
or the receipt of corticosteroids equivalent to or greater than 40 mg of prednisone 
per day or for more than 14 days in the prior 30 days.  (see Appendix 2) Exception: 
Systemic corticosteroids administered within 24 hours of treatment group


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assignment or any time after treatment group assignment as adjunctive therapy for 
the current episode of CABP (at any dosage) is allowed. 
9. PORT Risk Class I, IV, or V patients. 
10. Known or suspected primary or metastatic neoplastic lung disease, aspiration 
pneumonia, active tuberculosis, cystic fibrosis, bronchiectasis, bronchial obstruction 
(eg, post-obstructive pneumonia), chronic neurological disorder preventing clearance 
of pulmonary secretions, or severe chronic obstructive pulmonary disease (COPD) 
(severe COPD is defined as known forced expiratory volume in 1 second [FEV1] < 
50% of predicted in a patient with FEV1/forced vital capacity [FVC] < 70%; note that 
spirometry or pulmonary function testing is not required during Screening).  
11. Has a life expectancy of less than or equal to 3 months. 
12. Pregnant or nursing (breastfeeding) women.  
13. Has any contraindication to receiving a tetracycline, including: 
 History of hypersensitivity or allergic reaction (eg, anaphylaxis, urticaria, other 
significant reaction) to any tetracycline (eg, minocycline, doxycycline, or 
tigecycline). 
 History of pseudotumor cerebri, or prior (within 2 weeks prior to Screening) or 
planned concomitant use of isotretinoin. 
 History of systemic lupus erythematosus or lupus-like syndrome. 
 Current clinical suspicion or diagnosis of pancreatitis. 
14. Use of other investigational drugs 30 days prior to Screening. 
15. Has previously been treated with omadacycline within 30 days of screening or 
previously enrolled in this study. 
16. Any planned medical intervention that might interfere with the ability to comply with 
the study requirements. 
17. Has 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. 
 
Test Article; Dose; and Mode of Administration:  
Test Article 
Study Day 
Study Day 
Study Days 
1 
2 
3-10 
Omadacycline 
300 mg po BID 
300 mg po QD 
300 mg po QD 
po = per oral, a dosing day is a 24-hour day not a calendar day 
a The total duration of treatment is 7 to 10 days. Treatment duration can be extended to up to 14 days for 
subjects with bacteremia that, in the opinion of the investigator, requires more than 10 days of treatment.   
Duration of Treatment:  
The total duration of po treatment is 7 to 10 days. Subjects with baseline bacteremia (ie, 
confirmed from local blood culture drawn at screening) can receive up to 14 days of 
treatment after consultation with the medical monitor.  
 


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Pharmacokinetic Assessments 
Blood Collection (plasma): 
Blood samples will be collected and analyzed for omadacycline concentration at the 
following times: 
 Day 1:  within an hour prior to Dose 1, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (12 hour 
taken immediately before Dose 2);  
Dose 2 administered (times relative to Dose 1); 13, 13.5, 14, 14.5, 15, 16, 24 hours 
post dose 
 Day 2:  within an hour prior to dose, 1, 1.5, 2, 2.5, 3, 4, 6 hours 
 Day 3: prior to the Day 3 dose 
 EOT:  anytime during the visit 
 
Safety Assessments: 
 Physical examinations; 
 Vital signs (body weight, blood pressure, heart rate, pulse oximetry, respiratory rate 
(RR) and body temperature); 
 Laboratory tests (Hematology, serum chemistry); 
 AEs, and serious adverse events (SAEs); 
 Concomitant medications; 
 Urinalysis and Pregnancy assessments (Screening only). 
 
Efficacy Assessments: 
 Investigator’s assessment of clinical response at EOT and PTE visits.  Clinical success 
is defined as resolution of signs and symptoms of the infection to the extent that further 
antibacterial therapy is not necessary 
 Clinical Stability 
 Final Follow-up Assessment of signs and symptoms of CABP by the investigator 
 
Resource Utilization: 
 Hospital admission 
 Emergency Department and Physician visits 


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Statistical Methods: 
The following subject populations have been defined for the various analyses: 
 The PK population will consist of all assigned subjects who receive omadacycline and 
have PK samples collected.  
 The Safety population will consist of all assigned subjects who receive at least one 
dose of omadacycline.  
 The intent-to-treat (ITT) population will consist of all assigned subjects. 
 
Demography and Baseline Characteristics:  Subject disposition, demographics, and 
baseline characteristics will be summarized overall for all subjects in the ITT population. 
Pharmacokinetic Analyses:  The observed omadacycline concentration-time data after an 
oral dosing regimen, BID on Day 1 and QD on Day 2, in CABP patients will be evaluated. 
300mg administered orally is the dose that provided equivalent total exposure as measured 
by AUC relative to the 100mg IV dose (CPTK796-A2104).  The oral bioavailability of 
omadacycline is 34%.   
 
Using the superposition principle, the AUC of a single 100mg IV dose on Day 1 for n=63 
healthy subjects were totaled to evaluate the AUC(0-48) of the established omadacycline IV 
dosing regimen (q12h on Day 1 followed by q24h on Day 2).  AUC(0-48) values are then 
summarized and serve as the comparator for this current study.  Safety and efficacy in 
CABP patients were demonstrated for this dosing regimen (PTK796-CABP-1200), but 
only sparse PK sampling was conducted.  The final population PK model for 
omadacycline, which includes CABP patients from the PTK0796-CABP-1200 study, 
generated similar AUC(0-48) values for the 100mg IV dosing regimen. 
 
The comparative bioavailability assessment between the test, 300mg po in CABP patients, 
and the reference, 100mg IV in healthy subjects, will be based on 90% confidence 
intervals (CIs) for the geometric mean ratios (GMR) of AUC(0-48) for the two dosing 
regimens being within 80% and 125%.   
 
Individual plasma concentration, time deviation data and PK parameters will be presented 
in data listings.  Plasma concentration data and PK parameters will be summarized by time 
point using descriptive statistics (number of subjects, mean, standard deviation (SD), 
coefficient of variation (CV), median, minimum, and maximum).  Mean and individual 
plasma concentration versus time profiles will be presented in figures on both linear and 
semilogarithmic scales.  Geometric means will be included for area under the 
concentration-time curve (AUC) and maximum observed plasma concentration (Cmax).  
 
Safety Analyses:  Adverse events will be coded by preferred term (PT) and system organ 
class (SOC) using the latest version of the Medical Dictionary for Regulatory Activities 
(MedDRA).  All AE data will be presented in a data listing.  All AEs will be summarized 


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overall, as well as by severity, and relationship to study drug.  Any serious AEs and AEs 
leading to discontinuation of study drug will also be presented in a data listing. 
Clinical laboratory test results (hematology and serum chemistry) and vital sign 
measurements will be summarized by time point.  Prior and concomitant medications and 
therapies will be coded using the latest version of the World Health Organization Drug 
Dictionary and will presented in a data listing. 
Efficacy Analyses:  The number and percentage of subjects with investigator assessment 
of clinical response will be presented at each time point (EOT and PTE).  The number and 
percentage of subjects who achieve clinical stability will be presented for each day, EOT 
and PTE. 
Rationale for Number of Subjects:  This study is designed to evaluate the PK profile of 
an oral dosing regimen, BID on Day 1 and QD on Day 2, in adults with CABP.  The 
sample size determination is based on consideration of the precision of the estimate, GMR 
of AUC(0-48) for 300mg po to 100mg IV, derived from model-based simulations of 
omadacycline concentration data (Phase I studies). 
 
With 20 evaluable subjects, there will be 90% probability that the 90% CIs of the GMR for 
AUC(0-48) will be within 80% and 125%. Up to 30 subjects will be enrolled so that at least 
20 subjects are evaluable for bioavailability estimation.  The number may be adjusted as 
needed to meet this requirement. 
 
  


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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................2 
TABLE OF CONTENTS .........................................................................................................11 
LIST OF TABLES ...................................................................................................................14 
LIST OF APPENDICES ..........................................................................................................14 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................15 
1
DISCLOSURE STATEMENT ........................................................................................18 
2
CONTACTS ....................................................................................................................19 
 
Emergency Contacts ..............................................................................................19 
 
Additional Contacts ...............................................................................................19 
3
INTRODUCTION ...........................................................................................................20 
 
Community Acquired Bacterial Pneumonia ..........................................................20 
 
Omadacycline ........................................................................................................20 
4
STUDY OBJECTIVES ....................................................................................................20 
 
Primary Objective ..................................................................................................20 
 
Secondary Objectives .............................................................................................21 
 
Exploratory Objectives ..........................................................................................21 
5
INVESTIGATIONAL PLAN ..........................................................................................22 
 
Overall Study Description ......................................................................................22 
 
Rationale for Study Design ....................................................................................22 
 
Approximate Duration of Subject Participation ....................................................23 
 
Approximate Duration of Study .............................................................................23 
 
Approximate Number of Subjects .........................................................................23 
6
STUDY POPULATION SELECTION ...........................................................................24 
 
Study Population ....................................................................................................24 
 
Inclusion and Exclusion Criteria ............................................................................24 
 
Screen Failures .......................................................................................................27 
7
STUDY TREATMENT(S) ..............................................................................................28 
 
Treatments Administered .......................................................................................28 
 
Identity of the Investigational Product:  Omadacycline ........................................28 
 
Dose Selection Rationale .......................................................................................28 
 
Description of Treatments ......................................................................................29 
 
Test Article Administration ...................................................................................29 
7.5.1 
Oral Treatment .............................................................................................29 
 
Management While on Oral Test Article ...........................................29 
 
Dose Adjustments and Interruptions of Test Article .............................................30 
7.6.1 
Subject Numbering ......................................................................................30 
 
Dispensing Test Article..........................................................................................30 


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Prior and Concomitant Therapy .............................................................................30 
 
Prohibited Therapy .................................................................................................30 
 
Permitted Treatments .............................................................................................31 
 
Treatment Compliance ...........................................................................................31 
 
Packaging and Labeling .........................................................................................31 
 
Storage and Accountability ....................................................................................31 
 
Investigational Product Retention at Study Site ....................................................31 
8
STUDY PROCEDURES .................................................................................................32 
 
Informed Consent...................................................................................................32 
 
Subject Demographics/Other Baseline Characteristics .........................................32 
 
Medical History .....................................................................................................32 
 
Physical Examination.............................................................................................33 
 
Vital Signs ..............................................................................................................33 
 
Height and Weight .................................................................................................33 
 
Assessment of CABP Symptom Severity ..............................................................33 
 
Radiologic Evaluation of Pneumonia ....................................................................34 
 
PORT Risk Class ...................................................................................................34 
 
Clinical Laboratory Tests .......................................................................................34 
8.10.1 
Hematology and Serum Chemistry ..............................................................34 
8.10.2 
Pregnancy Assessment .................................................................................35 
8.10.3 
Urinalysis .....................................................................................................35 
 
Pharmacokinetic Assessments ...............................................................................36 
8.11.1 
PK Blood Collection and Processing ...........................................................36 
8.11.2 
Storing and Shipping of PK Samples...........................................................36 
 
Efficacy Assessments .............................................................................................36 
8.12.1 
Investigator’s Assessment of Clinical Response .........................................36 
 
Investigator’s Assessment of Clinical Response at EOT ...................36 
 
Investigator’s Assessment of Clinical Response at PTE ...................37 
8.12.2 
Clinical Stability ..........................................................................................38 
 
Adverse Events ......................................................................................................38 
 
Serious Adverse Events .........................................................................................38 
 
Other Reportable Information ................................................................................39 
 
Overdose ................................................................................................................40 
 
Medication Errors ..................................................................................................40 
 
Recording and Reporting .......................................................................................40 
8.18.1 
Serious Adverse Event Reporting ................................................................41 
8.18.2 
Assessment of Relatedness ..........................................................................41 
8.18.3 
Assessment of Severity ................................................................................41 
8.18.4 
Laboratory Findings .....................................................................................42 


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8.18.5 
Worsening or Progression of Disease Under Study .....................................42 
8.18.6 
Pregnancies ..................................................................................................42 
 
Concomitant Medication Assessments ..................................................................43 
 
Subject Discontinuation or Withdrawal .................................................................43 
8.20.1 
Replacements ...............................................................................................43 
9
STUDY ACTIVITIES .....................................................................................................44 
 
Screening Phase .....................................................................................................44 
 
Treatment Phase .....................................................................................................44 
 
EOT Visit Procedures ............................................................................................44 
 
Follow-up Phase.....................................................................................................44 
9.4.1 
Post-Treatment Evaluation Visit Procedures ...............................................44 
9.4.2 
Final Follow-up ............................................................................................44 
10 STUDY SUSPENSION, TERMINATION, AND COMPLETION ................................45 
 
Study Completion and Post-Study Test Article .....................................................45 
 
Study Suspension or Termination ..........................................................................45 
11 QUALITY CONTROL AND ASSURANCE .................................................................46 
12 PLANNED STATISTICAL METHODS ........................................................................47 
 
General Considerations ..........................................................................................47 
 
Determination of Sample Size ...............................................................................47 
 
Analysis Populations ..............................................................................................47 
 
Demographics and Baseline Characteristics ..........................................................48 
 
Primary Endpoint(s) ...............................................................................................48 
12.5.1 
Pharmacokinetic Endpoint ...........................................................................48 
 
Secondary Endpoint(s) ...........................................................................................49 
12.6.1 
Safety Endpoint(s) .......................................................................................49 
12.6.2 
Exploratory Endpoint(s) ...............................................................................49 
12.6.3 
Resource Utilization Endpoint(s) .................................................................50 
 
Data Handling Conventions...................................................................................50 
 
Multiple Comparisons and Multiplicity .................................................................50 
 
General Data Summaries .......................................................................................50 
13 ADMINISTRATIVE CONSIDERATIONS ....................................................................51 
 
Investigators and Study Administrative Structure .................................................51 
 
Institutional Review Board or Independent Ethics Committee Approval .............51 
 
Ethical Conduct of the Study .................................................................................51 
 
Patient Information and Consent ...........................................................................51 
 
Direct Access, Data Handling, and Record Keeping .............................................52 
13.5.1 
Investigator ..................................................................................................52 
13.5.2 
Sponsor ........................................................................................................52 


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Protocol Adherence ................................................................................................52 
13.6.1 
Violations/Deviations ..................................................................................52 
13.6.2 
Protocol Amendments ..................................................................................52 
 
Subject Injury .........................................................................................................53 
 
Pre-Study Documentation ......................................................................................53 
 
Retention of Data ...................................................................................................54 
 Publication and Disclosure Policy .........................................................................54 
14 REFERENCE LIST .........................................................................................................55 
LIST OF TABLES 
Table 1 
Hematology .............................................................................................................34 
Table 2 
Serum Chemistry .....................................................................................................35 
Table 3 
Urine Dipstick .........................................................................................................35 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events .......................................................................................56 
Appendix 2 
Equations and Conversion Factors...............................................................60 
Appendix 3 
Community-Acquired Bacterial Pneumonia Subject Symptom Severity 
Guidance Framework for Investigator Assessment ................................................61 
Appendix 4 
PORT Risk Class Calculation ......................................................................62 
Appendix 5 
Sponsor Signature ........................................................................................64 
Appendix 6 
Investigator’s Signature ...............................................................................65 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
ABG 
arterial blood gas 
ABSSSI 
acute bacterial skin and skin structure infections 
AE 
adverse Event 
AIDS 
Acquired Immune Deficiency Syndrome 
ALT 
alanine aminotransferase (SGPT) 
AST 
aspartate aminotransferase (SGOT) 
AUC 
area under the plasma concentration time curve 
AUC0-24 
AUC from time 0 to 24 hours after dosing 
AUClast 
AUC from time 0 to the last quantifiable concentration 
β-hCG 
serum β-human chorionic gonadotropin 
BP 
blood pressure 
CABP 
community-acquired bacterial pneumonia 
CD4 
cluster of differentiation 4 
CFR 
Code of Federal Regulations 
Cmax 
maximum observed plasma concentration 
COPD 
chronic obstructive pulmonary disease 
CrCl 
creatinine clearance 
CRF 
case report form 
CSA 
clinical study agreement 
CSR 
Clinical Study Report 
CT 
computed tomography 
CV 
coefficient of variation 
CXR 
chest X-ray 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOT 
end of treatment 
FDA 
Food and Drug Administration 


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FEV1 
forced expiratory volume in one second 
FFU 
Follow-up visit 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
HIV 
Human Immunodeficiency Virus 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IUD 
intrauterine device 
IV 
intravenous 
IxRS 
interactive voice/web response system 
LPF 
low power field 
MDR-SP 
Multi-drug resistant Streptococcus pneumoniae 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIC 
minimum inhibitory concentration 
PaO2 
partial pressure of arterial oxygen 
PI 
Principal Investigator 
PK 
pharmacokinetics 
po 
per oral 
PORT 
Pneumonia Outcomes Research Team 
PT 
preferred term 
PTE 
Post Therapy Evaluation 
QD 
once per day 
q12h 
every 12 hours 
RAC 
accumulation factor 
REB 
Research Ethics Board 


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RR 
respiratory rate 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
Tmax 
time to reach maximum observed plasma concentration 
T1/2 
terminal-phase elimination half-life 
ULN 
Upper Limit of Normal 
US 
United States 
UTI 
urinary tract infection  
WBC 
White Blood Cell (Count) 


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1 
DISCLOSURE STATEMENT 
Restricted Distribution of Documents 
This document contains information that is confidential and proprietary to the sponsor.  This 
information is being provided to you solely for the purpose of evaluating and/or conducting a 
clinical study for the sponsor.  You may disclose the contents of this document only to study 
personnel under your supervision, Institutional Review Boards (IRBs)/Independent Ethics 
Committees (IECs)/Research Ethics Boards (REBs), or duly authorized representatives of 
regulatory agencies for this purpose under the condition that they maintain confidentiality.  
The contents of this document may not be used in any other clinical study, disclosed to any 
other person or entity, and/or published without the prior written permission of the sponsor.  
The foregoing shall not apply to disclosure required by any regulations; however, you will 
give prompt notice to the sponsor of any such disclosure.  All other nonpublic information 
provided by the sponsor and any information that may be added to this document also is 
confidential and proprietary to the sponsor and must be kept in confidence in the same 
manner as the contents of this document. 


