Clinical trial NCT03613649
Conditions: Electrocardiogram Repolarisation Abnormality Gonococcal Infection
Keywords: AZD0914 Cardiac ETX0914 Healthy Moxifloxacin Repolarization Study TQT Volunteers Zoliflodacin
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2018-09-25; Completion date: 2019-01-02
Enrollment: 72 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The Phase I Thorough QT/QTc (TQT) study will be performed in a single center, the Vince \& Associates Clinical Research, Inc., clinical trials unit (CTU), in 72 healthy male or female subjects, aged 18 to 45 years inclusive, to evaluate the effect of zoliflodacin on the corrected QT interval of the electrocardiogram (ECG) using Fridericia's Formula (QTcF) and other ECG parameters; the correlation of the drug concentrations (and pharmacokinetic (PK) profile) with time-matched, placebo-corrected, baseline-adjusted difference in QTcF interval (delta delta QTcF); and the PK and safety profiles of the new zoliflodacin formulation. Each subject will receive one dose of each of four treatments: zoliflodacin 2 g orally, zoliflodacin 4 g orally, placebo for zoliflodacin 4 g orally, and moxifloxacin 400 mg orally. The study will last approximately 12 weeks with a subject participation duration of up to 55 days. The primary hypothesis to be tested is that following administration of zoliflodacin 2 g and 4 g, the upper bound of the one-sided 95% confidence interval (CI) of treatment effect on delta delta QTcF is \> / = 10 msec for at least one of the ECG assessments, against the alternative hypothesis that all mean effects are \< 10 msec. The primary objective is to evaluate the effect of zoliflodacin on the corrected QT interval of the ECG using Fridericia's formula (QTcF).

Detailed description:
The Phase I Thorough QT/QTc (TQT) study will be performed in a single center, the Vince \& Associates Clinical Research, Inc., clinical trials unit (CTU), according to a randomized, double-blinded (except for the use of moxifloxacin), placebo-controlled, four-period, four-treatment, crossover design balanced with respect to first-order carryover effect in 72 healthy male or female subjects, aged 18 to 45 years inclusive, to evaluate the effect of zoliflodacin on the corrected QT interval of the electrocardiogram (ECG) using Fridericia's Formula (QTcF) and other ECG parameters; the correlation of the drug concentrations (and pharmacokinetic (PK) profile) with time-matched, placebo-corrected, baseline-adjusted difference in QTcF interval (delta delta QTcF); and the PK and safety profiles of the new zoliflodacin formulation. Each subject will receive one dose of each of four treatments: zoliflodacin 2 g orally, zoliflodacin 4 g orally, placebo for zoliflodacin 4 g orally, and moxifloxacin 400 mg orally. The study will last approximately 12 weeks with a subject participation duration of up to 55 days. The primary hypothesis to be tested is that following administration of zoliflodacin 2 g and 4 g, the upper bound of the one-sided 95% confidence interval (CI) of treatment effect on delta delta QTcF is \> / = 10 msec for at least one of the ECG assessments, against the alternative hypothesis that all mean effects are \< 10 msec. The primary objective is to evaluate the effect of zoliflodacin on the corrected QT interval of the ECG using Fridericia's formula (QTcF). The secondary objectives are: 1) to evaluate the effects of zoliflodacin on other ECG parameters (PR, QRS, and RR intervals, and heart rate (HR)); 2) to evaluate the sensitivity of QTcF measurement using moxifloxacin; 3) to evaluate the effect of zoliflodacin on T-wave morphology; 4) to evaluate the PK of 2 g and 4 g oral zoliflodacin under fasting state; 5) to evaluate the relationship between zoliflodacin PK and time-matched QTcF pharmacodynamics (PD); 6) to evaluate the safety and tolerability of 2 g and 4 g oral zoliflodacin.

Arms: arm 1: 2 g of zoliflodacin administered orally on Day 1 of each dosing period, n=72 arm 2: 4 g of zoliflodacin administered orally on Day 1 of each dosing period, n=72 arm 3: Placebo for zoliflodacin administered orally on Day 1 of each dosing period, n=72 arm 4: 400 mg of moxifloxacin administered orally on Day 1 of each dosing period, n=72
Interventions: intervention 1: AZD0914 intervention 2: Moxifloxacin intervention 3: Placebo
Intervention descriptions: intervention 1: Spiropyrimidinetrione antibacterial drug, which inhibits bacterial DNA synthesis by a novel mechanism. Powder will be reconstituted in 60 mL of tap water and dosed orally after an overnight fast. After the cup containing 60 mL of zoliflodacin is taken, approximately 60 mL of tap water will be added to the cup and consumed by the subject to chase the initial dose. intervention 2: Broad-spectrum 8-methoxy fluoroquinolone with activity against both Gram-positive and Gram-negative bacteria, including anaerobes. A single, commercially-available, film-coated, 400-mg tablet of moxifloxacin hydrochloride will be administered orally with 120 mL of tap water. intervention 3: Composed of 4 g of the same excipients found in zoliflodacin. Powder will be reconstituted in 60 mL of tap water and dosed orally after an overnight fast. After the cup containing 60 mL of placebo is taken, approximately 60 mL of tap water will be added to the cup and consumed by the subject to chase the initial dose.

Protocol documents:
Prot_000.pdf: 
 
 
A Phase 1, Randomized, Double-blinded, Four-period Crossover, 
Thorough QT/QTc (TQT) Clinical Trial to Evaluate the Effect of 
Zoliflodacin on Cardiac Repolarization in Healthy Male and Female 
Subjects 
 
 
DMID Protocol Number: 16-0110 
 
 
DMID Funding Mechanism: Phase 1 Clinical Trial Unit 
 
 
Pharmaceutical Support: Entasis Therapeutics 
 
 
IND Sponsor: Division of Microbiology and Infectious Diseases (DMID), 
National Institute of Allergy and Infectious Diseases (NIAID), National Institutes 
of Health (NIH) 
 
 
Site Principal Investigator: Martin Kankam, MD, PhD, MPH 
 
 
DMID Clinical Project Manager: Meg Gordon, RN 
 
 
Version Number: 4.0 
 
 
27 November 2018 
 
 


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2 
Statement of Compliance 
The clinical trial will be carried out in accordance with Good Clinical Practice (GCP) and as 
required by the following: 
• United States (US) 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 Council for Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use E6(R2) Good Clinical Practice (ICH E6 GCP): Integrated 
Addendum to ICH E6(R1) Guidance for Industry, published in the Federal Register (83 
Federal Register 8882 (2018)), including the latest finalized.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 subjects are protected, consistent with principles that originate 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 US federal regulations and ICH guidelines. 
 
 
 
Site Investigator: 
 
 
_________________________________________________ 
Name/Title (Print) 
 
 
Signature: 
 
_________________________________________________ 
 
Date:  
 
_________________________________________________ 
 
 
 
 
 
 


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Table of Contents 
 
 
Page 
Statement of Compliance .................................................................................................................2 
Signature Page .................................................................................................................................3 
Table of Contents .............................................................................................................................4 
List of Tables ...................................................................................................................................9 
List of Figures ................................................................................................................................10 
List of Abbreviations .....................................................................................................................11 
Protocol Summary .........................................................................................................................15 
1 
Key Roles ..............................................................................................................................19 
2 
Background Information and Scientific Rationale ...............................................................21 
2.1 
Background Information ...........................................................................................21 
2.1.1 Overview of the Disease: Gonorrhea and its Treatment ...............................21 
2.1.2 Zoliflodacin Development ............................................................................21 
2.2 
Rationale ...................................................................................................................26 
2.2.1 Study Rationale .............................................................................................26 
2.2.2 Rationale for Dose Selection ........................................................................27 
2.3 
Identified and Potential Risks and Benefits ..............................................................28 
2.3.1 Zoliflodacin Risks .........................................................................................28 
2.3.2 Moxifloxacin Risks .......................................................................................30 
2.3.3 Venipuncture and IV Catheter Placement Risks ...........................................31 
2.3.4 Additional Risks............................................................................................31 
2.3.5 Known Potential Benefits .............................................................................32 
2.3.6 Risk/Benefit Ratio .........................................................................................32 
3 
Objectives and Outcome Measures.......................................................................................33 
3.1 
Study Objectives .......................................................................................................33 
3.1.1 Primary ..........................................................................................................33 
3.1.2 Secondary ......................................................................................................33 
3.2 
Study Outcome Measures .........................................................................................33 
3.2.1 Primary ..........................................................................................................33 
3.2.2 Secondary ......................................................................................................33 
4 
Study Design .........................................................................................................................35 
4.1 
Sub-studies ................................................................................................................36 
5 
Study Enrollment and Withdrawal .......................................................................................37 
5.1 
Subject Inclusion Criteria .........................................................................................37 
5.2 
Subject Exclusion Criteria ........................................................................................38 
5.3 
Treatment Assignment Procedures ...........................................................................41 
5.3.1 Enrollment and Randomization Procedures..................................................41 
5.3.2 Masking Procedures ......................................................................................42 


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5.3.3 Reasons for Withdrawal and Discontinuation of Study Drug 
Administration ..............................................................................................42 
5.3.4 Handling of Withdrawals and Discontinuation of Administration ...............43 
5.3.5 Lost to Follow-up ..........................................................................................43 
5.3.6 Termination of Study ....................................................................................43 
6 
Study Intervention/investigational product ...........................................................................44 
6.1 
Description of Study Products ..................................................................................44 
6.1.1 Acquisition ....................................................................................................44 
6.1.2 Formulation, Packaging, and Labeling .........................................................45 
6.1.3 Product Storage and Stability........................................................................45 
6.2 
Dosage, Preparation, and Administration of Study Intervention/ Investigational 
Products.....................................................................................................................46 
6.3 
Modification of the Study Intervention/ Investigational Products for a Subject ......47 
6.3.1 Overdose .......................................................................................................47 
6.4 
Accountability Procedures for the Study Intervention/ Investigational Products .....47 
6.5 
Assessment of Subject Compliance with the Study Intervention/ Investigational 
Products.....................................................................................................................48 
6.6 
Prior and  Concomitant Medications/Treatments .....................................................48 
6.7 
Subject Restrictions ..................................................................................................49 
6.7.1 Physical Activity ...........................................................................................49 
6.7.2 Fluid and Food intake ...................................................................................49 
6.7.3 Alcohol, Marijuana and Illicit Drugs ............................................................50 
6.7.4 Other Restrictions .........................................................................................50 
7 
Study Schedule .....................................................................................................................51 
7.1 
Recruitment ...............................................................................................................51 
7.2 
Screening Visit (Day -21 to Day -2) .........................................................................51 
7.3 
Check-in / Baseline (Day-1 in each dosing period)                                          
(Overall, Days -1, 8, 16, and 24 for dosing periods 1, 2, 3 and 4, respectively) ......52 
7.4 
Inpatient period (Days 1-2 in each dosing period)                                          
(Overall, Days 1-2, 9-10, 17-18, and 25-26 for dosing periods 1, 2, 3 and 4,  
respectively) ..............................................................................................................53 
7.4.1 Randomization (Day 1, Dosing Period 1 only) .............................................53 
7.4.2 Administration of Study Drug (Day 1 of each dosing period)                          
(Overall, Days 1, 9, 17, and 25 for dosing periods 1, 2, 3 and 4, 
respectively) ..................................................................................................53 
7.4.3 Inpatient Follow-up (Day 2 of each dosing period)                                            
(Overall, Days 2, 10, 18, and 26 for dosing periods 1, 2 3 and 4, 
respectively) ..................................................................................................55 


