A Phase 1 Clinical Trial to Evaluate the Plasma Pharmacokinetics, Safety, and Tolerability of a Single Oral Dose of Zoliflodacin in Healthy Male and Female Subjects
Phase: PHASE1
Conditions: Gonorrhoea
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

 
 
A Phase 1 Clinical Trial to Evaluate the Plasma Pharmacokinetics, Safety, 
and Tolerability of a Single Oral Dose of Zoliflodacin in Healthy Male and 
Female Subjects 
 
DMID Protocol Number: 16-0118 
 
 
DMID Funding Mechanism: Phase 1 Clinical Trial Unit 
 
 
Pharmaceutical Support Provided by: Entasis Therapeutics 
 
 
IND Sponsor: Division of Microbiology and Infectious Diseases, National 
Institute of Allergy and Infectious Diseases, National Institutes of Health 
 
 
Site Principal Investigator: Barbara Lomeli, MD 
 
 
DMID Clinical Project Manager: Meg Gordon, RN 
 
 
DMID Medical Officer: Rick Fairhurst, MD, PhD 
 
 
DMID Medical Monitor: Soju Chang, MD 
 
 
Version Number: 2.0 
 
 
25 January 2018 
 
 

DMID Protocol 16-0118 
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Zoliflodacin 
25 January 2018 
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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with Good Clinical Practice (GCP) as required by: 
• United States Code of Federal Regulations (CFR) applicable to clinical trials (45 CFR Part 
46, 21 CFR Part 50, 21 CFR Part 54, 21 CFR Part 56, and 21 CFR Part 312); 
• International Conference on Harmonization (ICH) E6; 62 Federal Register 25692 (1997); 
• National Institutes of Health (NIH) Clinical Terms of Award, as applicable. 
Compliance with these standards provides public assurance that the rights, safety, and well-being 
of study subjects are protected, consistent with the principles that have their origin in the 
Declaration of Helsinki. 
All key personnel (all individuals responsible for the design and conduct of the trial) have 
completed Human Subjects Protection Training.  

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SIGNATURE PAGE 
The signature below constitutes the approval of the protocol and its attachments, and provides 
the necessary assurances that the trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable United States of America (US) federal regulations and 
ICH guidelines. 
 
 
 
Site Investigator: 
 
 
_________________________________________________ 
Name/Title (Print) 
 
 
Signature: 
 
_________________________________________________ 
 
Date:  
 
_________________________________________________ 
 
 
 
 
 
 

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TABLE OF CONTENTS 
 
 
Page 
1 
Key Roles ..............................................................................................................................15 
2 
Background Information and Scientific Rationale ...............................................................18 
2.1 
Background Information ...........................................................................................18 
2.1.1 Overview of the Disease: Gonorrhea and its Treatment ...............................18 
2.1.2 Zoliflodacin Development ............................................................................18 
2.2 
Rationale ...................................................................................................................23 
2.2.1 Rationale for Use of Zoliflodacin .................................................................23 
2.2.2 Rationale for Dose Selection ........................................................................23 
2.3 
Identified and Potential Risks and Benefits ..............................................................23 
2.3.1 Identified Risks .............................................................................................23 
2.3.2 Potential Risks ..............................................................................................23 
2.3.3 Known Potential Benefits .............................................................................25 
3 
Objectives and Outcome Measures.......................................................................................26 
3.1 
Study Objectives .......................................................................................................26 
3.1.1 Primary ..........................................................................................................26 
3.1.2 Secondary ......................................................................................................26 
3.2 
Study Outcome Measures .........................................................................................26 
3.2.1 Primary ..........................................................................................................26 
3.2.2 Secondary ......................................................................................................26 
4 
Study Design .........................................................................................................................27 
4.1 
Sub-studies ................................................................................................................27 
5 
Study Enrollment and Withdrawal .......................................................................................28 
5.1 
Subject Inclusion Criteria .........................................................................................28 
5.2 
Subject Exclusion Criteria ........................................................................................29 
5.3 
Treatment Assignment Procedures ...........................................................................32 
5.3.1 Enrollment Procedures ..................................................................................32 
5.3.2 Masking Procedures ......................................................................................32 
5.3.3 Reasons for Withdrawal and Discontinuation of Study Product 
Administration ..............................................................................................32 
5.3.4 Handling of Withdrawals and Discontinuation of Administration ...............33 
5.3.5 Lost to Follow-up ..........................................................................................33 
5.3.6 Termination of Study ....................................................................................33 
6 
Study Intervention/investigational product ...........................................................................34 
6.1 
Study Product Description ........................................................................................34 
6.1.1 Acquisition ....................................................................................................34 
6.1.2 Formulation, Packaging, and Labeling .........................................................34 

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6.1.3 Product Storage and Stability........................................................................34 
6.2 
Dosage, Preparation, and Administration of Study Intervention/ Investigational 
Product ......................................................................................................................35 
6.3 
Modification of Study Intervention/Investigational Product for a Subject ...............35 
6.3.1 Overdose .......................................................................................................36 
6.4 
Accountability Procedures for the Study Intervention/Investigational Product(s) ...36 
6.5 
Assessment of Subject Compliance with Study Intervention/ Investigational 
Product/Device ..........................................................................................................36 
6.6 
Prior and  Concomitant Medications/Treatments .....................................................36 
6.7 
Subject Restrictions ..................................................................................................37 
6.7.1 Physical Activity ...........................................................................................37 
6.7.2 Fluid and Food intake ...................................................................................38 
6.7.3  Alcohol, Marijuana and Illicit Drugs ............................................................38 
6.7.4 Other Restrictions .........................................................................................38 
7 
Study Schedule .....................................................................................................................39 
7.1 
Recruitment ...............................................................................................................39 
7.2 
Screening Visit (Day -21 to Day -2) .........................................................................39 
7.3 
Enrollment/Baseline ..................................................................................................40 
7.3.1 Admission Visit (Day -1, Unit Check-in) .....................................................40 
7.4 
Inpatient period (Days 1 to 4) ...................................................................................40 
7.4.1 Administration of Study Drug (Day 1) .........................................................40 
7.4.2 In-patient Follow-up Day 2 ...........................................................................41 
7.4.3 In-patient Follow-up Day 3 ...........................................................................41 
7.4.4 Discharge from Unit (Day 4) ........................................................................42 
7.5 
Final Study Visit (Day 8 ± 2) ....................................................................................42 
7.6 
Early Termination Visit (if needed) ..........................................................................43 
7.7 
Unscheduled Visit (if needed) ..................................................................................43 
8 
Study Procedures/evaluations ...............................................................................................44 
8.1 
Clinical Procedures/Evaluations ...............................................................................44 
8.1.1 Informed Consent..........................................................................................44 
8.1.2 Demographics ...............................................................................................44 
8.1.3 Inclusion/Exclusion Criteria .........................................................................44 
8.1.4 Medical History ............................................................................................44 
8.1.5 Physical Examination....................................................................................45 
8.1.6 Vital Signs .....................................................................................................45 
8.1.7 Electrocardiogram .........................................................................................46 
8.2 
Laboratory Evaluations .............................................................................................46 
8.2.1 Clinical Laboratory Evaluations ...................................................................46 

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8.2.1.1 Screening and Safety Clinical Laboratory (Hematology, Chemistry, 
and Urinalysis) Tests.........................................................................46 
8.2.1.2 Viral Serology Testing ......................................................................47 
8.2.1.3 Pregnancy Testing .............................................................................47 
8.2.1.4 Serum FSH testing ............................................................................47 
8.2.1.5 Urine Toxicology Screening .............................................................47 
8.2.1.6 Alcohol testing by breathalyzer ........................................................48 
8.2.2 Special Assays or Procedures .......................................................................48 
8.2.2.1 Pharmacokinetics Assay of Zoliflodacin ..........................................48 
8.2.3 Specimen Preparation, Handling, and Shipping ...........................................48 
8.2.3.1 Instructions for Specimens Preparation, Handling, and Storage ......48 
8.2.3.2 Specimen Shipment ..........................................................................48 
9 
Assessment of Safety ............................................................................................................50 
9.1 
Specification of Safety Parameters ...........................................................................50 
9.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters .................................................................................................................50 
9.2.1 Adverse Events .............................................................................................50 
9.2.1.1 Severity of Events .............................................................................51 
9.2.1.2 Relationship to Study Products .........................................................51 
9.2.1.3 Reporting Adverse Events ................................................................51 
9.2.2 Reactogenicity (for Vaccine Studies and Some Therapeutic Trials) ............52 
9.2.3 Serious Adverse Events ................................................................................52 
9.2.4 Procedures to be Followed in the Event of Abnormal Laboratory Test 
Values or Abnormal Clinical Findings .........................................................52 
9.3 
Reporting Procedures ................................................................................................53 
9.3.1 Serious Adverse Events ................................................................................53 
9.3.2 Regulatory Reporting for Studies Conducted Under DMID Sponsored 
IND ...............................................................................................................54 
9.3.3 Other Adverse Events (if applicable) ............................................................55 
9.3.3.1 Reporting of Overdose ......................................................................55 
9.3.4 Reporting of Pregnancy ................................................................................55 
9.4 
Type and Duration of Follow-up of Subjects after Adverse Events .........................55 
9.5 
Halting Rules ............................................................................................................56 
9.5.1 Study Halting Criteria ...................................................................................56 
9.6 
Safety Oversight (ISM plus SMC) ............................................................................56 
9.6.1 Independent Safety Monitor (ISM) ...............................................................56 
9.6.2 Safety Monitoring Committee (SMC) ..........................................................56 
10 
Clinical Monitoring...............................................................................................................58 
10.1 
Site Monitoring Plan .................................................................................................58 

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11 
Statistical Considerations ......................................................................................................59 
11.1 
Study Hypotheses......................................................................................................59 
11.1.1 Study Objectives and Outcome Measures ....................................................59 
11.1.1.1 Study Objectives ...............................................................................59 
11.1.1.2 Study Outcome Measures .................................................................59 
11.2 
Sample Size Considerations ......................................................................................60 
11.3 
Safety Review ...........................................................................................................60 
11.4 
Final Analysis Plan ...................................................................................................60 
11.4.1 Analysis Populations .....................................................................................60 
11.4.2 Demographics and Baseline Characteristics .................................................61 
11.4.3 Safety Analysis Plan .....................................................................................61 
11.4.3.1 Adverse and Serious Adverse Events ...............................................61 
11.4.3.2 Additional Safety Analyses...............................................................61 
11.4.4 PK Analysis Plan ..........................................................................................61 
11.4.5 Missing Values and Outliers .........................................................................62 
12 
Source Documents and Access to Source Data/Documents .................................................63 
13 
Quality Control and Quality Assurance ................................................................................64 
14 
Ethics/Protection of Human Subjects ...................................................................................65 
14.1 
Ethical Standard ........................................................................................................65 
14.2 
Institutional Review Board .......................................................................................65 
14.3 
Informed Consent Process ........................................................................................65 
14.4 
Exclusion of Women, Minorities, and Children (Special Populations) ....................67 
14.5 
Subject Confidentiality .............................................................................................67 
14.6 
Study Discontinuation ...............................................................................................67 
15 
Data Handling and Record Keeping .....................................................................................69 
15.1 
Data Management Responsibilities...........................................................................69 
15.2 
Data Capture Methods ..............................................................................................69 
15.3 
Types of Data ............................................................................................................69 
15.4 
Timing/Reports .........................................................................................................70 
15.5 
Study Records Retention...........................................................................................70 
15.6 
Protocol Deviations ...................................................................................................70 
16 
Publication Policy .................................................................................................................71 
17 
Literature References ............................................................................................................72 
18 
Appendices............................................................................................................................74 
Appendix A: Schedule of Study Procedures ad Evaluations .................................................................75 
Appendix B: Acceptable Ranges of Screening Laboratory and Vital Sign Measurements ......................77 
Appendix C: Adverse Events Toxicity Grading Criteria ......................................................................81 
Appendix D: Blood Volume withdrawn during the Trial .....................................................................89 
 

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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
AP 
Alkaline phosphatase 
AST 
Aspartate aminotransferase 
AUC 
Area Under the Curve 
BMI 
Body Mass Index 
BP 
Blood Pressure 
bpm 
Beats per Minute 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CDC 
Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
Cmax 
Maximum Plasma Concentration 
CMS 
Clinical Materials Services 
ConMed(s) 
Concomitant Medication(s) 
CPM 
Clinical Project Manager 
CROMS 
Clinical Research Operations and Management Support 
CSR 
Clinical Study Report 
CTU 
Clinical Trial Unit 
CV% 
Coefficient of Variation 
DCC 
Data Coordinating Center 
DMID 
Division of Microbiology and Infectious Diseases 
DNA 
Deoxyribonucleic acid 
eCRF 
Electronic Case Report Form 
EC 
Ethics Committee 
ECG  
Electrocardiogram 
EDC 
Electronic Data Capture 
ET 
Early Termination 

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FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
FWA 
Federalwide Assurance 
g 
Gram(s) 
GCP 
Good Clinical Practice 
g/dL 
Gram(s) per Deciliter 
h 
Hour(s) 
HBsAg 
Hepatitis B Surface Antigen 
HCG (β-HCG) 
Human Chorionic Gonadotropic Hormone 
Hct 
Hematocrit 
Hgb 
Hemoglobin 
HCV 
Hepatitis C Virus 
HEENT 
Head, Eyes, Ears, Nose, and Throat 
HIV 
Human Immunodeficiency Virus 
HPLC-MS/MS 
High-Performance Liquid Chromatography with Tandem Mass 
Spectrometry 
 
HR 
Heart Rate 
IB 
Investigator’s Brochure 
IC50 
50% Inhibitory Concentration 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
ICMJE 
International Committee of Medical Journal Editors 
IM 
Intramuscular 
IND 
Investigational New Drug  
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
IV 
Intravenous 
kg 
Kilogram 
LLN 
Lower Limit of Normal 
MDMA 
3,4-methylenedioxy-methamphetamine 
MedDRA 
Medical Dictionary for Regulatory Activities 

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MH 
Medical History 
µg 
Microgram(s) 
µM 
Micromolar 
µmol 
Micromole(s) 
mg 
Milligram(s) 
mg/dl 
Milligram(s) per Deciliter 
MIC 
Minimum Inhibitory Concentration 
mL 
Milliliter(s) 
mm 
Millimeter(s) 
MM 
Medical monitor 
MMA 
Mouse Micronucleus Aberration Assay 
mmHg 
Millimeters of Mercury 
min 
Minute(s) 
MOP 
Manual of Procedures 
msec 
Milliseconds(s) 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
NOAEL 
No observable adverse effect level 
NSAIDs 
Nonsteroidal Anti-Inflammatory Drugs 
OCRR 
Office of Clinical Research Resources 
PD 
Pharmacodynamic(s) 
PE 
Physical Examination 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PO 
Oral 
POC 
Point of Contact 
PVG 
Pharmacovigilance Group 
QTc 
Corrected QT Interval 
RBC 
Red Blood Cell 
RP 
Research Pharmacist 
SAE 
Serious Adverse Event 

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SAP 
Statistical Analysis Plan 
sec 
Second(s) 
SMC 
Safety Monitoring Committee 
Tmax 
Time to Maximum Plasma Concentration 
TCA 
Tricyclic antidepressants 
UA 
Urinalysis 
VS 
Vital Signs 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell Count 
WHO 
World Health Organization 
 
 
 

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PROTOCOL SUMMARY  
Title: 
 
A Phase 1 Clinical Trial to Evaluate the Plasma Pharmacokinetics (PK), 
Safety, and Tolerability of a Single Oral Dose of Zoliflodacin in Healthy Male 
and Female Subjects  
Phase: 
1 
Population: 
Eight healthy male and female subjects aged 18 to 45 years inclusive  
Number of Sites: 
 
One (IQVIA Phase One Services, LLC, Overland Park, KS) 
Study Duration: 
 
Approximately 4 weeks   
Subject 
Participation 
Duration: 
 
Up to 10 days (from dosing to final visit) 
Description of 
Agents: 
The study drug, zoliflodacin (also known as AZD0914 and ETX0914), is a 
spiropyrimidinetrione antibacterial agent. Its chemical name is (2R,4S,4aS)-
11-fluoro-2,4-dimethyl-8-[(4S)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]-1,2,4,4a-
tetrahydro-2'H,6H-spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-g]quinoline-5,5'-
pyrimidine]-2',4',6'(1'H,3'H)-trione. It is formulated as a powder in sachets 
containing 2 grams (g) of the active agent and inactive excipients. 
Objectives: 
 
Primary: 
• To evaluate the plasma PK of zoliflodacin after administration of a 
single 4-g oral dose under fasting conditions 
Secondary: 
• To evaluate the safety and tolerability of a single 4-g oral dose of 
zoliflodacin 
Outcome 
Measures:  
 
 
 
 
Primary: 
Cmax, Tmax, AUC(0-last), and other PK parameters for zoliflodacin 
determined using plasma concentrations of zoliflodacin in blood 
samples collected on Day 1 [baseline (30 min before dosing) and 0.5 h, 
1 h, 2 h, 3 h, 4 h, 6 h, 8 h, and 12 h after dosing], Day 2 [24 h and 36 h 
after dosing], Day 3 [48 h after dosing], and Day 4 [72 h after dosing], 

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or early termination (ET), and measured using a validated HPLC-
MS/MS method 
Secondary: 
• The occurrence of treatment-emergent serious adverse events (SAEs) 
from administration of zoliflodacin on Day 1 to Final Visit (Day 8 ± 2), 
or ET 
• The occurrence of unsolicited treatment-emergent adverse events 
(AEs) from administration of zoliflodacin on Day 1 to Final Visit (Day 
8 ± 2), or ET 
• The changes from baseline (up to 60 min before dosing) in vital signs 
(VS) following administration of zoliflodacin, as measured on Day 1 [1 
h, 2 h, and 4 h after dosing], Days 2, 3, and 4 [24 h, 48 h, and 72 h, 
respectively, after dosing], and Final Visit (Day 8 ± 2), or ET 
• The changes from baseline (Day -1) in clinical laboratory values 
following administration of zoliflodacin, as measured on Day 4, or ET 
• The changes from baseline (up to 60 min before dosing) in 
electrocardiogram (ECG) parameters following administration of 
zoliflodacin, as measured on Day 1 [1 h, 2 h, and 4 h after dosing] and 
Day 4 [72 h after dosing], or ET 
Description of 
Study Design: 
 
The trial is an open-label, non-randomized evaluation of the PK and safety 
profiles of a single 4-g oral dose of zoliflodacin in eight healthy male or 
female subjects. Each subject will receive zoliflodacin reconstituted in 
 
 after at least an 8-h fast, which will continue for at least 4 h after 
dosing. Consumption of water is permitted during the fasting period. All 
subjects will be dosed in the morning of Day 1 in a staggered fashion with a 
minimum of several minutes apart.  
 