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2 
CONTACTS 
 
Emergency Contacts 
Name/Title: 
 
 
 
 
 
 
 
Global Medical Monitor 
Phone (during business hours): 
 
Phone (after business hours):  
 
E-mail (not for emergencies):  
 
Address:  
 
 
 
 
 
 
 
 
Additional Contacts 
SAE contact information: 
E-Mail: 
 
 
 
 
 
 
 


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3 
INTRODUCTION 
Community Acquired Bacterial Pneumonia 
Community Acquired Bacterial Pneumonia (CABP) is a leading cause of morbidity and 
mortality in the United States (US) and throughout the world (Mandell).  Four to 6 million 
cases of CABP occur per year in the US, resulting in 10 million physician visits, 
600,000 hospitalizations, and tens of thousands of deaths.  The total cost of CABP to the 
annual US health care budget exceeds $10 billion (in 2007-adjusted dollars) (Niederman).  
Furthermore, there is increasing resistance to antibiotics among common pathogens, with a 
resulting critical need for new antibiotics (Spellberg).  Bacterial resistance to the most 
frequently prescribed, currently available antibiotics has limited their potential to treat 
infections, which prevents their use as a first-line empiric monotherapy.  Methicillin-resistant 
Staphylococcus aureus and multi-drug resistant Streptococcus pneumoniae in the community 
have posed treatment challenges because of resistance to penicillins (resistance rate 100% for 
both), cephalosporins (100% and 11%, respectively, for ceftriaxone), macrolides (83% and 
86%, respectively, for azithromycin/erythromycin), and quinolones (73% and 2%, 
respectively, for levofloxacin), in CABP.  In addition, the growing concern about, “collateral 
damage” associated with use of quinolone and beta-lactam class antibiotics further 
underscores the need for new antibiotic treatment options for CABP (Paterson).  
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. 
Omadacycline 
The investigational product, omadacycline (formerly named PTK 0796), is the first member 
of the aminomethylcycline class of antibiotics, which are semi synthetic derivatives of the 
tetracycline class.  As a class, the tetracyclines have been in use for approximately 70 years. 
They are well-tolerated and have proven effective in the treatment of a variety of bacterial 
infections.  NUZYRA® (omadacycline) has been approved by the US Food and Drug 
Administration (FDA) for the treatment of adult patients with CABP caused by susceptible 
microorganisms.   
Omadacycline has demonstrated activity against the most common CABP pathogens, 
including isolates resistant to older antibiotics.  This study is intended to evaluate the 
pharmacokinetics (PK) of an oral dosing regimen on Days 1 and 2 in adults with CABP. 
Please refer to the current version of the Investigator's Brochure or the NUZYRA® 
(omadacycline) USPI for additional information on omadacycline. 
4 
STUDY OBJECTIVES 
Primary Objective 
The primary objective of this study is:  


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x To evaluate the PK of oral (po) only omadacycline in adults with CABP. 
 
Secondary Objectives  
The secondary objectives of this study are: 
x To evaluate the safety of omadacycline in the treatment of adults with CABP.   
 
Exploratory Objectives 
x To evaluate the efficacy of oral only omadacycline in the treatment of adults with CABP.  
 


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5 
INVESTIGATIONAL PLAN 
 
Overall Study Description 
This is an open-label Phase 1b study evaluating oral omadacycline in the treatment of adults 
with CABP.   
This study is intended to evaluate the PK of an oral dosing regimen in adults with CABP.  
Subjects will initiate treatment with an oral loading dose of 300 mg BID on Day 1 followed 
by 300 mg QD on subsequent days. 
Following a screening period of up to 24 hours, eligible subjects will be assigned to receive 7 
to 10 days of po treatment. Subjects with baseline bacteremia (ie, confirmed from local blood 
culture drawn at screening) can receive up to 14 days of treatment after consultation with the 
medical monitor. 
Subjects may receive oral treatment in either inpatient or outpatient settings, provided that all 
assessments can be completed at the timepoints required by protocol. 
Eligible subjects will be assigned to the following treatment groups.  
Test Article 
Study Day 
Study Day 
Study Days 
1 
2 
3-10 
Omadacycline 
300 mg po BID 
300 mg po QD 
300 mg po QD 
po = per oral, a dosing day is a 24-hour day not a calendar day 
a The total duration of treatment is 7 to 10 days. Treatment duration can be extended to up to 14 days for 
subjects with bacteremia that, in the opinion of the investigator, requires more than 10 days of treatment.   
Refer to the Schedule of Events (Appendix 1) for the summary of subject visits and 
assessments through end of treatment (EOT).  
Subjects will return to the study site for a Post Therapy Evaluation (PTE) 5 to 10 days after 
the last dose of test article.  A Final Follow-up visit (FFU) will be conducted within 30 to 37 
days following the first dose of test article.  The FFU assessment may be conducted via 
telephone contact or by another interactive technology for subjects who had an outcome of 
Clinical Success in the opinion of the investigator at EOT and PTE and had no AEs or 
clinically significant laboratory or electrocardiogram (ECG) abnormalities noted at or after 
the PTE visit.  Otherwise, this assessment is to be performed with an in-person study visit.  
The planned length of subject participation in the study is up to 37 days.   
 
Rationale for Study Design  
The dosing regimen of omadacycline selected for this study is based on the nonclinical and 
clinical experience to date, including in vitro antibacterial activity, PK characteristics, 


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clinical efficacy in prior studies, the overall safety and tolerability profile, and the FDA 
approved dosing regimen for CABP.   
A regimen of 200 mg omadacycline administered by intravenous (IV) infusion OR 100 mg 
omadacycline administered by IV infusion every 12 hours (q12h) on Day 1 followed by 
100 mg of omadacycline administered by IV infusion once daily OR 300 mg of 
omadacycline administered orally once daily has been approved by US FDA for the 
treatment of adult patients with CABP and acute bacterial skin and skin structure infections 
(ABSSSI) caused by susceptible microorganisms.  In addition, an oral only regimen of 
450 mg for Days 1 and 2, followed by 300 mg has been approved by US FDA for ABSSSI.  
The total approved treatment duration is 7 to 14 days.  The oral only regimen is also being 
studied for the treatment of uncomplicated urinary tract infection (UTIs). 
The duration for the po only regimen in this study will be 7 to 10 days.  The shorter regimen 
is supported by the efficacy observed in the previously completed CABP Phase 3 study 
which included Pneumonia Outcomes Research Team (PORT) Risk Classification II, III and 
IV subjects, PTK0796-CABP-1200 where by Day 7 of treatment, > 80% of patients in the 
omadacycline treatment group had symptom improvement (as defined by the Early Clinical 
Response endpoint) and had reached clinical stability.  In the current study, PORT Risk Class 
I, IV, and V subjects will be excluded. 
 
Approximate Duration of Subject Participation 
Subjects will participate in the study for up to 37 days.  Following a screening period of up to 
24 hours, eligible subjects will be assigned to receive treatment.  Eligible subjects will be 
assigned to receive 7 to 10 days of po treatment.  Subjects with baseline bacteremia (ie, 
confirmed from local blood culture drawn at screening) can receive up to 14 days of 
treatment after consultation with the medical monitor. 
 
Approximate Duration of Study 
The study is expected to be complete in approximately 6 months.  
 
Approximate Number of Subjects 
Up to 30 subjects will be enrolled at approximately 5 sites in the US to ensure that at least 20 
subjects complete all PK sample collections.  The number may be adjusted as needed to meet 
this requirement. 


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6 
STUDY POPULATION SELECTION 
Each subject must participate in the informed consent process and sign and date an 
IRB/IEC/REB approved informed consent form (ICF) before any procedures specified in this 
protocol are performed. 
 
Study Population 
Up to 30 subjects will be enrolled at approximately 5 sites in the US to ensure that at least 20 
subjects complete all PK sample collections.  The number may be adjusted as needed to meet 
this requirement. 
 
Inclusion and Exclusion Criteria  
Each subject must meet all of the following criteria to be enrolled in this study: 
Main Criteria for Inclusion: 
1. Written and signed informed consent must be obtained before any protocol specific 
assessment is performed.   
2. Male or female, age 18 years or older. 
3. Has at least 3 of the following symptoms: 
x Cough 
x Production of purulent sputum 
x Dyspnea (shortness of breath) 
x Pleuritic chest pain 
4. Has at least TWO of the following abnormal vital signs: 
x
Fever or hypothermia documented by the investigator (temperature > 38.0°C 
[100.4°F] or < 36.0°C [95.5°F]) 
x Hypotension with systolic blood pressure (SBP) < 90 mm Hg 
x Heart rate > 90 beats per minute (bpm) 
x Respiratory rate (RR) > 20 breaths/minute 
5. Has at least 1 clinical sign or laboratory finding associated with CABP: 
x Hypoxemia (partial pressure of arterial oxygen [PaO2] < 60 mm Hg by arterial blood 
gas [ABG] or oxygen saturation < 90% by pulse oximetry) 
x Physical examination findings of pulmonary consolidation (eg, dullness on 
percussion, bronchial breath sounds, or egophony) 
x An elevated total white blood cell (WBC) count (> 12,000 cells/mm3) or leucopenia 
(WBC < 4,000 cells/mm3) or elevated immature neutrophils (> 15% band forms), see 
% bands calculation in Appendix 2 (regardless of total peripheral WBC count) 
6. Has disease categorized as being PORT Risk Class II or III at Screening where initiation 
of antibiotics with oral therapy is appropriate in the opinion of the investigator, whether 
inpatient or outpatient setting (see PORT Risk Class calculation in Appendix 4). 


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7. Radiographically-confirmed pneumonia, ie, new or progressive pulmonary infiltrate(s) on 
chest X-ray (CXR) or chest computed tomography (CT) scan consistent with acute 
bacterial pneumonia within 48 hours prior to the first dose of test article.   
8. Ability to swallow up to 3 tablets in succession. 
9. Females must have a negative urine pregnancy test at Screening and agree to comply with 
using an acceptable method of birth control as per your local requirements (eg, 
abstinence, oral contraceptive, intrauterine device [IUD], barrier contraception [condom], 
tubal ligation, hysterectomy, bilateral oophorectomy, postmenopausal, or vasectomized 
partner) from Screening through PTE.  Males must agree to use an acceptable method of 
birth control with female partner(s) and must not donate sperm from Screening through 
PTE. 
Main Criteria for Exclusion: 
1. Has received more than 24 hours (ie, a single dose of a daily therapy or the recommended 
daily frequency of a short acting therapy) of a potentially effective systemic antibacterial 
treatment within the 72 hours prior to the first dose of test article.  A subject will be 
considered to have received a potentially effective systemic antibacterial treatment if the 
pathogen identified as causing infection is shown to be susceptible to the antibacterial 
given or, in the circumstance where a pathogen is not identified, if the antibacterial agent 
is approved for treatment of pneumonia or is known to have activity against any of the 
leading causes of CABP (eg, Streptococcus pneumoniae, Haemophilus influenzae, 
Moraxella catarrhalis, S. aureus, Legionella pneumophila).   
2. Is known or suspected to have CABP caused by a pathogen that may be resistant to test 
article (eg, Pseudomonas aeruginosa, Proteus spp., Morganella morganii, 
Providencia spp., Pneumocystis jiroveci, obligate anaerobes, mycobacteria, fungal 
pathogens). 
3. Suspected or confirmed empyema (a parapneumonic pleural effusion is not an exclusion 
criterion) or lung abscess. 
4. Subjects who reside in a long-term care or subacute/intermediate healthcare facility (eg, 
nursing home) or a subject diagnosed with pneumonia following a recent hospitalization 
(overnight admission within 90 days prior to current admission).   
5. Has a known history of having experienced unstable cardiac disease (eg, unstable angina, 
myocardial infarction, acute congestive heart failure, unstable cardiac arrhythmia) within 
the 3 months prior to Screening or presents with a tachyarrhythmia (excluding sinus 
tachycardia). 
6. Has any of the following at Screening: 
 alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 3 × Upper 
Limit of Normal (ULN)  
 total bilirubin > 1.5 × ULN 
 suspected or confirmed clinical evidence of end-stage liver disease (eg, ascites, 
hepatic encephalopathy) 
7. Requires any form of dialysis (eg, hemodialysis, peritoneal dialysis), has a history or 
evidence of severe renal disease, or has a calculated creatinine clearance (CrCl) 
of < 30 mL/minute, using the Cockcroft-Gault equation (see calculation in Appendix 2). 
8. Significant immunological compromise determined by any of the following: 


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 Current or anticipated neutropenia defined as < 500 neutrophils/mm3 
 Known infection with Human Immunodeficiency Virus (HIV) 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 
 The receipt of cancer chemotherapy, radiotherapy, or potent, non-corticosteroid 
immunosuppressant drugs (eg, cyclosporine, azathioprine, tacrolimus, 
immune-modulating monoclonal antibody therapy, etc.) within the past 3 months, or 
the receipt of corticosteroids equivalent to or greater than 40 mg of prednisone per 
day or for more than 14 days in the prior 30 days.  (see Appendix 2) Exception:  
Systemic corticosteroids administered within 24 hours of treatment group assignment 
or any time after treatment group assignment as adjunctive therapy for the current 
episode of CABP (at any dosage) is allowed. 
9. PORT Risk Class I, IV, or V patients. 
10. Known or suspected primary or metastatic neoplastic lung disease, aspiration pneumonia, 
active tuberculosis, cystic fibrosis, bronchiectasis, bronchial obstruction (eg, 
post-obstructive pneumonia), chronic neurological disorder preventing clearance of 
pulmonary secretions, or severe chronic obstructive pulmonary disease (COPD) (severe 
COPD is defined as known forced expiratory volume in 1 second [FEV1] < 50% of 
predicted in a patient with FEV1/forced vital capacity [FVC] < 70%; note that spirometry 
or pulmonary function testing is not required during Screening).  
11. Has a life expectancy of less than or equal to 3 months. 
12. Pregnant or nursing (breastfeeding) women.  
13. Has any contraindication to receiving a tetracycline, including: 
 History of hypersensitivity or allergic reaction (eg, anaphylaxis, urticaria, other 
significant reaction) to any tetracycline (eg, minocycline, doxycycline or tigecycline). 
 History of pseudotumor cerebri, or prior (within 2 weeks prior to Screening) or 
planned concomitant use of isotretinoin. 
 History of systemic lupus erythematosus or lupus-like syndrome. 
 Current clinical suspicion or diagnosis of pancreatitis. 
14. Use of other investigational drugs 30 days prior to Screening. 
15. Has previously been treated with omadacycline within 30 days of screening or previously 
enrolled in this study. 
16. Any planned medical intervention that might interfere with the ability to comply with the 
study requirements. 
17. Has 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. 
 


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Screen Failures 
Subjects who sign the ICF but withdraw or are withdrawn from the study before treatment 
are defined as screen failures.  All screen failures should be recorded on the subject master 
list.  Limited information including reason for screen failure will be recorded on the 
electronic case report form (eCRF) or interactive voice/web response system (IxRS), if used, 
for screen failures.  Screen failure subjects may be re-screened at the discretion of the 
investigator and in consultation with the medical monitor as needed.  Any subject who 
discontinues participation or is withdrawn before receiving a treatment assignment, and who 
is re-screened at a later time will be assigned a new subject number and recorded as re-
screened. 


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7 
STUDY TREATMENT(S) 
 
Treatments Administered 
Test articles will be supplied by Paratek Pharma, Inc (the sponsor).  Test articles will be 
labeled according to regulations. 
The test articles should be administered only to subjects who have provided informed 
consent and who meet all of the inclusion criteria and none of the exclusion criteria.  Once 
the test article has been assigned to a subject, it must not be reassigned to another subject. 
Following a Screening period of up to 24 hours, eligible subjects will be assigned a dosing 
regimen of omadacycline  
 
Identity of the Investigational Product:  Omadacycline 
Oral Formulation (Omadacycline) 
Name 
Omadacycline Tablet, 150 mg 
Excipients 
Lactose monohydrate, microcrystalline cellulose, sodium stearyl fumarate, 
crospovidone, colloidal silicone dioxide, sodium bisulfite, polyvinyl alcohol, titanium 
dioxide, talc, glycerol monocaprylocaprate, sodium lauryl sulfate, iron oxide yellow 
How supplied 
4-count wallet 
Storage 
Store at 25˚C (77˚F).  Excursions permitted to 15°C-30°C (59˚F -86˚F) (Per Pharmacy 
Manual) 
Preparation and 
handling 
No special requirements 
Administration 
Please reference Section 7.5 
 
Dose Selection Rationale 
The dosing regimen of omadacycline selected for this study is based on the nonclinical and 
clinical experience to date, including in vitro antibacterial activity, PK characteristics, clinical 
efficacy in prior studies, the overall safety and tolerability profile, and the FDA approved 
dosing regimen for CABP.   
A regimen of 200 mg omadacycline administered by IV infusion OR 100 mg omadacycline 
administered by IV infusion q12h on Day 1 followed by 100 mg of omadacycline 
administered by IV infusion once daily OR 300 mg of omadacycline administered orally 
once daily has been approved by US FDA for the treatment of adult patients with CABP and 
ABSSSI caused by susceptible microorganisms.  In addition, an oral only regimen of 450 mg 
for Days 1 and 2, followed by 300 mg has been approved by US FDA for ABSSSI.  The total 
approved treatment duration is 7 to 14 days.  The oral only regimen is also being studied for 
the treatment of uncomplicated UTIs. 


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The duration for the po only regimen in this study will be 7 to 10 days.  The shorter regimen 
is supported by the efficacy observed in the previously completed CABP Phase 3 study 
which included PORT Risk Classification II, III and IV subjects, PTK0796-CABP-1200 
where by Day 7 of treatment, > 80% of patients in the omadacycline treatment group had 
symptom improvement (as defined by the Early Clinical Response endpoint) and had reached 
clinical stability.  In the current study, PORT Risk Class I, IV, and V subjects will be 
excluded. 
 
Description of Treatments 
Subjects will be assigned to the following treatment group: 
Test Article 
Study Day 
Study Day 
Study Days 
1 
2 
3-10 
Omadacycline 
300 mg po BID 
300 mg po QD 
300 mg po QD 
po = per oral, a dosing day is a 24-hour day not a calendar day 
a The total duration of treatment is 7 to 10 days. Treatment duration can be extended to up to 14 days for 
subjects with bacteremia that, in the opinion of the investigator, requires more than 10 days of treatment.   
 
Test Article Administration 
7.5.1 
Oral Treatment 
Subjects should receive their first dose of test article on the morning following enrollment. 
All doses of oral test article should be taken with water.    
All oral doses should be taken in a fasted state.  Fasting is defined as no food, antacids, or 
multivitamins containing multivalent cations (eg, aluminum, magnesium, calcium, bismuth, 
iron, or zinc) or drink except water for at least 6 hours before dosing.  After dosing, no food 
is permitted for 2 hours as well as no dairy products, antacids, or multivitamins containing 
multivalent cations (eg, aluminum, magnesium, calcium, bismuth, iron, or zinc) for 4 hours. 
 
Management While on Oral Test Article 
While the subject is receiving po therapy, the investigator will assess the subject and choose 
one of the following outcomes based on the overall clinical response of the subject: 
x Continue po test article 
x Discontinue test article – this decision will prompt the EOT evaluation (even if the 
subject does not complete the minimum days of dosing) 
At all times during the study the decision to continue or discontinue test article is made based 
on the clinical judgment of the investigator.  Each daily decision is to be recorded on source 
documents and the information transferred to eCRFs by study site personnel. 


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Dose Adjustments and Interruptions of Test Article
No dose adjustments or planned interruptions of test article will be permitted during this 
study. 
7.6.1 
Subject Numbering 
Upon signing the informed consent, the subject will be assigned a unique subject number.  
Subjects who have been pre-screened, but who do not sign an ICF will not be assigned a 
subject number.  A subject who discontinues participation or is withdrawn before receiving a 
treatment assignment, and who is re-screened at a later time will be assigned a new subject 
number and recorded as re-screened.  Re-screening is at the discretion of the investigator and 
in consultation with the medical monitor.  The investigator will maintain a subject master list 
to document every subject who has signed an ICF.  A copy of this list should be retained in 
the investigator’s study files. 
 
Dispensing Test Article 
Each study site will be supplied by the sponsor with the investigational product.  The po test 
article will be supplied to the sites in wallets that contain active omadacycline tablets.  
 
Prior and Concomitant Therapy 
Treatments that have been administered within the 7 days prior to the date of informed 
consent, or during the Screening phase, will be recorded in the eCRF.  The investigator is to 
instruct the subject to notify the study site about any new medications he/she takes after the 
start of the test article.  All medications and significant non-drug therapies (including 
physical therapy and blood transfusions) administered after the subject starts treatment with 
test article must be listed in the eCRF (see Section 9).  In addition, for antibacterial agents 
and anti-emetics administered 30 days prior to screening and concomitantly, the dose, unit, 
frequency and route must be entered in the eCRF. 
 