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7.5 
Outpatient period (Days 3-7 for each dosing period                           (Overall, 
Days 3-7, 11-15, 19-23 and 27-31 for dosing periods 1, 2, 3 and 4, respectively) ...55 
7.6 
Final Visit (Day 32, 8 ±2 days after last dose in Dosing Period 4) ..........................55 
7.7 
Early Termination Visit (if needed) ..........................................................................56 
7.8 
Unscheduled Visit (if needed) ..................................................................................56 
8 
Study Procedures/evaluations ...............................................................................................57 
8.1 
Clinical Procedures/Evaluations ...............................................................................57 
8.1.1 Informed Consent..........................................................................................57 
8.1.2 Demographics ...............................................................................................57 
8.1.3 Inclusion/Exclusion Criteria .........................................................................57 
8.1.4 Medical History ............................................................................................57 
8.1.5 Physical Examination....................................................................................58 
8.1.6 Vital Signs .....................................................................................................58 
8.1.7 12-lead Standard Electrocardiogram (ECG) .................................................59 
8.2 
Laboratory Evaluations .............................................................................................59 
8.2.1 Clinical Laboratory Evaluations (Hematology, Chemistry, and 
Urinalysis) .....................................................................................................59 
8.2.2 Viral Serology Testing ..................................................................................60 
8.2.3 Pregnancy Testing .........................................................................................60 
8.2.4 Serum FSH Testing .......................................................................................60 
8.2.5 Urine Toxicology Screening .........................................................................60 
8.2.6 Urine Alcohol Testing...................................................................................61 
8.3 
Special Procedures and Assays .................................................................................61 
8.3.1 Continuous 24-h ECG Monitoring (Holter ECG Monitoring) .....................61 
8.3.1.1 TQT and ECG Extraction Technique ...............................................62 
8.3.1.2 T-wave Morphology Analysis and Measurement of PR and QRS 
Intervals.............................................................................................62 
8.3.2 Pharmacokinetics ..........................................................................................63 
8.3.2.1 Assay for Zoliflodacin ......................................................................63 
8.3.2.2 Assays for Placebo and Moxifloxacin Samples ................................63 
8.3.3 Specimen Preparation, Handling, and Shipping ...........................................64 
8.3.3.1 Instructions for Specimens Preparation, Handling, and Storage ......64 
8.3.3.2 Specimen Shipment ..........................................................................64 
9 
Assessment of Safety ............................................................................................................65 
9.1 
Specification of Safety Parameters ...........................................................................65 
9.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters .................................................................................................................65 
9.2.1 Adverse Events .............................................................................................65 
9.2.1.1 Severity of Events .............................................................................66 


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9.2.1.1.1 Relationship to Study Products ........................................... 66 
9.2.1.2 Reporting Adverse Events ................................................................66 
9.2.2 Serious Adverse Events ................................................................................67 
9.2.3 Procedures to be Followed in the Event of Abnormal Laboratory Test 
Values or Abnormal Clinical Findings .........................................................67 
9.3 
Reporting Procedures ................................................................................................68 
9.3.1 Serious Adverse Events ................................................................................68 
9.3.2 Regulatory Reporting for Studies Conducted Under DMID-Sponsored 
IND ...............................................................................................................69 
9.3.3 Other Adverse Events (if applicable) ............................................................69 
9.3.3.1 Reporting of Overdose ......................................................................69 
9.3.4 Reporting of Pregnancy ................................................................................70 
9.4 
Type and Duration of Follow-up of Subjects after Adverse Events .........................70 
9.5 
Halting Rules ............................................................................................................70 
9.5.1 Study Halting Criteria ...................................................................................70 
9.5.1.1 Halting Criteria for Zoliflodacin and Placebo Periods .....................70 
9.5.1.2 Halting Criteria for Moxifloxacin Periods ........................................71 
9.6 
Safety Oversight........................................................................................................71 
9.6.1 Independent Safety Monitor (ISM) ...............................................................71 
9.6.2 Safety Monitoring Committee (SMC) ..........................................................71 
10 
Clinical Monitoring...............................................................................................................73 
10.1 
Site Monitoring Plan .................................................................................................73 
11 
Statistical Considerations ......................................................................................................74 
11.1 
Study Hypotheses......................................................................................................74 
11.2 
Sample Size Considerations ......................................................................................74 
11.3 
Safety Review ...........................................................................................................74 
11.4 
Final Analysis Plan ...................................................................................................74 
11.4.1 Analysis Populations .....................................................................................75 
11.4.2 Demographics and Baseline Characteristics .................................................75 
11.4.3 Safety Analysis .............................................................................................76 
11.4.3.1 Adverse and Serious Adverse Events ...............................................76 
11.4.3.2 Additional Safety Analyses...............................................................76 
11.4.4 PK Analysis ..................................................................................................76 
11.4.5 Missing Values and Outliers .........................................................................77 
11.4.6 Analysis of Continuous ECG Parameters (Pharmacodynamics) ..................77 
11.4.6.1 ECG Analysis and Interpretation ......................................................77 
11.4.6.2 Primary Analysis: QTcF Effect ........................................................77 
11.4.6.3 Secondary Analyses: Non-QTc Intervals..........................................78 
11.4.6.4 Assay Sensitivity ...............................................................................78 


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11.4.6.5 Categorical Analyses ........................................................................78 
11.4.6.6 Cardiac Abnormalities: .....................................................................79 
11.4.7 Concentration-QTcF Modeling .....................................................................79 
12 
Source Documents and Access to Source Data/Documents .................................................80 
13 
Quality Control and Quality Assurance ................................................................................81 
14 
Ethics/Protection of Human Subjects ...................................................................................82 
14.1 
Ethical Standard ........................................................................................................82 
14.2 
Institutional Review Board .......................................................................................82 
14.3 
Informed Consent Process ........................................................................................82 
14.4 
Exclusion of Women, Minorities, and Children (Special Populations) ....................84 
14.5 
Subject Confidentiality .............................................................................................84 
14.6 
Certificate of Confidentiality ....................................................................................84 
14.7 
Study Discontinuation ...............................................................................................85 
15 
Data Handling and Record Keeping .....................................................................................86 
15.1 
Data Management Responsibilities...........................................................................86 
15.2 
Data Capture Methods ..............................................................................................86 
15.3 
Types of Data ............................................................................................................87 
15.4 
Timing/Reports .........................................................................................................87 
15.5 
Study Records Retention...........................................................................................87 
15.6 
Protocol Deviations ...................................................................................................87 
16 
Publication Policy .................................................................................................................89 
17 
Literature References ............................................................................................................90 
18 
Appendices............................................................................................................................93 
Appendix A: Schedule of Study Procedures and Evaluations ...................................................... 94 
Appendix B: Acceptable Ranges of Screening Laboratory and Vital Sign Measurements .......... 97 
Appendix C: Adverse Events Toxicity Grading Criteria ............................................................ 101 
Appendix D: Blood Volume Withdrawn During the Trial ......................................................... 109 
Appendix E: A Partial List of Drugs Causing QTc Prolongation and Torsade de Pointes ........ 111 
 
 


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List of Tables 
Table 1: Dosing ............................................................................................................................. 35 
Table 2: T-wave Morphology Categories ..................................................................................... 63 
Table 3: Schedule of Events ......................................................................................................... 94 
Table 4: Acceptable Ranges of Screening Laboratory and Vital Sign Measurements – 
Hematology and Chemistry .......................................................................................................... 97 
Table 5: Acceptable Ranges of Screening Laboratory and Vital Sign Measurements – Urinalysis
....................................................................................................................................................... 99 
Table 6: Acceptable Ranges of Screening Laboratory and Vital Sign Measurements – Vital Signs
..................................................................................................................................................... 100 
Table 7: Toxicity Grading Tables – Clinical AEs ...................................................................... 102 
Table 8: Toxicity Grading Tables – Laboratory AEs ................................................................. 106 
Table 9: Toxicity Grading Tables – ECG ................................................................................... 108 
Table 10: Laboratory Samples and Estimated Total Blood Volume (mL) ................................. 109 
Table 11: A Partial List of Drugs Causing QTc Prolongation and Torsade de Pointes.............. 111 
 


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List of Figures 
Figure 1: Description Schematic of Study Design ........................................................................ 18 
 
 
 


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List of Abbreviations 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AP 
Alkaline Phosphatase 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
β-HCG 
Beta Human Chorionic Gonadotropin 
BID 
Twice-Daily 
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 
CHEM 
Chemistry Panel 
CI 
Confidence Interval 
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 
DCC 
Data Coordinating Center 
ΔΔQTcF 
Time-matched, placebo-corrected, baseline-adjusted difference in QTcF 
interval 
dL 
Deciliter 
DMID 
Division of Microbiology and Infectious Diseases 
DNA 
Deoxyribonucleic Acid 
eCRF 
Electronic Case Report Form 


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EC 
Ethics Committee 
ECG  
Electrocardiogram 
EDC 
Electronic Data Capture 
ET 
Early Termination 
FDA 
Food and Drug Administration 
FSH 
Follicle-Stimulating Hormone 
FWA 
Federalwide Assurance 
g 
Gram(s) 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
h 
Hour(s) 
HBsAg 
Hepatitis B Surface Antigen 
Hct 
Hematocrit 
HCV 
Hepatitis C Virus 
HEENT 
Head, Eyes, Ears, Nose, and Throat 
HEM 
Hematology Tests 
Hgb 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 
HPF 
High-Powered Field 
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 Council for   Harmonization 
ICMJE 
International Committee of Medical Journal Editors 
IM 
Intramuscular 
IND 
Investigational New Drug  
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
IV 
Intravenous 