Subjects who consent to participate will be enrolled in the trial if they meet all 
of the inclusion and none of the exclusion eligibility criteria. Laboratory 
assessments at Screening Visit will include testing for serology [human 
immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), and 
hepatitis C virus (HCV)], drugs of abuse, and alcohol. Serum pregnancy 
testing will be done in all females and serum FSH levels will be measured only 
in post-menopausal females. Safety assessments at scheduled visits will 
include medical history (MH), vital signs (VS), physical examination (PE), 12-
lead ECG, and clinical laboratory values including complete blood count 
(CBC) with differential, comprehensive metabolic (chemistry) panel, and 
urinalysis (UA) for blood, glucose, and protein. Treatment-emergent AEs and 
SAEs will be assessed from the time of dosing to the end of the trial. Plasma 

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for PK analysis will be collected at scheduled time points before and after 
dosing on Day 1 and through Day 4, or ET. 
Estimated Time 
to Complete 
Enrollment: 
Up to 10 days (from dosing to last visit) 
Halting Criteria 
Decision Process: 
 
If criteria for halting the trial (as listed in Section 9.5.1) are met during dosing 
on Day 1 prior to all subjects being dosed, an ad hoc Safety Monitoring 
Committee (SMC) meeting will be held to review all available safety data and 
to make recommendations about the dosing of all further subjects in the trial. 
A scheduled SMC meeting will be held after all subjects complete the trial to 
review all safety data, and advise on using the 4-g dose in a subsequent 
thorough QTc study. 
 

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1 
KEY ROLES 
Program Principal Investigator: 
George A Saviolakis, MD, PhD 
Medical Director 
DynPort Vaccine Company, LLC 
110 Thomas Johnson Drive, Suite 200 
Frederick, MD 21702 
Office: 240-651-8116 
Mobile: 
 
Email: George.Saviolakis@csra.com 
 
Site Principal Investigator: 
Barbara Lomeli, MD 
IQVIATM 
6700 West 115th Street 
Overland Park, KS 66211 
Office: 913-708-6999 
Mobile: 
 
Email: barbara.lomeli@Quintilesims.com 
  
DMID Clinical Project Manager: 
Meg Gordon, RN 
OCRR/DMID/NIAID/NIH 
5601 Fishers Lane, Room 7G37  
Bethesda, MD 20892-9826 
Office: 301-761-7604 
Mobile: 
 
Email: meg.gordon@nih.gov 
 
DMID Medical Officer: 
Rick Fairhurst, MD, PhD 
OCRR/DMID/NIAID/NIH 
5601 Fishers Lane, Room 8B22 
Bethesda, MD 20892-9826 
Office: 301-761-5077 
Mobile: 
 
Email: rfairhurst@niaid.nih.gov 
 
 
 

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DMID Medical Monitor: 
Soju Chang, MD 
OCRR/DMID/NIAID/NIH 
5601 Fishers Lane, Room 7E59  
Bethesda, MD 20892-9826 
Office: 240-292-4178 
Email: changsoju@niaid.nih.gov 
 
Pharmaceutical Sponsor 
Medical Monitor: 
 
Robin Isaacs, MD 
Chief Medical Officer 
Entasis Therapeutics 
 
 
  
 
 
Safety and Pharmacovigilance 
Contractor: 
Pharmacovigilance Group 
CROMS/DMID/NIAID/NIH 
6500 Rock Spring Drive, Suite 650 
Bethesda, MD 20817 
SAE Hot Line: 1-800-537-9979 
SAE Fax: 1-800-275-7619 
SAE Email: PVG@dmidcroms.com 
 
Data Coordinating Center: 
The Emmes Corporation 
401 N. Washington Street, Suite 700 
Rockville, MD 20850 
Phone: 301-251-1161 
Fax: 301-576-3558 
Email: phase1@emmes.com 
 

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Study Agent Repository: 
Fisher BioServices 
c/o DMID Clinical Materials Services (CMS) 
20439 Seneca Meadows Parkway 
Germantown, MD 20876 
Phone: 240-477-1350  
Fax: 240-477-1360 
Email: DMID.CMS@thermofisher.com 
 
Clinical Laboratory: 
IQVIA Early Clinical Development Laboratory 
6700 West 115th Street 
Overland Park, KS 66211 
Phone: 913-708-6023 
Fax: 913-800-6564 
 
Bioanalytical Laboratory: 
KCAS Bioanalytical Services 
12400 Shawnee Mission Parkway 
Shawnee, KS 66216 
POC: Marsha Luna 
          Senior Manager, PBI 
Phone: 913-248-3042 
Email: marsha.luna@kcasbio.com 
  

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2 
BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
2.1 
Background Information 
2.1.1 Overview of the Disease: Gonorrhea and its Treatment 
Neisseria gonorrhoeae, currently the second most common bacterial sexually transmitted 
infection worldwide (after Chlamydia trachomatis), is a serious public health problem.1,2 In 
2008, the World Health Organization (WHO) estimated 106 million cases of gonorrhea among 
adults worldwide.3 In 2012, the Centers for Disease Control and Prevention (CDC) reported 
311,404 cases of gonorrhea in the US; however, due to incomplete reporting, up to 820,000 cases 
may occur annually.4 N. gonorrhoeae has developed resistance to all antimicrobial treatments for 
gonorrhea. The CDC recently released its report “Antibiotic Resistance Threats in the US, 2013,” 
which ranks drug-resistant N. gonorrhoeae as an “Urgent Threat,” defined as “an immediate 
public health threat that requires urgent and aggressive action.”5 This level of resistance has 
demanded alternative oral treatments, which until recently have been readily available.6 
Examples of drug classes that are widely used to treat gonorrhea, but are no longer recommended 
as monotherapy due to resistance, include sulfanilamides, penicillin, tetracyclines, and 
fluoroquinolones. 1,2 Most recently, N. gonorrhoeae resistance to macrolides (including 
azithromycin), cefixime, and ceftriaxone, and consequent clinical failures, have been reported. 
Since two extended-spectrum cephalosporins, ceftriaxone and cefixime, have recently been the 
only first-line options for treating gonorrhea, resistance and treatment failures with these drugs 
are particularly concerning. It is only a matter of time before gonococci with full resistance to 
extended-spectrum cephalosporins emerge and spread globally.7 The threat of widespread 
ceftriaxone resistance and untreatable N. gonorrhoeae infection is real.5,6  The clinical 
development of zoliflodacin (also known as AZD0914 and ETX0914) addresses the need for 
new antibiotics that can be used alone or with other agents to treat uncomplicated gonorrhea 
caused by emergent N. gonorrhoeae strains that are resistant to existing antibiotics.8,9 
2.1.2 Zoliflodacin Development  
Zoliflodacin is a spiropyrimidinetrione antibacterial drug, which inhibits bacterial DNA 
synthesis by a novel mechanism. Zoliflodacin demonstrates in vitro activity against 
N. gonorrhoeae strains that are susceptible or resistant to current available therapies and in vivo 
efficacy, including in patients with uncomplicated gonorrhea. 8,9,10,11 
This section provides a summary of zoliflodacin. Nonclinical and clinical data are provided in 
more detail in the Investigator’s Brochure (IB). 
 
 

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Chemistry 
The chemical name for zoliflodacin is (2R,4S,4aS)-11-fluoro-2,4-dimethyl-8-[(4S)-4-methyl-2-
oxo-1,3-oxazolidin-3-yl]-1,2,4,4a-tetrahydro-2'H,6H-spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-
g] quinoline-5,5'-pyrimidine]-2',4',6'(1'H,3'H)-trione. 
Mechanism of Action 
Zoliflodacin inhibits bacterial Type II topoisomerases, specifically bacterial gyrases. The activity 
and mode of inhibition of bacterial gyrase by zoliflodacin has been assessed in several in vitro 
assays. Zoliflodacin stabilizes the 
 
, but in addition prevents its
 
 is further supported 
 
 N. gonorrhoeae 
resistance to 
.8 
Microbiological Activity  
In vitro: Zoliflodacin has demonstrated activity in vitro against N. gonorrhoeae, including strains 
that are resistant to penicillin, ciprofloxacin, tetracycline, azithromycin, ceftriaxone, and 
cefixime. Minimum inhibitory concentration (MIC)90 values ranged from 0.125 to 0.25 μg/mL. 
Zoliflodacin has also shown bactericidal activity at an MIC90 of 0.25 μg/mL against C. 
trachomatis, which often co-infects patients with gonorrhea. 8,9,10  
In vivo: Mouse model of Staphylococcus aureus infection: An animal model for N. gonorrhoeae 
has not been established due to spontaneous bacterial eradication. To estimate a human 
efficacious exposure of zoliflodacin for N. gonorrhoeae, a surrogate pathogen approach, which 
utilizes pharmacokinetics/pharmacodynamics (PK/PD) determinations from a S. aureus 
neutropenic mouse thigh model that correlates with human clinical efficacy, was used. In this 
model, zoliflodacin was efficacious in vivo against clinical S. aureus isolates. The MIC values of 
zoliflodacin against S. aureus and N. gonorrhoeae and the clinical doses suggest that efficacy 
can be translated across pathogens based on AUC/MIC targets. From this analysis, the 
efficacious human exposure for zoliflodacin was estimated utilizing a PK/PD target that covers a 
mean fAUC/MIC of 66 (range 43–98) for S. aureus in the mouse thigh model. This target, 
combined with the MIC90 of zoliflodacin for N. gonorrhoeae and the human unbound fraction 
(fu) of 17%, translated to a predicted efficacious mean AUC in humans of 49 µg*h/mL. 8,9 
In vivo: Human Phase 2 trial: Zoliflodacin was recently investigated in a multi-center, 
randomized, Phase 2 trial to assess the safety and efficacy of zoliflodacin administered orally to 
adults to treat uncomplicated urogenital gonorrhea compared to treatment with ceftriaxone 
administered intramuscularly. Subjects were randomly assigned to receive a single oral dose of 2 
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ceftriaxone. In the per-protocol population, microbiological cure was observed 
 
. 8 
Human Pharmacokinetics 
A single-center, multi-part, Phase 1 trial with an oral suspension of zoliflodacin versus placebo 
was conducted in healthy men and women. In part A, 48 subjects received single ascending 
doses of zoliflodacin ranging from 200 mg to 4 g, or placebo (6:2, zoliflodacin:placebo). In Part 
B, zoliflodacin was administered in doses of 1.5 g (N=8) and 3 g (N=10) to evaluate the effect of 
food on the PK of zoliflodacin. Zoliflodacin was absorbed relatively quickly under fasting 
conditions, with a median Tmax ranging from 
. 
Following Cmax, plasma drug concentrations 
. The 
terminal elimination phase started at approximately 
, 
zoliflodacin concentrations declined with a half-life ranging from 
 
. Exposures 
 
, suggesting a 
 
. When 
 of zoliflodacin was administered, a 
 
 was seen if the drug was 
 
 The Cmax 
 
 consistent with 
.8 
In a Phase 2 trial of patients with gonorrhea, 
 
. 
The AUC and Cmax values for zoliflodacin at the various doses also point to a margin of safety, 
as seen by multiples to rat and dog NOAEL (no observable adverse effect level) values.8 
Potential for Drug-Drug Interactions 
Zoliflodacin is a 
 in preclinical studies. In vitro and in vivo 
metabolism across species indicate that the compound is 
 
. As a single dose therapy with no evidence of 
, the compound is not expected to show lasting 
effects. The potential for drug-drug interactions has been evaluated using a physiologically-based 
PK model developed with the 
 
.8 In summary: 
1. Zoliflodacin as a victim: Single doses of zoliflodacin ranging from 
 
 
 
 
 
 
. The primary 

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PK driver for efficacy of zoliflodacin is 
 
. 
2. Zoliflodacin as a perpetrator: Zoliflodacin is predicted to 
 
 
. The extent of the interaction is not predicted to differ 
between the zoliflodacin 
. This
 
 
 administration of zoliflodacin. 
Safety 
In vitro studies: There was no 
 
 There was no inhibition of 
 
  
Some fluoroquinolones induce QT prolongation leading to arrhythmias and torsades de pointes, 
which have been correlated with binding to the hERG K+ channel. In contrast, zoliflodacin 
showed 
 
 
 
 
Animal pharmacology and toxicology studies: Zoliflodacin was well tolerated – as a 
 
 
. There was 
 
 
 
 
 
 
 
 
 
 At 
this highest dose tested, 
 
 
 These effects were 
 
 There were 
 
 
 

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.8 
Effects of zoliflodacin on female fertility and embryofetal development have been assessed  
 Effects on 
  
Following administration of zoliflodacin at doses of 
 
 
 
. At all dose levels, there were 
 
 
 
 
 
 
 
The effects of zoliflodacin on male fertility have been assessed 
 
 Administration at 
 
 
 
 
. 
Human trials: Three trials have evaluated the safety of zoliflodacin in humans.8 
In healthy subjects in the Phase 1 trials, 
 
 
 
.8,12 
In patients in the Phase 2 trial, zoliflodacin was generally safe and well tolerated. AEs reported 
were generally mild, were non-serious, and none led to trial discontinuation. The AE and 
laboratory safety profiles of zoliflodacin were generally similar to those of ceftriaxone. The AE 
profile of zoliflodacin 2 g was generally similar to that of zoliflodacin 3 g; headache was more 
common in the zoliflodacin 3-g group (9%) compared to the zoliflodacin 2-g group (0%). 
Dysgeusia was not reported in the Phase 2 trial. Vomiting was reported by one patient receiving 
zoliflodacin 3 g.8,13 
There were no AEs reported at a frequency of ≥5% when the AE profiles of the zoliflodacin 2-g 
and zoliflodacin 3-g groups were combined. The most common AEs reported with zoliflodacin 
(≥3% based on the zoliflodacin 2-g and zoliflodacin 3g groups combined and excluding 
infection-related AEs) were diarrhea, headache, and nausea. 8,13 

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2.2 
Rationale 
2.2.1 Rationale for Use of Zoliflodacin  
A single PO dose of zoliflodacin has been shown to be effective against uncomplicated 
gonorrhea caused by N. gonorrhoeae strains susceptible or resistant to currently available 
therapies. These findings supported the ongoing clinical development of zoliflodacin as a 
potential new therapeutic option for uncomplicated gonorrhea. The recently completed Phase 2 
clinical trial suggests that zoliflodacin doses in the range of 2 g to 3 g are therapeutic. The 
present clinical trial will further characterize the PK characteristics and safety profile of a high 4-
g dose of zoliflodacin and evaluate whether it can be used in a planned thorough QTc study. 
2.2.2 Rationale for Dose Selection 
Regulatory guidance ICH/FDA E14 has emphasized the need to obtain robust data on the effect 
of new chemical entities on ECG parameters, focusing on cardiac repolarization as measured by 
the QTc.14 To obtain these data, the potential of a single therapeutic dose and a single 
supratherapeutic dose of the study drug to prolong cardiac repolarization is measured. The 4-g 
dose of a previous formulation of zoliflodacin was found to be safe and well tolerated in a Phase 
1 trial. The current trial will further characterize the PK and safety profiles of the 4-g dose of a 
new zoliflodacin formulation. This dose could result in drug exposures that are multiples of the 
proposed 2-g therapeutic dose and meet the requirements for a supratherapeutic dose according 
to the ICH/FDA E14 Guidance for thorough QTc studies. 14 
2.3 
Identified and Potential Risks and Benefits 
2.3.1 Identified Risks 
Single zoliflodacin doses ranging from 200 mg to 4 g were generally safe and well tolerated in 
the Phase 1 and Phase 2 clinical trials conducted to date in healthy subjects and patients with 
uncomplicated gonorrhea.8,12,13 The most common AEs reported with zoliflodacin in the Phase 1 
trials were dysgeusia and headache, and in the Phase 2 trial (≥3% based on the zoliflodacin 2-g 
and zoliflodacin 3-g groups combined and excluding infection-related AEs) were diarrhea, 
headache, and nausea. These events will continue to be monitored and evaluated. 
2.3.2 Potential Risks 
The potential risks to subjects participating in the trial are those related to PO dosing of 
zoliflodacin, and associated study procedures (venipuncture, IV catheter insertion, ECG patch 
application, and blood sampling). 
 

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Zoliflodacin-Associated Risks 
As for any drug, exposure to zoliflodacin could result in an allergic or hypersensitivity reaction 
that could be mild or life-threatening. Should a reaction occur, medically-appropriate diagnostic 
and therapeutic measures will be taken immediately by trained site clinicians and staff. 
In a Phase 1 trial, analysis of 
 
 
. 
Monitoring of 
 will continue in the trial. 
In a Phase 1 and Phase 2 trial, no trends 
 
. 
Standard clinical monitoring of 
 
 
 
 The incidence of these 
findings typically 
 
 
 
 
 
 in the first-in-human trial. 
 
. These findings are not considered to preclude 
administration of zoliflodacin to healthy male subjects with appropriate informed consent. 
Effects of chronic dosing of zoliflodacin on 
 
. With respect to 
 
 
 
 
 
 
 
. The effects of zoliflodacin 
 
 
 Based on these preclinical data and the 
gonorrheal clinical indication, in current and future clinical trials: 
• Female subjects will be pregnancy tested prior to administration of zoliflodacin and at the 
end of the trial and will be required to use specified birth control methods for 30 days 
following final study visit.  