Prohibited Therapy  
All investigational medications or devices used during the 30 days prior to Screening are 
prohibited.   
All of the following therapies are excluded starting from the time of consent through EOT 
visit: 
x More than 24 hours (ie, a single dose of a daily therapy or the recommended daily 
frequency of a short acting therapy) of a potentially effective systemic antibacterial 
treatment within the 72 hours prior to the first dose of test article. 
x Antacids and multivitamins containing multivalent cations (eg, aluminum, magnesium, 
calcium, bismuth, iron, or zinc) for 6 hours before and within 4 hours after oral doses.  
 


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  Permitted Treatments 
All other treatments not specified as prohibited are permitted during the study.  Subjects 
requiring additional or alternative antibacterial therapy for their CABP will be judged as 
Clinical Failures and test article will be discontinued.  Further treatment for their infection is 
at the discretion of the investigator or the subject’s health care provider and will be 
considered as a concomitant medication. 
Subjects should be encouraged to contact site personnel before starting any new treatment. 
For all treatments received by the subject during the study, relevant information must be 
recorded on the subject’s eCRF. 
 Treatment Compliance  
Compliance and any unresolved discrepancies will be documented in the source document 
and on the drug inventory record.  The test article eCRF should reflect the reconciled dosing 
information provided by the subject charts.   
 Packaging and Labeling 
The investigational test article, omadacycline will be packaged by the sponsor and supplied 
to the investigator.  
 Storage and Accountability 
Test article must be received at the study site by a designated person, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and 
designated staff have access.  Upon receipt, the test article should be stored according to the 
instructions specified on the drug labels.  Storage conditions must be adequately monitored, 
and appropriate temperature logs maintained as source data. 
The designated study personnel must maintain an accurate record of the shipment and 
dispensing of test articles in the study specific medication accountability ledger.  
 Investigational Product Retention at Study Site 
At the conclusion of the study, and as appropriate during the course of the study, with 
instruction from the sponsor, the designated study personnel will destroy on site as permitted 
by local site operating procedures, or return all unused test articles, packaging, and drug 
labels.  Destruction/return of all test article will be documented and maintained in the site 
files.   


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8 
STUDY PROCEDURES 
Written, signed, and dated informed consent will be obtained before any study-related 
procedures have been performed.  Upon signing the informed consent, the subject will then 
be assigned a study subject number.  Adverse events (AEs) must be recorded from the time 
the ICF is signed.  Subjects who have been pre-screened on the telephone but who do not 
sign an ICF will not be assigned a subject number.  The investigator will maintain a subject 
master list to document every subject who has signed an ICF.  A copy of this list should be 
retained in the investigator’s study files. 
 
Informed Consent 
The investigator will provide for the protection of the subjects by following all applicable 
regulations.  These regulations are available upon request from the sponsor.  The ICF must 
be reviewed by the sponsor and approved by the IRB/IEC/REB. 
Before any procedures specified in the protocol are performed, a subject must: 
x Be informed of all pertinent aspects of the study and all elements of informed consent  
x Be given time to ask questions and time to consider the decision to participate 
x Voluntarily agree to participate in the study 
x Sign and date an IRB/IEC/REB approved ICF 
 
Subject Demographics/Other Baseline Characteristics 
Subject demographic and Baseline characteristic data to be collected on all subjects include:  
date of birth, gender, and race/ethnicity.   
 
Medical History 
The investigator will perform a comprehensive history at the Screening visit.  Significant 
medical history (at any time) and any medical history within the past 6 months including 
ongoing medical conditions at the time of signing of the ICF will be recorded.  In addition, 
subject’s history of prior CABP will be captured and the following: 
x Predisposing factors that may affect lung function (eg, prior lung infection, mild to 
moderate COPD, symptomatic asthma with wheezing, history of smoking, chronic cough 
with and without sputum production, etc.).  
x Cardiovascular disease and risk factors  
x History of pneumococcal vaccination (eg, Pneumovax, Prevnar 13). 
x All systemic antimicrobials from onset of the infection will be recorded under 
concomitant medications. 
Where possible, diagnoses are to be recorded.  Any event or change in the subject’s condition 
or health status occurring after signing the ICF will be reported as an AE. 


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Physical Examination 
At Screening, a full physical examination will include the examination of general 
appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, 
back, lymph nodes, extremities, and vascular and neurological systems.   
Information for all physical examinations must be included in the source documentation at 
the study site.  Significant and relevant findings that are present prior to the start of test 
article must be included in the subject’s eCRF.  Relevant findings that are present prior to the 
start of test article must be included in the relevant medical history/current medical 
conditions screen on the subject’s eCRF.  Significant findings made after the start of test 
article which meet the definition of an AE must be recorded on the AE screen of the subject’s 
eCRF. 
 
Vital Signs 
Vital signs include blood pressure (BP), heart rate, pulse oximetry, RR, and body 
temperature.  
x Blood pressure and heart rate should be measured within 30 min before, and 
approximately (± 15 minutes) 1 hour after the completion of the first dose.  
The subject’s BP and heart rate should be captured after at least 5 minutes (+ 5 minutes) of 
rest while in a non-standing position (supine or semi-recumbent, head of bed from 0° to 90°).  
Subsequent vital sign measurements should be captured in the same non-standing position. 
Systolic and diastolic BP will be measured using an automated calibrated device, with an 
appropriately sized cuff.  
A pulse oximeter should be used to capture oxygen saturation.  
Heart rate will be measured using an automated calibrated device, when available.  If not 
available, heart rate will be measured manually.  
Temperature will be obtained using an electronic (rapid reading) device whenever possible.   
 
Height and Weight 
Height and body weight will be collected. 
 
Assessment of CABP Symptom Severity 
The investigator will specifically assess the presence and severity level of the subject’s 
symptoms of cough, sputum production, pleuritic chest pain, and dyspnea on a 4-point scale 
(absent, mild, moderate, or severe) based upon the Community Acquired Bacterial Pneumonia 
Subject Symptom Severity Guidance Framework for Investigator Assessment (see Appendix 
3) and enter the symptom severity level into the eCRF.  Subjects must have at least 3 of these 
4 symptoms of CABP to be eligible for randomization in the study. 


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Radiologic Evaluation of Pneumonia 
A CXR or CT scan will be obtained for all subjects at Screening (within 48 hours prior to the 
first dose of test article, see Inclusion Criterion 7).  These studies 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.  If a CXR or CT scan is obtained during the course of therapy or 
during the study period up to the Final Follow-up assessment, the results of the study will be 
collected.  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, reviewed by the investigator or qualified 
personnel and the conclusions of this review will be the basis for subject inclusion.  The 
review report should be included in the source documents. 
 
PORT Risk Class 
All subjects who are being screened for the study will have their PORT Risk Class assessed 
at the Screening evaluation only (see Appendix 4).  All subjects must have disease 
characterized as PORT Risk Class of II or III at randomization. 
 Clinical Laboratory Tests
All laboratory testing will be performed by the local laboratory at each site. The relevant 
local laboratory results from Screening will be used to assess eligibility as per the 
inclusion/exclusion criteria. 
8.10.1 
Hematology and Serum Chemistry 
Blood testing will include the hematology and serum chemistry parameters as shown in 
Table 1 and Table 2, respectively. These results for the study timepoints indicated in 
Appendix 1 will be recorded in the eCRF.   
 
Table 1 
Hematology 
Hematocrit  
Hemoglobin 
Mean cell volume 
WBC count 
Platelet count  
White blood cell differential (as % cell counts) 
 
-Neutrophils  
 
-Lymphocytes  
 
-Monocytes  
 
-Eosinophils  
 
-Basophils  
.


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Table 2 
Serum Chemistry 
Blood glucose 
Urea 
Creatinine 
Sodium 
Potassium 
Chloride 
Bicarbonate 
ALT 
AST 
AP 
Total bilirubin 
Total protein 
Magnesium 
Albumin 
LDH 
CK 
Calcium 
Phosphate 
Cholesterol 
Uric Acid 
GGT 
Amylase 
Lipase 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; AP = alkaline phosphatase; 
LDH = lactate dehydrogenase; CK = creatine phosphokinase; GGT = gamma-glutamyl transpeptidase. 
8.10.2 
Pregnancy Assessment 
All female subjects will have a local laboratory urine or serum pregnancy test at Screening.  
Results are required for eligibility and will be retained in source documents but will not be 
entered in the eCRF. If a positive urine or serum pregnancy test result is obtained during 
Screening, the subject is not to be enrolled.   
Should a positive pregnancy test be reported after a subject is enrolled, test article 
administration should be discontinued (see Section 8.18.6). 
8.10.3 
Urinalysis 
A urine dipstick test will be performed at the local laboratory at Screening, which will 
include (at minimum) the parameters shown in Table 3. Results are intended to assist in the 
eligibility assessment (e.g., assessment of potential renal disease), and will be retained in 
source documents but will not be entered in the eCRF.   
Table 3 
Urine Dipstick 
pH 
Glucose 
Ketones 
Bilirubin 
Blood 
WBC/Leukocyte Esterase. 


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 Pharmacokinetic Assessments 
Instructions will be provided to sites with detailed information on sample collection, 
handling, and shipment requirements.  All samples will be given a unique identifier.  The 
exact clock time of dosing, date and time of last food intake, as well as actual sample 
collection date and time will be entered on the eCRF.  The total volume of blood collected 
for pharmacokinetic assessments from each subject will be approximately 108 mL (7 
tablespoons) over the course of the study.   
8.11.1 
PK Blood Collection and Processing 
Blood Collection (plasma): 
Blood samples will be collected and analyzed for omadacycline concentration at the following 
times: 
x Day 1:  within an hour prior to Dose 1, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (12 hour 
taken immediately before Dose 2);  
Dose 2 administered (times relative to Dose 1); 13, 13.5, 14, 14.5, 15, 16, 24 hours 
post dose 
x Day 2:  within an hour prior to dose, 1, 1.5, 2, 2.5, 3, 4, 6 hours 
x Day 3: prior to the Day 3 dose 
x EOT:  anytime during the visit 
8.11.2 
Storing and Shipping of PK Samples 
After all PK samples from a single subject have been collected and frozen at - 20°C or 
colder, the primary samples from each time point can be batched together and carefully 
packaged and shipped frozen at - 20°C or colder to the central laboratory designated by the 
sponsor.  Samples are to be shipped with sufficient dry ice to remain frozen during overnight 
transit.  For each subject and time point, the remaining stored aliquots will be retained on site 
at - 20°C or colder until released or requested by the sponsor. 
 Efficacy Assessments 
8.12.1 
Investigator’s Assessment of Clinical Response 
 
Investigator’s Assessment of Clinical Response at EOT 
EOT assessments should be performed on the calendar day of, or within 2 days following the 
last dose of any test article.  If a subject withdraws prematurely or terminates participation in 
the study prior to completion of the planned antibiotic therapy, the EOT visit should be 
conducted. 
The investigator will determine whether or not the subject meets the criteria of 1 of the 
following clinical outcomes: 


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Clinical Success:  the subject is alive and the infection is sufficiently resolved such that 
further antibacterial therapy is not needed.  These subjects may have some residual findings 
related to infection (ie, cough) requiring ancillary (ie, non-antibiotic) treatment (eg, 
expectorant).  In order for the subject to be considered a Clinical Success at EOT, the subject 
may not meet any criteria for Clinical Failure or Indeterminate at EOT.   
Clinical Failure:  the subject requires alternative antibacterial treatment for CABP prior to 
EOT related to either (a) progression or development of new symptoms of CABP or (b) 
development of infectious complications of CABP (eg, empyema, lung abscess) or (c) 
subject developed an AE that required discontinuation of study therapy.  Other reasons for 
Clinical Failure are: 
x Subject is receiving antibacterial therapy that may be effective for the infection under 
study for a different infection from the 1 under study. 
x Death prior to EOT visit. 
x Other specified reason. 
 
Indeterminate:  the clinical response to test article could not be adequately inferred due to: 
x Subjects were not seen for EOT evaluation because they withdrew consent, were lost to 
follow-up, other reason (specify). 
x Other specified reason. 
 
 
Investigator’s Assessment of Clinical Response at PTE 
The PTE assessment is to be performed 5 to 10 days after the subject’s last day of therapy.  
The investigator will determine whether or not the subject meets the criteria of 1 of the 
following clinical outcomes: 
Clinical Success:  survival after completion of a test article regimen without receiving any 
systemic antibacterial therapy other than test article, resolution of signs and symptoms of the 
infection present at Screening with no new symptoms or complications attributable to CABP 
and no need for further antibacterial therapy.   
Clinical Failure:  the subject requires alternative antibacterial treatment for CABP prior to 
PTE related to either (a) progression or development of new symptoms of CABP or (b) 
development of infectious complications of CABP (eg, empyema, lung abscess). 
x The subject is receiving antibiotics that may be effective for the infection under study for 
a different infection from the 1 under study. 
x Death prior to PTE. 
x Other specified reason. 
 
Indeterminate:  the clinical response to test article could not be adequately inferred due to: 


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x Subjects were not seen for PTE evaluation because they withdrew consent, were lost to 
follow-up, other (specify). 
x Other specified reason. 
 
8.12.2 
Clinical Stability 
The formal determination of the subject’s Clinical Stability will be done programmatically 
using the investigator’s assessment of the subject’s vital signs entered into the eCRF.  The 
investigator is not responsible for categorizing the subject’s Clinical Stability.  Clinical 
Stability will be determined daily and analyzed by day, EOT, and PTE. 
Patients will be considered clinically stable if they achieve all of the following criteria:  
x temperature ≤37.8°C (100°F);  
x heart rate ≤100 beats/minute;  
x RR ≤24 breaths/minute;  
x systolic blood pressure ≥ 90 mmHg; and  
x arterial oxygen saturation ≥ 90% or PaO2 ≥ 60 mmHg on room air. 
 
 Adverse Events  
An AE is any untoward, undesired, or unplanned event in the form of signs, symptoms, 
disease, or laboratory or physiologic observations occurring in a person given a test article or 
in a clinical study.  The event does not need to be causally related to the test article or clinical 
study.  An AE includes, but is not limited to, the following: 
x Any clinically significant worsening of a preexisting condition. 
x An AE occurring from overdose of a test article, whether accidental or intentional.  
Overdose is a dose greater than that specified in the protocol. 
x An AE occurring from abuse (eg, use for nonclinical reasons) of a test article. 
x An AE that has been associated with the discontinuation of the use of a test article. 
 Serious Adverse Events 
A serious adverse event (SAE) is an AE that: 
x Results in death 
x Is life-threatening (see below) 
x Requires hospitalization or prolongation of an existing hospitalization (see below) 
x Results in a persistent or significant disability or incapacity (see below) 
x Results in a congenital anomaly or birth defect 
x Additionally, important medical events that may not result in death, be life-threatening, 
or require hospitalization may be considered SAEs when, based on appropriate medical 


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judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent any one (1) of the outcomes listed above in this definition.  
Examples of such events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias, or convulsions that do not result in 
hospitalization, or development of drug dependency or drug abuse. 
Life-threatening refers to immediate risk of death as the event occurred per the reporter.  A 
life-threatening experience does not include an experience, had it occurred in a more severe 
form, might have caused death, but as it actually occurred, did not create an immediate risk 
of death.  For example, hepatitis that resolved without evidence of hepatic failure would not 
be considered life-threatening, even though hepatitis of a more severe nature can be fatal.  
Similarly, an allergic reaction resulting in angioedema of the face would not be 
life-threatening, even though angioedema of the larynx, allergic bronchospasm, or 
anaphylaxis can be fatal. 
Hospitalization is official admission to a hospital.  Hospitalization or prolongation of a 
hospitalization constitutes criteria for an AE to be serious; however, it is not in itself 
considered an SAE.  In absence of an AE, a hospitalization or prolongation of a 
hospitalization should not be reported as an SAE by the participating investigator.  This is the 
case in the following situations: 
x The hospitalization or prolongation of hospitalization is needed for a procedure required 
by the protocol. 
x The hospitalization or prolongation of hospitalization is part of a routine procedure 
followed by the center (eg, stent removal after surgery).  This should be recorded in the 
study file. 
x A hospitalization for a preexisting condition that has not worsened.  
Disability is defined as a substantial disruption in a person’s ability to conduct normal life 
functions. 
If there is any doubt about whether the information constitutes an SAE, the information is 
treated as an SAE. 
 Other Reportable Information  
Certain information, although not considered an SAE, must be recorded, reported, and 
followed up as indicated for an SAE.  This includes: 
x Pregnancy exposure to a test article:  If a pregnancy is confirmed, use of the test article 
must be discontinued immediately.  Information about pregnancy exposure includes the 
entire course of pregnancy and delivery, and perinatal and neonatal outcomes, even if 
there are no abnormal findings.  Both maternal and paternal exposures are considered 
other reportable information.  For exposure involving the female partner of a male 
subject, the necessary information must be collected from the subject, while respecting 
the confidentiality of the partner. 


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x Lactation exposure to a test article with or without an AE. 
x Overdose of a test article as specified in this protocol with or without an AE. 
x Inadvertent or accidental exposure to a test article with or without an AE. 
 Overdose 
Any administration of omadacycline of greater than 1350 mg within a 24-hour period will be 
an overdose, regardless of whether the overdose is intentional or accidental, it is a reportable 
event and the sponsor must be notified within 1 business day.  The site personnel will retain 
this confirmation report.  
The physician managing the overdose may order any test he/she thinks is necessary to 
manage the subject properly. 
 Medication Errors 
Medication errors are the result of administration or consumption of the wrong product, by 
the wrong subject, at the wrong time, and/or by the wrong administration route, due to human 
error.   
Medication errors include, but are not limited to, the following: 
x The administration and/or consumption of test article that has not been assigned to the 
subject 
x Administration of expired test article 
All AEs and SAEs must be handled as specified in this protocol whether or not they are 
associated with a medication error.  A medication error associated with an SAE (including 
overdose, inadvertent exposure, and/or accidental exposure) will be reported with the SAE on 
the SAE Report Form.  All other medication errors will be reported by e-mailing the Clinical 
Test Article Error Incident Report Form as indicated in the Emergency Contacts (see 
Section 2). 
 Recording and Reporting 
A subject’s AEs and SAEs will be recorded and reported from the signing of the ICF to the 
time of the Final Follow-up assessment.  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 eCRFs. 
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. 