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kg 
Kilogram(s) 
LLN 
Lower Limit of Normal 
LQTS 
Long QT Syndrome 
MDMA 
3,4-methylenedioxy-methamphetamine 
MedDRA 
Medical Dictionary for Regulatory Activities 
µg 
Microgram(s) 
mg 
Milligram(s) 
MH 
Medical History 
MIC 
Minimum Inhibitory Concentration 
min 
Minute(s) 
mL 
Milliliter(s) 
MM 
Medical Monitor 
mmHg 
Millimeters of Mercury 
µmol 
Micromole(s) 
MOP 
Manual of Procedures 
msec 
Milliseconds(s) 
mV 
Millivolt 
N 
Number (typically refers to the total number of subjects) 
n 
Number (typically refers to a subset of the total number of subjects) 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
NOAEL 
No Observable Adverse Effect Level 
NSAID 
Nonsteroidal Anti-Inflammatory Drug 
OCRR 
Office of Clinical Research Resources 
OTC 
Over-the-Counter 
PBPK 
Physiologically-Based Pharmacokinetic 
PD 
Pharmacodynamic(s) 
PE 
Physical Examination 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
PO 
Oral 


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POC 
Point of Contact 
PVG 
Pharmacovigilance Group 
QTc 
Corrected QT Interval of the ECG 
QTcF  
Corrected QT interval of the ECG using Fridericia’s Formula 
RBC 
Red Blood Cell 
RP 
Research Pharmacist 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
sec 
Second(s) 
SMC 
Safety Monitoring Committee 
TCA 
Tricyclic Antidepressant 
TdP 
Torsade de Pointes 
Tmax 
Time to Maximum Plasma Concentration 
TQT 
Thorough QT/QTc 
UA 
Urinalysis 
ULN 
Upper Limit of Normal 
US 
United States 
VS 
Vital Signs 
WBC 
White Blood Cell 
WHO 
World Health Organization 
 
 
 


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Protocol Summary 
Title: 
A Phase 1, Randomized, Double-blinded, Four-period Crossover, Thorough 
QT/QTc (TQT) Clinical Trial to Evaluate the Effect of Zoliflodacin on Cardiac 
Repolarization in Healthy Male and Female Subjects 
Phase: 
1 
Population: 
72 randomized (at least 56 evaluable) healthy male and female subjects aged 
18 to 45 years inclusive  
Number of Sites: 
 
One (Vince & Associates Clinical Research, Inc., Overland Park, KS) 
Study Duration:  
 
Approximately 12 weeks  
Subject 
Participation 
Duration: 
 
Up to 55 days (from Screening Visit to Final Visit) 
The trial will consist of: 
• A Screening Period of up to 20 days (Day -21 to Day -2);  
• Four Dosing Periods, each lasting 3 days/2 nights (Days -1, 1, and 2 in each 
period), totaling 12 days;  
• Four Outpatient Periods, each lasting 5 days (Days 3-7 after each Dosing 
Period), totaling 20 days; and 
• A Final Visit 8 ±2 days after dosing in Dosing Period 4, totaling 1 day. 
Description of 
Agents: 
The following four treatments will be administered to all subjects using a 
randomized, double-blinded, four-period, crossover design. Each subject will 
be randomized to a treatment sequence containing all four treatments:  
• Treatment A: zoliflodacin 2 g (investigational product) 
• Treatment B: zoliflodacin 4 g (investigational product) 
• Treatment C: placebo (for zoliflodacin) 
• Treatment D: moxifloxacin 400 mg (positive comparator) 
 
Single 2-g and single 4-g doses of zoliflodacin were safe and well-tolerated in 
previous clinical trials. The 2-g dose (of the new formulation) has been 
selected as the therapeutic dose for further clinical testing of zoliflodacin. The 
4-g dose was shown to result in drug exposures higher than the 2-g dose and 
should provide exposures that will be achieved in patients when used with 
other drugs that may interact with zoliflodacin. Based on pharmacokinetic 


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(PK) data from study DMID 16-0118, exposures for 4 g of the new 
formulation are similar to those for the previous formulation. For this reason, 
the 4-g dose was selected as the supratherapeutic dose for this TQT trial. 
Placebo for zoliflodacin was selected to control for natural diurnal changes in 
the electrocardiogram (ECG). Moxifloxacin was selected as a positive 
comparator to evaluate QTcF assay sensitivity, as it predictably causes a mild 
prolongation of the QTcF interval but has a very low risk for inducing cardiac 
arrhythmias.   
Objectives: 
 
Primary: 
• To evaluate the effect of zoliflodacin on the corrected QT interval of 
the ECG using Fridericia’s formula (QTcF) 
Secondary:  
• To evaluate the effects of zoliflodacin on other ECG parameters [PR, 
QRS, and RR intervals, and heart rate (HR)]  
• To evaluate the sensitivity of QTcF measurement using moxifloxacin 
• To evaluate the effect of zoliflodacin on T-wave morphology 
• To evaluate the PK of 2 g and 4 g oral zoliflodacin under fasting state 
• To evaluate the relationship between zoliflodacin PK and time-matched 
QTcF pharmacodynamics (PD)  
• To evaluate the safety and tolerability of 2 g and 4 g oral zoliflodacin  
Outcome 
Measures:  
 
 
 
 
 
 
 
 
 
Primary: 
• The upper bound of the one-sided 95% confidence interval (CI) for the 
largest time-matched, placebo-corrected, baseline-adjusted mean QTcF 
interval (∆∆QTcF) collected in the 24-h period after 2 g and 4 g dose of 
zoliflodacin is <10 msec 
Secondary: 
• Time-matched, placebo-corrected, baseline-adjusted non-QT intervals 
(PR, QRS, and RR intervals) and HR collected in the 24-h period after 
2 g and 4 g dose of zoliflodacin  
• The lower bound of the one-sided 95% CI of the ∆∆QTcF is >5 msec 
at one or more individual time points between 1 h and 4 h after a single 
dose of moxifloxacin 400 mg  
• Incidence of abnormal T-wave morphology using defined categories in 
the 24-h period after 2 g and 4 g dose of zoliflodacin 


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• Single-dose plasma concentrations (and PK exposure parameters, such 
as Cmax and AUC) of zoliflodacin collected up to 24 h after 2 g and 4 g 
dose of zoliflodacin 
• Relationship between plasma concentrations of zoliflodacin (and PK 
exposure parameters, such as Cmax and AUC) and ∆∆QTcF up to 24 h 
after 2 g and 4 g dose of zoliflodacin 
• Occurrence of treatment-emergent serious adverse events (SAEs), other 
unsolicited treatment-emergent adverse events (AEs), and changes 
from baseline in vital signs (VS), clinical laboratory values, and ECG 
parameters following administration of zoliflodacin and moxifloxacin 
from time of dosing to Final Visit, or Early Termination (ET) Visit. 
Description of 
Study Design: 
The TQT clinical trial will be performed according to a randomized, double-
blinded (except for the use of moxifloxacin), placebo-controlled, four-period, 
four-treatment, crossover design in 72 healthy male and/or female subjects. 
Subjects who consent to participate will be enrolled in the trial if they meet all 
inclusion and no exclusion eligibility criteria. Laboratory assessments at 
Screening Visit will include clinical laboratory tests [hematology (HEM), 
chemistry (CHEM), and urinalysis (UA)], testing for viral serology [human 
immunodeficiency virus (HIV) antibody, hepatitis B surface antigen (HBsAg), 
and hepatitis C virus (HCV) antibody], drugs of abuse, and alcohol. Serum 
pregnancy testing will be done in all females and serum follicle-stimulating 
hormone (FSH) levels will be measured only in post-menopausal females. 
Subjects who meet eligibility criteria will be randomly allocated to one of 12 
dosing sequences and receive a single dose of the four study drugs according 
to their randomly-assigned dosing sequence during four dosing periods. The 
dosing interval between dosing periods will be 8 days to allow for adequate 
wash-out of drug before the next dose. Safety assessments at scheduled visits 
after dosing will include medical history (MH), VS, physical examination 
(PE), 12-lead ECG, and clinical laboratory tests. Continuous 12-lead Holter 
ECGs will be initiated 1 h before dosing and continue for 24 h after dosing. At 
scheduled timepoints, replicate Holter ECGs will be selected for measurement 
of QTcF and other ECG intervals, and assessment of T-wave morphologies. 
Plasma will be collected during each dosing period at scheduled timepoints 
that are time-matched to Holter ECGs before and after dosing on Day 1 and 
through Day 2 (24 h after dosing), or ET if within 24 h after dosing, but drug 
concentration bioanalysis and PK analysis will be done only for zoliflodacin. 
Treatment-emergent AEs and SAEs will be assessed from time of dosing to 
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Estimated Time 
to Complete 
Enrollment: 
Up to 12 weeks (from dosing of first subject to Final Visit of last subject) 
Halting Criteria 
Decision Process: 
If criteria for halting the trial (as listed in Section 9.5.1) are met following 
dosing in any dosing period, administration of all study drugs will be 
suspended and 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 
safety assessments in future clinical trials with zoliflodacin. 
 
 
Figure 1: Description Schematic of Study Design 
 
Screen
Washout between dosing
At least 8 days
Treatment
 Period 1
A
B
etc.
FINAL VISIT
8 + 2 days
After last dose
SCREENING
Up to 21 days
Before 1st dose
Treatment
 Period 2
B
C
etc.
Treatment
 Period 3
C
D
etc.
Treatment
 Period 4
D
A
etc.
Final Visit
Randomization 
Sequences*
ABCD
BCDA
etc.
RANDOMIZATION 
before dosing on
Day +1 of 
Treatment Period 1
 
 
NOTE: A, B, C, and D refer to each of the study treatments. This is a four-treatment, four-period, crossover trial. 
Treatments and treatment sequences will be randomized using a 12-sequence design balanced for period and first-
order carryover effects, and double-blinded, except for administration of moxifloxacin. Six subjects will be 
randomized to each treatment sequence. The schematic displays only two of the 12 sequences.  
* See Section 4 for details and a complete list of planned treatment sequences. 
 