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• Male subjects will be required to use specified birth control methods for 90 days 
following final study visit and will be advised not to donate sperm during this period.  
Venipuncture and IV Catheter Placement Risks 
Venipuncture: Venipuncture causes transient discomfort and may cause fainting. Bruising at the 
site of venipuncture may occur, but can be prevented or lessened by applying pressure for several 
min. Infection at the site is possible but highly unlikely as aseptic technique will be used. 
IV catheter placement: An indwelling catheter may be placed in an arm vein (preferably 
antecubital) for frequent blood drawing for PK measurements. The catheter may cause phlebitis 
with signs of redness and warmth at or near the IV insertion site, and thrombophlebitis with a 
hard area palpable near the IV insertion site. These risks are minimal as the IV catheters, when 
used, are only used briefly after dosing. Careful inspection of the catheter site, including 
visualization of blood return, and withdrawal of the catheter if needed will minimize this risk. 
There is a risk of infection; however, this is a small risk as aseptic technique will be used. 
Additional Risks 
ECG: Possible side effects from ECG patches include a rash or minor irritation of the skin. 
Blood draws: The amount of blood drawn is about 18 mL during the Screening Visit and Day -1 
period, 74 mL during the inpatient period (Days 1-4), and 92 mL during the entire trial 
(Appendix D). Additionally, small amounts of blood loss may occur if an IV catheter is used or 
additional blood samples are collected (for repeat laboratory testing, evaluation of AE, etc.). 
Overall, the amount of blood that may be drawn during the trial is within the amount that 
considered safe to be drawn during short or extended periods, respectively, and not excessive for 
the safety and PK assessment requirements of Phase 1 trials. However, there is a small risk that 
some subjects may develop mild symptoms of hypovolemia or anemia during the trial. These are 
reversible with specific treatment (fluid replacement, good nutrition, vitamins, or iron 
supplementation). 
2.3.3 Known Potential Benefits 
The trial has no benefit for the subjects participating in the trial. Knowledge gained in the trial 
could be of benefit to public health and to individuals with gonorrhea or at risk of acquiring it. 

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3 
OBJECTIVES AND OUTCOME MEASURES 
3.1 
Study Objectives 
3.1.1 Primary 
• To evaluate the plasma PK of zoliflodacin after administration of a single 4-g oral dose 
under fasting conditions 
3.1.2 Secondary 
• To evaluate the safety and tolerability of a single 4-g oral dose of zoliflodacin 
3.2 
Study Outcome Measures 
3.2.1 Primary  
• Cmax, Tmax, AUC(0-last), and other PK parameters for zoliflodacin determined using plasma 
concentrations of zoliflodacin in blood samples collected on Day 1 [baseline (30 min 
before dosing) and 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, and 12 h after dosing], Day 2 [24 h 
and 36 h after dosing], Day 3 [48 h after dosing], and Day 4 [72 h after dosing], or ET, 
and measured using a validated HPLC-MS/MS method 
3.2.2 Secondary 
• The occurrence of treatment-emergent SAEs from administration of zoliflodacin on Day 
1 to Final Visit (Day 8 ± 2), or ET 
• The occurrence of unsolicited treatment-emergent AEs from administration of 
zoliflodacin on Day 1 to Final Visit (Day 8 ± 2), or ET 
• The changes from baseline (up to 60 min before dosing) in VS following administration 
of zoliflodacin, as measured on Day 1 [1 h, 2 h, and 4 h after dosing], Days 2, 3, and 4 
[24 h, 48 h, and 72 h, respectively, after dosing], and Final Visit (Day 8 ± 2), or ET 
• The changes from baseline (Day -1) in clinical laboratory values following administration 
of zoliflodacin, as measured on Day 4, or ET 
• The changes from baseline (up to 60 min before dosing) in ECG parameters following 
administration of zoliflodacin, as measured on Day 1 [1 h, 2 h, and 4 h after dosing] and 
Day 4 [72 h after dosing], or ET 
 

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4 
STUDY DESIGN 
The trial will be performed as an open-label, non-randomized, single-dose design in eight 
healthy male or female subjects to evaluate the PK and safety profiles of the zoliflodacin 
formulation. All subjects will be dosed in the morning of Day 1 in a staggered fashion with a 
minimum of several minutes apart. Each subject will receive a single 4g dose of zoliflodacin (2 x 
2 g sachets of zoliflodacin) after at least an 8-h fast, which will continue for at least 4 h after 
dosing. Consumption of water will be permitted during the fasting period. Subjects will be 
monitored as inpatients in the Clinical Trial Unit (CTU) up to Day 4 and at the Final Visit (Day 8 
± 2). 
Subjects who consent to participate will be enrolled in the trial if they meet all inclusion and 
none of the exclusion eligibility criteria. Laboratory assessments at Screening Visit will include 
testing for serology (HIV, HBsAg, and HCV), drugs of abuse, and alcohol. Serum pregnancy 
testing will be done in all women and serum FSH levels will be measured only in post-
menopausal women. Safety assessments at scheduled visits will include MH, VS, PE, 12-lead 
ECG, and clinical laboratory tests including CBC with differential, comprehensive metabolic 
(chemistry) panel, and UA. Treatment-emergent AEs and SAEs will be assessed from the time of 
dosing to the end of the trial. Plasma for PK analysis will be collected at scheduled time points 
before and after initiation of dosing on Day 1 and through Day 4, or ET. 
Safety Monitoring and SMC Role 
A SMC will be appointed to oversee the safe conduct of the trial. A scheduled SMC meeting will 
be held after all subjects complete the trial to review safety data, and advise on using the 4-g 
dose in a subsequent thorough QTc study. If criteria for halting the trial (as listed in Section 
9.5.1) are met during dosing on Day 1, an ad hoc SMC meeting will be held to review all 
available safety data and to make recommendations about the dosing of all further subjects in the 
trial. An independent safety monitor (ISM), who is local to the CTU, will review SAEs and other 
severe safety signals and provide an independent analysis to the Site PI, SMC, and DMID. 
4.1 
Sub-studies 
No sub-studies are planned. 

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5 
STUDY ENROLLMENT AND WITHDRAWAL 
Only subjects who meet all inclusion criteria and none of the exclusion criteria will be eligible 
for enrollment into the trial. No exemptions are granted on Inclusion/Exclusion Criteria in DMID 
sponsored trials. 
Eight healthy male and female subjects, aged 18 to 45 years inclusive, will be enrolled in a single 
cohort. Up to two alternates will be recruited. 
5.1 
Subject Inclusion Criteria 
All must be answered YES for the subject to be eligible for study participation: 
1) Informed consent form (ICF) understood and signed before initiating any study 
procedures 
2) Healthy male or female, as assessed by the authorized site clinician (listed on FDA Form 
1572)  
3) Willingness to comply with and be available for all protocol procedures including 
inpatient confinement for about 4 days and availability for follow-up for the duration of 
the trial 
4) Aged 18 to 45 years inclusive on the day of study drug dosing 
5) Body Mass Index (BMI) ≥18.5 and ≤30 kg/m2 and weight ≥50 kg (110 lbs.) and 
≤100 kg (220 lbs.) 
6) In female subjects of childbearing potential, a negative serum pregnancy test at Screening 
Visit and on Day -1 
• Note: A woman is considered of childbearing potential unless post-menopausal (≥ 1 
year without menses without other known or suspected cause and with a FSH level in 
the menopausal range), or surgically sterilized (hysterectomy, salpingectomy, 
oophorectomy or tubal ligation/occlusion) 
7) If female, not pregnant, not breast feeding, and not planning on becoming pregnant 
during the trial and for 30 days after study participation 
8) Females of childbearing potential and males agree to use acceptable contraception for the 
duration of the trial and for 30 days (females) or 90 days (males) after final study visit 
• Note: A highly effective method of birth control is defined as one with a low failure 
rate (i.e., less than 1 percent per year) according to the CDC criteria.15 These include 
progestin implants, intrauterine devices (IUDs), surgical (hysterectomy, 
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Use of methods with higher failure rate (such as progestin injectables, combined oral 
hormonal contraceptives, condoms, and diaphragms) will not be acceptable when 
used alone, but they could be considered if used in combination with another method 
(e.g., a female using combined oral contraceptives if her male partner is sterile, or if 
she and her non-sterile male partner use a double-barrier method), after consultation 
with the DMID Medical Officer. 
9) Male subjects must agree to refrain from sperm donation for the duration of the trial and 
for 90 days after Final Visit 
10) Laboratory tests, as outlined in Section 8.2.1.1, are in the normal reference range with 
acceptable exceptions as noted in Section 8.2.1.1 and Appendix B  
11) VS, as outlined in Section 8.1.6, are within the acceptable range per Appendix B 
12) Has adequate venous access for blood collection  
13) Urine drug screen is negative for tested substances (see Section 8.2.1.5) 
14) Alcohol test (breathalyzer) is negative 
15) Willing to abstain from alcohol consumption for 2 days before Day -1 and during the trial 
5.2 
Subject Exclusion Criteria 
All must be answered NO for the subject to be eligible for study participation: 
1) History of a chronic medical or surgical condition that would interfere with the accurate 
assessment of the trial’s objectives or increase the subject’s risk profile 
• Note: Chronic medical conditions include: diabetes mellitus; asthma requiring use of 
medication in the year before screening; autoimmune disorder such as lupus 
erythematosus, Wegener’s, rheumatoid arthritis, thyroid disease; cardiovascular 
disease, including coronary artery disease or cerebrovascular disease, or surgery; 
syncope related to cardiac arrhythmia or unexplained; chronic hypertension; 
malignancy except low-grade (squamous and basal cell) skin cancer thought to be 
cured; chronic renal, hepatic, pulmonary, or endocrine disease, myopathy, or 
neuropathy; gastrointestinal or biliary surgery. 
2) History of hypersensitivity or severe allergic reaction of any type to medications, bee 
stings, food, or environmental factors 
• Note: Severe allergic reaction is defined as any of the following: anaphylaxis, 
urticaria, or angioedema 
 
3)  Active allergic symptoms to seasonal and animal allergens that require treatment   

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4) A marked baseline prolongation of ECG intervals, or HR <45 bpm or >100 bpm on ECG 
measurements 
• Note: The following are considered prolonged ECG intervals: QTc/QTcF >449 msec 
in males and females; PR >209 msec; and QRS >110 msec 
5) Clinically significant abnormal ECG results 
Note: Clinically significant abnormal ECG results include: complete left or right 
bundle branch block; other ventricular conduction block; 2nd degree or 3rd degree 
atrioventricular (AV) block; sustained atrial or ventricular arrhythmia; two premature 
ventricular contractions in a row; pattern of ST elevation felt consistent with cardiac 
ischemia; evidence of a previous myocardial infarction (MI), left ventricular 
hypertrophy (LVH), or more than minor non-specific ST-T wave changes; or any 
condition deemed clinically significant by a study investigator. 
6) Abnormal renal function  
Note: Normal renal function is defined as normal creatinine [per criteria in Appendix B] 
and normal estimated glomerular filtration rate (eGFR) [i.e., >80.0 mL/min] values 
according to Cockroft-Gault. 
7) Positive serology results for HIV, HBsAg, or HCV 
8) Febrile illness with temperature >37.6°C for <7 days before dosing 
9) Donated whole blood or blood products within 60 days before dosing, or plans to donate 
before Final Visit (Day 8 ± 2) 
•  Note: Blood products include RBCs, WBCs, platelets, and plasma 
10) Known allergic reactions to any of the study drug components present in the formulation 
or in its processing, as listed in the IB 
11) Treatment with another investigational product within 30 days of dosing or 5 half-lives or 
twice the duration of the biological effect of the study drug (whichever is longer)  
• Note: Investigational products include a drug, vaccine, biologic, device or blood 
product 
12) Active drug or alcohol use, abuse, or dependence within 12 months before Screening 
Visit that, in the opinion of the investigator, would interfere with adherence to study 
requirements 
13) Use of any prescription medication within 30 days before dosing or planned use during 
the study period except as noted below and approved by the designated study clinician 
• Note 1: Prohibited medications include moderate or strong CYP3A4 inducers (per 
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immunosuppressive agents; immune modulators; oral corticosteroids; anti-neoplastic 
agents; any vaccine (licensed or investigational) except licensed influenza vaccine 
during the flu season, which is allowed 7 days before or after dosing. 
• Note 2: Allowed medications include: oral contraceptives; H1 antihistamines; 
topical/ intranasal corticosteroids; nonsteroidal anti-inflammatory drugs [NSAIDS]; 
licensed influenza vaccine during the flu season, 7 days before or after dosing. 
14) Use of any non-prescription medication, herbal preparation, or nutritional supplement 
within 15 days before dosing or planned use during the study unless approved by the 
study clinician 
• Note: Exceptions: St. John’s wart is not allowed within 30 days of dosing, vitamins 
and OTC medications taken for a brief period (<48 h) for the treatment of common 
symptoms (such as headache, indigestion, muscle pain) may be allowed as approved 
by the designated study clinician. 
 
15) Intake of caffeinated beverages or food within 72 h before dosing or a history of high 
caffeine consumption (e.g., in the last 4 months drinking >5 cups of coffee/day) 
16) Smoking or use of tobacco or nicotine-containing products within 15 days before dosing 
17) Engagement in strenuous exercise within 15 days before dosing (e.g., marathon running, 
long distance cycling, weight lifting) and during the study period 
18) Any specific behavioral or clinical condition that in the judgment of the investigator 
precludes participation because it could affect compliance with study procedures or 
subject safety 
19) Plans to enroll or is already enrolled in another clinical trial that could interfere with 
safety assessment of the study drug at any time during the study period 
• Note: Includes trials that have a study intervention such as a drug, biologic, or 
device. 
20) Is a study site employee or staff member who is paid entirely or partially by the 
OCRR/NIAID contract for the DMID-funded trial 
• Note: Site employees or staff include the PIs, sub-investigators, or staff who are 
supervised by the PI or sub-investigators. 

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5.3 
Treatment Assignment Procedures 
5.3.1 Enrollment Procedures 
This is a Phase 1, open-label clinical trial of a single dose of zoliflodacin. Eight healthy subjects 
who consent to participate in the trial and meet the eligibility criteria will be enrolled following 
admittance to the CTU and confirmation of eligibility. Subjects will be registered using a web-
based application developed by The Emmes Corporation, the Data Coordinating Center (DCC) 
for the trial. 
Per ICH guideline E6: GCP, screening records will be kept at the participating site to document 
the reason why an individual was screened but did not meet trial entry criteria, by recording it in 
the DCC AdvantageEDCSM (Electronic Data Capture System). 
Subjects will be enrolled online using the enrollment module of AdvantageEDCSM after the 
demographic and eligibility data have been entered into the system. 
Instructions for using the enrollment module are included in the AdvantageEDCSM User’s Guide. 
5.3.2 Masking Procedures 
This is an open-label clinical trial. The study staff participating in the administration of the study 
drug and assessment of subjects will be aware of the administered study drug. 
The SMC will review aggregate data in the open session. Grouped data will be reviewed by the 
SMC in the closed session only. 
5.3.3 Reasons for Withdrawal and Discontinuation of Study Product Administration 
A subject may withdraw from the trial at any time for any reason, without any consequences. 
A study subject will be discontinued from participation in the trial if any of the following reasons 
occur before dosing: 
• Request by the subject to terminate participation; 
• Failure to receive the study drug due to difficulty ingesting it. 
 
A subject may be removed from the trial after dosing for the following reasons; however, 
whenever possible the subject should be followed for safety per protocol: 
• Failure to adhere to protocol requirements; 
• Loss to follow-up; 
• Request of primary care provider; 
• Request of the Institutional Review Board (IRB)/Ethics Committee (EC), Food and 
Drug Administration (FDA), or DMID; 

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• The subject’s well-being, based on the opinion of the investigator; 
• The occurrence of an SAE or AE warranting withdrawal; 
• Failure to ingest the entire volume of drug suspension; 
• Vomiting within 24 h after dosing. 
5.3.4 Handling of Withdrawals and Discontinuation of Administration 
Subjects who are withdrawn before dosing may be replaced. Following dosing, one subject may 
withdraw before Day 4 without being replaced. A subject who cannot ingest the entire volume of 
drug suspension or a subject who took the entire dose but vomits up to 24 h after dosing will also 
be replaced. Subjects who ingest the entire volume of the initial 
 drug suspension but who 
do not ingest the content of the second 
 study drug suspension will not be withdrawn from 
the study or replaced. Subjects who received any amount of the study drug but withdraw from 
the trial will be encouraged to continue follow-up (with subjects’ consent) for safety assessments 
and PK sample collection. Subjects withdrawing will be asked to complete a final termination 
visit if they do not wish to be followed per protocol. 
5.3.5 Lost to Follow-up 
In the case of subjects who fail to appear for a follow-up assessment, extensive effort (i.e., three 
documented contact attempts via phone calls, e-mail, etc., made on separate occasions and 
followed by a certified letter) will be made to locate or recall them, or at least to determine their 
health status. These efforts will be documented in the subjects’ records. 
5.3.6 Termination of Study 
Although the sponsor (DMID) has every intention of completing the trial, it reserves the right to 
terminate the trial at any time for clinical or administrative reasons. In addition, the trial may be 
terminated or suspended at the request of the FDA, SMC, or IRB/EC. 

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6 
STUDY INTERVENTION/INVESTIGATIONAL PRODUCT 
6.1 
Study Product Description 
The chemical name for zoliflodacin (also known as ETX0914 and AZD0914) is (2R,4S,4aS)-11-
fluoro-2,4-dimethyl-8-[(4S)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]-1,2,4,4a-tetrahydro-2'H,6H-
spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-g]quinoline-5,5'-pyrimidine]-2',4',6'(1'H,3'H)-trione.  
Zoliflodacin is a spiropyrimidinetrione antibacterial agent, with a novel mode of action. It is a 
first-in-class oral gyrase inhibitor being developed for treatment of uncomplicated gonococcal 
infection, including cases caused by isolates with resistance to currently available treatments. 
6.1.1 Acquisition 
Zoliflodacin sachets are currently stored at a GMP facility. Upon request by DMID, the study 
drug will be shipped to the following address:    
DMID-Clinical Materials Services (CMS) 
Fisher BioServices 
20439 Seneca Meadows Parkway 
Germantown, MD 20876 
Tel: 240-477-1350 
Fax: 240-477-1360 
E-mail: DMID.CMS@ThermoFisher.com  
The study drug will be shipped from DMID-CMS to the CTU upon request and approval by 
DMID. Details will be provided in the protocol-specific Manual of Procedures (MOP). 
6.1.2 Formulation, Packaging, and Labeling 
Zoliflodacin is presented as granules for oral suspension, 50 % wt/wt, packaged in a single 
sachet. Each sachet contains 2 g spray-dried Zoliflodacin, co-formulated with 
 
 
. 
Each sachet will be labeled in compliance with applicable regulatory requirements, including the 
FDA-required cautionary statement “Caution- New drug -Limited by Federal (or United States) 
Law to Investigational Use Only.”   
6.1.3 Product Storage and Stability 
The zoliflodacin granules for oral suspension, 50% (w/w) should be stored at 2-8°C in the 
primary packaging.  