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Adverse events 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?"  Whenever possible, AEs should be reported as a 
diagnosis rather than individual signs and symptoms.  If a definitive diagnosis is not possible, 
the individual signs and symptoms should be recorded using standard medical terminology. 
If an AE requires a surgical or diagnostic procedure, the illness leading to the procedure 
should be recorded as the AE, not the procedure itself. 
Death should be recorded in the eCRF as an outcome of an AE.  Any unanticipated risks to 
the subjects must be reported promptly to the IRB/IEC/REB.  
8.18.1 
Serious Adverse Event Reporting 
All SAEs and follow-up information must be reported within 1 business day or 24 hours as 
required by local regulations by emailing a completed SAE Report to the email address 
below.  
Serious Adverse Event (SAE) contact information: 
E-Mail: 
 
8.18.2 
Assessment of Relatedness 
The investigator will assess causality (ie, whether there is a reasonable possibility that test 
article caused the event) for all AEs and SAEs.  The relationship will be characterized using 
the following classification: 
 Not related:  This relationship suggests that there is no association between test article 
and the reported event.  The event can be explained by other factors such as an 
underlying medical condition, concomitant therapy, or accident, and no plausible 
temporal or biologic relationship exists between test article and the event. 
 Related:  This relationship suggests that a definite causal relationship exists between test 
article administration and the AE, or there is a reasonable possibility that the event was 
caused by the study medication, and other conditions (concurrent illness, 
progression/expression of disease state, or concurrent medication reaction) do not appear 
to explain the event. 
Adverse events and SAEs also will be assessed for their potential relationship to the protocol.  
A protocol-related AE is one that is not related to the test article but is considered by the 
investigator or the medical monitor (or designee) to be related to the research conditions, ie, 
related to the fact that a subject is participating in the study.  For example, a protocol-related 
AE may be an untoward event related to a medical procedure required by the protocol. 
8.18.3 
Assessment of Severity 
The severity (or intensity) of an AE will be classified using the following criteria: 


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 Mild:  These events are usually transient, require minimal or no treatment, and do not 
interfere with the subject’s daily activities. 
 Moderate:  These events result in a low level of inconvenience or concern with the 
therapeutic measures.  Moderate events may cause some interference with normal 
functioning but pose no significant or permanent risk of harm. 
 Severe:  These events interrupt a subject’s usual daily activity and may require systemic 
drug therapy or other treatment.  Severe events are usually incapacitating. 
Changes in the severity of an AE should be documented as a new event to allow an 
assessment of the duration of the event at each level of intensity to be performed. 
8.18.4 
Laboratory Findings 
Protocol-defined safety laboratory test results will be analyzed as part of specific laboratory 
safety analyses.  Additional laboratory test results at other time points may be available to the 
investigator as part of standard clinical practice.  Throughout the study, laboratory-related 
abnormalities should be recorded as AEs only if considered clinically significant, outside the 
range of expected values given the subject’s Baseline assessments and clinical course, and 
not known to be part of another AE diagnosis. 
8.18.5 
Worsening or Progression of Disease Under Study 
Worsening or progression of the qualifying CABP should be recorded as a clinical failure (as 
part of the efficacy assessment), rather than an AE, unless the worsening/progression also 
meets the criteria for a serious AE (in which case the event also should be reported as an 
SAE).  In contrast, any new or secondary infections that the investigator considers to be 
distinct from the qualifying CABP should be reported as AEs in all cases, whether 
non-serious or serious. 
8.18.6 
Pregnancies 
To ensure subject safety, each pregnancy in a subject on test article must be reported to the 
sponsor within 1 business day of learning of its occurrence.  Test article should be 
discontinued immediately, and the pregnancy should be followed up to determine outcome, 
including spontaneous or voluntary termination, details of the birth, and the presence or 
absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the sponsor.  Pregnancy follow-up should be recorded on the same form and 
should include an assessment of the possible relationship to the test article of any pregnancy 
outcome.  Any SAE experienced during pregnancy must be reported on the SAE Report 
Form. 


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 Concomitant Medication Assessments 
The investigator should instruct the subject to notify the study site about any new 
medications they take after the start of the test article.   
All prescription medications, over-the-counter drugs, and recreational drugs taken within the 
timeframe defined in the entry criteria prior to the start of the study and during the study, 
must be recorded on the Concomitant Medications/Non-Drug Therapies page of the eCRF.  
Medication entries should be specific to trade name, the single dose and unit, the frequency 
and route of administration, the start and discontinuation dates, and the reason for therapy. 
 Subject Discontinuation or Withdrawal 
Reasons why a subject may discontinue or be withdrawn from the study include, but are not 
limited to, AE, lost to follow up, withdrawal by subject, physician decision, death, and other 
(specify reason eg, subject non-compliance or study termination by the sponsor).  Subjects 
may voluntarily withdraw from the study for any reason at any time.  Subjects are considered 
withdrawn from the study if they state an intention to withdraw, or fail to return for visits, or 
become lost to follow up for any other reason.  If premature withdrawal from the study 
occurs for any reason, the investigator should determine the primary reason for a subject’s 
premature withdrawal from the study and record this information on the eCRF. 
Subjects who discontinue study treatment should not be considered withdrawn from the study 
(unless the subject withdraws informed consent).  The date and primary reason for 
discontinuation of study treatment should be recorded.  Subjects who discontinue study 
treatment prematurely should complete the EOT visit, PTE visit and Final Follow-up 
Assessment, if possible (see Schedule of Events - Appendix 1).  The site should also collect 
subject safety information through the Final Follow-up assessment.   
Site personnel should also contact the IxRS, if used to register the subject’s discontinuation 
from test article.   
For subjects who are lost to follow up, the investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the subject, eg, dates of 
telephone calls, registered letters, etc. 
8.20.1 
Replacements 
Any subject who is withdrawn or discontinued from the study may be replaced at the 
discretion of the sponsor to meet the target of at least 20 subjects with complete PK 
sampling. 


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9 
STUDY ACTIVITIES 
The full assessment schedule is presented in the Schedule of Events (see Appendix 1).  
Subjects should be seen for all visits on the designated day.   
Screening Phase 
The Screening visit should be completed within a 24-hour period prior to randomization.    
The Screening procedures will be used to establish subject eligibility and Baseline 
characteristics for each subject.  Following the signing of an ICF, the site staff will 
collect/perform the assessments detailed in Appendix 1. 
Treatment Phase 
The open label treatment period is 7 to 10 days in duration.  Additionally, subjects with 
bacteremia confirmed from local blood culture drawn at screening can receive up to 14 days 
of treatment.  Subjects who meet all of the inclusion criteria and none of the exclusion 
criteria may be assigned. 
EOT Visit Procedures 
The EOT evaluation should be conducted on the day of or within the 2 days following the 
last dose of test article.  If the subject voluntarily withdraws or is discontinued from her 
dosing regimen, the visit procedures should be performed on that day. 
Follow-up Phase 
9.4.1 
Post-Treatment Evaluation Visit Procedures 
The PTE visit should be conducted 5 to 10 days after the last dose.  This evaluation should 
also be conducted for any prematurely withdrawn subject. 
9.4.2 
Final Follow-up 
The FFU assessment should be conducted within 30-37 days following the subject’s first
dose of test article.  This evaluation should also be conducted for any prematurely withdrawn 
subject with the exception of subjects who withdraw consent.  The Final Follow-up 
assessment may be conducted via telephone contact or by another interactive technology for 
subjects who are a Clinical Success and had no AEs or clinically significant laboratory, or 
ECG abnormalities noted at or after the PTE visit.  Otherwise, the visit must be conducted in 
person.  


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10 STUDY SUSPENSION, TERMINATION, AND COMPLETION 
Study Completion and Post-Study Test Article 
A subject will have successfully completed the study after the planned test article regimen 
has been administered, and all assessments and visits have been performed up through the 
FFU assessment.  The study will be completed when the last subject has either discontinued 
or completed the FFU assessment.   
No long-term follow-up of subjects is planned, with the exception of pregnancies, as 
described in Section 8.18.6, and SAEs described in Section 8.18.1. 
Sites will be notified by either the Sponsor or IxRS, if used to stop enrollment when the 
desired number of treated subjects have been enrolled.  Subjects already consented, but not 
yet assigned will be allowed to continue Screening procedures. 
Upon study completion, the investigator will provide the sponsor, IRB/IEC/REB, and 
regulatory agency with final reports and summaries as required by regulations.  The 
investigator must submit a written report to the sponsor and the IRB/IEC/REB within 
3 months after the completion or termination of the study. 
Study Suspension or Termination 
The sponsor may suspend or terminate the study at any time for any reason.  Should this be 
necessary, subjects should be seen as soon as possible and treated as described in Sections 
8.20 and 9.3 for prematurely withdrawn subjects.  The investigator may be informed of 
additional procedures to be followed in order to ensure that adequate consideration is given 
to the protection of the subject’s interests.  The investigator will be responsible for informing 
IRBs and/or Ethics Committees (ECs) of the early termination of the study. 
If the investigator suspends or prematurely terminates their participation in the study, the 
investigator will promptly inform the sponsor and the IRB/IEC/REB and provide them with a 
detailed written explanation.  Subjects should be seen as soon as possible and treated as 
described in Sections 8.20 and 9.3 for prematurely withdrawn subjects.  The investigator will 
also return all test articles, containers, and other study materials to the sponsor. 


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11 QUALITY CONTROL AND ASSURANCE 
The sponsor performs quality control and assurance checks on all clinical studies that it 
sponsors.  Before enrolling any subjects in this study, sponsor personnel and the investigator 
review the protocol, the Investigator’s Brochure, the case report forms (CRFs) and 
instructions for their completion, the procedure for obtaining informed consent, and the 
procedure for reporting AEs and SAEs.  A qualified representative of the sponsor monitors 
the conduct of the study by visiting the site and by contacting the site by telephone and 
e-mail.  During these site visits, information recorded in the CRFs is verified against source 
documents. 


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12 PLANNED STATISTICAL METHODS 
 General Considerations 
This section describes the statistical analysis as foreseen at the time of planning the study.  
Changes, additions, and further details about the analyses will be described in the statistical 
analysis plan (SAP).  After finalization of the SAP, any additional analyses or changes to 
analyses that may be required will be fully disclosed in the Clinical Study Report (CSR.). 
Analyses will be performed after the database lock at which all eCRFs are completed, 
entered and source data verified; all safety laboratory results have been reported; all AEs 
fully characterized (e.g., relationship to test article determined) and coded; characterization 
of protocol deviations as major/minor completed, and all queries have been resolved.    
Exploratory analyses may also be performed.  Listings of individual subject’s data will be 
produced. 
 Determination of Sample Size 
This study is designed to evaluate the PK profile of an oral dosing regimen, 300mg BID on 
Day 1 and QD on Day 2, in adults with CABP.  The sample size determination is based on 
consideration of the precision of the estimate, GMR of AUC(0-48) for 300mg po to 100mg IV, 
derived from model-based simulations of omadacycline concentration data (Phase I studies). 
With 20 evaluable subjects, there will be 90% probability that the 90% CIs of the GMR for 
AUC(0-48) will be within 80% and 125%. Up to 30 subjects will be enrolled so that at least 20 
subjects are evaluable for bioavailability estimation.   
The number may be adjusted as needed to meet this requirement.  
Analysis Populations 
The following subject analysis populations have been defined for the various analyses of PK, 
safety and efficacy: 
x The PK population will consist of all assigned subjects who receive test article and have 
PK samples collected.  
x The Safety population will consist of all assigned subjects who receive at least one dose 
of test article.  
x The intent-to-treat (ITT) population will consist of all assigned subjects. 
 
Additional populations may be defined in the SAP as appropriate.  


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 Demographics and Baseline Characteristics 
Demographics (including age, ethnicity and race) and baseline characteristics will be 
summarized.  Descriptive statistics of the duration of test article treatment will be provided.  
The number and percentage of subjects who prematurely discontinued test article and the 
reason for discontinuation and the number and percentage of subjects prematurely 
discontinuing the study and the primary reason for discontinuation will be presented. 
 Primary Endpoint(s) 
12.5.1 
Pharmacokinetic Endpoint 
The following plasma PK parameters will be determined:  
x Area under the plasma concentration time curve (AUC) from time 0 to 48 hours after 
dosing (AUC0-48)  
x Area under the plasma concentration time curve (AUC) from time 0 to 24 hours after 
dosing (AUC0-24)  
x AUC from time 0 to the last quantifiable concentration (AUClast) 
x Maximum observed plasma concentration (Cmax) 
x Time to reach maximum observed plasma concentration (Tmax) 
x Elimination half-life associated with the terminal slope of the semilogarithmic 
concentration-time curve (T1/2) 
 
The observed omadacycline concentration-time data after an oral dosing regimen, BID on 
Day 1 and QD on Day 2, in CABP patients will be evaluated. 300mg administered orally is 
the dose that provided equivalent total exposure as measured by AUC relative to the 100mg 
IV dose (CPTK796-A2104).  The oral bioavailability of omadacycline is 34%.   
Using the superposition principle, the AUC of a single 100mg IV dose on Day 1 for n=63 
healthy subjects were totaled to evaluate the AUC(0-48) of the established omadacycline IV 
dosing regimen (q12h on Day 1 followed by q24h on Day 2).  AUC(0-48) values are then 
summarized and serve as the comparator for this current study.  Safety and efficacy in CABP 
patients were demonstrated with this dosing regimen (PTK796-CABP-1200), but only sparse 
PK sampling was conducted.  The final population PK model for omadacycline, which 
includes CABP patients from the PTK0796-CABP-1200 study, generated similar AUC(0-48) 
values for the 100mg IV dosing regimen. 
 
The comparative bioavailability assessment between the test, 300mg po in CABP patients, 
and the reference, 100mg IV in healthy subjects, will be based on 90% confidence intervals 
(CIs) for the geometric mean ratios (GMR) of AUC(0-48) for the two dosing regimens being
within 80% and 125%. 
Plasma concentration data and PK parameters will be summarized by time point using 
descriptive statistics (number of subjects, mean, standard deviation (SD), coefficient of 


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variation (CV), median, minimum, and maximum).  Mean and individual plasma 
concentration versus time profiles will be presented in figures on both linear and 
semilogarithmic scales.  Geometric means will be included for area under the concentration-
time curve (AUC) and maximum observed plasma concentration (Cmax).  
Individual plasma concentration, time deviation and PK parameters will be presented in data 
listings.   
Any additional exploratory PK calculations will be further described in the SAP. 
 Secondary Endpoint(s) 
12.6.1 
Safety Endpoint(s) 
All safety analyses will utilize the Safety population.  Summary tables will be provided for 
all treatment-emergent adverse events (TEAEs).  A TEAE is defined as an AE with a start 
date and time on or after the first dose of test article.  Adverse events will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) and will be summarized by 
presenting the number and percentage of subjects having each TEAE by system organ class 
(SOC) and preferred term (PT), by SOC, PT and severity, and by SOC, PT and relationship 
to test article.  Additional tabulations will provide summaries by SOC and PT of subjects 
experiencing SAEs and TEAEs leading to discontinuation of test article.  
Treatment-emergent adverse events leading to dose interruption of test article, and TEAEs of 
special interest. 
The following variables will be analyzed descriptively in the Safety population: 
x Vital signs (systolic and diastolic BP, pulse/heart rate, body temperature, pulse oximetry, 
RR), including change from Baseline by time point measured 
x Clinically notable vital signs (meeting predefined criteria as specified in the SAP) by 
time point measured 
x
Laboratory parameters, including change from Baseline by visit and overall worst 
post-baseline 
x Clinically notable laboratory parameters (meeting predefined criteria as specified in the 
SAP) by visit and overall worst post-baseline 
12.6.2 
Exploratory Endpoint(s) 
The efficacy outcome is defined as the Investigator’s Assessment of Clinical Response with 
outcomes of Clinical Success, Clinical Failure or Indeterminate (see Section 8.12.1) in the 
ITT population.   
An Indeterminate Response is included in the denominator for the calculation of the 
percentage of subjects with a Clinical Success in the ITT population and thus, is essentially 
considered a Clinical Failure.   


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The following is a list of key assessments that will be performed:  
x Assessment of signs and symptoms of CABP by the investigator 
x Clinical Stability 
12.6.3 
Resource Utilization Endpoint(s) 
Data for resource utilization will be collected through the Final Follow-up assessment and 
will include: 
x Hospital admission 
x Emergency Department and Physician visits  
Descriptive statistics for the resource utilization parameters will be provided for the purpose 
of health economic evaluation.   
 Data Handling Conventions 
For all variables, only the observed data from the patients will be used in the statistical 
analyses, ie, there is no plan to estimate missing data, unless otherwise specified.  Detailed 
data imputation rules will be described in the SAP. 
If available, pharmacokinetic parameters from the concentration-time profile data of patients 
who drop out or are withdrawn will be calculated but will be excluded from the final 
statistical analysis. 
 Multiple Comparisons and Multiplicity 
No formal comparisons are planned. 
 General Data Summaries 
For continuous variables, descriptive statistics (number [n], mean, SD, median, minimum, 
and maximum) will be provided.  
For categorical variables, patient counts, and percentages will be provided.  Categories for 
missing data will be presented if necessary. 


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13 ADMINISTRATIVE CONSIDERATIONS 
 Investigators and Study Administrative Structure 
The investigator will permit study-related monitoring, audits, IRB/IEC/REB review, and 
regulatory inspections by providing direct access to source data and documents. 
All information will be recorded on source documents.  All required data will be recorded in 
the eCRFs. 
If an investigator retires, relocates, or otherwise withdraws from conducting the study, the 
investigator must notify the sponsor to agree upon an acceptable solution including but not 
limited to storage for all study-related documents.  Regulatory agencies will be notified with 
the appropriate documentation. 
An updated form 1572 will be filed with the sponsor for any changes in the study personnel 
reported in the current form 1572. 
 Institutional Review Board or Independent Ethics Committee Approval 
The protocol and the proposed ICF must be reviewed and approved by a properly constituted 
IRB/IEC/REB before study start.  A signed and dated statement that the protocol and ICF 
have been approved by the IRB/IEC/REB must be given to the sponsor before study 
initiation.  Prior to study start, the investigator is required to sign a protocol signature page 
confirming his/her agreement to conduct the study in accordance with these documents and 
all of the instructions and procedures found in this protocol and to give access to all relevant 
data and records to the sponsor, monitors, auditors, designated agents of the sponsor, 
IRBs/IECs/REBs, and regulatory authorities as required.  If an inspection of the clinical site 
is requested by a regulatory authority, the investigator must inform the sponsor immediately 
that this request has been made.   
 Ethical Conduct of the Study 
This clinical study was designed and shall be implemented and reported in accordance with 
the International Council on Harmonisation (ICH) Harmonized Tripartite Guidelines for 
Good Clinical Practice (GCP), with applicable local regulations (including European 
Directive 2001/20/EC, US 21 Code of Federal Regulations (CFR), and Japanese Ministry of 
Health, Labor, and Welfare), and with the ethical principles laid down in the Declaration of 
Helsinki. 
 Patient Information and Consent 
The investigator will provide for the protection of the subjects by following all applicable 
regulations.  These regulations are available upon request from the sponsor.  The ICF must 
be reviewed by the sponsor and approved by the IRB/IEC/REB. 
Before any procedures specified in the protocol are performed, a subject must: 


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x Be informed of all pertinent aspects of the study and all elements of informed consent; 
x Be given time to ask questions and time to consider the decision to participate; 
x Voluntarily agree to participate in the study; and 
x Sign and date an IRB/IEC/REB-approved ICF. 
 Direct Access, Data Handling, and Record Keeping 
13.5.1 
Investigator 
The investigator will permit study-related monitoring, audits, IRB/IEC/REB review, and 
regulatory inspections by providing direct access to source data and documents. 
All information will be recorded on source documents.  All required data will be recorded in 
the eCRFs. 
If an investigator retires, relocates, or otherwise withdraws from conducting the study, the 
investigator must notify the sponsor to agree upon an acceptable storage solution.  
Regulatory agencies will be notified with the appropriate documentation. 
An updated form 1572 will be filed with the sponsor for any changes in the study personnel 
reported in the current form 1572. 
13.5.2 
Sponsor 
The data is entered into an electronic database via eCRFs.  The Sponsor Medical Monitor 
reviews the data for safety information.  The data is reviewed for completeness and logical 
consistency.  Automated validation checks identify missing data, out-of-range data, and other 
data inconsistencies. Requests for data clarification are forwarded to the investigative site for 
resolution. 
 Protocol Adherence 
13.6.1 
Violations/Deviations 
Investigators will agree to apply due diligence to avoid protocol deviations.  Under no 
circumstances should the investigator contact the sponsor or its agents to request approval of 
a prospective protocol deviation, as no authorized deviations are permitted.  If the 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by the 
sponsor and approved by the IRB/IEC/REB, it cannot be implemented.  All significant 
protocol deviations will be recorded and reported in the CSR. 
13.6.2 
Protocol Amendments 
Any change or addition to the protocol can only be made in a written protocol amendment 
that must be approved by the sponsor, Health Authorities where required, and the 
IRB/IEC/REB.  Only amendments that are required for subject safety may be implemented 


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prior to IRB/IEC/REB approval.  Notwithstanding the need for approval of formal protocol 
amendments, the investigator is expected to take any immediate action required for the safety 
of any subject included in this study, even if this action represents a deviation from the 
protocol.  In such cases, the sponsor should be notified of this action and the IRB/IEC/REB 
at the study site should be informed within 10 working days. 
 Subject Injury 
In general, subject to specific provisions in the clinical study agreement (CSA), if a subject is 
injured as a direct result of a test article, the sponsor will pay for reasonable and necessary 
medical treatment for the injury, to the extent that such expenses are not covered by the 
subject’s medical insurance, a government program, or other responsible third party.  If laws 
or regulations of the locality in which the study is taking place require additional payment of 
expenses, the sponsor shall comply with such laws or regulations.  Where applicable, the 
sponsor has taken specific national insurance. 
 Pre-Study Documentation 
The investigator must provide the sponsor with the following documents before enrolling any 
subjects: 
x Completed and signed form 1572 or equivalent 
x All applicable country-specific regulatory forms 
x Current signed and dated curricula vitae for the investigator, sub-investigators, and other 
individuals having significant investigator responsibility who are listed on the 
form 1572 or equivalent, or the clinical study information form 
x Copy of the IRB/IEC/REB approval letter for the protocol and informed consent.  All 
advertising, recruitment, and other written information provided to the subject must be 
approved by the IRB/IEC/REB.  Written assurance of continuing approval (at least 
annually) as well as a copy of the annual progress report submitted to the IRB/IEC/REB 
must also be provided to the sponsor.   
x Copy of the IRB/IEC/REB-approved informed consent document to be used 
x Where applicable, a list of the IRB/IEC/REB members and their qualifications, and a 
description of the committee’s working procedure 
x Copy of the protocol sign-off page signed by the investigator 
x Fully executed CSA 
x Where applicable, a financial disclosure form 
x A written document containing the name, location, certification number, and date of 
certification of the laboratories to be used for laboratory assays and those of other 
facilities conducting tests.  This document should be returned along with the statement of 
investigator form.  The sponsor must be notified if the laboratory is changed or if any 
additional laboratory is to be used.  