 


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1 
KEY ROLES 
Site Principal Investigator: 
Martin Kankam, MD, PhD, MPH  
Vince & Associates Clinical Research, Inc. 
10103 Metcalf Avenue 
Overland Park, KS 66212 
Office: 913-696-1601   
Email: mkankam@vinceandassociates.com  
  
DMID Clinical Project Manager: 
Meg Gordon, RN 
DMID/NIAID/NIH 
5601 Fishers Lane, Room 7G37  
Bethesda, MD 20892-9826 
Office: 301-761-7604 
Email: meg.gordon@nih.gov  
 
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  
 
ECG and Cardiac Services  
Quintiles Research (India) Private Ltd.  
Natraj by Rustomjee 
602 A, 6th Floor,  
194, MV Road,  
Near Western Express Highway Metro Station 
Andheri (East) 
Mumbai 400 069 
Maharashtra 
India 
Phone: +91 226 218 7000  
Email: Priti.Somani@quintiles.com 
 


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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 (previously called 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. Detailed nonclinical and clinical data are 
provided 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 
 This novel 
mode of inhibition is further supported by the observation that
 
N. gonorrhoeae 
resistance to zoliflodacin has been mapped 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 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 area under the curve (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 Phase 2, multi-center, 
randomized trial to assess the safety and efficacy of oral zoliflodacin to treat uncomplicated 
urogenital gonorrhea in adults compared to intramuscular (IM) ceftriaxone. Subjects were 
randomly assigned to receive a single oral dose of 2 g of zoliflodacin, 3 g of zoliflodacin, or a 
single IM dose of 500 mg of ceftriaxone. In the per-protocol population, microbiological cure 
was observed in 96% and 100% in patients treated with 2 g and 3 g of zoliflodacin, respectively.8 


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Human Pharmacokinetics 
A Phase 1, single-center, multi-part trial with an oral suspension of zoliflodacin vs. 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 time to maximum plasma concentration (Tmax) ranging from 
 
 Following maximum plasma concentration (Cmax), plasma 
drug concentrations 
 The terminal elimination phase 
started at approximately 
 zoliflodacin concentrations 
 
 Exposures
 
 suggesting a 
 
 When 
 zoliflodacin was administered, 
 
 was seen if the drug was 
 The Cmax 
 
 consistent with 
 
.8 
In a Phase 2 trial of patients with gonorrhea, 2-g and 3-g doses of zoliflodacin were selected to 
maximize the probability of achieving the target plasma 
 
The AUC and Cmax values for zoliflodacin at the various doses also 
 
 values.8 
The PK of a single 4-g dose of zoliflodacin, packaged in the new formulation that will be used in 
the current trial, was evaluated in a recent Phase 1 trial in healthy subjects (DMID 16-0118) and 
was compared to PK data obtained in the previously completed trials.8,12 This analysis 
demonstrated that the PK of the 4-g dose of the new formulation of zoliflodacin is similar to the 
previous one, and higher exposure at the 4-g dose compared to the 2-g dose.   
Potential for Drug-Drug Interactions 
Zoliflodacin is a 
 in preclinical studies. In vitro and in vivo 
metabolism across species indicate that the compound is extensively metabolized via cytochrome 
P450- and non-P450-mediated pathways.
 The potential for drug-drug interactions has been evaluated using a physiologically-based 
PK (PBPK) model developed with 
.8 In summary: 
1. Zoliflodacin as a victim: Single doses of zoliflodacin ranging from 
 
 are predicted to 
 
 based upon Phase 1 PK data in healthy subjects, 
 


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 Since the 
primary PK driver for efficacy of zoliflodacin is 
. 
2. Zoliflodacin as a perpetrator: Zoliflodacin is predicted to increase 
 
 
. The extent of the interaction is not predicted to differ 
between the zoliflodacin 
. This interaction 
 
 
 administration of zoliflodacin. 
Safety 
In vitro studies: There was no
 
 There was no inhibition of 
 
.  
Some fluoroquinolones induce QT prolongation leading to arrhythmias and torsade de pointes 
(TdP), which have been correlated with binding to the hERG K+ channel. In contrast, 
zoliflodacin showed
 
 
 
 
Animal pharmacology and toxicology studies: Zoliflodacin was well-tolerated –
 
 
 There was 
 on any evaluated 
endpoints including 
 
 
were observed up to the highest dose tested. 
 
 were evident at either primary or recovery necropsy. 
 
 was established at 
 and correlated with 
 
 
At 
this highest dose tested, 
 was observed, consistent with
 
 These effects were 
 


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can be monitored in the clinical setting. There were 
 
 with zoliflodacin administration. 
 
 
, there were
 
.8 
Effects of zoliflodacin on female fertility and embryofetal development have been assessed in 
. Effects on 
  
Following administration of zoliflodacin at doses of 
 
 
 At all dose levels, there were 
 
. 
 were given zoliflodacin at 
 
 there was
 
there was 
 
 was considered to be 
. 
The effects of zoliflodacin on male fertility have been assessed in 
 were 
dosed 
. Administration at 
 
 was associated with a 
 
 which was 
 
. 
Human trials: Four trials have evaluated the safety of zoliflodacin in humans.  
In healthy subjects in the Phase 1 trials, 
 
 The most common AEs in the zoliflodacin groups were 
 
 There were 
 
.8,12 
In patients in the Phase 2 trial, zoliflodacin was generally safe and well-tolerated. Reported AEs 
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 with zoliflodacin 3 g (9%) compared to zoliflodacin 2 g (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 


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(≥3% based on the zoliflodacin 2-g and zoliflodacin 3-g groups combined and excluding 
infection-related AEs) were diarrhea, headache, and nausea.8,13 
In a recently completed Phase I open-label clinical trial (DMID 16-0118), a single 4-g dose of 
zoliflodacin formulated by the new method was shown to be safe and well-tolerated, and there 
were no differences in the safety profile from earlier studies.  
2.2 
Rationale 
2.2.1 
Study Rationale 
The current clinical trial will be conducted to assess the effect of zoliflodacin on cardiac 
repolarization. Medicinal products that prolong cardiac repolarization may have a proarrhythmic 
effect and have been associated with a specific, potentially fatal polymorphic ventricular 
tachycardia termed torsade de pointes (TdP). This tachycardia is usually observed in the setting 
of a prolonged QT interval, is often initiated after extrasystolic pauses, and is identified by the 
continuously twisting appearance of the QRS complex in the 12-lead ECG recording. Additional 
risk factors associated with a potential predisposition to the proarrhythmic effect include cardiac 
disease, congenital Long QT Syndrome (LQTS), hypokalemia, hypomagnesemia, bradycardia, 
and concurrent administration of other medicinal products known to prolong the QT interval. 
The QT interval, which represents ventricular recovery time, reflects the time between the 
depolarization of the first myocardial cells and the completion of repolarization of the last 
myocardial cells. Like ventricular refractoriness, it is influenced by the autonomic nervous 
system and changes in HR, and also by electrolyte disturbances and medications.14,15 The 
duration of the QT interval has prognostic implications in both healthy and diseased   
populations, with an abnormally prolonged QT interval becoming an increasingly accepted 
marker of risk for malignant ventricular tachyarrhythmias.16 
There are a number of compounds in various therapeutic classes that have proarrhythmic 
potential, including, among others, imidazoles, psychotropic agents, antihistamines, and 
antibiotics.17 Of particular concern is concurrent administration of other medicinal products 
known to prolong the QT interval and/or that are metabolized by and compete for cytochrome 
P4503A4 (CYP3A4) enzymes. A partial list of drugs considered to be associated with high-risk 
of TdP when associated with QTc prolongation is presented in Appendix E: A Partial List of 
Drugs Causing QTc Prolongation and Torsade de Pointes.   
Regulatory guidance has emphasized the need to obtain clear robust data on the effect of new 
chemical entities on ECG parameters with focus on cardiac repolarization as measured by the 
corrected QT interval (QTc) duration.16 Though many Phase 1, 2, and 3 studies may be 
conducted, they usually have insufficient sample size, infrequent sampling of ECG data, or the 
use of inadequate controls to overcome the high rate of spontaneous change in QTc duration. 


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This has resulted in regulatory guidance recommending a dedicated TQT study to define the 
ECG effects of new drugs.16 
Therefore, this four-arm crossover trial will include therapeutic and supratherapeutic dosing with 
zoliflodacin, placebo as a negative control, and oral moxifloxacin as a positive control. The trial 
will be conducted in accordance with relevant ICH E14 and Food and Drug Administration 
(FDA) guidance.16 
The positive control (moxifloxacin) will serve to validate the sensitivity of the assay to detect 
small increases from baseline in the QTc interval corrected using Fridericia’s formula (QTcF). 
Moxifloxacin will be used because it has been demonstrated to increase QTc by a mean of 6 
msec (time-averaged analysis: standard deviation (SD) = 26 msec; N = 787) after a 400-mg oral 
dose.16,18 However, thorough ECG studies have shown that this dose of moxifloxacin can be 
expected to show, for a time-matched analysis, a mean change of 10-15 msec, generally within 
1-6 h after dosing.19 
This trial will be performed in healthy subjects to eliminate variables known to change ECG 
parameters (e.g., concomitant drugs or diseases) among subjects. The sample size is driven by 
the need to do a time-matched statistical analysis on the primary endpoint as per ICH E14 
guidance. A crossover study design was chosen so that subjects will act as their own controls. A 
crossover trial can be conducted since the half-life of zoliflodacin is approximately 6 h. A wash-
out phase of 8 ±2 days after Day 1 of each dosing period is considered sufficient to prevent a 
carryover effect of the study drug between treatments. 
2.2.2 
Rationale for Dose Selection 
The zoliflodacin 2-g dose chosen for this trial is intended to achieve the drug exposure achieved 
in gonorrhea patients for the anticipated therapeutic single dose of 2-3 g. Several elements were 
considered in the selection of the zoliflodacin supratherapeutic dose including the anticipated 
clinical usage, the Phase 1 data with the original formulation, including utilization of population 
PK modeling and PBPK modeling, the potential for drug-drug interactions to influence 
zoliflodacin Cmax, and lack of availability of an IV formulation: 
1. Anticipated clinical usage: Zoliflodacin is being studied as a single-dose oral therapy for 
the treatment of uncomplicated gonorrhea. The product is not intended for multiple-dose 
administration, which has not been studied. The Cmax for zoliflodacin 4 g is anticipated to 
be supratherapeutic to peak concentrations observed for a therapeutic dose of 2-3 g when 
the drug is taken in the fasted state. 
2. Phase 1 data including utilization of population PK modeling and PBPK modeling: 
In a Phase 1 study, in the dose range
 
 
 The population PK model that has been developed adequately described the 
clinical data observed in healthy subjects 