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The clinical supplies storage area at the site must be monitored by the site staff for temperature 
consistency with the acceptable storage temperature range specified in this protocol or in the 
study drug label. Documentation of temperature monitoring should be maintained. Further 
details are described in the MOP. 
6.2 
Dosage, Preparation, and Administration of Study Intervention/ 
Investigational Product 
All subjects will receive a single 4-g PO dose (2 sachets of 2 g) of zoliflodacin in the morning of 
Day 1 in a staggered fashion several minutes apart. 
The study drug will be inspected for damage, contamination, discoloration, or particulate matter 
before use. Any study drug that fails inspection should be quarantined at 2-8°C (35.6-46.4°F) 
and labeled ‘Do Not Use’ until further notice. The Site PI or responsible person should 
immediately contact the DMID Product Support Team at 
DMIDProductSupportTeam@niaid.nih.gov and DMID Clinical Project Manager (CPM) for 
further instructions before administering any additional study drug. Based on the information 
collected, DMID and/or Entasis will determine whether the affected study drug can be used. If it 
cannot be used, the site will receive specific instructions on how to return it to DMID CMS or 
destroy it on site. 
A detailed procedure will be described in the MOP.  
Eligible subjects who provide informed consent, undergo screening procedures, and qualify, 
meeting all inclusion and none of the exclusion criteria for the trial, will receive a single 4-g dose 
(2 sachets of 2 g of zoliflodacin reconstituted on the same day and administered in a total of 
 
) orally after an overnight fast. The dose will be administered in a standardized 
cup as described in the MOP. After the 
 of zoliflodacin is administered, an additional 
 
will be added to the same cup and consumed by the subject to chase the initial 
dose. Dosing should be completed within 5 minutes after each study product suspension. After 
dosing, subjects will continue to fast for an additional 4 h while water is allowed ad lib. 
Refer to the protocol-specific MOP for detailed information on the preparation and administration 
of zoliflodacin. 
6.3 
Modification of Study Intervention/Investigational Product for a 
Subject 
Not applicable for a single cohort study. See Study Halting Criteria, Section 9.5.1 

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6.3.1  Overdose 
An overdose is defined as a dose greater than the high-dose level evaluated in the trial. All 
overdoses should be reported; if the overdose is associated with an AE, then the AE should also 
be reported. In the event of an overdose of zoliflodacin, the investigator should use clinical 
judgment in treating the overdose and contact the DMID Medical Monitor (MM). The 
investigator should refer to the relevant document(s) for detailed information regarding 
warnings, precautions, contraindications, AEs, and other significant data pertaining to 
zoliflodacin. Such documentation may include but not be limited to the IB. 
6.4 
Accountability Procedures for the Study Intervention/Investigational 
Product(s)  
The Site PI is responsible for the distribution and disposition of the study drug, and has ultimate 
responsibility for accountability. The Site PI may delegate this responsibility to the Site RP. If 
delegated, the Site RP will be responsible for maintaining complete records and documentation 
of the study drug’s receipt, accountability, dispensation, temperature monitoring, storage 
conditions, and final disposition. 
All study drugs, whether administered or not, must be documented on the appropriate study drug 
accountability record or dispensing log. Used and unused zoliflodacin sachets will be retained 
until monitored and released for disposition per DMID requirements.  
Upon completion of the trial and after the final monitoring visit, any remaining unused study 
drug will either be returned or destroyed appropriately at the clinical site as per sponsor 
requirements and instructions, or in accordance with disposition plans. 
6.5 
 Assessment of Subject Compliance with Study Intervention/ 
Investigational Product/Device  
Since each dose of zoliflodacin will be administered by site personnel, subject compliance is not 
anticipated to be an issue. Complete information regarding any partial or interrupted dosing will 
be documented. Subjects unable to ingest the full amount of the initial 
 of study drug 
suspension or who vomit within 24 h after dosing will be withdrawn from the study and replaced 
(See Section 5.3.3 and 5.3.4). Subjects who do not ingest the content of the second 
 study 
drug suspension will not be withdrawn from the study. 
6.6 
Prior and  Concomitant Medications/Treatments 
Medications include the following: prescription drugs, birth control hormonal preparations, non-
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substances. Medications taken before or after dosing will be reported as Prior Medications or 
Concomitant Medications (ConMeds), respectively. 
Prior prescription medication information will be recorded at Screening Visit and, except for 
hormonal contraceptives, should not be taken for 30 days before dosing or during the study 
period.  
Zoliflodacin should not be co-administered in subjects using strong (i.e. avasimibe, 
carbamazepine, phenytoin, rifampin, and St. John's wort) or moderate (i.e. efavirenz, bosentan, 
etravirine, modafinil, and nafcillin) inducers of CYP3A4. These drugs should not be taken for 30 
days before dosing and during the study period. 
A vaccine should not be received within 30 days before dosing or before the end of the trial, 
except for licensed influenza vaccine during the flu season, which may be administered up to 7 
days before or after dosing.  
Non-prescription medications, herbs, vitamins, and nutritional supplements should not be taken 
within 15 days before dosing. OTC medications taken for a brief period (<48 h) for the treatment 
of common symptoms (such as headache, indigestion, muscle pain) may be allowed as approved 
by the designated study clinician. 
Allowed medications include: oral contraceptives; H1 antihistamines; topical/ intranasal 
corticosteroids; nonsteroidal anti-inflammatory drugs (NSAIDS); licensed influenza vaccine 
during the flu season, 7 days before or after dosing.  
Blood/blood products (RBCs, WBCs, platelets, and plasma) should not be donated within 60 
days of dosing or received before Final Visit. 
Following dosing, each new concomitant medication and changes to existing medications will be 
recorded. Subjects will be required not to utilize non-study medication during the trial except 
those deemed necessary by the Site PI or sub-investigator. 
Any drug (e.g., non-prescription medications, herbal supplements, vitamins, or prescription 
medications) or vaccine or blood/blood products used by the subject during the trial will be 
recorded in the subject’s source documents and on the appropriate electronic case report form 
(eCRF), and the PI or authorized study clinician (listed on FDA Form 1572) will note whether 
the use was medically indicated and immediately necessary. Any use of medications not 
authorized by the study PI or authorized clinician will be recorded as a deviation.  
 
6.7 
Subject Restrictions 
6.7.1 Physical Activity 
Subjects will be asked to refrain from rigorous physical activity 15 days before dosing and 
during the trial.  

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6.7.2 Fluid and Food intake 
Subjects will be provided food and non-alcoholic beverages by the CTU during the inpatient 
period of the trial. Subjects will fast for at least 8 h before dosing and 4 h after dosing. For 
clinical laboratory blood draws, subjects will fast for at least 4 h. Otherwise, there will be no 
restrictions regarding food and fluid intake.  
6.7.3  Alcohol, Marijuana and Illicit Drugs 
Alcohol should not be used at least two days before administration of study drug and during the 
trial.  
Marijuana and illicit drugs are exclusionary if detected before dosing and prohibited during the 
trial. 
6.7.4 Other Restrictions 
Smoking or use of tobacco or nicotine-containing products is prohibited within 15 days before 
dosing and during the trial. Caffeinated beverages or foods containing caffeine are prohibited 
within 72 h before dosing and during the trial. 
 
 

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7 
STUDY SCHEDULE 
The Schedule of Study Procedures and Evaluations is included as Appendix A. 
7.1 
Recruitment 
The subject population will be recruited from the local to the site surrounding area utilizing the 
CTU subject database and IRB-approved advertisements and social media. IRB-approved, 
prescreen questionnaires will be used to determine if subjects meet study requirements before 
scheduling screening visits. 
7.2 
Screening Visit (Day -21 to Day -2) 
The following will be done within 21 days before study drug dosing: 
• Obtain informed consent 
• Assign a study ID number to subjects who consent to participate 
• Review inclusion/exclusion criteria to ensure the subject is eligible for enrollment 
• Record demographics including age, gender, race, and ethnicity 
• Obtain contact information 
• Obtain MH   
• Review history of prior medications, including all taken within 30 days 
• Perform complete PE (except genital, rectal, and breast exams) by licensed clinician 
listed on Form FDA 1572 
• Obtain height and weight, and calculate BMI (wt [kg] / ht [m2]) 
• Take VS (supine systolic and diastolic BP, HR, respiratory rate, and oral temperature) 
• Obtain blood and urine samples for clinical laboratory tests  
• Obtain blood samples for viral serology  
• Obtain serum for β-HCG pregnancy test from all women  
• Obtain serum for FSH level from only post-menopausal women  
• Obtain urine sample for toxicology  
• Perform breathalyzer test for alcohol use 
• Obtain a 12-lead ECG with 10-sec rhythm strip 
• Counsel on the avoidance of pregnancy for women of childbearing potential 
• Counsel both male and females on the use of contraception 
• Counsel on the avoidance of alcohol, marijuana, illicit drugs, and prohibited medications 
Subjects who meet the eligibility criteria will be contacted by site personnel and asked to return 
to the CTU for Day -1 assessments and possible inpatient admission.  

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Subjects who fail screening due to a medical condition or abnormal laboratory tests including 
pregnancy test and positive tests for hepatitis B, hepatitis C, and HIV will be informed of the 
findings and counseled to seek medical care for further evaluation and treatment. If subjects test 
positive for HIV, HBsAg, and/or HCV infection, they will be informed that test results may be 
reported to the local Health Authorities according to State or Local Law. 
7.3 
Enrollment/Baseline  
7.3.1 Admission Visit (Day -1, Unit Check-in) 
Subjects meeting all of the inclusion and none of the exclusion criteria at Screening Visit will 
check into the CTU on Day -1 and the following procedures will be performed: 
• Review inclusion/exclusion criteria to ensure the subject remains eligible for enrollment 
• Update MH 
• Update Prior Medications  
• Perform abbreviated PE (An abbreviated complete PE will be performed if the Screening 
PE was completed >7 days from dosing) 
• Obtain VS 
• Obtain weight 
• Obtain blood and urine samples for clinical laboratory tests (if screening samples were 
collected >7days from dosing) 
• For all women, a serum β-HCG pregnancy test will be done, and negative results 
confirmed before dosing 
• Obtain urine sample for toxicology  
• Perform breathalyzer test for alcohol use 
• Obtain 12-lead ECG with 10-sec rhythm strip 
 
Subjects who meet the eligibility criteria on Day -1 will be admitted to the CTU on the same day. 
The subject will fast at least 8 h before dosing, but will have access to water during that period. 
7.4 
Inpatient period (Days 1 to 4) 
7.4.1 Administration of Study Drug (Day 1) 
A subject will be enrolled in the trial and receive the study drug on Day 1 if he/she continues 
meeting the eligibility criteria by assessments performed before dosing 
 

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Before Dosing:   
• Withhold breakfast but allow access to water   
• Update MH 
• Update Prior Medications 
• Obtain VS (within 60 min before dosing) 
• Perform symptom-directed PE (if applicable) 
• Obtain 12-lead ECG with 10-sec rhythm strip (within 60 min before dosing) 
• May insert IV catheter for blood collection into a forearm vein 
• Obtain blood (plasma) PK sample (30 min before dosing)  
Dosing:  
• Administer a single 4-g dose of zoliflodacin orally as a 
 followed by 
 
chase 
• Withhold food until 4 h after dosing but allow access to water 
After Dosing: 
• Obtain VS at 1 h (±10 min), 2 h (±10 min), and 4 h (±10 min) after dosing; more frequent 
monitoring will be at the PI’s discretion based on subject’s clinical presentation 
• Perform symptom-directed PE (if applicable) 
• Perform AE and SAE assessments 
• Obtain 12-lead ECG with 10-sec rhythm strip at 1 h (±10 min), 2 h (±10 min), and 4 h 
(±10 min) after dosing 
• Obtain blood (plasma) PK samples at 0.5 h (±5 min), 1 h (±5 min), 2 h (±5 min), 3 h (±10 
min), 4 h (±10 min), 6 h (±10 min), 8 h (±15 min), and 12 h (±15 min) after dosing 
• Document ConMeds 
7.4.2 In-patient Follow-up Day 2 
• Update MH 
• Obtain VS 
• Perform symptom-directed PE (if applicable) 
• Perform AE and SAE assessments 
• Obtain blood (plasma) PK samples at 24 h (±2 h) and 36 h (±2 h) after dosing 
• Document ConMeds 
7.4.3 In-patient Follow-up Day 3  
• Update MH 
• Obtain VS 
• Perform symptom-directed PE (if applicable) 

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• Perform AE and SAE assessments 
• Obtain blood (plasma) PK samples at 48 h (±2 h) after dosing 
• Document ConMeds 
7.4.4 Discharge from Unit (Day 4) 
The subject is eligible for discharge from the CTU at 72 h (±2 h) after dosing, after the following 
assessments have been performed, and if no clinically important abnormalities are confirmed by 
the study PI or designated physician: 
• Update MH 
• Obtain VS 
• Perform abbreviated PE 
• Perform AE and SAE assessments 
• Document ConMeds 
• Obtain 12-lead ECG with 10-sec rhythm strip at 72 h (±2 h) after dosing 
• Obtain blood (plasma) PK samples at 72 h (±2 h) after dosing 
• Obtain blood and urine for clinical laboratory tests 
• Counsel women of childbearing potential on the avoidance of pregnancy 
• Counsel male and female subjects on the avoidance of pregnancy 
• Remind subjects to abstain from prohibited medications, alcohol, marijuana and illegal 
drugs 
• Instruct on the next scheduled visit 
• Discharge subject from the CTU after review of clinical laboratory tests, ECG, and other 
assessments by PI or authorized clinician 
7.5 
Final Study Visit (Day 8 ± 2) 
• Update MH 
• Obtain VS 
• Perform complete PE  
• Obtain weight 
• Collect blood for serum β-HCG pregnancy test in all females 
• Perform AE and SAE assessments 
• Update ConMeds 
• Counsel male and female subjects on the avoidance of pregnancy 
• Counsel female subjects to use appropriate contraception for 30 days after the final visit. 
• Counsel male subjects to use appropriate contraception and refrain from sperm donation 
for 90 days after the final visit. 

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• Discharge from trial after review of clinical laboratory tests, ECG, and other assessments 
by PI or authorized clinician 
7.6 
Early Termination Visit (if needed) 
• Update MH 
• Obtain VS 
• Perform complete PE  
• Perform AE and SAE assessments 
• Update ConMeds 
• Obtain 12-lead ECG with 10-sec rhythm strip 
• Obtain blood and urine for clinical laboratory tests  
• Collect blood for serum HCG pregnancy test in all females  
• Obtain blood PK sample 
• Counsel male and female subjects on the avoidance of pregnancy 
• Counsel female subjects to use appropriate contraception for 30 days after the ET visit. 
• Counsel male subjects to use appropriate contraception and refrain from sperm donation 
for 90 days after the ET visit. 
7.7 
Unscheduled Visit (if needed) 
A subject may return to the clinic for an unscheduled visit at any time. The following activities at 
a minimum should be performed:  
• Update MH 
• Obtain VS 
• Perform symptom-directed PE (if applicable) 
• Update ConMeds 
• Perform AE and SAE assessments 
• Obtain blood and/or urine for clinical laboratory tests (if applicable) 
• Counsel male and female subjects on the avoidance of pregnancy 
 

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8 
STUDY PROCEDURES/EVALUATIONS 
8.1 
Clinical Procedures/Evaluations 
8.1.1 Informed Consent 
The ICF must be approved by the reviewing IRB/EC and executed before performing any study-
related activities. 
Informed consent will be obtained for all subjects participating in the trial before performing any 
screening assessments. Subjects may withdraw consent at any time. Participation in the trial may 
be terminated at any time without the subject’s consent as determined by the investigator. 
8.1.2 Demographics 
Demographic information (date of birth, gender, ethnicity, and race) will be recorded on the 
subject’s source documents and eCRF at Screening Visit. Name, address, phone number, and 
emergency contact information will be documented in the source documents only. 
8.1.3 Inclusion/Exclusion Criteria 
Eligibility screening of healthy subjects will be completed within 21 days before study drug 
dosing and will be documented on the subject’s source documents and on the eCRF. 
Confirmation of eligibility will be performed before dosing on Day 1. 
Screening failures and the reason for failure to meet the study eligibility requirements will be 
documented in the source documents and entered into the study database. 
8.1.4 Medical History 
For subjects enrolled in the trial, the MH will be obtained by direct interview from the subject 
and recorded on the subject’s source document and eCRF. The MH will capture the subject’s 
current disease processes, past disease processes, history of hospitalization, history of surgery, 
allergies, and prior medications (taken 30 days before dosing). Subjects will be queried regarding 
a history of significant medical disorders of the head, eyes, ears, nose, throat (HEENT), mouth, 
skin, and the cardiovascular, gastrointestinal, renal, urological, nervous, hematological, 
lymphatic, endocrine, musculoskeletal, and genital/reproductive systems. A history of cancer, 
autoimmune disease, immunodeficiency, psychiatric illness, and substance abuse will be 
specifically solicited. The MH will be obtained at Screening Visit and updated upon admittance 
to the CTU and before dosing on Day 1. After the study treatment, an interim MH will be 
obtained on all study days by interview of subjects or by evaluating any reported symptoms, 
noting any changes since the previous study day or contact. Any worsening of pre-dosing MH or 
new symptoms will be evaluated and reported as AEs. 

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8.1.5 Physical Examination 
A complete PE – except genital, breast, and rectal exams – will be performed at Screening Visit  
and Final Visit (Day 8 ± 2), or ET, and will assess general appearance, HEENT, heart, lungs, 
abdomen, skin, musculoskeletal system, and lymph nodes, and include an abbreviated 
neurological exam. 
An abbreviated PE will be performed on Day -1 and Day 4. If a complete PE was performed ≤7 
days before dosing, then an abbreviated PE will not be performed on Day -1. An abbreviated PE 
differs from a complete PE in that the abdomen and neurological system are not evaluated.  
A symptom-directed PE will be performed before dosing on Day 1 and after dosing on Days 1, 2, 
and 3, to evaluate new symptoms or treatment-emergent AEs, respectively.  
Height and weight will be measured, and BMI calculated, at Screening Visit; only weight will be 
measured on Day -1 and at Final Visit (Day 8 ± 2). 
Refer to the protocol-specific MOP for further details. The findings of each examination will be 
recorded on the subject’s source documents and eCRF. Any new findings on examination or 
worsening of existing conditions after dosing are to be reported as AEs.  
8.1.6 Vital Signs 
VS including resting (measured after supine for at least 10 min) systolic and diastolic BP, HR, 
respiratory rate, and oral temperature will be measured at Screening Visit, on Day -1, before and 
after dosing on Day 1, on Days 2, 3, and 4, and at Final Visit, or ET. On Day 1, VS will be 
measured approximately 1 h before dosing, and 1 h (±10 min), 2 h (±10 min), and 4 h (±10 min) 
after dosing. On Days 2, 3, and 4, VS will be measured at 24 h (±2 h), 48 h (±2 h), and 72 h (±2 
h), respectively. Acceptable ranges are shown in Appendix B. 
VS that are considered aberrant due to an error in measurement may be repeated. During 
screening and after dosing, an abnormal VS measurement may be repeated twice more at rest, 
within 5 min of each other. If the second measurement is abnormal, it will be reported at the 
highest grade of the two measurements and the subject will be excluded (if at Screening Visit) or 
the event reported as an AE (if after dosing). If the second measurement is normal, a third 
measurement will be taken at least after 5 min at rest. If the third measurement is still normal, the 
subject is eligible (if at Screening Visit) or there is no AE (if after dosing); if it is abnormal, the 
subject will be excluded (if at Screening Visit) or an AE will be reported at the highest assessed 
grade (between first and third measurements) and graded for severity per Appendix C (if after 
dosing). 