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x List of normal laboratory values and units of measure for all laboratory tests required by 
the protocol.  This is required for each laboratory to be used during the study.  The 
sponsor must be notified if normal values or units of measurement change. 
 Retention of Data 
The investigator shall retain and preserve 1 copy of all data generated in the course of the 
study, specifically including but not limited to those defined by GCP as essential, for the 
longer of: (a) 2 years after the last marketing authorization for the investigational test article 
has been approved or the sponsor has discontinued its research with respect to such 
investigational test article or (b) such longer period as required by applicable global 
regulatory requirements.  At the end of such period, the investigator shall notify the sponsor 
in writing of its intent to destroy all such material.  The sponsor shall have 30 days to 
respond to the investigator’s notice, and the sponsor shall have a further opportunity to retain 
such materials at the sponsor’s expense. 
 Publication and Disclosure Policy 
The sponsor assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov.  In addition, upon study completion and 
finalization of the study report, the results of this study will be either submitted for 
publication and/or posted in a publicly accessible database of clinical study results. 
Upon completion of the study, the investigator may publish the results in recognized 
(refereed) scientific journals subject to the provisions of the CSA.  Unless otherwise 
specified in the CSA, the following process shall occur: 
The institution and Principal Investigator (PI) shall not publish or present data from an 
individual study center until the complete multi-center study has been presented in full or for 
2 years after the termination of the multi-center study, whichever occurs first.  Subsequent 
publications must refer to the multi-center findings.  Thereafter, if the PI expects to 
participate in the publication of data generated from this site, the institution and PI shall 
submit reports, abstracts, manuscripts, and/or other presentation materials to the sponsor for 
review before submission for publication or presentation.  The sponsor shall have 60 days to 
respond with any requested revisions, including, without limitation, the deletion of 
confidential information.  The PI shall act in good faith upon requested revisions, except that 
the PI shall delete any confidential information from such proposed publication.  The PI shall 
delay submission of such publication or presentation materials for up to an additional 90 days 
in order to have a patent application(s) filed. 


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14 REFERENCE LIST 
1. NUZYRA® (omadacycline) USPI  
2. Axelrod L.  Glucocorticoid therapy.  In:  Jameson JL & De Groot LJ, eds.  
Endocrinology 6th ed.  Philadelphia, PA:  Saunders;2010:1840. 
3. Fine MJ, Auble TE, Yealy DM, Hanusa BH, Weissfeld LA, Singer DE, et al.  A 
prediction rule to identify low-risk subjects with community-acquired pneumonia.  N 
Engl J Med.  1997;336:243-50.   
4. Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, 
et al.  Infectious Diseases Society of America/American Thoracic Society Consensus 
Guidelines on the Management of Community-Acquired Pneumonia in Adults.  Clin 
Infect Dis.  2007;44:S27-S72. 
5. Niederman, MS, McCombs JS, Unger AN, Kumar A, Popovian R.  The cost of 
treating community-acquired pneumonia.  Clin Ther.  1998;20(4):820-37. 
6. Paterson DL.  "Collateral damage" from cephalosporin or quinolone antibiotic therapy.  
Clin Infect Dis.  2004;38 Suppl 4:S341-5. 
7. Spellberg, et al.  The Epidemic of Antibiotic-Resistant Infections:  A Call to Action for 
the Medical Community from the Infectious Diseases Society of America.  CID.  
2008;46:155-164. 
 


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Appendix 1 
Schedule of Events 
Study Phase 
Screeninga 
Treatment Phase 
Follow-up Phase 
Study Dayb 
 
Day 1 
Day 2 
Day 3 
Day 7-10/ 
EOTc 
PTEd 
Final 
Follow-upe 
Signed Informed Consentf 
X 
 
 
 
 
 
 
Medical History, current medical 
conditions, demography 
X 
 
 
 
 
 
 
Assessment of CABP symptom 
severityg 
X 
 
X 
X 
X 
X 
 
Chest X-ray or CT scanh 
X 
 
 
 
 
 
 
PORT Risk Class, ABG (or pulse 
oximetry) i 
X 
 
 
 
 
 
 
Blood samples for local lab 
hematology/chemistry//pregnancy 
testj 
X 
 
 
 
X 
X 
 
Urine samples for local lab urine 
tests/pregnancy testj 
X 
 
 
 
 
 
 
Review of Inclusion and Exclusion 
criteria/Treatment Group Assignment 
(if Eligible) 
X 
 
 
 
 
 
 
Test Article Administration and 
Accountabilityl 
 
X 
X 
X 
X 
 
 
Physical examinationm 
X 
 
X 
X 
X 
X 
 
Vital signsn 
 
 
 
 
 
 
 
Height and weight 
X 
 
 
 
 
 
 
Body temperature 
X 
X 
X 
X 
X 
X 
 
Blood Pressure 
X 
Xo 
X 
X 
X 
X 
 
Pulse Oximetry 
X 
X 
X 
X 
X 
X 
 
Pulse/Heart Rate 
X 
Xo 
X 
X 
X 
X 
 
Respiratory Rate 
X 
X 
X 
X 
X 
X 
 


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Study Phase 
Screeninga 
Treatment Phase 
Follow-up Phase 
Plasma samples (in heparin) for 
PK analyses 
 
Xp 
Xq 
Xr 
Xs 
 
 
Assessment for need for 
continued therapyt 
 
X  ------------------------------------------------   X 
 
 
Investigator’s Assessment of Clinical 
Response 
 
 
 
 
X 
X 
 
Adverse Eventsu 
X  -------------------------------------------------------------------------------------------   X 
Prior/Concomitant Medications and 
Proceduresk 
X  -------------------------------------------------------------------------------------------   X 
Assessment of Resource Utilization 
X  -------------------------------------------------------------------------------------------   X 


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ABG = arterial blood gas, AE = adverse event, BP = blood pressure, β-hCG = beta – human Chorionic Gonadotropin, CABP = community-acquired 
bacterial pneumonia, CT = computed tomography, CXR = chest X-ray, eCRF = electronic case report form, EOT = end of treatment, ICF = informed 
consent form, IxRS = Interactive Voice Response System/Interactive Web Response System, PK = pharmacokinetics, PORT = Pneumonia Outcomes 
Research Team, PTE = post-therapy evaluation, RR = respiratory rate, SAE = serious adverse event. 
a 
Following the signing of an ICF, all Screening evaluations, with the exception of the radiographic confirmation of pneumonia, should be completed 
within the 24 hours prior to treatment group assignment.  The radiographic confirmation of pneumonia should be completed within the 48 hours 
prior to the first dose of test article.  
b 
Study Day 1 is the first day of test article administration.  Subsequent study visit days may be consecutive calendar days. 
c 
To be conducted on the day of, or within 2 days following the last dose of test article.  Should also be conducted for any prematurely withdrawn 
subject. 
d 
To be conducted 5 to 10 days after the subject’s last day of therapy. 
e 
To be conducted 30 to 37 days after the start of the first dose of test article.  The Final Follow-up 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 PTE visit.  Otherwise, the visit must be conducted in person. 
f 
Written and signed ICF must be obtained before any assessment is performed. 
g 
The investigator should assess the severity of the subject’s CABP symptoms of cough, sputum production, pleuritic chest pain, and dyspnea based 
upon the Community Acquired Bacterial Pneumonia Subject Symptom Severity Guidance Framework for Investigator Assessment (Appendix 3). 
h 
Subjects must have a confirming CXR or CT scan consistent with acute bacterial pneumonia within the 48 hours prior to the first dose of test 
article. 
i 
Only subjects with a PORT Risk Class of II or III for whom oral only treatment for CABP is appropriate are eligible for enrollment. 
j 
Hematology and serum chemistry evaluations will be performed at each of the timepoints indicated. A serum or urine pregnancy test (for women 
only) and urine dipstick will be performed only at Screening.  The relevant local laboratory results from Screening will be used to assess eligibility 
as per the inclusion/exclusion criteria. 
k 
Treatments that have been administered within the 7 days prior to the date of signing the ICF or during the Screening phase will be recorded in the 
eCRF.  All medications and significant non-drug therapies administered after the first dose of test article must be recorded in the eCRF.  Additional 
information, including start and stop time, will be collected for any prior or concomitant antibiotic. 
l 
 All oral doses should be taken in a fasted state (no food, antacids, or multivitamins containing multivalent cations [eg, aluminum, magnesium, 
calcium, bismuth, iron, or zinc] or drink except water for at least 6 hours before dosing).  Subjects discharged with po test article will be asked to 
return all unused test article and packaging at each visit and site staff will perform accountability.  The total duration of test article therapy for all 
subjects will be 7 to 10, up to 14 for bacteremia.   
m 
A full physical examination will be completed at Screening, thereafter only changes from Screening measurements should be recorded as AEs in 
the eCRFs. 
n 
Vital signs include body temperature, BP, pulse oximetry, pulse/heart rate, and RR. 
o 
BP and heart rate should be measured within 30 min before, and approximately (± 15 minutes) 1-hour after the completion of the doses on Day 1. 
p 
PK sample collection on Day 1:within an hour prior to Dose 1, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (12 hour taken immediately before Dose 2); Dose 2 
administered (times relative to Dose 1); 13, 13.5, 14, 14.5, 15, 16, 24 hours post dose 
q 
PK sample collection on Day 2:within an hour prior to dose, 1, 1.5, 2, 2.5, 3, 4, 6 hours r PK sample collection on Day 3:  prior to the Day 3 dose 
s 
PK sample collection on EOT is anytime during the visit after the final dose. 


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Study Phase 
Screeninga 
Treatment Phase 
Follow-up Phase 
t 
The total duration of test article therapy for all subjects will be 7 to 10 days, up to 14 days for bacteremia.  
u 
A subject’s AEs and SAEs will be recorded and reported from signing of the ICF to the Final Follow-up assessment.  
 
 
 


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Appendix 2 
Equations and Conversion Factors 
1. Cockcroft-Gault equation to calculate creatinine clearance (CrCl) (See Sections 6.2): 
(140-age [years]) * weight (kg) * (Z) 
Z = 1.0, if Male  
Z = 0.85, if Female 
Cr (mg/dL) * 72 
 
2. Corticosteroid conversions (Sections 6.2): 
The following have equivalent glucocorticoid activitya 
Hydrocortisone 
160 mg 
Prednisone 
40 mg 
Prednisolone 
40 mg 
Methylprednisolone 
32 mg 
Triamcinolone 
32 mg 
Dexamethasone 
6 mg 
a 
Axelrod. 
 
3. Conversion of immature neutrophils (band) forms in K/μL or K/mL to % bands 
(Sections 6.2): 
([bands K/μL]/[total WBC K/μL]) × 100 = % bands 
OR 
([bands K/mL]/[total WBC K/mL]) × 100 = % bands 
 
 


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Appendix 3 
Community-Acquired Bacterial Pneumonia Subject 
Symptom Severity Guidance Framework for Investigator 
Assessment 
COUGH? 
Absent 
Mild 
Moderate 
Severe 
 
No cough or 
resolution (to 
pre-CABP 
Baseline) 
Cough present but 
it does not interfere 
with subject’s usual 
daily activities 
Cough present, 
frequent and it does 
interfere with some 
of the subject’s 
usual daily 
activities 
Cough is present 
throughout the day 
and night; it limits 
most of the 
subjects’ usual 
daily activities and 
sleep patterns 
PLEURITIC 
CHEST PAIN? 
Absent 
Mild 
Moderate 
Severe 
 
No chest pain or 
resolution of chest 
pain related to 
CABP 
Chest pain present 
occasionally with 
deep breathing but 
it does not interfere 
with subject’s usual 
daily activities 
Chest pain is 
present with normal 
breaths and it does 
interfere with the 
subject’s usual 
daily activities 
Chest pain is 
present at rest 
and/or with shallow 
breathing; it limits 
most of the 
subject’s usual 
daily activities 
SHORTNESS OF 
BREATH? 
Absent 
Mild 
Moderate 
Severe 
 
No shortness of 
breath or resolution 
(to pre-CABP 
Baseline) 
Shortness of breath 
with strenuous 
activities only but it 
does not interfere 
with subject’s usual 
daily activities 
Shortness of breath 
with usual activities 
and it does interfere 
with the subject’s 
usual daily 
activities  
Shortness of breath 
with minimal 
exertion or at rest; 
it limits most of the 
subject’s usual 
daily activities 
PHLEGM/ 
SPUTUM 
PRODUCTION? 
Absent 
Mild 
Moderate 
Severe 
 
No coughing up of 
phlegm/sputum or 
resolution (to pre-
CABP Baseline) 
Subject coughs up 
a small amount of 
phlegm/sputum 
Subject coughs up 
a moderate amount 
of phlegm/sputum 
Subject coughs up 
a large amount of 
phlegm/sputum 
 
 


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Appendix 4 
PORT Risk Class Calculation 
Adapted from Fine.   
Subject Characteristic 
Point Assignment 
Age 
Male 
Age (years) 
Female 
Age (years) -10 
Nursing home residenta 
+10 
Coexisting illnesses 
Neoplastic diseaseb 
+30 
Liver diseasec 
+20 
Congestive heart failured 
+10 
Cerebrovascular diseasee 
+10 
Renal diseasef 
+10 
Physical-examination findings 
Altered mental statusg 
+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 
+30  
Blood urea nitrogen ≥ 30 mg/dL (11 mmol/L)f  
+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)  
+10 
Pleural effusion 
+10 
PORT Score 
Sum of numbers above 
 
 
PORT Risk Class 
PORT Score 
I (ineligible for study) 
0-50 
II 
51-70 
III 
71-90 
IV (ineligible for study) 
91-130 
V (ineligible for study) 
≥ 131 
Crcl = creatinine clearance, CT = computed tomography, PORT = Pneumonia Outcomes Research Team 
a 
Subjects that reside in a nursing home or assisted living facility that provides 24-hour medical 
supervision are excluded from the study and should not be enrolled per Exclusion Criterion #4. 
b 
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 #10. 
c 
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 #7 should not be enrolled. 
d 
Congestive heart failure is defined as systolic or diastolic ventricular dysfunction documented by 
history, physical examination, and chest radiograph, echocardiogram, multiple gated acquisition scan, or 
left ventriculogram.  Subjects with acute congestive heart failure are excluded from the study and should 
not be enrolled per Exclusion Criterion #5. 
e 
Cerebrovascular disease is defined as a clinical diagnosis of stroke or transient ischemic attack or 
stroke documented by magnetic resonance imaging or CT.   


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Subject Characteristic 
Point Assignment 
f 
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 who require dialysis or who have 
severely impaired renal function (CrCl < 30 mL/min) are excluded from the study and should not be 
enrolled per Exclusion Criteria. 
g 
Altered mental status is defined as disorientation with respect to person, place, or time that is not 
known to be chronic, stupor, or coma.   
 
 




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Appendix 6 
Investigator’s Signature 
Study Title: 
A Phase 1 Multi-Center Study to Measure the Pharmacokinetics of 
Oral Omadacycline in Adult Subjects with Community-Acquired 
Bacterial Pneumonia (CABP) 
Study Number: 
PTK0796-CABPPO-19109 
Final Date: 
26 August 2019 
I have read the protocol described above.  I agree to comply with all applicable regulations 
and to conduct the study as described in the protocol.  
Signed: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date:  
 
 
 
 
 
 
Investigator Name:___________________________________ 
Investigator Title:____________________________________  
Investigator Affiliation:_______________________________ 
Investigator Address:_________________________________ 
Investigator Phone Number:____________________________ 

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Statistical Analysis Plan:  PTK0796-CABPPO-19109 
 
Study Title: 
A Phase 1 Multi-Center Study to Measure the 
Pharmacokinetics of Oral Omadacycline in 
Adult Subjects with Community-Acquired 
Bacterial Pneumonia (CABP) 
Study Number: 
PTK0796-CABPPO-19109 
Study Phase:  
1b 
Sponsor: 
Paratek Pharma, LLC 
A wholly-owned subsidiary of Paratek 
Pharmaceuticals, Inc. 
75 Park Plaza, 4th Floor 
Boston, MA 02116 USA 
Tel:  +1 617-275-0040 
Version: 
Final Version 1.0 
Date: 
02-Jan-2020 
 
 
Prepared by: 
 Biostatistics Consultant, Paratek Pharma, LLC 
 
 
 
 
 
 
Confidentiality Statement 
This document contains confidential and proprietary information and is not to 
be distributed to any third party. 
 