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.8 
 
. Based on the 
population PK model, therefore, 
 
 
3. PBPK modeling: In addition to the population PK model, a PBPK model incorporating 
physicochemical properties, absorption, distribution, and elimination of zoliflodacin was 
developed to investigate the systemic exposure of the drug after oral administration to 
healthy adults and determine the potential for drug-drug interactions 
 
8. The PBPK model was utilized to assess 
 
. The model 
 
 
. Based on these simulations, 
 
  
4. Potential for drug-drug interactions to influence zoliflodacin Cmax levels: Using the 
PBPK model 
8, the potential for zoliflodacin to be 
either a victim and/or a perpetrator in drug-drug interactions was evaluated. Although 
metabolic clearance of zoliflodacin is mediated predominantly by 
 
 
 
. Based on these simulations, 
 
. 
5. The only formulation under development is the oral formulation: There is no IV 
formulation available for use in the TQT study. 
In the recently completed Phase 1 trial assessing PK parameters in healthy subjects 
 
. Thus, the 4-g dose will be used as the supratherapeutic dose required by the ICH 
E14 Guidance for TQT studies.16 Both the 2-g and 4-g doses of zoliflodacin were shown to be 
safe in previous studies. The 400-mg dose of moxifloxacin to be used is the highest dose 
recommended for use in the clinic and is commonly used as a positive control in TQT studies to 
ensure assay sensitivity for detecting potentially clinically significant changes in the QT/QTc 
interval.16,20,21  
2.3 
Identified and Potential Risks and Benefits 
2.3.1 
Zoliflodacin Risks 
 


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Identified Risks 
There are no identified risks associated with zoliflodacin to date. 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. 
Potential 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 
 
 
Continuous monitoring of 
 will be implemented in this trial. 
In a Phase 1 and Phase 2 trial, no trends in
 
 
. Standard clinical monitoring 
 
. 
 
 
. The incidence of these 
findings typically 
 
 
 
 
 
 in the first-in-human trial. 
 
.  
Effects of chronic dosing of zoliflodacin on 
 
 With respect to 
 
 
 
 
 
 


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. 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 before administration of zoliflodacin and at the 
end of the trial and will be required to use specified birth control methods during the trial 
and for 30 days after Final Visit.  
• Male subjects will be required to use specified birth control methods during the trial and 
for 90 days after Final Visit and will be advised not to donate sperm during this period.  
2.3.2 
Moxifloxacin Risks 
Moxifloxacin is a broad-spectrum 8-methoxy fluoroquinolone with activity against both Gram-
positive and Gram-negative bacteria, including anaerobes. It is a licensed antibiotic for serious 
and life-threatening bacterial infections and can be used when other drugs fail. The maximum 
recommended dosage is 400 mg daily.18, 22  
Overdose: Single oral overdoses up to 2.8 g were not associated with any SAEs. In case of acute 
overdose, the stomach should be emptied, and adequate hydration maintained. ECG monitoring 
is recommended due to the possibility of QT interval prolongation, and the patient should be 
carefully observed and given supportive treatment. The administration of activated charcoal as 
soon as possible after oral overdose may prevent excessive systemic moxifloxacin exposure.  
Adverse reactions: AEs judged by investigators to be at least possibly drug-related, occurring in 
≥2% of moxifloxacin-treated patients, were nausea (6%), diarrhea (5%), and dizziness (2%).  
Electrocardiogram: Prolongation of the QT interval in the ECG has been observed in some 
patients receiving moxifloxacin. Following oral dosing with 400 mg of moxifloxacin the mean (± 
SD) change in QTc from the pre-dose value at the time of maximum drug concentration was 6 
msec (± 26) (n = 787). Following a course of daily IV dosing (400 mg; 1-h infusion each day), 
the mean change in QTc from the Day 1 pre-dose value was 9 msec (± 24) on Day 1 (n = 69) and 
3 msec (± 29) on Day 3 (n = 290). No cardiovascular morbidity or mortality attributable to QTc 
prolongation occurred with moxifloxacin treatment in over 9,200 patients in controlled clinical 
trials, including 223 patients who were hypokalemic at the start of treatment, and there was no 
increase in mortality in over 18,000 moxifloxacin tablet-treated patients in a post-marketing 
observational study in which ECGs were not performed. 
In post-marketing studies, rare AEs were reported in patients treated with moxifloxacin. These 
include the following: 
Tendinopathy and tendon rupture: Fluoroquinolones, including moxifloxacin, are associated 
with an increased risk of tendinitis and tendon rupture in all ages. This AE most frequently 


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involves the Achilles tendon, and rupture of the Achilles tendon may require surgical repair. 
Tendon rupture can occur during or after completion of therapy; cases occurring up to several 
months after completion of therapy have been reported. 
Photosensitivity: Photosensitivity, which can appear as skin eruption or severe sunburn, can 
occur in some patients taking quinolone antibiotics after exposure to sunlight or artificial 
ultraviolet light (e.g., tanning beds).   
Central nervous system: Quinolones may cause central nervous system events including 
convulsions, dizziness, confusion, tremors, hallucinations, depression, and, rarely, suicidal 
thoughts or acts. Nervousness, agitation, insomnia, anxiety, nightmares or paranoia have also 
been reported. These reactions may occur following the first dose. 
Subjects will be closely monitored for all of these risks. 
2.3.3 
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. 
2.3.4 
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 17.5 mL at Screening Visit, 9 mL on Day -1, 
69 mL during each inpatient period (Days 1-2), 9 mL at Final Visit, and 338.5 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, AE evaluation, 
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 treatments (e.g., fluid replacement, good nutrition, vitamins, or iron 
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2.3.5 
Known Potential Benefits 
The trial has no direct benefit for 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. 
In accordance with the Health Insurance Portability and Accountability Act (HIPAA) regulation, 
subjects will be promptly notified of any clinical test results that would have an impact on their 
health. Screening evaluations may detect previously unknown abnormalities that could be 
clinically significant. This could benefit a subject, as it may lead to earlier diagnostic evaluation 
and treatment of an underlying disorder. 
2.3.6 
Risk/Benefit Ratio 
This ratio cannot be calculated by available data. The risk for an SAE, including a significant 
ventricular arrhythmia, occurring in a subject treated with single doses of 2 g and 4 g of 
zoliflodacin or 400 mg of moxifloxacin is thought to be low. Subjects will be treated in an 
inpatient unit and closely monitored during the trial, so that emergency care can be provided 
immediately if an acute arrhythmia or other event occurs. In addition, should a significant QTcF 
prolongation occur, with or without TdP, the subject will receive appropriate treatment if needed, 
and counseled to obtain further consultation to rule out a genetic predisposition towards 
development of LQTS after using licensed drugs. Data collected in the clinical development of 
zoliflodacin to date, especially preliminary data in Phase 2 studies in patients with uncomplicated 
gonorrhea, support further development of zoliflodacin. The benefit of a potential new addition 
to the drugs available for the treatment of gonorrhea outweighs the known risks of the 
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3 
OBJECTIVES AND OUTCOME MEASURES 
3.1 
Study Objectives 
3.1.1 
Primary 
• To evaluate the effect of zoliflodacin on the corrected QT interval of the ECG using 
Fridericia’s formula (QTcF)  
3.1.2 
Secondary 
• To evaluate the effects of zoliflodacin on other ECG parameters (PR, QRS, and RR 
intervals, and HR)  
• To evaluate the sensitivity of QTcF measurement using moxifloxacin 
• To evaluate the effect of zoliflodacin on T-wave morphology 
• To evaluate the PK of 2 g and 4 g oral zoliflodacin under fasting state 
• To evaluate the relationship between zoliflodacin PK and time-matched QTcF PD 
• To evaluate the safety and tolerability of 2 g and 4 g oral zoliflodacin 
3.2 
Study Outcome Measures 
3.2.1 
Primary 
• The upper bound of the one-sided 95% confidence interval (CI) for the largest time-
matched, placebo-corrected, baseline-adjusted mean QTcF interval (∆∆QTcF) collected 
in the 24-h period after 2 g and 4 g dose of zoliflodacin is <10 msec 
3.2.2 
Secondary 
• Time-matched, placebo-corrected, baseline-adjusted non-QT intervals (PR, QRS and RR 
intervals) and HR collected in the 24-h period after 2 g and 4 g dose of zoliflodacin 
• The lower bound of the one-sided 95% CI of the ∆∆QTcF is >5 msec at one or more 
individual timepoints between 1 h and 4 h after a single dose of moxifloxacin 400 mg  
• Incidence of abnormal T-wave morphology using defined categories in the 24-h period 
after 2 g and 4 g dose of zoliflodacin 
• Single-dose plasma concentrations (and PK exposure parameters, such as Cmax and AUC) 
of zoliflodacin collected up to 24 h after 2 g and 4 g dose of zoliflodacin 
• Relationship between plasma concentrations of zoliflodacin (and PK and exposure 
parameters, such as Cmax and AUC) and ∆∆QTcF up to 24 h after 2 g and 4 g dose of 
zoliflodacin 
• Occurrence of treatment-emergent SAEs, other unsolicited treatment-emergent AEs, and 
changes from baseline in VS, clinical laboratory values, and ECG parameters following 


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administration of zoliflodacin and moxifloxacin from time of dosing to Final Visit, or ET 
Visit 
 


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4 
STUDY DESIGN 
The TQT study will be performed in a single center, the Vince & Associates Clinical Research, 
Inc., clinical trials unit (CTU), according to a randomized, double-blinded (except for the use of 
moxifloxacin), placebo-controlled, four-period, four-treatment, crossover design balanced with 
respect to first-order carryover effect in 72 healthy male or female subjects, aged 18 to 45 years 
inclusive, to evaluate the effect of zoliflodacin on QTcF and other ECG parameters, the 
correlation of the drug concentrations (and PK profile) with ∆∆QTcF, and the PK and safety 
profiles of the new zoliflodacin formulation.  
Subjects who consent to participate will be enrolled in the trial if they meet all inclusion and no 
exclusion eligibility criteria. Laboratory assessments at Screening Visit will include routine 
clinical laboratory tests (HEM, CHEM, and UA), testing for viral serology (HIV antibody, 
HBsAg, and HCV antibody), 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.  
Each subject will receive one dose of each of four treatments, labeled A through D: 
• Treatment A: zoliflodacin 2 g PO (investigational drug, therapeutic dose) 
• Treatment B: zoliflodacin 4 g PO (investigational drug, supratherapeutic dose) 
• Treatment C: placebo PO (for zoliflodacin 4 g) 
• Treatment D: moxifloxacin 400 mg PO (positive control comparator) 
In the dosing phase, each subject will be randomly allocated to one of 12 dosing sequences 
before dosing on Day 1, Dosing Period 1, and receive a single dose of the following four study 
drugs on different days according to their randomly-assigned dosing sequence, as follows: 
Table 1: Dosing Sequences 
ABCD 
ACDB 
ADBC 
BADC 
BDCA 
BCAD 
CDAB 
CABD 
CBDA 
DCBA 
DBAC 
DACB 
Six of the planned 72 subjects will be included in each treatment sequence. The design is 
balanced for period and first-order carryover effects. 
Subjects will be dosed in the morning of Day 1 in each dosing period, in a staggered fashion at 
least several minutes apart, and will receive study drug at approximately the same time in each 