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8.1.7 Electrocardiogram 
A 12-lead ECG and 10-sec rhythm strip will be obtained at Screening Visit and on Days -1, 1, 
and 4, or ET. On Day 1, a 12-lead ECG and 10-sec rhythm strip will be recorded within 1 h 
before dosing and 1 h (±10 min), 2 h (±10 min), and 4 h (±10 min) after dosing. The ECGs will 
be reviewed by the PI or a designated clinician (listed in FDA Form 1572). ECGs will be 
performed after the subject rests quietly in a supine position for at least 5 min. To be eligible for 
participation, the QT/QTcF interval must be normal, and there must be no clinically significant 
ECG abnormalities. If a question regarding ECG interpretation arises, the study investigators will 
have the ECG reviewed by a cardiologist. 
8.2 
Laboratory Evaluations 
Venipuncture schedule and blood volumes are shown in Appendix A and Appendix D. The 
blood volume for hematology and chemistry tests will be approximately 9 mL per sample 
(Appendix D). 
8.2.1 Clinical Laboratory Evaluations 
8.2.1.1 Screening and Safety Clinical Laboratory (Hematology, Chemistry, and 
Urinalysis) Tests 
Blood and urine samples for clinical laboratory tests will be collected at Screening Visit, and on 
Days -1 (if not collected ≤7 days of dosing) and 4, or ET. These tests will include: 
• Hematology (HEM): hemoglobin (Hgb), hematocrit (Hct), red blood cell (RBC) count, 
platelet count, and white blood cell (WBC) count with absolute differential count 
• Chemistry (CHEM): serum creatinine, with estimation of GFR, blood urea nitrogen 
(BUN), glucose (fasting at least 4 h), total bilirubin, direct bilirubin, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AP), 
total protein, albumin, sodium, chloride, potassium, bicarbonate (CO2), magnesium 
• Urinalysis (UA): Routine dipstick testing of clean-catch urine for blood, protein, and 
glucose; other coincidental tests will be recorded   
 Clinical laboratory tests at Screening Visit and Day -1 should be in the normal reference range 
with acceptable exceptions, as shown below and in Appendix B: 
Elevated bilirubin due to documented Gilbert’s syndrome that is Grade 1 is allowable, but Grade 
2 or higher is exclusionary. (To document a subject has Gilbert syndrome, a diagnosis from the 
medical record must be provided or the PI may make a ‘presumptive’ diagnosis of Gilbert 
syndrome in subjects with unconjugated hyperbilirubinemia on repeated testing (at least 2 
samples separated in time) who have otherwise normal serum ALT/AST and AP concentrations, 
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Elevated serum glucose, sodium, potassium, bicarbonate (CO2), total protein, and AP with a 
toxicity grade of 1 is allowable. 
Serum chloride and albumin above the upper limit of normal (ULN) is allowable. 
If UA by dipstick is not within acceptable ranges per Appendix B for blood, protein, or glucose, a 
complete UA with microscopic evaluation will be performed and the results will supersede those 
of the dipstick. Menstruating females failing inclusion criteria due to a positive urine dipstick or 
microscopic UA may be retested following cessation of menses. Do not exclude subjects with ≤6 
RBC/HPF. 
Laboratory values that are outside the range of eligibility but are thought to be due to an acute 
condition or due to collection or laboratory error may be repeated once.   
Laboratory values will be transferred in AdvantageEDCSM.  
Abnormal safety laboratory values after dosing will be graded per the Toxicity Table, Appendix 
C. Abnormal values within the acceptable range per Appendix B noted at screening or baseline 
will only be considered AEs if they deteriorate after study drug dosing. 
8.2.1.2 Viral Serology Testing 
Serological testing for HIV antibody, HCV antibody, and HBsAg will be performed at Screening 
Visit. These tests must be negative for study eligibility. In cases where a false-positive result is 
suspected, confirmatory testing (e.g., Polymerase Chain Reaction) may be performed. 
8.2.1.3 Pregnancy Testing 
In all women, a serum β-HCG level will be measured at Screening Visit and on Day -1; results 
must be negative for entry into the trial. Serum pregnancy test will also be performed at Final 
Visit, or ET. 
8.2.1.4 Serum FSH testing 
A serum FSH level for confirmation of post-menopausal status in female subjects will be 
measured at Screening Visit only.   
8.2.1.5 Urine Toxicology Screening 
A urine toxicology screen will be performed at Screening Visit and on Day -1 to detect the 
presence of amphetamines, cocaine, barbiturates, benzodiazepines, opiates, 
tetrahydrocannabinol, MDMA, methadone, TCA, oxycodone, and phencyclidine. Results must 
be negative for study eligibility. Urine creatinine will be measured as part of the profile to assess 
quality of collected sample.  

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8.2.1.6 Alcohol testing by breathalyzer  
Detection of recent alcohol consumption by breathalyzer will be performed at Screening Visit 
and on Day -1. Results must be negative for study eligibility.  
8.2.2 Special Assays or Procedures 
8.2.2.1 Pharmacokinetics Assay of Zoliflodacin  
Blood (plasma) samples will be collected in K2EDTA tubes at the following study days and time 
points: On Day 1 at 30 min before dosing, and 0.5 h (±5 min), 1 h (±5 min), 2 h (±5 min), 3 
h (±10 min), 4 h (±10 min), 6 h (±10 min), 8 h (±15 min), and 12 h (±15 min) after dosing; on 
Day 2 at 24 h (± 2 h) and 36 h (± 2 h) after dosing; on Day 3 at 48 h (±2 h) after dosing; and on 
Day 4 at 72 h (±2 h) after dosing, or ET. 
Sample collections will be scheduled for the nominal time point and actual collection times 
recorded in the source documents. 
Plasma concentrations of zoliflodacin will be determined using a validated HPLC-MS/MS 
method. 
8.2.3 Specimen Preparation, Handling, and Shipping 
8.2.3.1 Instructions for Specimens Preparation, Handling, and Storage 
Details regarding the specimen preparation, handling, and storage are described in the protocol-
specific MOP. 
8.2.3.2 Specimen Shipment 
Specimen shipment will occur at intervals during the trial following all applicable International 
Air Transport Association (IATA) requirements and according to the specifics for storage 
temperature and documentation as detailed in the central (clinical) laboratory manual and 
protocol-specific MOP, as appropriate. 
All specimens for clinical screening and safety laboratory evaluations will be transported from 
the CTU to the local clinical laboratory. 
Plasma samples for bioanalytical assays will be shipped from the CTU to the DMID-CMS 
(Fisher BioServices) at: 
 
Fisher BioServices 

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c/o DMID Clinical Materials Services (CMS) 
20439 Seneca Meadows Parkway 
Germantown, MD 20876 
Phone: 240-477-1350  
Fax: 240-477-1360 
Email: DMID.CMS@thermofisher.com 
The plasma samples will then be provided by DMID-CMS to the bioanalytical lab, KCAS Inc., 
at:  
KCAS Bioanalytical Services  
12400 Shawnee Mission Parkway 
Shawnee, KS 66216 
POC:  Marsha Luna 
           Senior Manager, PBI 
Office: 913-248-3042  
Email: marsha.luna@kcasbio.com 
 
 
 

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9 
ASSESSMENT OF SAFETY 
Regulatory requirements including FDA regulations and ICH Guidelines for GCP set forth safety 
monitoring and reporting responsibilities of sponsors and investigators to ensure the safety and 
protection of human subjects participating in clinical trials. 
Responsibilities: 
Investigators participating in this clinical trial are responsible for and will: 
• Evaluate subject safety including assessment of AEs for seriousness, severity, and 
causality (relatedness to study drug); 
• Notify the sponsor (DMID) of SAEs within 24 h of site awareness; 
• Provide detailed written reports, including necessary documentation requested by the 
sponsor or IRB/EC, promptly following immediate initial reports; 
• Inform the IRB/EC of SAEs and AEs as required by applicable regulatory requirements. 
9.1 
Specification of Safety Parameters 
Safety will be assessed by the timing, frequency, relatedness to study drug, and severity of: 
1. Treatment-emergent SAEs occurring from dosing through Final Visit (Day 8 ± 2), or ET; 
2. Clinical laboratory AEs occurring from dosing through Final Visit (Day 8 ± 2), or ET; 
3. Non-serious, unsolicited treatment-emergent AEs occurring from dosing through Final 
Visit (Day 8 ± 2), or ET. 
9.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters 
9.2.1 Adverse Events 
Definitions 
Adverse events 
ICH E6 defines an AE as any untoward medical occurrence in a subject or clinical investigation 
subject who was administered a pharmaceutical product, regardless of its causal relationship to 
the product. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with use of the product. 
The occurrence of an AE may come to the attention of study personnel during study visits and 
interviews, or by a subject presenting for medical care. 
The FDA defines an AE as any untoward medical occurrence associated with the use of a drug in 
humans, whether it is considered drug-related or not. 

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Any medical condition that is present at the time that the subject is screened should be 
considered as baseline and not reported as an AE. However, if the condition increases in severity 
or frequency at any time during the trial, it should be recorded as an AE. 
All AEs must be graded for severity and relationship to the study drug. 
9.2.1.1 Severity of Events 
Intensity of AEs will be graded as follows, unless otherwise specified in Appendix C: 
Mild: Require minimal or no treatment; do not interfere with the subject’s daily activities. 
Moderate: Result in a low level of inconvenience or concern with therapeutic measures; may 
cause some interference with functioning. 
Severe: Interrupt a subject’s usual daily activity and may require systemic drug therapy or other 
treatment; are usually incapacitating. 
9.2.1.2 Relationship to Study Products 
AEs and SAEs must be assessed by the investigator to determine relationship to the study drug, 
using the following two terms. In a clinical trial, the study drug must always be suspect.   
• Related: There is a reasonable possibility that the study drug caused the AE/SAE; that is, 
there is evidence to suggest a causal relationship 
• Not Related: There is not a reasonable possibility that the study drug caused the AE/SAE 
The investigator must provide an assessment of association or relationship of each AE/SAE to 
the study drug based on: 
• Temporal relationship of the AE/SAE to study drug dosing; 
• Whether an alternative etiology has been identified; 
• Biological plausibility; 
• Existing therapy and/or ConMeds. 
9.2.1.3 Reporting Adverse Events 
AEs will be captured on the appropriate subject’s source document and eCRF. Information 
collected for AEs includes event description, time of onset, investigator assessment of severity, 
relationship to the study drug, date of resolution of the event, seriousness, and outcome. 
All AEs will be documented from the time of drug dosing up to and including Final Visit. AEs 
will be followed to resolution or until considered stable in the clinical judgment of the study 
investigator. Evaluation of AEs may require unscheduled visits and clinical and laboratory 
investigations, according to the clinical judgment of the Site PI and study physicians. 

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9.2.2 Reactogenicity (for Vaccine Studies and Some Therapeutic Trials) 
Not applicable. 
9.2.3 Serious Adverse Events 
An SAE is any AE that meets at least one of the following criteria: 
• Death; 
• Life-threatening AE*; 
• Inpatient hospitalization or prolongation of existing hospitalization; 
• Persistent or significant disability or incapacity, or substantial disruption of the ability to 
conduct normal life function; 
• Congenital anomaly/birth defect; 
• Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
*Life-threatening AE. An AE is considered “life-threatening” if, in the view of either the 
investigator or sponsor, its occurrence places the subject at immediate risk of death. It 
does not include an AE that, had it occurred in a more severe form, might have caused 
death. 
SAEs will be: 
• Assessed for severity and relationship to study product and alternate etiology by an 
authorized study physician (listed on FDA Form 1572); 
• Recorded on the appropriate SAE data collection form and eCRF; 
• Followed through resolution; 
• Reviewed and evaluated by an ISM (as deemed necessary), the SMC (periodic review 
unless related), DMID, and the IRB. 
9.2.4 Procedures to be Followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings 
A licensed study clinician (listed on FDA Form 1572) will make the determination of 
seriousness, severity, and causality; provide a medical evaluation of AEs; and classify AEs based 
upon medical judgment. 
Abnormal laboratory values or clinical findings for all enrolled subjects, including values and 
findings noted at screening and baseline, will be assessed using the toxicity scales in Appendix 
C. Abnormal values and findings noted at screening or baseline will only be considered AEs if 

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they deteriorate after study drug dosing. For abnormalities noted from the time of study drug 
dosing, any Grade 1 or higher laboratory abnormality listed on the toxicity table in Appendix C 
will be entered in the database as an AE. Safety laboratory results that are abnormal according to 
the local laboratory reference range, but not considered a Grade 1 abnormality, will be evaluated 
by the study site clinician and reported as Grade 1 abnormality if clinically significant. If not 
clinically significant, these will not be considered laboratory AEs and will thus not be graded, 
but will be recorded in the source document and followed-up clinically at the discretion of the 
study site clinician. Abnormal laboratory values, performed as part of the complete CBC, clinical 
chemistry or UA but not listed in this toxicity table will be evaluated by the study clinicians, 
recorded in the source document and, if clinically significant, considered AEs and graded 
according to the criteria in Section 9.2.1. 
Protocol-specific laboratory normal range values in effect at the time of protocol submission are 
included in Appendix B. Changes in these ranges during the trial will be handled as 
administrative protocol amendments and toxicity grades will be calculated using the new ranges 
from the effective date of the change. A regular protocol amendment will be submitted for these 
changes if a revised laboratory normal range value meets criteria for Grade 2 toxicity. 
Gross blood in urine that is confirmed due to a menstrual cycle is not an AE (but is for all other 
reasons). 
9.3 
Reporting Procedures 
9.3.1 Serious Adverse Events 
SAEs will be followed until resolution even if this extends beyond the study-reporting period.  
Resolution of an AE is defined as the return to pretreatment status or stabilization of the 
condition with the expectation that it will remain chronic. 
All SAEs will be: 
• Recorded on the appropriate SAE report form and sent to DMID Pharmacovigilance 
Group (PVG) 
• Entered into the appropriate subject source document and eCRF in AdvantageEDCSM 
• Reported to the Site ISM and the IRB 
• Reviewed and followed to resolution or stability by an authorized study physician (listed 
on FDA Form 1572) 
• Collected on each subject until Final Visit  
Any AE that meets a protocol-defined serious criterion must be submitted immediately (within 
24 h of site awareness) on an SAE report form to DMID PVG: 
 