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TABLE OF CONTENTS 
TABLE OF CONTENTS ...........................................................................................................2 
LIST OF APPENDICES ............................................................................................................3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................................4 
1 
INTRODUCTION .............................................................................................................6 
2 
STUDY OBJECTIVES AND ENDPOINTS .....................................................................7 
2.1 
Study Objectives and Endpoints ..............................................................................7 
3 
STUDY DESIGN...............................................................................................................9 
4 
ASSESSMENT OF CABP SYMPTOM SEVERITY FOR EFFICACY ........................10 
5 
GENERAL STATISTICAL CONSIDERATIONS .........................................................11 
5.1 
Sample Size Determination....................................................................................11 
5.2 
Study Analysis Populations ...................................................................................11 
5.2.1 
Intent-to-Treat (ITT) Population ..................................................................11 
5.2.2 
Safety (SAF) Population ..............................................................................11 
5.2.3 
Pharmacokinetic (PK) Population................................................................12 
6 
STUDY POPULATION SUMMARIES .........................................................................13 
6.1 
Disposition .............................................................................................................13 
6.2 
Demographics and Baseline Characteristics ..........................................................13 
6.3 
Medical History .....................................................................................................14 
6.4 
Inclusion and Exclusion Criteria ............................................................................14 
6.5 
Treatment Compliance and Exposure ....................................................................15 
7 
PHARMACOKINETIC ANALYSIS ..............................................................................16 
7.1 
Pharmacokinetic Sample Concentrations ..............................................................16 
7.2 
Pharmacokinetic Parameters ..................................................................................16 
7.3 
Treatment Comparison...........................................................................................17 
7.4 
Analysis of EOT PK concentration data ................................................................19 
8 
SAFETY AND TOLERABILITY ...................................................................................20 
8.1 
Adverse Events ......................................................................................................20 
8.2 
Vital Signs ..............................................................................................................21 
8.3 
Laboratory Values ..................................................................................................21 
8.4 
Physical Examinations ...........................................................................................22 
9 
EXPLORATORY EFFICACY MEASURES..................................................................23 
9.1 
Investigator’s Assessment of Clinical Response ...................................................23 
9.1.1 
Investigator’s Assessment of Clinical Response at EOT .............................23 
9.1.2 
Investigator’s Assessment of Clinical Response at PTE .............................23 
9.2 
Clinical Stability ....................................................................................................24 
9.3 
Clinical Outcomes ..................................................................................................24 


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10 DATA HANDLING CONVENTIONS ...........................................................................26 
10.1 
Premature Withdrawal and Missing Data ..............................................................26 
10.2 
Derived and Transformed Data ..............................................................................27 
10.2.1 
Reference Dates ...........................................................................................27 
10.2.2 
Study day for Safety Measures and Efficacy ...............................................27 
10.2.3 
Duration and  Elapsed Time ........................................................................27 
10.2.4 
Creatinine Clearance (CrCl) ........................................................................27 
10.2.5 
Baseline Definition ......................................................................................28 
10.2.6 
Change from Baseline ..................................................................................28 
10.2.7 
Pharmacokinetic Parameters ........................................................................28 
10.3 
Assessment Windows ............................................................................................28 
10.4 
Clinically Notable Values ......................................................................................29 
11 OTHER RELEVANT DATA ANALYSES/SUMMARIES ...........................................30 
11.1 
Prior and Concomitant Medications ......................................................................30 
11.2 
Resource Utilization Analyses ...............................................................................30 
12 CHANGES FROM THE PROTOCOL ...........................................................................31 
13 REFERENCES ................................................................................................................32 
14 APPENDICES .................................................................................................................33 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events ...........................................................................................34 
Appendix 2 
Adverse Event and Prior/Concomitant Medication Date Imputations ............37 
Appendix 3 
Modified Division of Microbiology and Infectious Diseases Adult 
Toxicity Table ..................................................................................................38 
Appendix 4 
Criteria for Clinically Notable Vital Signs ......................................................40 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ABG 
arterial blood gas 
ABSSSI 
acute bacterial skin and skin structure infections 
AE 
adverse Event 
ALT 
alanine aminotransferase (SGPT) 
AST 
aspartate aminotransferase (SGOT) 
AUC 
area under the plasma concentration time curve 
AUC0-24 
AUC from time 0 to 24 hours after dosing 
AUClast 
AUC from time 0 to the last quantifiable concentration 
β-hCG 
serum β-human chorionic gonadotropin 
BP 
blood pressure 
CABP 
community-acquired bacterial pneumonia 
Cmax 
maximum observed plasma concentration 
COPD 
chronic obstructive pulmonary disease 
CrCl 
creatinine clearance 
CRF 
case report form 
CSR 
Clinical Study Report 
CT 
computed tomography 
CV 
coefficient of variation 
CXR 
chest X-ray 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EOT 
end of treatment 
FFU 
Follow-up visit 
ICF 
Informed Consent Form 
IND 
Investigational New Drug 
ITT 
intent-to-treat 
IV 
Intravenous 
IxRS 
interactive voice/web response system 


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MedDRA 
Medical Dictionary for Regulatory Activities 
PaO2 
partial pressure of arterial oxygen 
PK 
Pharmacokinetics 
Po 
per oral 
PORT 
Pneumonia Outcomes Research Team 
PT 
preferred term 
PTE 
Post Therapy Evaluation 
QD 
once per day 
RR 
respiratory rate 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
Tmax 
time to reach maximum observed plasma concentration 
T1/2 
terminal-phase elimination half-life 
ULN 
Upper Limit of Normal 
US 
United States 
WBC 
White Blood Cell (Count) 
 
 


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1 
INTRODUCTION 
This document presents the Statistical Analysis Plan (SAP) for the protocol 
PTK0796-CABPPO-19109, “A Phase 1 multi-center, open label study to measure the 
Pharmacokinetics of Oral Omadacycline in Adult Subjects with Community-Acquired 
Bacterial Pneumonia (CABP).”  The statistical plan described is an a priori plan and no 
analysis prior to the preparation of this plan has been conducted.  This SAP summarizes the 
study design and objectives and provides details of the outcome definitions and statistical 
methods that will be used to analyze the data from protocol PTK0796-CABPPO-19109.   
All decisions regarding final analysis, as defined in this SAP document, have been made 
prior to database freeze of the study data. 


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2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Study Objectives and Endpoints 
Primary Objective 
Primary Endpoint 
 To evaluate the PK of oral (po) only 
omadacycline in adults with CABP. 
The following plasma PK parameters will 
be determined:  
 Area under the plasma concentration 
time curve (AUC) from time 0 to 
48 hours after dosing (AUC0-48)  
 Area under the plasma concentration 
time curve (AUC) from time 0 to 
24 hours after dosing (AUC0-24)  
 AUC from time 0 to the last quantifiable 
concentration (AUClast) 
 Maximum observed plasma 
concentration (Cmax) 
 Time to reach maximum observed 
plasma concentration (Tmax) 
 Elimination half-life associated with the 
terminal slope of the semilogarithmic 
concentration-time curve (T1/2) 
 
 
Secondary Objective 
Secondary Endpoint 
 To evaluate the safety of omadacycline 
in the treatment of adults with CABP.   
The following variables will be analyzed 
descriptively in the Safety population: 
 Adverse Events (AEs), and Serious 
Adverse Events (SAEs) 
 Vital signs (systolic and diastolic BP, 
pulse/heart rate, body temperature, pulse 
oximetry, RR), including change from 
Baseline by time point measured 
 Clinically notable vital signs (meeting 
predefined criteria as specified in the 
SAP) by time point measured 
 Laboratory parameters (Hematology and 
Serum Chemistry), including change 


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from Baseline by visit and overall worst 
post-baseline 
 Clinically notable laboratory parameters 
(meeting predefined criteria as specified 
in the SAP) by visit and overall worst 
post-baseline 
 Concomitant Medications 
 Urinalysis and Pregnancy assessments 
(Screening only) 
 
 
Exploratory Objectives  
Exploratory Endpoint 
 To evaluate the efficacy of oral only 
omadacycline in the treatment of adults 
with CABP.  
 
The following is a list of key assessments 
that will be performed:  
 Assessment of signs and symptoms of 
CABP by the investigator 
 Clinical Stability 
 Final Follow-up Assessment of signs 
and symptoms of CABP by the 
investigator 
 


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3 
STUDY DESIGN 
This is an open-label Phase 1b study evaluating oral omadacycline in the treatment of adults 
with CABP.   
This study is intended to evaluate the PK of an oral dosing regimen in adults with CABP.  
Subjects will initiate treatment with an oral loading dose of 300 mg BID on Day 1 followed 
by 300 mg on subsequent days. 
Following a screening period of up to 24 hours, eligible subjects will be assigned to receive 7 
to 10 days of po treatment. Subjects with baseline bacteremia (i.e., confirmed from local 
blood culture drawn at screening) can receive up to 14 days of treatment after consultation 
with the medical monitor. 
Subjects may receive oral treatment in either inpatient or outpatient settings, provided that all 
assessments can be completed at the timepoints required by protocol. 
Eligible subjects will be assigned to the following treatment groups.  
Test Article 
Study Day 
1 
Study Day 
2 
Study Days 
3-10 
Omadacycline 
300 mg po BID 
300 mg po QC 
300 mg po QC 
po = per oral, a dosing day is a 24-hour day not a calendar day 
a  The total duration of treatment is 7 to 10 days. Treatment duration can be extended to up to 14 days for 
subjects with bacteremia that, in the opinion of the investigator, requires more than 10 days of treatment. 
 
Refer to the Schedule of Events (Appendix 1) for the summary of subject visits and 
assessments through end of treatment (EOT).  
Subjects will return to the study site for a Post Therapy Evaluation (PTE) 5 to 10 days after 
the last dose of test article.  A Final Follow-up visit (FFU) will be conducted within 30 to 37 
days following the first dose of test article.  The FFU assessment may be conducted via 
telephone contact or by another interactive technology for subjects who had an outcome of 
Clinical Success in the opinion of the investigator at EOT and PTE and had no AEs or 
clinically significant laboratory or electrocardiogram (ECG) abnormalities noted at or after 
the PTE visit.  Otherwise, this assessment is to be performed with an in-person study visit.  
Subjects will participate in the study for up to 37 days.  Following a screening period of up to 
24 hours, eligible subjects will be assigned to receive treatment.  Eligible subjects will be 
assigned to receive 7 to 10 days of po treatment.  Subjects with baseline bacteremia (i.e., 
confirmed from local blood culture drawn at screening) can receive up to 14 days of 
treatment after consultation with the medical monitor. 
The study is expected to be complete in approximately 6 months.  


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4 
ASSESSMENT OF CABP SYMPTOM SEVERITY FOR EFFICACY 
The investigator will specifically assess the presence and severity level of the subject’s 
symptoms of cough, sputum production, pleuritic chest pain, and dyspnea on a 4-point scale 
(absent, mild, moderate, or severe) based upon the Community Acquired Bacterial Pneumonia 
Subject Symptom Severity Guidance Framework for Investigator Assessment (see Protocol 
Appendix 2) and enter the symptom severity level into the eCRF.  Subjects must have at least 
3 of these 4 symptoms of CABP to be eligible for the study. 
 


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5 
GENERAL STATISTICAL CONSIDERATIONS 
All data collected will be presented in data listings. Data from subjects excluded from an 
analysis population will be presented in the data listings, but not included in the calculation 
of summary statistics. 
For categorical variables, frequencies and percentages will be presented. Continuous 
variables will be summarized using descriptive statistics (number of subjects, mean, median, 
standard deviation [SD], minimum, and maximum). 
During the analysis and reporting process, any deviations from the statistical analysis plan 
designed for this protocol will be described and justified in the final clinical study report 
(CSR). 
Unless specified otherwise, baseline will be defined as the last non-missing assessment prior 
to the study drug administration for each treatment period. Unscheduled visits will be used in 
determining baseline. 
Missing values will not be imputed for safety endpoints. The handling rule for missing PK 
concentration will be described in Section 6.2. 
5.1 
Sample Size Determination 
This study is designed to evaluate the PK profile of an oral dosing regimen, 300mg BID on 
Day 1 and QD on Day 2, in adults with CABP.  The sample size determination is based on 
consideration of the precision of the estimate, GMR of AUC (0-48) for 300mg po to 100mg IV, 
derived from model-based simulations of omadacycline concentration data (Phase I studies). 
With 20 subjects evaluable for PK population, there will be 90% probability that the 90% CIs 
of the GMR for AUC (0-48) will be within 80% and 125%. Up to 30 subjects will be enrolled 
so that at least 20 subjects are evaluable for bioavailability estimation.   
The total number of subjects may be adjusted to ensure that there are 20 subjects evaluable 
for PK population.  
5.2 
Study Analysis Populations 
5.2.1 
Intent-to-Treat (ITT) Population 
The ITT population will consist of all enrolled subjects regardless of whether the subject 
received test article.   
5.2.2 
Safety (SAF) Population 
The Safety population will consist of all enrolled subjects who receive test article.  All safety 
analyses will be conducted in this population.   


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5.2.3 
Pharmacokinetic (PK) Population  
The pharmacokinetic population is defined as subjects who receive test article and have at 
least 1 evaluable PK parameter. If any subject has an emesis within 4 hours after dosing, the 
subject will be excluded from PK Analysis.  If any subject discontinues dosing before  48 
hours with incomplete PK profile for 0-24 or 0-48 hours, the subject will be excluded from 
the PK analysis for AUC0-24 and AUC0-48, respectively.  
This population will be used for listings, summary tables, and plotting of individual and 
mean/median concentration-time profiles. 
 


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6 
STUDY POPULATION SUMMARIES 
6.1 
Disposition 
The number of subjects included in each of the analysis populations (i.e., ITT, Safety, and 
PK) will be summarized.   A table will summarize the reasons for exclusion from each 
population and a listing will be provided that indicates each subject’s inclusion in/exclusion 
from the populations and the reason for exclusion from each of the populations.   
A listing will be provided of enrolled subjects who did not meet all inclusion/exclusion 
criteria, and which criteria were not met.  The number and percentage of subjects completing 
the study (defined as receiving at least 1 dose of test article and returning for all the EOT, 
PTE, and Follow-up Visits), not completing the study, missing each of the EOT and PTE 
Visits, and prematurely discontinuing from test article will be presented for the ITT 
population.   Reasons for premature discontinuation of test article, not completing the study, 
and for missing each of the visits, as recorded on the eCRF will be summarized (number and 
percentage) for the ITT populations.  A listing of all subjects who prematurely discontinued 
from test article or not completing the study will be presented, and the primary reason for 
discontinuation of test article or not completing the study, as well as the visit(s) missed and 
the reason for missing the visit(s), will be provided.   
6.2 
Demographics and Baseline Characteristics 
Except where indicated, demographic data and baseline characteristics will be presented for 
the ITT population.  A table will present the subject demographics (e.g., gender, age, 
ethnicity, and race) and baseline characteristics (height, weight, BMI, and creatinine 
clearance categorized before the start of test article as: 
• 
severe renal impairment [< 30 mL/min],  
• 
moderate renal impairment [30-50 mL/min],  
• 
mild renal impairment [> 50-80 mL/min], and  
• 
normal renal function [> 80 mL/min]).  
 
Age will be calculated from the date of birth to the informed consent date.  Age will be 
summarized as a continuous variable and in the categories, 18-45, >45-65, and > 65 years.   
Creatinine clearance will be calculated from the local laboratory data since these data were 
used for determination of the inclusion and exclusion criteria and will be determined from the 
Cockcroft-Gault equation. 


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A table will provide the frequency counts and percentages for subjects who received prior 
antibiotics, and PORT Risk Class (from the eCRF) for the ITT population.  PORT score will 
also be summarized as a continuous variable.   
Baseline assessments of clinical symptoms, clinical signs, abnormal vital signs, and abnormal 
laboratory signs of CABP will be presented for the ITT, and PK populations.   
The number and percentage of subjects with each of the CABP symptoms (cough, pleuritic 
chest pain, dyspnea, and phlegm/sputum production) by severity (absent, mild, moderate, 
severe) will be presented.  The number and percentage of subjects with the presence by 
severity (i.e., absent, mild, moderate, severe) of the following clinical signs will be provided:  
rales, rhonchi, dullness on percussion, bronchial breath sounds, wheezing, decreased breath 
sounds, and egophony.  The number and percentage of subjects with fever (defined as body 
temperature  38C [100.4F] oral or rectal), hypothermia (defined as body temperature 
< 36C [95.5F] oral or rectal), hypotension with systolic blood pressure < 90 mmHg, heart 
rate > 90 bpm, respiratory rate > 20 breaths/min, hypoxemia (defined as PaO2 < 60 mmHg by 
arterial blood gas or oxygen saturation < 90% by pulse oximetry), elevated total WBC count 
(> 12,000 cells/mm3), leucopenia (WBC < 4,000 cells/mm3), elevated immature neutrophils 
(> 15% band forms regardless of total peripheral WBC count) and any of elevated total WBC 
count, leucopenia or elevated immature neutrophils will be summarized.    
Risk factors for CABP will be presented for the ITT population.  Risk factors include 
smoking (current, past, and descriptive statistics of the number of years since quitting for 
those subjects who were previous smokers), receipt of pneumococcal vaccine, prior lung 
infection, whether the subject had mild to moderate COPD, symptomatic asthma with 
wheezing, and chronic cough with or without sputum production.  
Readings of baseline chest radiographs, including the type of assessment (CXR or CT scan), 
presence of pleural effusion, whether the pleural effusion is unilateral or bilateral, whether 
the pulmonary infiltrate was uni- or multi-lobar and the location of the pulmonary infiltrate 
(combining left upper lobe and lingula) will be summarized for all subjects in the ITT 
population. 
A listing will be provided that includes all baseline microbiology isolates. 
6.3 
Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA, version to be delineated in the CSR). Medical history will be presented in a data 
listing. 
Other medical and surgical history will be summarized based on MedDRA system organ 
class for the ITT and Safety populations.   
6.4 
Inclusion and Exclusion Criteria 
All inclusion/exclusion criteria deviations recorded in the electronic case report form (eCRF) 
will be presented in a data listing. 


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6.5 
Treatment Compliance and Exposure 
Exposure summary will be presented for the Safety population.  The distribution of subjects 
by the total number of days on therapy, will be presented.  
Treatment compliance is defined as the number of oral doses received divided by the number 
of doses expected (× 100) over the time period defined by the first dose date and the last dose 
date.  Descriptive statistics for treatment compliance and the number and percentage of 
subjects at least 80% compliant will be presented for the ITT population.   
 


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7 
PHARMACOKINETIC ANALYSIS 
7.1 
Pharmacokinetic Sample Concentrations 
Blood samples for PK assessments of omadacycline will be collected from all subjects at the 
following time points:   
 Day 1:  within an hour prior to Dose 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (12 hour taken 
immediately before Dose 2);  
Dose 2 administered (times relative to Dose 1); 13, 13.5, 14, 14.5, 15, 16, 24 hours 
post dose 
 Day 2:  within an hour prior to dose, 1, 1.5, 2, 2.5, 3, 4, 6 hours 
 Day 3: prior to the Day 3 dose 
 EOT:  anytime during the visit 
Individual plasma concentration of omadacycline and time deviation data for Safety Analysis 
Set will be presented in data listings.  Plasma concentration data will be summarized by 
scheduled time point for the PK Analysis Set for each treatment using descriptive statistics 
(number of subjects, mean, SD, CV, median, minimum, and maximum). Concentrations that 
are below the limit of quantification (BLQ) before the first quantifiable concentration will be 
treated as zero for descriptive statistics. Below the limit of quantification values after the first 
quantifiable concentration will be set as missing and excluded for summary statistics. Mean 
BLQ concentrations will be presented as BLQ, and the SD and CV will be reported as not 
applicable, if all individual values are BLQ. 
Mean (±SD) plasma concentrations versus nominal time will be plotted by treatment on both 
linear and semi-logarithmic scales for the PK Analysis Set. Individual plasma concentrations 
versus actual time will be plotted on both linear and semi-logarithmic scales for the Safety 
Analysis Set. 
7.2 
Pharmacokinetic Parameters 
Individual plasma concentration versus actual time data will be used to estimate the PK 
parameters of omadacycline in plasma by standard noncompartmental methods using 
WinNonlin (Phoenix) validated SAS programs. For the calculation of PK parameters, BLQ 
values before the first quantifiable concentration will be treated as zero.  Below the limit of 
quantification values after the first quantifiable concentration will be set as missing.  Missing 
concentrations will be treated as missing.  If consecutive BLQ concentrations are followed by 
quantifiable concentrations in the terminal phase, those concentrations after BLQ 
concentrations will be treated as missing.  