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subsequent dosing period. Each treatment will be administered 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. Zoliflodacin or placebo will be reconstituted in 60 mL of tap water. After the cup 
containing the 60 mL of zoliflodacin or placebo is taken, approximately 60 mL of tap water will 
be added to the cup and consumed by the subject to chase the initial dose. Moxifloxacin will be 
administered orally with 120 mL of water.  
Safety assessments post-dosing will include VS, PE, 12-lead standard ECG, and clinical 
laboratory tests including HEM, CHEM, and UA. Treatment-emergent AEs and SAEs will be 
assessed from time of dosing to end of trial. 
Continuous 12-lead Holter ECGs will be performed on Day 1 starting approximately 1 h before 
dosing and lasting 25 h. At timepoints for ECG extraction (see Section 8.3.1), subjects will be 
resting in the supine position for at least 10 min before and 5 min after the nominal time, without 
any ongoing stimulation (e.g., television). Three replicate ECGs will be extracted at each 
timepoint to measure ECG intervals and assess T-wave morphologies. 
Plasma for PK analysis will be collected at scheduled timepoints that match timepoints for ECG 
extraction before and after dosing on Day 1 and through Day 2, or ET if it occurs within 24 h 
after dosing. 
Subjects will be monitored as inpatients in the CTU up to 24 h after each dose (Day 2). They will 
then be discharged from the inpatient CTU and followed as outpatients for at least 5 days (Days 
3-7) after dosing in Dosing Periods 1-3. The total time to wash-out of the previously-received 
study drug is at least 8 days. The Final Visit will be 8 ±2 days after the last dose. 
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 safety monitoring 
in subsequent clinical trials with zoliflodacin. If criteria for halting the trial (as listed in Section 
9.5.1) are met in any dosing period, dosing will be suspended, and 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 
principal investigator (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 no exclusion criteria will be eligible for 
enrollment into the trial. No exemptions are granted on Inclusion/Exclusion Criteria in DMID-
sponsored trials. 
72 healthy male and female subjects, aged 18 to 45 years inclusive, will be enrolled in the trial.  
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 authorized site clinician (listed on FDA Form 1572)  
3) Willingness to comply with and be available for all protocol procedures, including 
inpatient confinement for 3 days in each dosing period and follow-up for the duration of 
the trial 
4) Aged 18 to 45 years inclusive on the day of first 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 all female subjects, whether of childbearing potential or post-menopausal by MH, a 
negative serum pregnancy test at Screening Visit and on Day -1 of each dosing period 
• 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 to become pregnant during 
the trial and for 30 days after Final Visit 
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 Visit 
• Note: A highly effective method of birth control is defined as one with a low failure 
rate (i.e., <1% per year) according to CDC criteria.23 These include progestin 
implants, intrauterine devices (IUDs), surgical (hysterectomy, salpingectomy, 
oophorectomy, or tubal ligation/occlusion; vasectomy), or abstinence. Use of 
methods with higher failure rate (such as progestin injectables, combined oral 
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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 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, are in the normal reference range with 
acceptable exceptions as noted in Section 8.2.1 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 8.2.5) 
14) Urine alcohol test is negative 
15) Willing to abstain from alcohol consumption for 2 days before Day -1 of Period 1 and for 
the duration of the trial 
5.2 
Subject Exclusion Criteria 
All must be answered NO for the subject to be eligible for study participation: 
1) History of acute or chronic cardiovascular disease or surgery 
• Note: Conditions include: congestive heart failure; coronary artery disease 
(myocardial infarction, unstable angina); cerebrovascular disease ( cerebrovascular 
accident or stroke or transient ischemic attack (TIA); chronic hypertension; or 
coronary revascularization surgery (coronary artery bypass grafting or percutaneous 
transluminal coronary angioplasty) 
2) History of cardiac arrhythmia or syncope related to cardiac arrhythmia or unexplained, or 
use of a cardiac pacemaker  
• Note: Conditions include: atrial fibrillation, atrial flutter, or non-sustained or 
sustained ventricular tachycardia); use of a cardiac pacemaker; personal or family 
history of LQTS; or family history of sudden death    
3) History of any other 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; malignancy except 


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low-grade (squamous and basal cell) skin cancer thought to be cured; chronic renal, 
hepatic, pulmonary, or endocrine disease, myopathy, or neuropathy; gastrointestinal 
surgery including weight loss surgery or biliary surgery 
4) Major surgical interventions are not permitted within 4 weeks of first dosing and during 
the trial. Minor surgical interventions are not allowed within 2 weeks of first dosing and 
during the trial. 
5) 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 
6) Active allergic symptoms to seasonal and animal allergens that are moderate to severe, 
affect daily activity, and require continuous treatment   
7) 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 
8) 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; any 
characteristics that would make QT assessment unreliable, including flat T waves; or 
any condition deemed clinically significant by a study investigator 
9) 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 
10) Positive serology results for HIV, HBsAg, or HCV 
11) Febrile illness with temperature ≥38.0°C for <7 days before dosing in each treatment 
period 
12) Donated whole blood or blood products within 60 days before first dosing, or plans to 
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•  Note: Blood products include RBCs, white blood cells (WBCs), platelets, and plasma 
13) Known allergic reactions to fluoroquinolones or to components present in the formulation 
or processing of zoliflodacin and moxifloxacin 
14) Treatment with another investigational product within 30 days of first 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 
15) Active drug or alcohol binge consumption, abuse, or dependence within 12 months 
before Screening Visit that, in the opinion of the investigator, would interfere with 
adherence to study requirements 
16) Use of any prescription medication within 30 days before first dosing or planned use 
during the trial except as noted below and approved by the designated study clinician 
• Note 1: Prohibited medications include moderate or strong CYP3A4 inducers (per 
6.6) and other drugs with known risk for QT prolongation and TdP (Appendix E and 
17); antibiotics; injectable or oral antidiabetic drugs; anti-lipid drugs; 
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 up to 7 days before first dosing or 7 days after 
last dosing 
• Note 2: Allowed medications include: oral contraceptives; H1 antihistamines; all 
medications approved for control of intraocular pressure including topical 
ophthalmic non-selective β-blockers, such as betaxolol, carteolol, levobunolol, 
metipranolol, and timolol; topical/ intranasal corticosteroids; nonsteroidal anti-
inflammatory drugs (NSAIDS); licensed influenza vaccine during the flu season, 7 
days before first dosing or 7 days after last dosing 
17) Use of non-prescription medications, vitamins, herbs, or nutritional supplements within 
15 days before first dosing or planned use during the trial unless approved by the study 
clinician 
• Note 1: Intake of nutritional supplements, juice, and herbal preparations or other 
foods or beverages that may affect the various drug-metabolizing enzymes and 
transporters (e.g., grapefruit, grapefruit juice, grapefruit-containing beverages, apple 
or orange juice, vegetables from the mustard green family [e.g., kale, broccoli, 
watercress, collard greens, kohlrabi, Brussels sprouts, mustard], and charbroiled 
meats) within 7 days before dosing 
• Note 2: Exceptions: St. John’s wart is not allowed within 30 days of dosing; vitamins 


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and over-the-counter (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 
18) Intake of caffeinated beverages or food within 72 h before first dosing or a history of high 
caffeine consumption (e.g., in the last 4 months drinking >5 cups of coffee/day) 
19) Smoking or use of tobacco or nicotine-containing products within 30 days before first 
dosing 
20) Engagement in strenuous exercise within 15 days before first dosing (e.g., marathon 
running, long-distance cycling, weight lifting) and during the trial 
21) 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 
22) 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 trial 
• Note: Includes trials that have a study intervention such as a drug, biologic, or device 
23) Is a CTU employee or staff member who is paid entirely or partially by the Office of 
Clinical Research Resources (OCRR)/NIAID contract for the DMID-funded trial 
• Note: CTU employees or staff include the PIs, sub-investigators, or staff who are 
supervised by the PI or sub-investigators 
5.3 
Treatment Assignment Procedures 
5.3.1 
Enrollment and Randomization Procedures 
Seventy-two 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. 
Randomized sequence assignments will be generated by a statistician at the DCC for this study.  
Randomization will occur following admittance to the CTU and confirmation of eligibility is 
confirmed. 
Subjects will be randomized to one of 12 treatment sequences (Section 4) with equal allocation 
(1:1:1:1:1:1:1:1:1:1:1:1). The randomization list will be generated centrally through the 
AdvantageEDCSM (Electronic Data Capture [EDC] System, Emmes) by the unblinded study 
biostatistician, and a list will be transferred to the unblinded study pharmacist before starting the 
study for the purpose of an emergency back-up. 


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Per ICH guideline E6: GCP, screening records will be kept at the CTU to document the reason 
why an individual was screened but did not meet trial entry criteria, by recording it in 
AdvantageEDCSM. 
Enrollment of subjects will be done online using the enrollment module of AdvantageEDCSM.  
The randomization code will be prepared by statisticians at the DCC and included in the 
enrollment module for this trial. AdvantageEDCSM will assign each subject to a treatment 
sequence after the demographic and eligibility data have been entered into the system. A 
designated individual at the participating site will be provided with a code list for emergency 
unblinding purposes, which will be kept in a secure place. Instructions for using the enrollment 
module are included in the AdvantageEDCSM User’s Guide. 
5.3.2 
Masking Procedures 
This is a double-blinded clinical trial with respect to administration of zoliflodacin or placebo. 
The study staff administering the study drug and assessing subjects will not be aware of the 
administered zoliflodacin or placebo. Administration of moxifloxacin will be open-label.  
The SMC will review aggregate data in open session and review grouped data only in closed 
session. 
5.3.3 
Reasons for Withdrawal and Discontinuation of Study Drug Administration 
A subject may withdraw from the trial at any time for any reason, without any consequences. 
A subject will be discontinued from the trial if any of the following 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 will 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), FDA, or 
DMID; 
• The subject’s well-being, based on the opinion of the investigator; 
• The occurrence of QTcF interval prolongation >500 msec or ≥60 msec above baseline 
or occurrence of a symptomatic or asymptomatic ventricular tachyarrhythmia with or 
without QTcF prolongation;  
• The occurrence of an SAE or AE warranting withdrawal. 
 