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DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS) 
6500 Rock Spring Drive, Suite 650 
Bethesda, MD 20817, USA 
SAE Hot Line: 1-800-537-9979 (US) or 1-301-897-1709 (outside US) 
SAE FAX Number: 1-800-275-7619 (US) or 1-301-897-1710 (outside US) 
SAE Email Address: PVG@dmidcroms.com 
In addition to the SAE report form, selected SAE data fields must also be entered into 
AdvantageEDCSM. Please see the protocol-specific MOP for details regarding this procedure. 
Other supporting documentation of the SAE may be requested by DMID PVG and should be 
provided as soon as possible. 
The site will copy the ISM on SAE reports provided to the DMID PVG. The DMID MM and 
DMID CPM will be notified of the SAE by the DMID PVG. The DMID MM will review and 
assess the SAE for regulatory reporting and potential impact on study subject safety and protocol 
conduct. 
At any time after completion of the study, if the site PI or appropriate sub-investigator becomes 
aware of an SAE that is suspected to be related to study product, the site PI or appropriate sub-
investigator will report the event to the DMID PVG. 
9.3.2 Regulatory Reporting for Studies Conducted Under DMID Sponsored IND 
Following notification from the investigator, DMID, the Investigational New Drug (IND) 
sponsor, will report any suspected AE that is both serious and unexpected. DMID will report an 
AE as a suspected AE only if there is evidence to suggest a causal relationship between the drug 
and the AE. DMID will notify FDA and all participating investigators (i.e., all investigators to 
whom the sponsor is providing drug under its IND(s) or under any PI’s IND(s)) in an IND safety 
report of potential serious risks from clinical trials or any other source, as soon as possible, but in 
no case later than 15 calendar days after the sponsor determines that the information qualifies for 
reporting as specified in 21 CFR Part 312.32. DMID will also notify FDA of any unexpected 
fatal or life-threatening suspected AE as soon as possible, but in no case later than 7 calendar 
days after the sponsor’s initial receipt of the information. Relevant follow up information to an 
IND safety report will be submitted as soon as the information is available. Upon request from 
FDA, DMID will submit to FDA any additional data or information that the agency deems 
necessary, as soon as possible, but in no case later than 15 calendar days after receiving the 
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All serious events designated as “not related” to the study drug, will be reported to the FDA at 
least annually in a summary format. 
9.3.3 Other Adverse Events (if applicable) 
9.3.3.1 Reporting of Overdose 
An overdose is defined as a dose greater than the high-dose level evaluated in the trial as 
described in Section 6.3.1 of the protocol. All overdoses should be reported; if the overdose is 
associated with an AE, then the AE should also be reported. In the event of an overdose of study 
drug, the investigator should use clinical judgment in treating the overdose and contact the 
DMID MM. The investigator should refer to the relevant document(s) for detailed information 
regarding warnings, precautions, contraindications, AEs, and other significant data pertaining to 
zoliflodacin. Such documentation may include but not be limited to the IB. 
9.3.4 Reporting of Pregnancy 
Pregnancies that occur in female subjects during the study period will be reported via 
AdvantageEDCSM on a pregnancy report form. With the subject’s permission, all protocol-
required venous blood samples will be obtained and the subject will continue to be followed for 
safety until Final Visit. Efforts will be made to follow all pregnancies reported during the trial to 
pregnancy outcome, as described in the protocol-specific MOP (e.g., delivery, spontaneous 
abortion, or therapeutic abortion), pending the subject’s permission. 
A female subject who participates in the trial and becomes pregnant will be asked to inform 
study personnel of a pregnancy occurring 30 days after the final study visit. A male subject who 
participates in the trial and whose female partner becomes pregnant 90 days after the final study 
visit will be asked to inform study personnel of the pregnancy. For all reported pregnancies, 
subjects will be asked to provide pregnancy outcome upon delivery or pregnancy termination to 
the CTU.  
9.4 
Type and Duration of Follow-up of Subjects after Adverse Events 
Treatment-emergent SAEs and AEs will be followed until resolution or until considered stable in 
the clinical judgment of the investigator. Resolution of an AE is defined as the return to 
pretreatment status or stabilization of the condition in the clinical judgment of the study 
investigator, with the expectation that it will remain chronic. 
Follow-up procedures, evaluations, and outcomes will be recorded in the subject's source 
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9.5 
Halting Rules 
9.5.1 Study Halting Criteria 
Study dosing must be stopped and a review of available safety data will be conducted by the SMC 
if any of the following occur on Day 1 after dosing: 
1. Death of a subject following dosing regardless of relatedness to study drug;  
2. One subject with an SAE that is considered related to study drug by the study PI or 
designated physician; 
3. Two or more subjects with a Grade 3 systemic AE coded in the same organ system that is 
considered related to the study drug by the study PI or authorized clinician (listed in FDA 
Form 1572); 
Note: VS abnormalities should be considered part of a systemic disorder or an organ-
specific condition, as described in Appendix C, in order to be included among the 
Study Halting Criteria.  
4. An overall pattern of symptomatic, clinical non-serious events that the study PI or 
authorized clinician considers associated with study drug and that may appear minor in 
terms of individual events, but that may collectively represent a serious potential safety 
concern and pose a risk to continuing the subject in the trial. 
9.6 
Safety Oversight (ISM plus SMC) 
9.6.1 Independent Safety Monitor (ISM) 
The ISM is a physician with relevant expertise whose primary responsibility is to provide 
independent safety monitoring in a timely fashion. The ISM will review SAEs and other AEs as 
needed and provide an independent assessment to DMID. 
9.6.2 Safety Monitoring Committee (SMC) 
Safety oversight will be conducted by a SMC, which is an independent group of experts that 
monitors subject safety and advises DMID. SMC members will be separate and independent of 
study personnel participating in the trial and should not have scientific, financial, or other 
conflicts of interest related to the trial. The SMC will consist of members with appropriate 
expertise to contribute to the interpretation of the data from the trial. 
The SMC will meet as follows: 
• Organizational meeting (before study initiation) 
• Ad hoc meeting 
o When study halting criteria are met 
o At the request of DMID to review a potential safety concern identified by either the 
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• Scheduled meeting 
o The SMC will review all available safety data when available 
Procedures for SMC reviews/meetings will be defined in the SMC charter. The SMC will review 
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10 
CLINICAL MONITORING 
10.1 Site Monitoring Plan 
Site monitoring is conducted to ensure that human subject protections, study and laboratory 
procedures, study intervention administration, and data collection processes are of high quality 
and meet sponsor, GCP/ICH, and regulatory guidelines, when appropriate. Site visits may be 
conducted by an authorized representative of DMID or other regulatory agencies to inspect study 
data, subjects’ medical records, and eCRFs in accordance with ICH guidelines, GCP, and the 
respective local and national government regulations and guidelines. 
The investigator will permit authorized representatives of DMID and the respective local and 
national health authorities to inspect facilities and records relevant to the trial, if needed. 
A separate monitoring plan developed by DMID will describe protocol-specific items to be 
monitored. 
Site visits will be made at standard intervals defined by DMID and may be made more frequently 
as directed by DMID. Monitoring visits will include, but not be limited to, review of regulatory 
files, accountability records, subject’s source documents, eCRFs, ICFs, clinical and laboratory 
reports, and protocol and GCP compliance. Site monitors will have access to each participating 
site, study personnel, and all study documentation according to the DMID-approved site 
monitoring plan. Study monitors will meet with the Site PI to discuss any problems and actions 
to be taken and document visit findings and discussions. 
 

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11 
STATISTICAL CONSIDERATIONS 
11.1 Study Hypotheses 
There are no formal hypotheses being tested in this Phase 1 trial. The objectives of the trial are to 
obtain additional PK and safety data for a single 4-g oral dose of zoliflodacin. 
11.1.1 Study Objectives and Outcome Measures 
11.1.1.1 Study Objectives 
Primary Objective:  To evaluate the plasma PK of a single 4-g oral dose of zoliflodacin 
under fasting conditions  
Secondary Objective:  To evaluate the safety and tolerability of a single 4-g oral dose of 
zoliflodacin 
11.1.1.2 Study Outcome Measures 
Primary Endpoints:  Cmax, Tmax, AUC(0-last), and other PK parameters determined using 
plasma concentrations of zoliflodacin in blood samples collected on Day 1 [baseline (30 
min before dosing) and 0.5 h, 1 h , 2 h , 3 h , 4 h , 6 h , 8 h , and 12 h  after dosing], Day 2 
[24 h and 36 h after dosing], Day 3 [48 h after dosing], and Day 4 [72 h after dosing], or 
ET, and measured using a validated HPLC-MS/MS method 
Secondary Endpoints: 
• The occurrence of treatment-emergent SAEs from administration of zoliflodacin on 
Day 1 to Final Visit (Day 8 ± 2), or ET 
• The occurrence of unsolicited AEs from administration of zoliflodacin on Day 1 to 
Final Visit (Day 8 ± 2), or ET 
• The changes from baseline (up to 60 min before dosing) in VS following 
administration of zoliflodacin as measured on Day 1 [1 h, 2 h, and 4 h after dosing], 
Days 2, 3 and 4 [24 h, 48 h, and 72 h, respectively, after dosing], and Final Visit (Day 
8 ± 2) , or ET 
• The changes from baseline (tested on Day-1) in clinical laboratory test values 
following administration of zoliflodacin, as measured on Day 4 [72 h after dosing], or 
ET 
• The changes from baseline (up to 60 min before dosing) in ECG parameters 
following administration of zoliflodacin, as measured on Day 1 [1 h, 2 h, and 4 h after 
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11.2 Sample Size Considerations 
Since this is a pilot Phase 1, open-label trial with a single 4-g dose cohort of zoliflodacin, no 
formal sample size calculations based on testing a statistical hypothesis were constructed. Eight 
subjects will be enrolled and it is planned to have seven evaluable subjects given zoliflodacin. 
This sample size will provide sufficient information to estimate exposure to the 4-g dose of 
zoliflodacin and to assess its safety. 
11.3 Safety Review 
An SMC will be appointed to oversee the safe conduct of the trial. A scheduled SMC meeting 
will be held after all subjects complete the trial to review safety data, and advice on using the 4-g 
dose in a subsequent thorough QTc study. If criteria for halting the trial (as listed in Section 
9.5.1) are met during dosing on Day 1, an ad hoc SMC meeting will be held to review all 
available safety data and to make recommendations about the dosing of all further subjects in the 
trial. 
11.4 Final Analysis Plan 
The ICH/ FDA Guidance Document E9 (Statistical Principles for Clinical Trials) will be 
followed for all statistical content.16 For categorical data, summaries of frequencies and 
percentages will be presented. Summaries for continuous data will include minimum, median, 
mean, standard deviation, and maximum. Details of study analyses for safety and PK data and 
their presentation will be described in the Statistical Analysis Plan (SAP) and accompanying 
Tables, Listings and Figures (TLF) templates. The SAP will be prepared and finalized by the 
DCC prior to final data lock. Analyses included in the CSR will be performed by the DCC after 
final data lock. Any change from originally planned statistical analyses will be reported in the 
final clinical study report (CSR).   
11.4.1 Analysis Populations 
All subjects who received the study drug will be included in the safety population and analyzed 
as treated. The PK analysis population will consist of all subjects who received zoliflodacin and 
have at least one quantifiable post-dosing drug concentration measured. The PK analysis subset 
will be based on the PK population, which includes all subjects who completed the PK part of 
the trial without any protocol violations that would likely affect the PK results and who have 
evaluable plasma concentration data for zoliflodacin from whom at least a subset of the 
designated PK parameters can be determined.  

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11.4.2 Demographics and Baseline Characteristics 
Subject demographics and baseline characteristics will be summarized. The number of subjects 
who enroll in the trial, and the number and percentage of subjects who complete each 
assessment, will be presented. The percentage of subjects who withdraw from the trial or 
discontinue the study drug, and reasons for withdrawal or discontinuation, will be summarized. 
11.4.3 Safety Analysis Plan 
11.4.3.1 Adverse and Serious Adverse Events 
AEs will be coded using the latest version of the Medical Dictionary for Regulatory Activities® 
(MedDRA). All AEs occurring after study drug dosing will be summarized using frequency 
counts and percentages. The following summaries will be presented for AEs and SAEs:  
• Overall (i.e., regardless of severity or relationship to treatment); 
• By severity grade (mild, moderate, or severe); 
• By relationship to study drug; 
• By MedDRA level hierarchy (system organ class [SOC], higher level group term [HLGT], 
and preferred term [PT]). 
Unless otherwise specified, at each level of subject summarization in reporting the incidence of 
AEs, a subject will be counted once if the subject reported one or more AEs. If more than one 
occurrence of an AE is reported, the AE of the worst severity or the worst-case relationship 
assessment will be summarized.  
11.4.3.2 Additional Safety Analyses 
Descriptive summary statistics (mean, standard deviation, median, min, and max) for clinical 
laboratory data, ECG parameters, and VS at admission and each applicable post-dosing visit, 
including changes from baseline values, will be calculated. If multiple baseline values are 
obtained, only the most recent value will be analyzed. For change from screening summaries, 
subjects with an undefined change from screening, because of missing data, will be excluded.  
Clinical significance of abnormalities will be indicated in the listings. 
11.4.4  PK Analysis Plan 
PK parameters will be estimated for zoliflodacin by noncompartmental methods using version 
6.4 or higher of Phoenix® WinNonlin®. When evaluable, estimated PK parameters will include: 
• AUC(0-last): Area under the concentration time-curve from time zero to the last 
concentration above the lower limit of quantitation 
• AUC(0-∞): Area under the concentration time-curve from time zero to infinity  
• AUC(0-t: Area under the concentration time-curve from time zero to time t 
• Cmax: Maximum observed concentration 

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• Tmax: Time of maximum observed concentration 
• Ke: Elimination rate constant 
• t1/2: Terminal elimination half-life 
• CL/F: Apparent oral clearance 
• Vz/F: Apparent volume of distribution 
Other PK parameters may be calculated, as appropriate. Linearity of terminal elimination slope 
will be assessed statistically by linear regression, which provides estimates for the slope, 
intercept, and r2 (or adjusted r2) to calculate elimination rate constant, and helps define goodness 
of fit. Details will be provided in the SAP. 
The results will be listed by subject, and summarized with descriptive statistics including: n, 
mean, standard deviation, coefficient of variation (CV %), median, minimum, maximum, 
geometric mean, and geometric standard deviation.  
Graphical presentations of concentration vs. time profiles will be provided for zoliflodacin, and 
will include individual subject and mean concentration profiles. Semi-log concentration profiles 
will be provided for individual subjects. 
11.4.5  Missing Values and Outliers 
All attempts will be made to collect all data per protocol. No imputation will be performed for 
missing values. Outliers will not be excluded from the primary analyses. Outliers identified 
during the PK analysis will be discussed in the analysis report. 

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12 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
The site will maintain appropriate medical and/or research records for the trial, in compliance 
with ICH E6 GCP, Section 4.9, and regulatory and institutional requirements for the protection 
of confidentiality of subjects. As part of participating in a DMID-sponsored, DMID-affiliated, or 
manufacturer-sponsored trial, the site will permit authorized representatives of the sponsor 
(DMID), to include Emmes (the DCC), DynPort Vaccine Company, LLC (DVC), and regulatory 
agencies to review (and, when required by applicable law, to copy) clinical records for the 
purposes of quality assurance reviews, audits, and evaluation of the study safety and progress. 
Forms for use as source documents will be derived from eCRFs and will be provided by the 
DCC and the Site. Additional source data are all information, original records of clinical 
findings, observations, or other activities in a clinical trial necessary for the reconstruction and 
evaluation of the trial. Examples of these original documents and data records include, but are 
not limited to, hospital records, clinical and office charts, laboratory notes, memoranda, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic negatives, 
microfilm or magnetic media, x-rays, ECG print-outs, and subject files and records kept at the 
pharmacy, laboratories, and medico-technical departments involved in the clinical trial. 
 

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13 
QUALITY CONTROL AND QUALITY ASSURANCE 
Following a written DMID-accepted site quality management plan, the CTU is responsible for 
conducting routine quality assurance and quality control activities to internally monitor study 
progress and protocol compliance. The PI will provide direct access to the CTU, source 
data/documents, and reports for monitoring and auditing by the sponsor, and inspection by local 
and regulatory authorities. The PI will ensure all study personnel are appropriately trained and 
applicable documentations are maintained on site.  
The DCC will implement quality control procedures beginning with the data entry system and 
generate data quality control checks that will be run on the database. Any missing data or data 
anomalies will be communicated to the site(s) for clarification and resolution. 

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14 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
14.1 Ethical Standard 
The PI will ensure that the study is conducted in full conformity with principles of the Belmont 
Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research of 
the National Commission for the Protection of Human Subjects of Biomedical and Behavioral 
Research (April 18, 1979) and codified in 45 CFR 46, 21 CFR 50 and 56, and ICH E6; 62 
Federal Regulations 25692 (1997), if applicable. The PI’s institution will hold a current Federal 
Wide Assurance (FWA) issued by the Office of Human Research Protection for federally-funded 
research. 
14.2 Institutional Review Board 
The CTU will provide for the review and approval of this protocol and the associated ICFs by an 
appropriate IRB/EC listed on the FWA. Any amendments to the protocol or consent materials 
must also be approved before they are used, unless change is for the safety of the subject. Only 
those IRB members who are independent of the investigators and the sponsor should provide an 
opinion on study-related matters. Verification of IRB approval of the protocol and the written 
ICF will be transmitted by the investigator or designee before shipment of the study drug. No 
deviations from or changes to the protocol will be initiated without prior approval of an 
appropriate amendment unless change is for the safety of the subject. 
14.3 Informed Consent Process 
The written consent document will embody the elements of informed consent as described in the 
Declaration of Helsinki and will adhere to the ICH Harmonized Tripartite Guideline for GCP. 
Informed consent should be implemented before any protocol-specified procedures or 
interventions are carried out. Informed consent will be obtained in accordance with 21 CFR 
50.25 and 45 CFR 46. Information should be presented both orally and in written form. 
An investigator or designee will describe the protocol to potential subjects face-to-face. The ICF 
may be read to the subjects, but, in any event, the investigator shall give the subjects ample 
opportunity to inquire about details of the trial and ask any questions before signing the ICF. 
Study staff must inform subjects that the trial involves research, and explain the purpose of the 
trial, those aspects of the trial that are experimental, any expected benefits, all possible risks 
(including a statement that the particular treatment or procedure may involve risks to the subject 
or to the embryo or fetus, if the subject is or may become pregnant, that are currently 
unforeseeable), the expected duration of the subject’s participation in the trial, the procedures of 
the research study, including all invasive procedures, and the probability for random assignment 

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to treatment groups. Subjects will be informed that they will be notified in a timely manner if 
information becomes available that may be relevant to their willingness to continue participation 
in the trial. They must also be informed of alternative procedures that may be available, and the 
important potential benefits and risks of these available alternative procedures. Subjects must 
receive an explanation as to whether any compensation and any medical treatments are available 
if injury occurs, and, if so, what they consist of, or where further information may be obtained. 
Subjects must be informed of the anticipated financial expenses, if any, to the subject for 
participating in the trial, as well as any anticipated prorated payments, if any, to the subject for 
participating in the trial. They must be informed of whom to contact (e.g., the investigator) for 
answers to any questions relating to the research project. Information will also include the 
foreseeable circumstances and/or reasons under which the subject’s participation in the trial may 
be terminated. The subjects must be informed that participation is voluntary and that they are 
free to withdraw from the trial for any reason at any time without penalty or loss of benefits to 
which the subject is otherwise entitled. 
Neither the investigator, nor the trial staff, should coerce or unduly influence a subject to 
participate or continue to participate in the trial. The extent of the confidentiality of the subjects’ 
records must be defined, and subjects must be informed that applicable data protection 
legislation will be followed. Subjects must be informed that the monitor(s), auditor(s), IRB, 
NIAID, and regulatory authority(ies) will be granted direct access to the subject’s original 
medical records for verification of clinical trial procedures and/or data without violating the 
confidentiality of the subject, to the extent permitted by the applicable laws and regulations, and 
that, by signing a written ICF, the subject is authorizing such access. Subjects must be informed 
that records identifying the subject will be kept confidential, and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available and, if the results of the 
trial are published, the subject’s identity will remain confidential. 
ICFs must be in a language fully comprehensible to the prospective subjects. Informed consent 
shall be documented using a written consent form approved by the IRB and signed and dated by 
the subject and the person who conducted the informed consent discussion. The signature 
confirms that the consent is based on information that has been provided and all questions have 
been answered to the prospective participant’s satisfaction. Each subject’s signed ICF must be 
kept on file by the investigator for possible inspection by regulatory authorities and/or the 
sponsor and regulatory compliance persons. The subject should receive a copy of the signed and 
dated written ICF and any other written information provided to the subjects, and should receive 
copies of any signed and dated ICF updates and any amendments to the written information 
provided to subjects. 

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14.4 Exclusion of Women, Minorities, and Children (Special Populations) 
Children under age 18 years will be excluded from participation because insufficient data are 
available in adults to judge potential risk in children, and as a Phase I trial, there is no known 
benefit.   
Neither women nor minorities will be routinely excluded from participation in this study.  
Subjects will be recruited without regard to gender or race. It is expected that race and gender 
distributions in this study will approximate the proportion to their numbers within the 
community.   
Women of childbearing potential will be included but will be repeatedly counseled to use 
effective measures (Section 5.1) to avoid becoming pregnant from the time of screening until 30 
days after the last dose of study drug is received because the effect of the study drug on the 
unborn fetus are not known.    
14.5 Subject Confidentiality 
Subject confidentiality is held strictly in trust by the participating investigators, their staff, and 
the sponsor and their agents. This confidentiality is extended to cover testing of biological 
samples, and also clinical information related to participating subjects. 
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the trial or the data will be released to any 
unauthorized third party without prior written approval from the sponsor. This information and 
data will not be used by the Site PI or other study personnel for any purpose other than 
conducting the trial. These restrictions do not apply to: (1) information which becomes publicly 
available through no fault of the Site PI or other study personnel; (2) information which is 
necessary to disclose in confidence to an IRB solely for the evaluation of the trial; (3) 
information which is necessary to disclose in order to provide appropriate medical care to a study 
subject; or (4) study results which may be published as described in Section 16. 
The study monitors or other authorized representatives of the sponsor may inspect all documents 
and records required to be maintained by the Investigator, including, but not limited to, medical 
records (office, clinic, or hospital) and pharmacy records for the subjects in the trial. The CTU 
will permit access to such records. 
14.6 Study Discontinuation 
DMID has the right to terminate the trial or the site’s participation at any time. Reasons for 
terminating the trial may include, but are not limited to: 
• Incidence or severity of AEs indicates a potential health hazard 
• Data recording is inaccurate or incomplete 

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• Investigator does not adhere to the protocol or applicable regulatory guidelines in 
conducting the trial 
If the trial is discontinued, subjects who have signed the ICF and received the study drug will 
continue to be followed for safety for the duration of the trial. No further study treatments will be 
administered to other subjects. 