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The following PK parameters will be calculated for omadacycline in plasma, if data permits: 
Parameter 
Description 
Cmax 
Maximum observed plasma concentration 
Tmax 
Time to reach maximum observed plasma concentration 
AUC0-48 
Area under the plasma concentration versus time curve (AUC) from 
time 0 to 48 hours after dosing, calculated using the linear 
trapezoidal linear interpolation method 
AUC0-24 
Area under the plasma concentration versus time curve (AUC) from 
time 0 to 24 hours after dosing, calculated using the linear 
trapezoidal linear interpolation method 
AUClast 
AUC from time 0 to the time of last quantifiable concentration 
(Excluding the PK concentration at EOT timepoint), calculated 
using the linear trapezoidal linear interpolation method 
T1/2 
Plasma terminal elimination half-life, calculated as T1/2= ln (2)/ λz 
λz  =  Terminal elimination rate constant calculated by linear 
regression of the terminal portion of the natural log-plasma 
concentration versus time curve. This will be calculated after third 
dose of administration. 
 
The individual PK parameters will be presented in the data listings for the PK Analysis Set. 
The PK parameters will be summarized using the PK Analysis Set with the following 
descriptive statistics: n, mean, SD, CV, median, minimum and maximum. Descriptive 
statistics will include geometric mean and geometric mean CV for AUC (0-48), AUC (0-24), 
AUC (last) and Cmax. For individual parameters that are listed but not summarized in the 
descriptive statistics due to Rsq < 0.8, a footnote will be added. 
7.3 
Treatment Comparison 
The comparison of interest is the comparative bioavailability assessment between the test, 
300mg po in CABP patients, and the reference, 100mg IV in healthy subjects. The 
comparison will be based on 90% confidence intervals (CIs) for the geometric mean ratios 
(GMR) of AUC (0-48) for the two dosing regimens being within 80% and 125%.  
The PK parameter data for 100mg IV in healthy subjects comes from PTK 0796-SDES-
0501(n=5), PTK 0796-BEQU-0801(n=11), PTK 0796 WOIV-0703(n=12), 
CPTK796A2104(n=21), CPTK796A2201(n=6), PTK 0796-RENL-15102(n=8). Using the 


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day 1 plasma concentration profile of the 100mg IV QD dosing from these studies, a BID 
dosing on day 1 and a QD dosing on day 2 was simulated using the superposition principle. 
The simulation model-based AUC (0-48) characteristics for each study are shown in the table 
below: 
Study 
n 
Mean ln (AUC (0-48)) 
SD ln (AUC (0-48)) 
SDES-0501 
5 
9.5968 
0.1896 
BEQU-0801 
11 
9.8702 
0.1467 
WOIV-0703 
12 
10.017 
0.1630 
A2104 
21 
10.043 
0.1649 
A2201 
6 
10.129 
0.1752 
RENL-15102 
8 
10.039 
0.1838 
Total 
63 
9.9800 
0.2091 
 
The 90% CI of the GMR will be formed as follows: let 𝑦̅, 𝑠, and 𝑛 represent the average, 
standard deviation, and sample of the log (AUC (0-48)) data observed in the current study. The 
pooled standard deviation is 𝑠𝑝= √(63−1)0.20911172+(𝑛−1)𝑠2
63+𝑛−2
; the number of degrees of 
freedom is 𝑑𝑓= 63 + 𝑛−2; and critical value for the CI is 95th percentile of a t-
distribution, 𝑡𝑑𝑓,0.95. The 90% confidence interval on the log scale is 
𝑦̅ −9.980044 ± 𝑡𝑑𝑓,0.95𝑠𝑝√1
63 + 1
𝑛= (𝐿𝑜𝑤𝑒𝑟, 𝑈𝑝𝑝𝑒𝑟) 
and the CI for the GMR is (𝑒𝐿𝑜𝑤𝑒𝑟, 𝑒𝑈𝑝𝑝𝑒𝑟) × 100%. 
The following SAS code will be used: 


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7.4 
Analysis of EOT PK concentration data 
The sample at the EOT will be collected during the patient’s visit. The patients’ last dose will 
be recorded in a dosing diary and the time of sample collection will be recorded by the site 
during their visit. Since patients will be outpatient at their EOT visit and must be in a fasted 
state when dosing, dosing is likely to occur at home prior to their site visit.  
Therefore, the data collected at EOT will be used to qualitatively assesses patient’s 
compliance by using the concentration of the EOT sample taken at the recorded time after the 
last dose and compared to initial dose as the clinical efficacy is an exploratory endpoint that 
will be evaluated.  If the EOT visit is not completed on the day of last dose but within the 2-
day window as specified in the protocol, then the initial dose profile will be extrapolated  
using the terminal elimination rate constant and will be used to make the comparison.    


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8 
SAFETY AND TOLERABILITY 
All safety analyses will be conducted in the Safety population.  Safety parameters include 
adverse events (AEs), vital signs, and clinical laboratory parameters. 
8.1 
Adverse Events 
Verbatim descriptions of AEs will be coded using Version 17.1 or higher of MedDRA.  
Summary tables will be provided for all treatment-emergent adverse events (TEAEs), but all 
AEs will be provided in a listing.  A treatment-emergent AE is defined as any AE that newly 
appeared, increased in frequency, or worsened in severity on or after the initiation of active 
test article.  An AE is considered treatment emergent if the AE start date and time is on or 
after the start date and time of the first dose of active test article.  If time of the AE is missing 
and it occurred on the same date as the first dose of active test article, the AE will be defined 
as treatment emergent.  If the start date of the AE is partial or missing and it cannot be 
determined if the AE occurred prior to or after the first dose of test article, the AE should be 
defined as treatment emergent. 
An overall summary of AEs will include the number of subjects who experienced at least one 
AE of the following categories:  any AE, any TEAE, any drug-related TEAE, any severe 
TEAE, any serious TEAE, any drug-related SAE, any serious TEAE leading to death, any 
TEAE leading to premature discontinuation of test article, any TEAE leading to premature 
discontinuation from the study, any TEAE leading to dose interruption of test article, and any 
serious TEAE leading to premature discontinuation of test article.   
The number and percentage of subjects reporting a TEAE  will be tabulated by system organ 
class and preferred term; by system organ class, preferred term, and severity (mild, moderate, 
and severe); and by system organ class, preferred term, and relationship (unrelated or related 
to test article).  The incidence of TEAEs will be summarized by preferred term, sorted by 
decreasing frequency, for all TEAEs, related TEAEs, serious TEAEs, and TEAEs leading to 
study drug discontinuation.  The incidence of serious TEAEs, TEAEs leading to premature 
discontinuation of test article, and TEAEs leading to a dose interruption of test article will be 
summarized by system organ class and preferred term.  For all analyses of TEAEs, if the 
same AE (based on preferred term) is reported for the same subject more than once, the AE is 
counted only once for that preferred term and at the highest severity and strongest 
relationship to test article.   
In addition, all AEs (including non-TEAEs), serious TEAEs, TEAEs leading to 
discontinuation of test article, and TEAEs leading to dose interruption of test article will be 
provided in listings by   subject, verbatim term, MedDRA system organ class and preferred 
term, start and end date, seriousness flag, severity, relationship to test article, relationship to 
study protocol, action taken with test article, non-test article action taken and outcome.   


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8.2 
Vital Signs 
Vital signs include blood pressure (BP), heart rate, pulse oximetry, RR, and body 
temperature.  
Descriptive statistics of the change from baseline to each post-baseline time point and the 
highest and lowest post-baseline value will also be provided.  Baseline is defined as the value 
closest to but prior to the initiation of test article administration.   
Post-baseline vital signs will be defined as clinically notable (CN) if they meet the criterion 
value or both the criterion value and the change from baseline criterion listed in Appendix 4.  
The incidence of CN vital signs will be summarized by time point and will be listed and 
flagged in by-subject listings.  The overall post-baseline incidence of CN values for each 
vital sign parameter, which includes values from unscheduled post-baseline visits, will also 
be summarized.  A listing will also be provided of subjects with a CN vital sign and will list 
all values for a vital sign noted as CN. 
8.3 
Laboratory Values 
Summaries of laboratory data will include hematology, and chemistry, parameters.  
Laboratory parameters will be presented in alphabetic order with the following exceptions:  
differentials of white blood cell (WBC) counts will be presented following the WBC results, 
and chemistry parameters will first be grouped by organ class (renal, liver, electrolytes, and 
other) and presented alphabetically within each of these classes, as shown below. 
Table 1. 
Laboratory Parameters and Organ Class 
Organ Class 
Laboratory Parameter 
Renal 
Creatinine 
Renal 
Urea 
Liver 
Alkaline phosphatase (ALP) 
Liver 
ALT 
Liver 
AST 
Liver 
Total Bilirubin  
Liver 
GGT 
Electrolytes 
Bicarbonate 
Electrolytes 
Calcium 
Electrolytes 
Chloride 
Electrolytes 
Magnesium 
Electrolytes 
Potassium 
Electrolytes 
Sodium 
Other 
Albumin 
Other 
Amylase 
Other 
Blood glucose 
Other 
Cholesterol 
Other 
CK 
Other 
LDH 


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Table 1. 
Laboratory Parameters and Organ Class 
Organ Class 
Laboratory Parameter 
Other 
Lipase 
Other 
Phosphate 
Other 
Total protein 
Other 
Uric acid 
 
Baseline is defined the local lab value that is closest to and prior to the first dose of study 
drug. 
Several analyses of the laboratory data will be presented.  Descriptive statistics (based on 
International System [SI] units) for chemistry, hematology and the change from baseline will 
be summarized by treatment group at each time point ( EOT Visit and PTE Visit), and for the 
overall worst value post-baseline (which includes unscheduled visits).   
Clinically notable laboratory values will be defined as any lab values with at least a 2-grade 
increase from baseline.  Shift tables will be presented to show the number of subjects with a 
laboratory value with a grade of 0, 1, 2, 3 or 4 at baseline versus the value at each visit and 
the worst post-baseline value.  Number and percentage of subjects with at least a 2-grade 
increase from baseline (based on DMID criteria shown in Appendix 3) will be summarized.  
Percentages for each laboratory test will be based on the number of subjects with a baseline 
and post-baseline evaluation of the specific laboratory test.  A listing will be provided which 
gives all laboratory results for a given laboratory test for subjects who have at least one 2-
grade increase from baseline.  
Detailed subject listings of all laboratory data collected during the study will be provided, 
including calculated creatinine clearance (using the Cockcroft-Gault equation).  Laboratory 
values outside normal limits will be identified in the subject data listings with flags for low 
(L) and high (H) as will laboratory values that meet the clinically notable thresholds (CN) of 
at least a 2-grade increase from baseline. 
8.4 
Physical Examinations 
Subject listings of all physical examination results by body system will be provided.  Any 
clinically significant changes from baseline will be recorded as adverse events. 


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9 
EXPLORATORY EFFICACY MEASURES 
9.1 
Investigator’s Assessment of Clinical Response 
9.1.1 
Investigator’s Assessment of Clinical Response at EOT 
EOT assessments should be performed on the calendar day of, or within 2 days following the 
last dose of any test article.  If a subject withdraws prematurely or terminates participation in 
the study prior to completion of the planned antibiotic therapy, the EOT visit should be 
conducted. 
The investigator will determine whether or not the subject meets the criteria of 1 of the 
following clinical outcomes: 
Clinical Success:  the subject is alive, and the infection 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 ancillary (i.e., non-antibiotic) treatment (e.g., 
expectorant).  For the subject to be considered a Clinical Success at EOT, the subject may not 
meet any criteria for Clinical Failure or Indeterminate at EOT.   
Clinical Failure:  the subject requires alternative antibacterial treatment for CABP prior to 
EOT related to either (a) progression or development of new symptoms of CABP or (b) 
development of infectious complications of CABP (e.g., empyema, lung abscess) or (c) 
subject developed an AE that required discontinuation of study therapy.  Other reasons for 
Clinical Failure are: 
 Subject is receiving antibacterial therapy that may be effective for the infection under 
study for a different infection from the 1 under study. 
 Death prior to EOT visit. 
 Other specified reason. 
 
Indeterminate:  the clinical response to test article could not be adequately inferred due to: 
 Subjects were not seen for EOT evaluation because they withdrew consent or were lost to 
follow-up,  
 Other specified reason. 
 
9.1.2 
Investigator’s Assessment of Clinical Response at PTE 
The PTE assessment is to be performed 5 to 10 days after the subject’s last day of therapy.  
The investigator will determine whether or not the subject meets the criteria of 1 of the 
following clinical outcomes: 


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Clinical Success:  survival after completion of a test article regimen without receiving any 
systemic antibacterial therapy other than test article, resolution of signs and symptoms of the 
infection present at Screening with no new symptoms or complications attributable to CABP 
and no need for further antibacterial therapy.   
Clinical Failure:  the subject requires alternative antibacterial treatment for CABP prior to 
PTE related to either (a) progression or development of new symptoms of CABP or (b) 
development of infectious complications of CABP (e.g., empyema, lung abscess). 
 The subject is receiving antibiotics that may be effective for the infection under study for 
a different infection from the 1 under study. 
 Death prior to PTE. 
 Other specified reason. 
 
Indeterminate:  the clinical response to test article could not be adequately inferred due to: 
 Subjects were not seen for PTE evaluation because they withdrew consent or were lost to 
follow-up. 
 Other specified reason. 
 
9.2 
Clinical Stability 
The formal determination of the subject’s Clinical Stability will be done programmatically 
using the investigator’s assessment of the subject’s vital signs entered into the eCRF.  The 
investigator is not responsible for categorizing the subject’s Clinical Stability.  Clinical 
Stability will be determined daily and analyzed by day, early clinical response window, EOT, 
and PTE. 
Patients will be considered clinically stable if they achieve all the following criteria:  
 temperature ≤37.8°C (100°F);  
 heart rate ≤100 beats/minute;  
 RR ≤24 breaths/minute;  
 systolic blood pressure ≥ 90 mmHg; and  
 arterial oxygen saturation ≥ 90% or PaO2 ≥ 60 mmHg on room air. 
 
9.3 
Clinical Outcomes 
The number and percentage of subjects classified as a Clinical Success, Clinical Failure, and 
Indeterminate by the Investigator’s Assessment at EOT in the ITT population   will be 
presented.  The number and percentage of subjects in each response category for the overall 
assessment of Clinical response at PTE (based on the investigator's assessment) in the ITT 
population will also be presented.   


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The number and percentage of subjects with stabilization of all vital signs associated with 
CABP at EOT will be presented for the ITT population as will the number and percentage of 
subjects with stabilization of each vital sign.  These include temperature (no fever or 
hypothermia), SBP (> 90 mmHg), heart rate (< 90 bpm), RR (< 20 breaths/minutes), and 
PaO2 (> 60 mmHg by pulse oximetry or ABG).  WBC count (< 12,000 cells/mm3 or 
≥ 4,000 cells/mm3) and immature neutrophils (< 15%). 
 


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10 DATA HANDLING CONVENTIONS 
10.1 Premature Withdrawal and Missing Data 
If available, pharmacokinetic parameters from the concentration-time profile data of patients 
who drop out or are withdrawn will be calculated but will be excluded from the final 
statistical analysis. 
For all variables, only the observed data from the patients will be used in the statistical 
analyses, i.e., there is no plan to estimate missing data, unless otherwise specified.   
Missing data occurs when any of the requested data is not provided, leading to blank fields 
on the collection of the instrument. These data will be indicated by the use of  a “blank” in 
subject listing displays. Answers such as "Not applicable” and “Not evaluable” are not 
considered to be missing data and such be displayed as such. 
All missing and partial dates for adverse events or for medications received after enrollment 
will be queried for a value.  If no value can be obtained, substitutions will be made as 
detailed in Appendix 2.  These substitutions will be used in calculations; however, the actual 
value recorded on the eCRF will be used in all listings. 
Missing start and stop times for prior and concomitant antibiotics will be queried for a value.  
If no value can be obtained but the site indicates the antibiotic was received (onset time) prior 
to the first dose of test article, 00:01 will be used for the onset time.  If the site also indicates 
that the end time was prior to the first dose of test article, 00:01 will be used for end time.  
The actual value (blank) will be recorded on the eCRF and will be used in the listings. 
Subjects with the designation of  treatment relationship of adverse event (AE) and serious 
adverse events (SAEs) missing will have the worst case assumed to impure the relationship: 
if relationship to study treatment is missing it will be assumed to be “Yes”.  The severity and 
causality assessment for adverse events cannot be missing.  Missing data will be queried for a 
value.   
Missing times for assessments of CABP symptoms will be queried for a value.  If minutes 
are not available, the time will be recorded to the closest hour.   
If no value can be obtained for all other times for events and assessments occurring after 
enrollment, the time will not be imputed but will remain missing.   
For clinical response, missing data will be handled as follows:  
For investigator’s assessment of Clinical Response at the EOT and PTE Visits: 
o Subjects will be defined as an Indeterminate if the investigator cannot determine 
whether the subject is a Clinical Success or Failure at the EOT or PTE Visits or the 
subject has a missing response.  By definition, subjects with an Indeterminate 
response are included in the denominator for analyses in the ITT population, and thus, 
are considered Clinical Failures.   