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A subject may be removed from data analysis for a dosing period during which the following 
events occurred, but not withdrawn from the trial (see also Section 5.3.4): 
• Failure to ingest the entire 60 mL volume of zoliflodacin suspension or placebo 
suspension; 
• Vomiting up to 5 h after dosing with zoliflodacin or placebo or moxifloxacin. 
5.3.4 
Handling of Withdrawals and Discontinuation of Administration 
• Subjects who are withdrawn before dosing may be replaced with a subject assigned 
the same sequence.  
• A subject who cannot ingest the entire 60 mL volume of zoliflodacin or placebo 
suspension or a subject who took the entire dose but vomits up to 5 h after dosing 
with zoliflodacin or placebo or moxifloxacin will be withdrawn from data analysis for 
the period when the event occurred, but will not be withdrawn from the trial and may 
complete the remaining treatment periods in the assigned dosing sequence.  
• Subjects who ingest the entire volume of the initial 60-mL drug suspension but who 
do not ingest the content of the second 60-mL rinse will not be withdrawn from the 
trial.  
• Subjects who withdraw after receiving at least one treatment in a treatment sequence 
will not be replaced, unless more than 16 subjects withdraw from the trial.  
• Subjects who received any amount of the study drug but withdraw from the trial 
within 24 h after dosing will be encouraged to continue follow-up (with subjects’ 
consent) for safety assessments and PK sample collection.  
• Subjects withdrawing will be asked to complete an ET Visit if they do not wish to be 
followed per protocol. 
5.3.5 
Lost to Follow-up 
If subjects 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 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 
Description of Study Products  
Zoliflodacin will be the investigational drug in this clinical trial and its effects will be compared 
to placebo matching the 4-g dose. Moxifloxacin will be the positive control (comparator) drug. 
Zoliflodacin 
The drug product is presented as a powder for oral suspension in a single sachet, each containing 
2 g of zoliflodacin, a spiropyrimidinetrione antibacterial agent. The sachet contains both 
zoliflodacin and excipients. The excipient ratio for zoliflodacin is 
 
; the excipients are detailed in the IB and Manual of 
Procedures (MOP) or Pharmacy Manual. Further details regarding the method of reconstitution 
and administration will be provided in the MOP or Pharmacy Manual. 
Zoliflodacin placebo  
This is composed of 4 g of the same excipients found in the drug 
 
 
. The excipients are detailed in the IB and the MOP or Pharmacy Manual.  
Moxifloxacin Hydrochloride  
Moxifloxacin is a slightly yellow-to-yellow crystalline substance, formulated for human use as 
400-mg film-coated tablets. It is a synthetic broad-spectrum, fluoroquinolone antibacterial agent 
that is licensed for oral administration as an antibiotic. 
Moxifloxacin is available as the monohydrochloride salt of 1-cyclopropyl-7-[(S,S)-2,8-
diazabicyclo [4.3.0]non-8-yl]-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinoline carboxylic 
acid.18 The excipients include cellulose microcrystalline, croscarmellose sodium, magnesium 
stearate, ferric oxide red, ferric oxide yellow, hypromellose 2910, polyethylene glycol 400, 
polysorbate 80, sodium stearyl fumarate, talc, silicon dioxide, and titanium dioxide. 
6.1.1 
Acquisition 
Zoliflodacin sachets and placebo are currently stored at a Good Manufacturing Practice (GMP) 
facility. Upon request by DMID, they will be shipped to the following address:    
DMID-Clinical Materials Services (CMS) 
Fisher BioServices 
20439 Seneca Meadows Parkway 
Germantown, MD 20876 


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Tel: 240-477-1350 
Fax: 240-477-1360 
E-mail: DMID.CMS@ThermoFisher.com  
The study drugs will be shipped from DMID-CMS to the CTU upon request and approval by 
DMID. Details will be provided in the protocol-specific MOP. 
Moxifloxacin hydrochloride tablets, 400 mg, NDC 55111-0112-30 , will be purchased from the 
manufacturer, Dr. Reddy’s Laboratories Limited, Bachupally – 500 090, India, and will be stored 
at DMID-CMS before shipment to the CTU.  
6.1.2 
Formulation, Packaging, and Labeling 
Zoliflodacin 
Zoliflodacin is presented as granules for oral suspension, 50% wt/wt, packaged in a single 
sachet. Each sachet contains 2 g of spray-dried zoliflodacin,
 
 
. 
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.”  
Zoliflodacin Placebo 
The placebo is provided in powder form as a bulk mixture of the drug product formulation but 
excluding zoliflodacin. 
Moxifloxacin 
Moxifloxacin is available in a bottle containing 30 unit doses of film-coated tablets of 
moxifloxacin hydrochloride USP equivalent to 400 mg of moxifloxacin.  
6.1.3 
Product Storage and Stability 
Zoliflodacin  
The zoliflodacin granules for oral suspension, 50% (w/w), will be stored at 2-8°C in the primary 
packaging.  
Zoliflodacin Placebo 
The placebo will be stored at 20-25°C. 
Moxifloxacin 
Moxifloxacin tablets will be stored at 20-25°C (68-77°F). A high moisture (humidity) storage 
environment will be avoided. 


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The clinical supplies storage area at the CTU will be monitored by its staff for temperature 
consistency with the acceptable storage temperature range specified in this protocol or in the 
Manual of Operations. Documentation of temperature monitoring will be maintained. 
6.2 
Dosage, Preparation, and Administration of Study Intervention/ 
Investigational Products 
Treatment A: One sachet containing 2 g of zoliflodacin will be reconstituted in 60 mL of tap water by 
the unblinded pharmacist and dosed orally after an overnight fast. The dose will be administered as a 
mix-and-drink solution in a standardized cup as described in the MOP. After the cup containing 60 mL 
of zoliflodacin is taken, approximately 60 mL of tap water will be added to the cup and consumed by 
the subject to chase the initial dose. 
Treatment B: Two sachets containing 2 g of zoliflodacin each will be reconstituted in 60 mL of 
tap water by the unblinded pharmacist and dosed orally after an overnight fast. The dose will be 
administered as a mix-and-drink solution in a standardized cup as described in the MOP. After 
the cup containing 60 mL of zoliflodacin suspension is taken, approximately 60 mL of tap water 
will be added to the cup and consumed by the subject to chase the initial dose.  The second 60 
mL volume is called ‘the rinse”.  
Treatment C: A single dose of 4 g of placebo in powder form, whose quantity will match that in 
the 4-g dose of zoliflodacin, will be reconstituted in 60 mL of tap water by the unblinded 
pharmacist and dosed orally after an overnight fast. The dose will be administered as a mix-and-
drink solution in a standardized cup as described in the MOP. After the cup containing 60 mL of 
placebo is taken, approximately 60 mL of tap water will be added to the cup and consumed by 
the subject to chase the initial dose. The second 60 mL volume is called ‘the rinse”.  
Treatment D: A single, commercially-available, film-coated, 400-mg tablet of moxifloxacin 
hydrochloride will be administered orally with 120 mL of tap water.  
Dosing, which includes ingestion of the entire 120 mL of tap water for any of the treatments (60 
mL of zoliflodacin or placebo suspension and 60 mL of the rinse, or 120 mL for taking the 
moxifloxacin tablet), will be completed within 5 min of initial suspension for treatment A, B, and 
C and ingestion for treatment D by a subject. After dosing, subjects will continue to fast for an 
additional 4 h while water is allowed ad lib. 
The CTU unblinded pharmacists will complete appropriate documentation such that the 
reconstituted materials dispensed to the CTU are clearly identified in a document suitable for 
auditing and monitoring. Clinical staff will also maintain a record of the volume of study drug 
suspension administered to and consumed by the subject.   
The study drugs will be inspected for damage, contamination, discoloration, or particulate matter 
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and labeled ‘Do Not Use’ until further notice. The Site PI or responsible person will 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 CTU will receive specific 
instructions on how to return it to DMID CMS or destroy it on site. Refer to the protocol-specific 
MOP for detailed information on the preparation and administration of zoliflodacin, placebo, and 
moxifloxacin. 
6.3 
Modification of the Study Intervention/ Investigational Products for 
a Subject 
Not applicable for single-dose study drug trial. See Study Halting Criteria, Section 9.5.1. 
6.3.1 
Overdose 
An overdose is defined as a dose greater than the high-dose level evaluated in the trial. All 
overdoses will be reported; if the overdose is associated with an AE, then the AE will also be 
reported. In the event of an overdose of zoliflodacin, the investigator will use clinical judgment 
in treating the overdose and contact the DMID Medical Monitor (MM). The investigator will 
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 Products   
The Site PI is responsible for the distribution and disposition of the study drugs and has ultimate 
responsibility for accountability. The Site PI may delegate this responsibility to the Site Research 
Pharmacist (RP). If delegated, the Site RP will be responsible for maintaining complete records 
and documentation of the study drugs’ receipt, accountability, dispensation, temperature 
monitoring, storage conditions, and final disposition. 
All study drugs, whether administered or not, will be documented on the appropriate study drug 
accountability record or dispensing log. Used and unused zoliflodacin sachets, placebo and 
moxifloxacin will be retained until monitored and released for disposition per DMID 
requirements. Details will be provided in the MOP.  
Upon completion of the trial and after the final monitoring visit, any remaining unused study 
drugs will either be returned or destroyed appropriately at the CTU as per DMID requirements 
and instructions that will be communicated to the CTU by the DMID CPM. 