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15 
DATA HANDLING AND RECORD KEEPING 
The Site PI is responsible to ensure the accuracy, completeness, legibility, and timeliness of 
reported data. All data collection forms should be completed legibly to ensure accurate 
interpretation of data. Black or blue ink is required to ensure clarity of reproduced copies. When 
making changes or corrections, cross out the original entry with a single line, and initial and date 
the change. Do not erase, overwrite, or use correction fluid or tape on the original. 
Data collection forms will be provided by the DCC and the CTU and will be used by the CTU to 
record and maintain data for each subject enrolled in the trial. Data reported in the eCRF derived 
from source documents should be consistent with the source documents or the discrepancies 
should be explained. 
DMID and/or its designee will provide guidance to investigators and other study personnel on 
making corrections to the data collection forms, source documents, and eCRFs. 
15.1 Data Management Responsibilities 
All source documents and laboratory reports must be reviewed by the clinical team and data 
entry staff, who will ensure that they are accurate and complete. AEs must be graded, assessed 
for severity and causality, and reviewed by the Site PI or designee. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the Site PI. During the trial, the investigator must maintain complete and accurate documentation 
for the trial. 
Emmes will serve as the DCC for the trial, and will be responsible for data management, quality 
review, analysis, and reporting of the study data. 
15.2 Data Capture Methods 
Clinical data (including, but not limited to AE/SAEs, ConMeds, MH, and PE) and clinical 
laboratory data will be entered into a 21CFR11-compliant Internet Data Entry System provided 
by the DCC. The data system includes password protection and internal quality checks (e.g., 
automatic range checks) to identify data that appear inconsistent, incomplete, or inaccurate. 
Clinical data will be entered directly from the data collection forms completed by the study 
personnel.  
15.3 Types of Data 
Data for the trial will include clinical safety assessments, laboratory safety assessments, and PK 
parameters. 

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15.4 Timing/Reports 
A final CSR will be prepared after all safety and PK data are available. See Section 9.6.2 for 
additional reporting requirements.  
15.5 Study Records Retention 
Study files ICFs must be maintained for at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region, or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the study drug. These documents should be retained for a longer period, 
however, if required by local regulations. No records will be destroyed without the written 
consent of the sponsor, if applicable. It is the sponsor’s responsibility to inform the investigator 
when these documents no longer need to be retained. 
15.6 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or protocol-
specific MOP requirements. The noncompliance may be either on the part of the subject, the 
investigator, or the study site staff. Corrective actions for protocol deviations are to be developed 
by the site and implemented promptly. 
These practices are consistent with ICH E6: 
4.5 Compliance with Protocol, Sections 4.5.1, 4.5.2, and 4.5.3 
5.1 Quality Assurance and Quality Control, Section 5.1.1 
5.20 Noncompliance, Sections 5.20.1, and 5.20.2. 
It is the responsibility of the Site PI/study staff to use continuous vigilance to identify and report 
deviations within 5 working days of identification of the protocol deviation, or within 5 working 
days of the scheduled protocol-required activity. All deviations must be promptly reported to 
DMID via DCC’s AdvantageEDCSM. 
All protocol deviations, as defined above, must be addressed in study subject source documents. 
A completed copy of the DMID Protocol Deviation Form must be maintained in the regulatory 
file, as well as in the subject's source document. Protocol deviations must be sent to the local 
IRB/EC per their guidelines. The Site PI/study staff is responsible for knowing and adhering to 
their IRB requirements. 

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16 
PUBLICATION POLICY 
Following completion of the trial, the investigator is expected to publish the results of this 
research in a scientific journal. The International Committee of Medical Journal Editors (ICMJE) 
member journals have adopted a trials-registration policy as a condition for publication. This 
policy requires that all clinical trials be registered in a public trials registry such as 
ClinicalTrials.gov*, which is sponsored by the National Library of Medicine, on or before 
subject enrollment. Other biomedical journals are considering adopting similar policies. It is the 
responsibility of DMID to register the trial in an acceptable registry. 
The ICMJE defines a clinical trial as any research project that prospectively assigns human 
subjects to intervention or comparison groups to study the cause-and-effect relationship between 
a medical intervention and a health outcome. Studies designed for other purposes, such as to 
study PK or major toxicity (e.g., Phase I trials), are exempt from this policy. 
1. *Journal Citation: 
De Angelis C, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, et al. Clinical trial 
registration: a statement from the International Committee of Medical Journal Editors. N 
Engl J Med. 2004; 351:1250-1. 
 

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17 
LITERATURE REFERENCES 
1. Unemo M, Nicholas RA. Emergence of multidrug–resistant, extensively drug resistant 
and untreatable gonorrhea. Future Microbiol 2012;7(12):1401-22 
 
2. Barbee LA, Dombrowski JC. Control of Neisseria gonorrhoeae in the era of evolving 
antimicrobial resistance. Infect Dis Clin North Am 2013;27(4):723-37 
 
3. World Health Organization, Department of Reproductive Health and Research. 
Global incidence and prevalence of selected curable sexually transmitted infections - 
2008. Available at: 
http://www.who.int/reproductivehealth/publications/rtis/stisestimates/en/index.html  
(accessed on 10 July 2014) 
 
4. Centers for Disease Control and Prevention, (CDC). CDC Fact Sheet: STD Trends in 
the United States: 2011 National Data for Chlamydia, Gonorrhea, and Syphilis, 2013. 
Available at: http://www.cdc.gov/std/stats11/trends-2011.pdf  (accessed on 10 July 
2014) 
 
5. Centers for Disease Control and Prevention (CDC). Antibiotic Resistance Threats in 
the United States, 2013. Available at: https://www.cdc.gov/drugresistance/threat-report-
2013/pdf/ar-threats-2013-508.pdf (accessed on 10 July 2014) 
 
6. Unemo M, Shafer WM. Antibiotic resistance in Neisseria gonorrhoeae: origin, 
evolution, and lessons learned for the future. Ann N Y Acad Sci 2011;1230:E19-28 
 
7. World Health Organization. Antimicrobial resistance: global report of surveillance - 
2014. Available at: 
http://apps.who.int/iris/bitstream/10665/112642/1/9789241564748_eng.pdf  (accessed on 
10 July 2014)  
 
8. Investigator’s Brochure. Product Name, Zoliflodacin (Research number 
), 
 
 
9. Basarab GS, Kern GH, McNulty J, et al. Responding to the challenge of untreatable 
gonorrhea: ETX0914, a first-in-class agent with a distinct mechanism-of-action against 
bacterial Type II topoisomerases. Sci Rep. 2015 Jul 14;5:11827 
 
10. Huband MD, Bradford PA, Otterson LG, et al. In vitro antibacterial activity of AZD0914, 
a new spiropyrimidinetrione DNA gyrase/topoisomerase inhibitor with potent activity 
against Gram-positive, fastidious Gram-Negative, and atypical bacteria. Antimicrob 
Agents Chemother. 2015 Jan; 59(1): 467-74. 
  

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11. Su X-H, Wang B-X, Le W-J, et al. Multidrug-Resistant Neisseria gonorrhoeae Isolates 
from Nanjing, China, Are Sensitive to Killing by a Novel DNA Gyrase Inhibitor, 
ETX0914 (AZD0914). Antimicrob Agents Chemother. 2016 Jan; 60(1): 621–623 
 
12. A Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD0914 (Phase 1 
study). ClinicalTrials.gov Identifier: NCT01929629. 
https://clinicaltrials.gov/ct2/show/NCT01929629?term=AZD0914&rank=3 (accessed 
27July 2017). 
 
13. Randomized, Open-label Phase 2 Study of Oral AZD0914 in the Treatment of 
Gonorrhea. ClinicalTrials.gov Identifier: NCT02257918. 
https://clinicaltrials.gov/ct2/show/NCT02257918?term=AZD0914&rank=1 (accessed 27 
July 2017 
 
14. Guidance for Industry. E14:  Clinical Evaluation of QT/QTc Interval Prolongation and 
Proarrhythmic Potential for Non-Antiarrhythmic Drugs. FDA, October 2005. 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM073153.pdf (Accessed on 27 July 2017) 
 
15. U.S. Medical Eligibility Criteria for Contraceptive Use, 2016. CDC MMWR 65: (3): 1-
108, 2016 
 
16. Guidance for Industry. E9 Statistical Principles for Clinical Trials. FDA, September 
1998. 
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidan
ces/ucm073137.pdf (accessed on 27 July 2017) 
 
  
 
 
 

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18 
APPENDICES

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APPENDIX A: SCHEDULE OF STUDY PROCEDURES AND EVALUATIONS 
Study Visit 
Screening 1 
Check-in 
Inpatient Period 
Final Visit 
Unscheduled 
Early 
termination 
Dosing 
Follow Up 
Study Day / Assessments 
-21 to -2 
-1 
1 
2 
3 
4 
8 (± 2) 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Medical history update 
 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and ConMeds  2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete PE 3 
X 
 
 
 
 
 
X 
 
X 
Abbreviated PE 4 
 
X 
 
 
 
X 
 
 
 
Symptom-directed PE 5 
 
 
X 
X 
X 
 
 
X 
 
Height, weight, BMI 6 
X 
 
 
 
 
 
 
 
 
Weight 
 
X 
 
 
 
 
X 
 
 
Vital signs 7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical labs (HEM, 
CHEM, UA) 8 
X 
X 
 
 
 
X 
 
X 
X 
Viral serology 9 
X 
 
 
 
 
 
 
 
 
Serum pregnancy test 
X13 
X 
 
 
 
 
X 
 
X 
Serum FSH level 
X13 
 
 
 
 
 
 
 
 
Urine toxicology 
X 
X 
 
 
 
 
 
 
 
Alcohol breathalyzer test 
X 
X 
 
 
 
 
 
 
 
12-lead ECG 10 
X 
X 
X 
 
 
X 
 
 
X 
Study drug dosing 
 
 
X 
 
 
 
 
 
 
PK samples 11 
 
 
X 
X 
X 
X 
 
 
X 
Counsel on use of 
contraception and 
avoidance of pregnancy14 
X 
 
 
 
 
X 
X 
 
X 

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Study Visit 
Screening 1 
Check-in 
Inpatient Period 
Final Visit 
Unscheduled 
Early 
termination 
Dosing 
Follow Up 
Study Day / Assessments 
-21 to -2 
-1 
1 
2 
3 
4 
8 (± 2) 
 
 
Counsel to avoid use of 
prohibited medications, 
alcohol, marijuana and 
illicit drugs 
X 
X 
 
 
 
X 
X 
 
 
Interim medical history 
 
 
X 
X 
X 
X 
X 
X 
X 
AE and SAE review 12 
 
 
X 
X 
X 
X 
X 
X 
X 
Admit to CTU 
 
X 
 
 
 
 
 
 
 
Discharge from CTU 
 
 
 
 
 
X 
 
 
 
Discharge from trial 
 
 
 
 
 
 
X 
 
 
 
1. 
Screening Visit is completed within 21 days before study drug dosing and may require more than one visit. 
2. 
Prior medications include prescription drugs taken 30 days before dosing, and non-prescription drugs, herbs, vitamins, and nutritional supplements taken 15 days before 
dosing. Concomitant medications include those taken after dosing.  
3. 
Complete PE (except genital, breast, and rectal exam): at Screening, and Final Visit, or ET. 
4. 
Abbreviated PE: on Day -1 (not performed if the complete PE was performed ≤7 days from this visit) and Day 4. 
5. 
Symptom-directed PE: on Days 1 (predose and postdose), 2, and 3 for evaluation of new symptoms pre-dose and AEs post-dose. 
6. 
BMI is calculated as wt (kg) / ht (m2). 
7. 
Vital Signs (BP, HR, RR, T): at Screening Visit; on Days -1, 1, 2, 3, and 4; and at Final Visit, or ET. On Day 1, VS at baseline (approximately 1 h before dosing) and at 1 h (±5 
min), 2 h (±10 min), and 4 h (±10 min) after dosing. 
8. 
Clinical laboratory testing with minimum 4 h fast: HEM (Hgb, Hct, RBC, WBC with differential absolute count, platelet count); CHEM (creatinine with estimation of GFR, 
BUN, glucose, total bilirubin, direct bilirubin, AST, ALT, AP, total protein, albumin, electrolytes (sodium, potassium, chloride, bicarbonate (CO2), magnesium); and dipstick 
UA (blood, protein, glucose): at Screening, Day -1 (if not collected ≤7 days before dosing), Day 4, or ET. 
9. 
Viral Serology (HIV antibody, HBsAg, HCV antibody): at Screening Visit. 
10. 12-lead ECG with 10 sec rhythm strip: at Screening Visit, Day -1, Day 1 [within 1 h before dosing, and at 1 h (±10 min), 2 h (±10 min), and 4 h (±10 min) after dosing], and 
Day 4 [72 h (±2 h)] after dosing, or ET. 
11. Blood (plasma) PK samples: within 30 min before dosing, and at 0.5 h (±5 min), 1 h (±5 min), 2 h (±5 min), 3 h (±10 min), 4 h (±10 min), 6 h (±10 min), 8 h (±15 
min), 12 h (±15 min), 24 h (±2 h), 36 h (± 2 h), 48 h (± 2 h), and 72 h (± 2 h) after dosing, or ET. 
12. Collect all AEs from the time of dosing to and including Final Visit. Follow-up AEs and SAEs to resolution or stabilization in the clinical judgment of the 
study investigator.  
13. Serum pregnancy test in all women. FSH only in post-menopausal women. 
14. Females to use appropriate contraception and avoid pregnancy to 30 days after last study visit. Males to use appropriate contraception and refrain from 
donating sperm for 90 days after last study visit.   

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APPENDIX B: ACCEPTABLE RANGES OF SCREENING 
LABORATORY AND VITAL SIGN MEASUREMENTS  
HEMATOLOGY AND CHEMISTRY  
 
Lab test name 
Reference range 
Acceptable lower 
limit 
Acceptable 
upper limit 
Lab unit 
Hemoglobin (Hgb), male 
14-18 
13.5 
18.5 
g/dL 
Hemoglobin (Hgb), female 
12-15 
11.5 
16.5 
g/dL 
Hematocrit (Hct), male 
42-52 
40 
54 
% 
Hematocrit (Hct), female 
37-47 
35 
49 
% 
White blood cell count (WBC) 
4-11 
3.5 
11.5 
x103/µL 
Neutrophil count 
1.4-8.2 
1.2 
8.5 
x103/µL 
Lymphocyte count 
1-4.8 
0.8 
5 
x103/µL 
Monocyte count 
0-0.9 
0 
1.1 
x103/µL 
Eosinophil count 
0-0.3 
0 
0.6 
x103/µL 
Basophil count 
0-0.2 
0 
0.3 
x103/µL 
Platelet count 
150-400 
125 
475 
109/L 
Sodium 
137-145 
132 
148 
mmol/L 
Potassium 
3.5-5.1 
3.3 
5.3 
mmol/L 
Bicarbonate (CO2) 
22-30 
20 
32 
mmol/L 
Chloride 
98-107 
94 
115 
mmol/L 
Calcium  
8.4-10.2 
8.0 
11.0 
mg/dL 
Magnesium 
1.6-2.3 
1.1 
2.8 
mg/dL 
Blood urea nitrogen (BUN) 
7-20 
0 
25 
mg/dL 
Phosphorous 
2.5-4.5 
2.3 
4.8 
mg/dL 
Glucose, fasting 
74-106 
50 
120 
mg/dL 
Serum creatinine  
0.5-1.3 
<0.5 
1.4 
mg/dL 
Direct Bilirubin 
0.0-0.4 
0 
0.5 
mg/dL 
Total bilirubin  
0.2-1.3 
0 
1.5 
mg/dL 
Total protein 
6.3-8.2 
6.0 
8.6 
g/dL 
Albumin 
3.5-5.0 
3.2 
6.0 
g/dL 
Aspartate transferase (AST) 
3-42 
0 
46 
U/L 
Alanine transferase (ALT), male 
21-72 
0 
80 
U/L 
Alanine transferase (ALT), female 
10-44 
0 
50 
U/L 
Alkaline phosphatase 
38-126 
0 
150 
U/L 
Hepatitis B surface antigen 
non-reactive 
non-reactive 
non-reactive 
 n/a 
Hepatitis C antibodies 
non-reactive 
non-reactive 
non-reactive 
 n/a 
HIV test 
non-reactive 
non-reactive 
non-reactive 
 n/a 
Serum β-HCG (females only) 
negative 
negative 
negative 
 n/a 
FSH (post-menopausal) 
21.5-131 
21.5 
131 
mIU/mL 

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Footnotes: Exceptions to screening laboratory tests’ normal reference ranges are: 
a. 
Racially-based low total WBC or neutrophil counts up to toxicity Grade 1 in Appendix C Toxicity Tables, are allowed, but 
toxicity Grades 2 or 3 are exclusionary. 
b. 
Abnormalities in mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin 
concentration (MCHC), red cell distribution width (RDW), mean platelet volume (MPV), and nucleated red blood cell count 
(NRBC CT), which are included in a CBC with differential, will not be exclusionary. The results will be included in the database 
for comparison with results obtained as a part of safety laboratory tests.  
c. 
Abnormalities in serum creatinine, BUN, total bilirubin, AST, ALT, and chloride below the lower limit of normal (LLN) are 
allowable. 
d. 
Elevated bilirubin due to documented Gilbert’s syndrome that is Grade 1 is allowable, but Grade 2 or higher is exclusionary. (To 
document a subject has Gilbert syndrome, a diagnosis from the medical record must be provided or PI may make a ‘presumptive’ 
diagnosis of Gilbert syndrome in subjects with unconjugated hyperbilirubinemia on repeated testing (at least two samples 
separated in time) who have otherwise normal serum ALT, AST, and AP concentrations, and a normal CBC.  
e. 
Elevated serum glucose, sodium, potassium, bicarbonate (CO2), total protein, and AP, with toxicity Grade 1 values, are allowable. 
f. 
Serum chloride and albumin above the upper limit of normal (ULN) is allowable. 
g. 
Other laboratory values that are outside the range of eligibility but are thought to be due to an acute condition or due to collection 
or laboratory error may be repeated once.  
 