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10.2 Derived and Transformed Data 
10.2.1 
Reference Dates 
There are three reference dates: 
 Because age is an eligibility requirement, the reference date for age is the date of 
inform consent. 
 The safety reference date is the treatment start date and will be used to calculate the 
study day for safety assessments. 
 The efficacy reference date is the date of enrollment and will be used to calculate 
study day for efficacy measures and baseline characteristics (time since initial 
diagnosis) 
 
10.2.2 
Study day for Safety Measures and Efficacy 
If the date of interest occurs on or after the safety or efficacy reference date, then the study 
day will be calculated as: 
                 Study day = ( date of interest – reference date) + 1  
There is no safety or efficacy study day 0 
10.2.3 
Duration and  Elapsed Time  
Durations  (e.g. duration of an adverse event, duration of exposure, etc.) are calculated as: 
                     Duration = (Stop date – Start date) + 1 
Elapse times (e.g. time since initial diagnosis) are calculated as: 
 Reference date is on or after the event date = (reference date – event date) + 1 
 Reference date is before the event date  =  reference date – event date 
10.2.4 
Creatinine Clearance (CrCl)  
Cockcroft-Gault equation to calculate creatinine clearance (CrCl): 
(140-age[yrs])*weight [kg]* (Z) 
Z = 1.0, if Male 
Z = 0.85, if Female 
Cr (mg/dL) * 72 
 


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10.2.5 
Baseline Definition 
Baseline or pre-dose assessment is defined as the most recent, non-missing available 
assessment prior to time of first dose, unless is specified otherwise. If there are multiple 
assessments collected on the same scheduled time, the average of these assessments will be 
used. For tabulated safety summaries, only the schedule assessments will be included in the 
summary tables. 
10.2.6 
Change from Baseline 
The change from baseline will be calculated by subtracting the baseline values from the 
individual post-enrollment values. If either the baseline or the post-enrollment value is 
missing, the change from baseline is set to missing as well. 
10.2.7 
Pharmacokinetic Parameters 
Plasma pharmacokinetic parameters will be summarized and analyzed after undergoing log-
transformation (except tmax). 
10.3 Assessment Windows 
Actual dosing and PK sampling times will be used in the calculation of the PK parameters. 
Nominal times will be used for purposes of summarization. 
EOT assessments should be performed on the calendar day of, or within 2 days following the 
last dose of any test article.  If a subject withdraws prematurely or terminates participation in 
the study prior to completion of the planned antibiotic therapy, the EOT visit should be 
conducted on that day. 
The PTE assessment is to be performed 5 to 10 days after the subject’s last day of therapy. 
The final follow up  (FFU) assessment should be conducted within 30-37 days following the 
subject’s first dose of test article.   
For each safety outcome, analyses will utilize assessments occurring during the scheduled 
visit windows (provided below).  Thus, if a subject has a visit outside the scheduled visit 
window, for example, a PTE Visit occurred 20 days after the subject's last day of therapy, the 
assessment will not be summarized with the PTE Visit but will be considered an unscheduled 
assessment.  If a subject does not have an assessment at a scheduled visit and an unscheduled 
assessment was taken within the window for the time point (for example, 5 to 10 days after 
the subject's last day of therapy for PTE), these assessments will be summarized in the by 
time point analyses.  If more than one measurement is taken during the visit window, the 
value taken on the scheduled visit will be utilized or if no scheduled visit was done, the first 
(earliest) measurement in the visit window will be used.  If more than one measurement is 
taken on the same day, the assessment closest to the start of the dose will be used for on 
treatment values and the last measurement on the day will be used for post-treatment values.  


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For worst overall post-baseline analyses, all assessments including those obtained from 
unscheduled visits will be included.   
Scheduled Study Visits 
Study Visit 
Study Day  
Notes 
Baseline 
Day -1 or Day 1 
Except where indicated, last measurement prior to the first 
dose of test article.  Screening assessments are to be taken 
within 24 hours prior to the first dose of test article.  If no 
test article is taken, the date and time of enrollment is used 
in place of the first dose of test article. 
On Treatment 
Day 1-Day 10 
A Day 10 visit will be conducted for subjects with 
treatment extending beyond 9 days, unless this visit 
coincides with the EOT Visit. 
EOT 
 
Within 2 days following the last dose of test article 
PTE 
 
5-10 days after the subject's last day of therapy 
Final Follow-up 
Day 30-37 
30-37 days after the start of the first dose of test article 
 
10.4 Clinically Notable Values 
 Clinically notable laboratory parameters, meeting predefined criteria as values with 2 
grade increases will be listed  
 Clinically notable vital signs, meeting predefined criteria as specified in Appendix 4 by 
time point measured 
 


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11 OTHER RELEVANT DATA ANALYSES/SUMMARIES 
11.1 Prior and Concomitant Medications 
All medications taken within 7 days prior to the date of informed consent through the Final 
Follow-up Visit will be recorded on the eCRF.  Prior medications will be summarized by 
WHODRUG (Version 01 Dec 2014) Anatomical Therapeutic Chemical Classification (ATC) 
level 3 (third level indicates the therapeutic/pharmacologic subgroup) and generic medication 
name.  Medications are considered prior if taken prior to the first dose  of test article or if 
their start date is unknown.  Subjects will be counted only once for an ATC class and generic 
medication name.  Concomitant medications taken during and after the study treatment 
period will be similarly summarized.  Medications are considered concomitant if taken on or 
after the first dose of test article, or if their stop date is unknown or marked as continuing.   
The number and percentage of subjects who receive the following prior and concomitant 
medications will be summarized: 
• Systemic antibacterial medications taken within 72 hours prior to first dose of test article 
and the reasons for receipt (ITT) 
11.2 Resource Utilization Analyses 
The number of subjects who are in-patient at the start of the treatment and how many days 
were spent in hospital will be summarized. 


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12 CHANGES FROM THE PROTOCOL 
In the protocol, the PK Analysis Set was defined to include subjects who receive 
omadacycline and have PK samples collected. If any subject has an emesis within 2.5 x 
median Tmax after dosing, the subject may be excluded from PK Analysis Set. In the SAP, the 
PK Analysis Set has been defined to include subjects who receive study drug and have at 
least 1 evaluable PK parameter. If any subject has an emesis within 4 hours after dosing, the 
subject will be excluded from PK Analysis Set.  
Any changes from this statistical analysis plan will be documented in the CSR for this study. 


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13 REFERENCES 


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14 APPENDICES 
Appendix 1 
Schedule of Assessments and Procedures 
Appendix 2 
Adverse Event and Prior/Concomitant Medication Date Imputations 
Appendix 3 
Modified Division of Microbiology and Infectious Diseases Adult Toxicity 
Table 
Appendix 4 
Criteria for Clinically Notable Vital Signs 
 
 
 


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Appendix 1 
Schedule of Events 
Study Phase 
Screeninga 
Treatment Phase 
Follow-up Phase 
Study Dayb 
 
Day 1 
Day 
2 
Day 
3 
Day 7-
10/ 
EOTc 
PTEd 
Final 
Follow-upe 
Signed Informed Consentf 
X 
 
 
 
 
 
 
Medical History, current medical 
conditions, demography 
X 
 
 
 
 
 
 
Assessment of CABP symptom 
severityg 
X 
 
X 
X 
X 
X 
 
Chest X-ray or CT scanh 
X 
 
 
 
 
 
 
PORT Risk Class, ABG (or pulse 
oximetry) i 
X 
 
 
 
 
 
 
Blood samples for local lab 
hematology/chemistry//pregnancy 
testj 
X 
 
 
 
X 
X 
 
Urine samples for local lab urine 
tests/pregnancy testj 
X 
 
 
 
 
 
 
Review of Inclusion and 
Exclusion criteria/Treatment 
Group Assignment (if Eligible) 
X 
 
 
 
 
 
 
Test Article Administration and 
Accountabilityl 
 
X 
X 
X 
X 
 
 
Physical examinationm 
X 
 
X 
X 
X 
X 
 
Vital signsn 
 
 
 
 
 
 
 
Height and weight 
X 
 
 
 
 
 
 
Body temperature 
X 
X 
X 
X 
X 
X 
 
Blood Pressure 
X 
Xo 
X 
X 
X 
X 
 
Pulse Oximetry 
X 
X 
X 
X 
X 
X 
 
Pulse/Heart Rate 
X 
Xo 
X 
X 
X 
X 
 
Respiratory Rate 
X 
X 
X 
X 
X 
X 
 
Plasma samples (in heparin) 
for PK analyses 
 
Xp 
Xq 
Xr 
Xs 
 
 
Assessment for need for 
continued therapyt 
 
X  -----------------------------------
-------------   X 
 
 
Investigator’s Assessment of 
Clinical Response 
 
 
 
 
X 
X 
 
Adverse Eventsu 
X  ------------------------------------------------------------------------------
-------------   X 
Prior/Concomitant Medications 
and Proceduresk 
X  ------------------------------------------------------------------------------
-------------   X 
Assessment of Resource 
Utilization 
X  ------------------------------------------------------------------------------
-------------   X 


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ABG = arterial blood gas, AE = adverse event, BP = blood pressure, β-hCG = beta – human Chorionic 
Gonadotropin, CABP = community-acquired bacterial pneumonia, CT = computed tomography, CXR = 
chest X-ray, eCRF = electronic case report form, EOT = end of treatment, ICF = informed consent form, 
IxRS = Interactive Voice Response System/Interactive Web Response System, PK = pharmacokinetics, 
PORT = Pneumonia Outcomes Research Team, PTE = post-therapy evaluation, RR = respiratory rate, 
SAE = serious adverse event. 
a 
Following the signing of an ICF, all Screening evaluations, with the exception of the radiographic 
confirmation of pneumonia, should be completed within the 24 hours prior to treatment group 
assignment.  The radiographic confirmation of pneumonia should be completed within the 48 hours 
prior to the first dose of test article.  
b 
Study Day 1 is the first day of test article administration.  Subsequent study visit days may be 
consecutive calendar days. 
c 
To be conducted on the day of, or within 2 days following the last dose of test article.  Should also 
be conducted for any prematurely withdrawn subject. 
d 
To be conducted 5 to 10 days after the subject’s last day of therapy. 
e 
To be conducted 30 to 37 days after the start of the first dose of test article.  The Final Follow-up 
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 PTE visit.  Otherwise, the visit must be 
conducted in person. 
f 
Written and signed ICF must be obtained before any assessment is performed. 
g 
The investigator should assess the severity of the subject’s CABP symptoms of cough, sputum 
production, pleuritic chest pain, and dyspnea based upon the Community Acquired Bacterial 
Pneumonia Subject Symptom Severity Guidance Framework for Investigator Assessment 
(Appendix 3). 
h 
Subjects must have a confirming CXR or CT scan consistent with acute bacterial pneumonia within 
the 48 hours prior to the first dose of test article. 
i 
Only subjects with a PORT Risk Class of II or III for whom oral only treatment for CABP is 
appropriate are eligible for enrollment. 
j 
Hematology and serum chemistry evaluations will be performed at each of the timepoints indicated. 
A serum or urine pregnancy test (for women only) and urine dipstick will be performed only at 
Screening.  The relevant local laboratory results from Screening will be used to assess eligibility as 
per the inclusion/exclusion criteria. 
k 
Treatments that have been administered within the 7 days prior to the date of signing the ICF or 
during the Screening phase will be recorded in the eCRF.  All medications and significant non-drug 
therapies administered after the first dose of test article must be recorded in the eCRF.  Additional 
information, including start and stop time, will be collected for any prior or concomitant antibiotic. 
l 
 All oral doses should be taken in a fasted state (no food, antacids, or multivitamins containing 
multivalent cations [eg, aluminum, magnesium, calcium, bismuth, iron, or zinc] or drink except 
water for at least 6 hours before dosing).  Subjects discharged with po test article will be asked to 
return all unused test article and packaging at each visit and site staff will perform accountability.  
The total duration of test article therapy for all subjects will be 7 to 10, up to 14 for bacteremia.   
m 
A full physical examination will be completed at Screening, thereafter only changes from Screening 
measurements should be recorded as AEs in the eCRFs. 
n 
Vital signs include body temperature, BP, pulse oximetry, pulse/heart rate, and RR. 
o 
BP and heart rate should be measured within 30 min before, and approximately (± 15 minutes) 1-
hour after the completion of the doses on Day 1. 
p 
PK sample collection on Day 1:within an hour prior to Dose 1, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (12 
hour taken immediately before Dose 2); Dose 2 administered (times relative to Dose 1); 13, 13.5, 
14, 14.5, 15, 16, 24 hours post dose 
q 
PK sample collection on Day 2:within an hour prior to dose, 1, 1.5, 2, 2.5, 3, 4, 6 hours  
r 
PK sample collection on Day 3:  prior to the Day 3 dose 
s 
PK sample collection on EOT is anytime during the visit after the final dose. 


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Study Phase 
Screeninga 
Treatment Phase 
Follow-up Phase 
t 
The total duration of test article therapy for all subjects will be 7 to 10 days, up to 14 days for 
bacteremia.  
u 
A subject’s AEs and SAEs will be recorded and reported from signing of the ICF to the Final 
Follow-up assessment.  
 
 
 
 


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Appendix 2 
Adverse Event and Prior/Concomitant Medication Date 
Imputations 
Adverse Event Start/Stop Date Imputation  
Imputation Rules for Partial Dates (D = day, M = month, Y = year) 
Parameter 
Missing 
Additional Conditions 
Imputation 
Start date 
for AEs 
D 
M and Y same as M and Y of first dose of study drug 
Date of first dose of study drug 
M and/or Y not same as date of first dose of study drug 
First day of month 
D and M 
Y same as Y of first dose of study drug 
Date of first dose of study drug 
Y prior to Y of first dose of study drug but same as Y 
of screening date 
Date of screening date 
D, M, Y 
None - date completely missing 
Date of first dose of study drug 
Stop date 
for AEs 
D 
M and Y same as M and Y of last dose of study drug 
Date of last dose of study drug 
M and/or Y not same as date of last dose of study drug 
Use last day of month 
D and M 
Y same as Y of last dose of study drug 
Date of last dose of study drug 
Y not same as Y of last dose of study drug 
Use Dec 31 
D, M, Y 
None - date completely missing 
No imputation, but assume ongoing 
Note:  In all cases, if an estimated start date is after a complete stop date, use the first day of the stop date month. 
Similarly, if the estimated stop date is before a complete or imputed start date, use the last day of the start day month. 
In all cases, if it cannot be determined if the adverse event occurred prior to or after the first dose of test article, the adverse 
event should be defined as treatment emergent. 
 
Prior and Concomitant Medication Start Date Imputation  
Parameter 
Type of 
Medication 
Imputation 
Start date for con 
meds  
Non-
Antibacterial  
If it cannot be determined whether or not the start date of a medication 
(non-antibacterial) is prior to the first dose of study drug, it will be assumed that the 
medication was received prior to the first dose of study drug. 
Antibacterial 
 
Missing start dates for antibacterials will be queried for a value.  If it cannot be 
determined whether or not the start date of an antibacterial is prior to the first dose of 
study drug, it will be assumed that the medication was received prior to the first dose 
of study drug unless the indication notes that the medication was received after the 
first dose of study drug. 
 
Stop date for con 
meds  
Non-
Antibacterial 
If it cannot be determined whether or not the stop date of a medication (nonantibacterial) is 
after the first dose of study drug, it will be assumed that the medication was received 
after the first dose of study drug 
 
Antibacterial 
 
Missing stop dates for antibacterials will be queried for a value.  If it cannot be 
determined whether or not the stop date of an antibacterial is after the first dose of 
study drug, it will be assumed that the medication was received after the first dose of 
study drug unless the indication notes that the medication was received prior to the 
first dose of study drug.  If it cannot be determined whether the antibacterial was 
received prior to the assessment of Early Clinical Response, the EOT and/or the PTE 
Visit, the antibacterial will be assumed to have been received through the PTE Visit. 
 
 


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Appendix 3 
Modified Division of Microbiology and Infectious Diseases 
Adult Toxicity Table 
The DMID Adult Toxicity Table (21-NOV-2007) was modified to exclude the clinical 
component of the toxicity grading because clinical signs and symptoms related to abnormal 
laboratory values are not collected in this study.  In addition, Grade 0 was added to the table 
so that shifts from normal could be analyzed.  Grades for enzymes were modified as 
indicated in the table below. 
For toxicity grades based on a multiple of the ULN, the normal range from the central 
laboratory will be applied.   
For toxicity grades based on fixed values, the grades will be assigned regardless of the 
normal actual range values from the central laboratory.  For example, a hemoglobin value of 
10.0 gm/dL will be assigned a grade of 1 toxicity, even if the lower limit of normal from the 
laboratory was 9.8 gm/dL.   
HEMATOLOGY 
 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin (gm/dL) 
> 10.5 
9.5-10.5 
8.0-9.4 
6.5-7.9 
< 6.5 
Absolute Neutrophil 
Count (count/mm3) 
> 1500 
1000-1500 
750-999 
500-749 
< 500 
Platelets (count/mm3) 
≥ 100,000 
75,000-99,999 
50,000-74,999 
20,000-49,999 
< 20,000 
WBCs (count/mm3) 
1000-10,999 
11,000-12,999 
13,000-14,999  
15,000-30,000 
> 30,000 or 
< 1,000 
 
 
 


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CHEMISTRY 
 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hyponatremia (mEq/L) 
> 135 
130-135 
123-129 
116-122 
< 116  
Hypernatremia (mEq/L) 
< 146 
146-150 
151-157 
158-165 
> 165  
Hypokalemia (mEq/L) 
> 3.4 
3.0-3.4 
2.5-2.9 
2.0-2.4 
< 2.0 
Hyperkalemia (mEq/L) 
< 5.6 
5.6-6.0 
6.1-6.5 
6.6-7.0 
> 7.0 
Hypoglycemia (mg/dL) 
 65 
55-64 
40-54 
30-39 
< 30  
Hyperglycemia (mg/dL) 
(nonfasting and regardless 
of prior history of 
diabetes)* 
< 116 
116-160 
161-250 
251-500 
> 500  
Hypocalcemia (mg/dL) 
(corrected for albumin) 
> 8.4 
8.4-7.8 
7.7-7.0 
6.9-6.1 
< 6.1 
Hypercalcemia (mg/dL) 
(correct for albumin) 
 10.5 
10.6-11.5 
11.6-12.5 
12.6-13.5 
> 13.5 
Hypomagnesemia (mEq/L) 
> 1.4 
1.4- 1.2 
1.1-0.9 
0.8-0.6 
< 0.6 
Hypophosphatemia 
(mg/dL) 
 2.5 
2.0-2.4 
1.5-1.9 
1.0-1.4 
< 1.0 
Hyperbilirubinemia (total 
bilirubin) 
< 1.1×ULN 
1.1-1.5×ULN 
> 1.5-
2.5×ULN 
> 2.5-5×ULN 
> 5×ULN 
Urea 
< 1.25×ULN 
1.25-2.5×ULN 
> 2.5-5×ULN 
> 5-10×ULN 
> 10×ULN 
Hyperuricemia (uric acid) 
(mg/dL) 
< 7.5 
7.5–10.0 
10.1–12.0 
12.1–15.0 
> 15.0 
Creatinine 
< 1.1×ULN 
1.1-1.5×ULN  
> 1.5-
3.0×ULN 
> 3.0-6×ULN 
> 6×ULN  
*The DMID toxicity table reports hyperglycemia detected in nonfasting specimens obtained from subjects 
with no prior diabetes. 
 
ENZYMES 
 
Grade 0  
Grade 1  
Grade 2  
Grade 3  
Grade 4  
AST (SGOT) 
< 1.25×ULN 
1.25-2.5×ULN 
> 2.5-5×ULN 
> 5-10×ULN 
> 10×ULN 
ALT (SGPT) 
< 1.25×ULN 
1.25-2.5×ULN 
> 2.5-5×ULN 
> 5-10×ULN 
> 10×ULN 
GGT 
< 1.25×ULN 
1.25-2.5×ULN 
> 2.5-5×ULN 
> 5-10×ULN 
> 10×ULN 
Alkaline 
Phosphatase 
< 1.25×ULN 
1.25-2.5×ULN 
> 2.5-5×ULN 
> 5-10×ULN 
> 10×ULN 
Amylase 
< 1.1×ULN 
1.1-1.5×ULN 
> 1.5-2.0×ULN 
> 2.0-5.0×ULN 
> 5.0×ULN 
Lipase 
< 1.1×ULN 
1.1-1.5×ULN 
> 1.5-2.0×ULN 
> 2.0-5.0×ULN 
> 5.0×ULN 
 
 
 


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Appendix 4 
Criteria for Clinically Notable Vital Signs 
Vital Sign Parameter 
Flag 
Criterion Value 
Change from Baseline 
Systolic Blood Pressure 
(mmHg) 
High (CH) 
 180 
Increase of  20 mmHg 
Low (CL) 
 90 
Decrease of  20 mmHg 
Diastolic Blood Pressure 
(mmHg) 
High (CH) 
 105 
Increase of  15 mmHg 
Low (CL) 
 50 
Decrease of  15 mmHg 
Heart Rate (bpm) 
High (CH) 
 120 
Increase of  15 bpm 
Low (CL) 
 50 
Decrease of  15 bpm