 
 
 
 
 

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URINALYSIS a 
 
Lab test name 
Reference 
range limit 
Acceptable 
lower limit 
Acceptable 
upper limit 
Lab unit 
Urine dipstick 
Protein 
negative 
negative 
1+ b 
 
Blood 
negative 
negative 
trace b 
 
Glucose 
negative 
negative 
trace b 
 
Urine Microscopy 
WBCs in urine 
(sediment) 
0-5 
0 
6 
/field 
RBCs in urine 
(sediment) 
0-5 
0 
6 
/field 
Bacteria 
negative 
few 
b 
/field 
Hyaline casts 
0.5 
none 
trace b 
/field 
Crystals 
none 
0 
b 
 
Footnotes:   
a (1) If UA by dipstick is abnormal, a complete UA with microscopic evaluation will be performed and the 
results will supersede the results of the dipstick.  
(2) Menstruating females failing inclusion criteria due to a positive blood on a urine test (dipstick or 
microscopic UA) may be retested following cessation of menses. Do not exclude female subjects with ≤ 
6 RBC/HPF. 
b Per investigator judgment, based on medical history. 
 
 
 

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TOXICOLOGY  
 
Urine must be negative for all tested substances (amphetamines, cocaine (and metabolite), 
barbiturates, benzodiazepines, opiates, tetrahydrocannabinol, methamphetamines, 
methadone, TCA, MDMA, and phencyclidine). Urine creatinine will be measured as part of 
the profile to assess quality of collected sample.  
 
VITAL SIGNS 
 
Measurement 
lower limit 
upper limit 
lab unit 
Systolic BP 
90 
150 
mmHg 
Diastolic BP 
40 
90 
mmHg 
Pulse rate 
45 
100 
beats/min 
Respiratory rate 
8 
22 
breaths/min 
Oral temperature 
95.9 
(35.5) 
<100.4 
(<38.0) 
F 
(C) 
 
 
 

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APPENDIX C: ADVERSE EVENTS TOXICITY GRADING 
CRITERIA 
ABBREVIATIONS: Abbreviations utilized in the Table: 
LLN = Lower Limit of Normal 
Req = Required 
IV = Intravenous 
Dec = Decreased 
ESTIMATING SEVERITY GRADE 
For abnormalities NOT found elsewhere in the Toxicity Tables, use the scale below to 
estimate grade of severity: 
GRADE 1 
Mild 
Events require minimal or no treatment; do not interfere with the 
subject’s daily activities.  
GRADE 2 
Moderate 
Events result in a low level of inconvenience or concern with 
therapeutic measures; may cause some interference with 
functioning.  
GRADE 3 
Severe 
Events interrupt a subject’s usual daily activity and may require 
systemic drug therapy or other treatment; are usually 
incapacitating.  
SERIOUS OR LIFE-THREATENING AEs 
Clinical events considered to be serious or life-threatening include, but are not limited to:  
seizures, coma, tetany, diabetic ketoacidosis, disseminated intravascular coagulation, diffuse 
petechiae, paralysis, acute psychosis, and severe depression. 
COMMENTS REGARDING THE USE OF THESE TABLES 
• Standardized and commonly used toxicity tables (Division of AIDS, National Cancer 
Institute [NCI] Common Toxicity Criteria [CTC], and World Health Organization 
[WHO]) have been adapted for use by the Division of Microbiology and Infectious 
Diseases (DMID) and modified to better meet the needs of subjects in DMID trials. 
• For parameters not included in the following Toxicity Tables, the site should refer to the 
“Guide for Estimating Severity Grade” located above. 
• Criteria are generally grouped by body system. 

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Some protocols may have additional protocol specific grading criteria, which will supersede 
the use of these tables for specified criteria. 
Toxicity Grading Tables 
Clinical AEs 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Comments 
VITAL SIGNS 
Fever - °C 
 
Fever - °F 
38.0-38.4 
 
100.4-101.1 
38.5-38.9 
 
101.2-102.0 
>38.9 
 
>102.0 
No recent hot or cold 
beverages or 
smoking.  
A protocol should 
select either 0C or 0F 
for inclusion 
Tachycardia - bpm 
101-115 
116-130 
>130 or 
ventricular 
dysrhythmias 
 
Assume awake and in 
supine position for 5 
min at rest; for AE, 
measurements at least 
3 times with 2 
concordant results 
(Section 8.1.6) 
Bradycardia - bpm 
50-54 OR 45-50 if 
baseline <60 
 
45-49 OR 40-44 if 
baseline <60 
<45 OR <40 if 
baseline <60 
as above 
Hypertension 
(systolic) - mm Hg 
141-150 
151-160 
>160 
Assume awake, and 
in supine position for 
5 min at rest; for AE, 
measurements on 
same arm at least 3 
times with 2 
concordant results 
(Section 8.1.6) 
Hypertension 
(diastolic) - mm Hg 
91-95 
96-100 
>100 
As above 
 Hypotension 
(systolic) - mm Hg  
85-89 
80-84 
<80 
As above 
Tachypnea – breaths 
per min 
23-25 
26-30 
>30 
Assume awake and in 
supine position for 5 
min at rest; for AE, 
measurements at least 
3 times with 2 
concordant results 
(Section 8.1.6) 
Note: Isolated/individual abnormalities of vital signs would not be considered toward halting criteria. Abnormalities of vital 
signs should be described as “increase X” or “decrease X” (X = heart rate, blood pressure, respiratory rate, temperature) if 
asymptomatic, transient and not associated with a systemic or organ-specific disorder, and coded by MedDRA within the System 
Organ Class (SOC) “Investigations.” These abnormalities should be graded per criteria in Appendix C, but not considered in 
determining whether study stopping criteria have been met. On the other hand, abnormalities of vital signs that are either 

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secondary to systemic or organ-specific clinical syndrome or primary disorders should be coded in the appropriate SOC (e.g., 
"cardiac disorders", respiratory disorders", "immunological disorders", etc.). These abnormalities should be considered in 
determining whether stopping criteria have been met. 
 
Clinical AEs 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Comments 
CARDIOVASCULAR 
Arrhythmia 
Asymptomatic or 
transient signs; no 
medical intervention 
required 
Recurrent and/or 
persistent signs; 
symptomatic 
medical 
intervention 
required 
Hemorrhage 
Estimated blood loss 
<100 mL 
Estimated blood loss 
>100 mL; no 
transfusion required 
Blood transfusion 
required 
RESPIRATORY 
Cough  
Transient cough; no 
treatment required 
 
Persistent cough; 
treatment required 
Interferes with 
daily activities 
Bronchospasm, 
Acute 
Transient 
bronchospasm; no 
treatment required; 
FEV1 71-80% of 
predicted peak flow 
Requires treatment; 
normalizes with 
bronchodilator; 
FEV1 60-70% of 
predicted peak flow 
  
No normalization 
with 
bronchodilator; 
FEV1 <60% of 
predicted peak 
flow 
 
 
Dyspnea   
Does not interfere 
with usual and social 
activities 
Interferes with usual 
and social activities; 
no treatment 
Prevents usual 
and social 
activities, OR 
requires treatment 
GASTROINTESTINAL   
Nausea  
No interference with 
normal activity 
Some interference 
with normal activity 
 
Prevents daily 
activities 
Vomiting  
No interference with 
activity, OR 1-2 
episodes in a 24-h 
period 
Some interference 
with activity, OR >2 
episodes in a 24-h 
period 
Prevents daily 
activity, OR 
requires medical 
intervention 
 

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Clinical AEs 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Comments 
Diarrhea  
2-3 loose or watery 
stools in a 24-h 
period 
4-5 loose OR watery 
stools in a 24-h 
period 
6 or more loose 
or watery stools 
in a 24-h period, 
OR requires IV 
hydration OR 
requires medical 
intervention 
 
Oral Discomfort / 
Dysphagia 
 
Mild discomfort; no 
difficulty 
swallowing 
 
Some limits on eating 
/ drinking 
 
Eating / talking 
very limited; 
unable to swallow 
solid foods 
 
LOCAL IV CATHETER REACTION 
IV site reaction 
Not Applicable 
Erythema with 
associated symptoms 
(e.g., edema, pain, 
induration, phlebitis) 
Ulceration or 
necrosis; severe 
tissue damage; 
operative 
intervention 
indicated 
 
SYSTEMIC REACTIONS 
Anaphylaxis ** 
 
 
-- 
-- 
Symptomatic 
bronchospasm, 
with or without 
urticaria; 
parenteral 
intervention 
indicated; allergy-
related 
edema or 
angioedema; 
hypotension 
 
**Definition: A disorder characterized by an acute inflammatory reaction resulting from the release of histamine 
and histamine-like substances from mast cells, causing a hypersensitivity immune response. Clinically, it presents 
with breathing difficulty, dizziness, hypotension, cyanosis and loss of consciousness and may lead to death. 
Allergic Reaction  
Pruritus without rash 
Localized urticaria 
OR requires oral 
therapy 
Generalized 
urticaria; 
angioedema OR 
anaphylaxis OR 
requires 
epinephrine 
 
 

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Clinical AEs 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Comments 
Hypersensitivity 
(including drug 
fever) 
Transient flushing or 
rash; temperature 
38.0-38.4 °C (100.4-
101.1°F) 
Rash; flushing; 
urticaria; dyspnea; 
temperature 38.5 - 
38.9°C (101.2 – 
102.0°F) 
Symptomatic 
bronchospasm 
with or without 
urticaria; 
parenteral 
medication 
indicated; 
allergy-related 
edema or 
angioedema; 
hypotension; 
temperature 
>38.9°C 
(>102.0°F) 
 
 
Headache  
No interference with 
activity 
Repeated use of non-
narcotic pain reliever 
for more than 24 h 
OR some interference 
with activity 
 
Significant; any 
use of narcotic 
pain reliever OR 
prevents daily 
activity OR 
requires triptans 
Fatigue  
No interference with 
activity 
Some interference 
with activity 
Significant; 
prevents daily 
activity 
 
 
Myalgia 
No interference with 
activity 
Some interference 
with activity 
Significant; 
prevents daily 
activity 
SKIN 
Mucocutaneous 
Erythema, pruritus 
Diffuse, maculo-
papular rash, dry 
desquamation 
Vesiculation OR 
moist 
desquamation OR 
ulceration 
 
Pruritus 
No or minimal 
interference with 
usual social and 
functional activities  
Greater than minimal 
interference with 
usual social and 
functional activities  
Inability to 
perform usual 
social and 
functional daily 
activities 
 
ALL OTHER CONDITIONS 
Illness or clinical AE 
(as defined according 
to applicable 
regulations) 
No interference with 
activity 
Some interference 
with activity but not 
requiring medical 
intervention 
Prevents daily 
activity and 
requires medical 
intervention 
 

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Laboratory AEs 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Blood, serum, or plasma * 
Sodium decrease – mmol/L 
130 –132 
125 –130 
<125 
Sodium increase – mmol/L 
148 – 149 
150 – 153 
≥154 
Potassium increase – mmol/L 
5.3 – 6.0 
6.1 – 6.4 
≥6.5 
Potassium decrease – mmol/L 
3.0 – 3.3 
2.5 – 2.9 
<2.5 
Bicarbonate (CO2) increase – mmol/L 
32 - 34 
35 – 36 
>36 
Bicarbonate (CO2) decrease – mmol/L 
18 -- 20 
14 - 17 
<14 
Glucose decrease, fasting – mg/dL 
50 – 73 
45 – 49 
<45 
Glucose increase, fasting – mg/dL 
107– 125 
126 - 249 
≥250 
Glucose increase, non-fasting – mg/dL 
107- 160 
161 - 249 
≥250 
Blood urea nitrogen – mg/dL 
21 – 26 
27 – 31 
>31 
Creatinine increase – mg/dL 
1.4 – 1.7 
1.8 – 2.3 
>2.3 
Calcium decrease – mg/dL 
7.8 –8.0 
7.0 – 7.7 
<7.0 
Calcium increase – mg/dL 
11.0 – 11.4 
11.5 – 12.4 
≥12.5 
Phosphorous increase – mg/dL 
4.8 – 5.0 
5.1 – 5.5 
>5.5 
Phosphorous decrease – mg/dL 
2.0 – 2.4 
1.4 – 1.9 
<1.4 
Total protein decrease – g/dL 
5.2 – 6.0 
4.8 – 5.1 
<4.8 
Albumin decrease – g/dL 
2.8 – 3.4 
2.5 – 2.7 
<2.5 
AST increase – U/L 
43 – 104 
105 – 209 
≥210 
ALT increase, male – U/L 
73 – 179 
180 – 359 
≥360 
ALT increase, female – U/L 
45 – 109 
110 – 219 
≥220 
Alkaline phosphatase increase – U/L 
151 – 240 
241 – 360 
>360 
Total bilirubin (serum) increase – mg/dL 
(with other LFTs in the normal range) 
1.4 – 2.0 
2.1 – 2.5 
>2.5 
Total bilirubin (serum) increase – mg/dL 
(accompanied by a >3 x ULN increase in ALT or 
AST)** 
1.4 – 1.6 
1.7 – 2.0 
>2.0 
Hemoglobin decrease, female – g/dL 
11.0 – 11.5 
9.5 – 10.9 
< 9.5 
Hemoglobin decrease, male – g/dL 
12.0 –13.5 
10.0 – 11.9 
<10.0 
WBC increase – cell/mm3 
11,000 – 15,000 
15,001 – 20,000 
>20,000 
WBC decrease – cell/mm3 
2,500 –3,500 
1,500 – 2,499 
<1,500 
Neutrophils decrease – cell/mm3 
1,200 – 1,399 
1,000 – 1,199 
<1,000 
Lymphocytes decrease – cell/mm3 
750 – 999 
500 – 749 
<500 
Monocytes increase – cell/mm3 
1,101 – 2,000 
2,001– 3000 
>3,000 
Eosinophils increase – cell/mm3 
500 – 750 
751 – 1,500 
>1,500 
Basophils increase – cell/mm3 
201 – 500 
501 – 800 
>800 
Platelets decrease – cell/mm3 
120,000 – 125,000 
100,000 – 
<120,000 
<100,000 

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Laboratory AEs 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Urine* 
Protein 
1+ 
2+ 
>2+ 
Glucose 
1+ 
2+ 
>2+ 
Blood (dipstick) 
1+ 
2+ 
>2+ 
Blood (microscopic) - RBCs per HPF 
6-10 
11-50 
>50 and/or gross 
blood 
WBC (microscopic) – WBC per HPF 
5-10 
11-50 
>50 
Bacteria (microscopic) 
few 
moderate 
many 
* Institutional normal reference ranges and allowable ranges at screening are provided in Appendix B. 
**ALT, males: >216 U/mL; ALT, females: >132 U/mL; AST, male or female: >126 U/mL) 
Note 1: If a subject was accepted into the trial with a laboratory value of an analyte that overlaps with values used for grading 
Grade 1 (mild) laboratory abnormalities, an AE will be reported if the on-study value of the same analyte is different (worse) 
from the baseline. 
Note 2: Safety laboratory results that are abnormal according to the local laboratory reference range, but not considered a 
Grade 1 abnormality, will be evaluated by the study site clinician and reported as Grade 1 abnormality if clinically significant. If 
not clinically significant, these will not be considered laboratory AEs and will thus not be graded, but will be recorded in the 
source document and followed-up clinically at the discretion of the study site clinician.  
Note 3: Other laboratory parameters performed and reported as parted of the complete blood count, metabolic panel and 
urinalysis will be evaluated by the study physician, recorded in the source document, and reported as laboratory AEs if clinically 
significant, and graded according to the criteria in Section 9.2.1. 
Note 4: If US by dipstick is abnormal, a microscopic UA will be performed and the results will supersede the results of the 
dipstick UA. 
Note 5: Menstruating females with a positive urine dipstick or microscopic UA may be retested following cessation of menses. 
 
 

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ECG interval abnormality  
Grade 1 
Grade 2 
Grade 3 
QT/QTc interval (Fridericia’s correction) 
prolonged (msec) 
Asymptomatic, QTc 
450-479 msec, OR 
increase in interval 
<30 msec above 
baseline 
 
Asymptomatic, 
QTc 480-499 
msec OR increase 
in interval 30-59 
msec above 
baseline 
Asymptomatic, QTc 
≥500 msec OR 
increase in interval 
≥60 msec above 
baseline 
PR interval prolonged - sec 
0.21-0.25 sec 
>0.25 sec 
Type II 2nd degree 
AV block OR 
ventricular pause 
>3.0 sec 
Note: The events will be coded as SAE if there are life-threatening associated symptoms or signs (arrhythmia, CHF, hypotension, 
syncope, torsade’s de pointes, etc.) 
Note: If a male subject was accepted into the trial with a QT/QTc value that overlaps with values used for grading Grade 1 
(mild) QT/QTc prolongation, an AE will be reported if the on-study value of the QT/QTc is higher than the baseline.

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APPENDIX D: BLOOD VOLUME WITHDRAWN DURING THE TRIAL 
Laboratory Samples and Estimated Total Blood Volume (mL)  
 
Study visit 
SCREENING 
CHECK-
IN 
INPATIENT PERIOD 
FINAL 
Total volume 
Early term visit 
Study Day 
-21 to -2 
-1 
1 
2 
3 
4 
 
8 (±2) 
 
HEMATOLOGY 1 
4 
4 
 
 
 
4 
 
12 
4 
CHEMISTRY and serum β-
HCG, FSH, HIV, HBsAg, 
HCV 1 
5 
5 
 
 
 
5 
 
15 
5 
PK 2 
 
 
54 
12 
6 
6 
 
78 
6 
Total volume/visit 
9 
9 
54 
12 
6 
15 
0 
- 
15 
Cumulative total volume 
9 
18 
72 
84 
90 
105 
105 
105 
 
 
1 Clinical blood tests are drawn at Screening Visit, on Day-1, and on Day 4, or ET. 
2 PK serum samples are drawn on Day 1: 30 min before dosing and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 h after dosing, or ET.