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6.5 
Assessment of Subject Compliance with the Study Intervention/ 
Investigational Products  
Since each dose of zoliflodacin, placebo or moxifloxacin 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 
60-mL zoliflodacin or placebo suspension or the moxifloxacin tablet, or who vomit up to 5 h 
after dosing with zoliflodacin, placebo or moxifloxacin will be withdrawn from data analysis for 
the period when the event occurred, but will not be withdrawn from the trial and may complete 
the remaining treatment periods in the assigned dosing sequence. Subjects who do not ingest the 
content of the second 60-mL rinse will not be withdrawn from the trial. 
6.6 
Prior and Concomitant Medications/Treatments 
Medications include the following: prescription drugs, birth control hormonal preparations, non-
prescription medication, herbs, vitamins, nutritional supplements, and illicit and recreational 
substances.  
Medications taken before or after first dosing will be reported as Prior Medications or 
Concomitant Medications (ConMeds), respectively.  
Prior prescription medications will be recorded at Screening Visit and will not be taken for 30 
days before dosing or during the trial. Exceptions include: oral contraceptives; H1 
antihistamines; all medications approved for control of intraocular pressure including topical 
ophthalmic non-selective β-blockers, such as betaxolol, carteolol, levobunolol, metipranolol, and 
timolol; topical/ intranasal corticosteroids; NSAIDS; licensed influenza vaccine during the flu 
season, 7 days before the first dose or 7 days after the last dose. 
Zoliflodacin will not be co-administered in subjects taking medications that are strong (e.g., 
avasimibe, carbamazepine, phenytoin, rifampin, and St. John's wort) or moderate (e.g., efavirenz, 
bosentan, etravirine, modafinil, and nafcillin) inducers of CYP3A4. These medications will not 
be taken for 30 days before dosing and during the trial. 
Zoliflodacin will not be co-administered in subjects taking medications that pose a risk of TdP in 
association with prolonged QT/QTc (Appendix E and 17). These medications will not be taken 
for 30 days before dosing and during the trial.  
Moxifloxacin will not be co-administered in subjects taking multivalent cation-containing 
products including antacids, sucralfate, and multivitamins.  
A vaccine will not be received within 30 days before dosing or during the trial, except for 
licensed influenza vaccine during the flu season, which may be administered up to 7 days before 
the first dose or 7 days after the last dose.  


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Non-prescription medications, herbs, vitamins, and nutritional supplements will not be 
taken within 15 days before dosing and during the trial. Exceptions include: (1) nutritional 
supplements, juice, and herbal preparations or other foods or beverages that may affect various 
drug-metabolizing enzymes and transporters (e.g., grapefruit, grapefruit juice, grapefruit-
containing beverages, apple or orange juice, vegetables from the mustard green family [e.g., 
kale, broccoli, watercress, collard greens, kohlrabi, Brussels sprouts, mustard], and charbroiled 
meats) within 7 days before dosing; (2) St. John’s wart within 30 days before dosing and during 
the trial; and (3) vitamins and OTC medications taken for <48 h for the treatment of common 
symptoms (e.g., headache, indigestion, muscle pain) may be allowed if approved by the 
designated study clinician. 
Blood/blood products (RBCs, WBCs, platelets, and plasma) will not be donated within 60 days 
of dosing or received before Final Visit. 
Following dosing, each new ConMed and changes to existing medications will be recorded. 
Subjects will be required not to utilize non-study medications 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 vaccines 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 first dosing and 
during the trial.  
6.7.2 
Fluid and Food intake 
Subjects will be provided food and non-alcoholic beverages by the CTU during the dosing period 
of the trial. Subjects will fast for at least 8 h before dosing and 4 h after dosing. Water can be 
taken ad lib during those periods. For clinical laboratory blood draws, subjects will fast for at 
least 4 h. Meals during each dosing period will be standardized. Otherwise, there will be no 
restrictions regarding food and fluid intake.  


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6.7.3 
Alcohol, Marijuana and Illicit Drugs 
Alcohol will not be used at least 3 days before first study drug administration and during the 
trial. Marijuana and illicit drugs are exclusionary if detected before first dosing and prohibited 
during the trial. 
6.7.4 
Other Restrictions 
Smoking or use of tobacco or nicotine-containing products is prohibited within 30 days before 
first dosing and during the trial. Caffeinated beverages or foods containing caffeine are 
prohibited within 3 days before first 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 population surrounding the CTU, utilizing 
the CTU subject database and IRB-approved advertisements and social media. IRB-approved, 
prescreening 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 confirm 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 urine 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 
• Counsel to avoid rigorous physical activity 


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Subjects who meet the eligibility criteria will be contacted by CTU personnel and asked to return 
to the CTU for Day -1 assessments and possible inpatient admission.  
Subjects who fail screening due to a medical condition or abnormal laboratory tests including 
pregnancy test and positive tests for HIV, HBV, and HCV will be informed of the findings and 
counseled to seek medical care for further evaluation and treatment. If subjects test positive for 
HIV antibody, HBsAg, and/or HCV antibody, they will be informed that test results may be 
reported to the local health authorities according to state or local law. Subjects who fail screening 
will not be re-screened unless they had an inter-current, short-term medical illness. Subjects who 
meet eligibility criteria but could not be enrolled within permissible window may be rescreened.  
7.3 
Check-in / Baseline (Day-1 in each dosing period)                                          
(Overall, Days -1, 8, 16, and 24 for dosing periods 1, 2, 3 and 4, respectively) 
Subjects meeting all inclusion and no 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 confirm the subject remains eligible for enrollment 
• Update MH (Day -1 in Period 1 only) 
• Update Prior Medications  
• Perform abbreviated PE (Perform on each check-in. In Period 1, do not perform only if 
the screening PE was completed ≤7 days from dosing.)  
• Obtain VS 
• Obtain weight 
• Obtain blood and urine samples for clinical laboratory tests (collect on each check-in). In 
Period 1, do not collect if screening samples were collected ≤7 days 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 urine alcohol test for alcohol use 
• Obtain 12-lead standard ECG with 10-sec rhythm strip 
• Counsel to avoid rigorous physical activity 
• Review AEs/SAEs (Day -1 in Periods 2, 3, and 4, respectively, on study Days 8, 16, and 
24) 
 
Subjects who still meet the eligibility criteria on Day -1 before Period 1 will be admitted to the 
CTU on the same day.  
For subsequent dosing periods (2, 3, and 4), subjects will be admitted on Day -1.  Any new 
symptoms or abnormal assessments will be reviewed prior to dosing, and recorded as AEs.  


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Eligibility for continuation of dosing (dose 2, 3 and 4): 
Dosing for subsequent periods may proceed if: 
• A negative serum pregnancy test on Day -1 of each dosing period 
• Females of childbearing potential and males still agree to use acceptable contraception 
for the duration of the trial and for 30 days (females) or 90 days (males) after Final Visit 
• One of the following: 
o Subjects who did not experience any AE since the last dose administration  
o Any new or prior AEs were grade 1 or resolved, and in the opinion of the site 
principal investigator or appropriate sub-investigator, the AEs, individually or in 
cluster, do not pose a risk to the subject or would be likely to confound interpretation 
of the results. 
o Any new or prior AEs that were grade 2, should be either resolved or downgraded to 
Grade 1 and in the opinion of the site principal investigator or appropriate sub-
investigator, the AEs, individually or in cluster do not pose a risk to the subject or 
would be likely to confound interpretation of the results. 
o Any new or prior grade 3 AEs that were judged unrelated to study drug should be 
either resolved or downgraded to Grade 1 and in the opinion of the site principal 
investigator or appropriate sub-investigator, the AEs, individually or in cluster do not 
pose a risk to the subject or would be likely to confound interpretation of the results. 
If a subject has a Grade 3 AE judged related to study drug administration, this subject will be 
withdrawn from the study and will not receive subsequent dosing.  For all other AEs, dosing may 
be delayed up to 14 days in order to follow the AE for downgrading  or resolution according to 
the above.  If the subject does not meet the criteria for dosing specified above in 14 days, this 
subject will be withdrawn from the study and will not receive subsequent dosing. 
After admission to the CTU, the subject will fast at least 8 h before dosing but will have access 
to water during that period. 
7.4 
Inpatient period (Days 1-2 in each dosing period)                             
(Overall, Days 1-2, 9-10, 17-18, and 25-26 for dosing periods 1, 2, 3 and 4,  
respectively) 
7.4.1 
Randomization (Day 1, Dosing Period 1 only) 
A subject who continues to meet eligibility criteria by assessments performed before dosing will 
be enrolled in the trial and randomized on Day 1 of Dosing Period 1 to one of the 12 study 
treatment sequences. 
7.4.2 
Administration of Study Drug (Day 1 of each dosing period)                             
(Overall, Days 1, 9, 17, and 25 for dosing periods 1, 2, 3 and 4, respectively) 
Before Dosing:   
• Withhold breakfast but allow access to water   
• Review inclusion/exclusion criteria to confirm the subject remains eligible for dosing 


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• Update MH (Period 1) / AE review (Periods 2, 3, and 4) 
• Update Prior Medications /Document concomitant medications (ConMeds) (Periods 2, 3, 
and 4) 
• Obtain VS within 60 min before dosing 
• Perform symptom-directed PE, if applicable 
• Obtain 12-lead standard 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 within 30 min before dosing 
• Initiate 12-lead Holter ECG at least 1 h before dosing 
o Subjects will remain in a supine position at rest for at least 10 min before and 5 min 
after each of the following timepoints: 45, 30, and 15 min before dosing.  
o If timepoints for ECG extraction coincide with 12-lead standard ECGs, VS 
assessments, and PK blood draws, these procedures will be performed in this order: 
12-lead Holter ECG, 12-lead standard ECG, VS, and PK blood draw.   
Dosing:  
• Administer a single oral dose of the study drug with water, as described in Section 6.2, 
according to the randomization schedule for each treatment sequence and period 
• Withhold food until 4 h after dosing but allow access to water 
After Dosing: 
• Continue 12-lead Holter ECG: 
o Subjects will remain in a supine position at rest for at least 10 min before and 5 min 
after each of the following timepoints: 0.5, 1, 2, 3, 4, 6, 8, and 12 h after dosing.  
o If timepoints for ECG extraction coincide with 12-lead standard ECGs, VS 
assessments, and PK blood draws, these procedures will be performed in this order: 
12-lead Holter ECG, 12-lead standard ECG, VS, and PK blood draw.  
• Obtain 12-lead standard ECG with 10-sec rhythm strip at 1 h (±10 min), 2 h (±10 min), 
and 4 h (±10 min) 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 status 
• 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 
• Perform symptom-directed PE, if applicable 
• Perform AE and SAE assessments 
• Document ConMeds 


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7.4.3 
Inpatient Follow-up (Day 2 of each dosing period)                                            
(Overall, Days 2, 10, 18, and 26 for dosing periods 1, 2 3 and 4, respectively) 
• Continue 12-lead Holter ECG: 
o 
Subjects will remain in a supine position at rest for at least 10 min before and 5 min 
after the following timepoint: 24 h (±2 h) after dosing.  
o 
If the timepoint for ECG extraction coincides with 12-lead standard ECG, VS 
assessment, and PK blood draw, these procedures will be performed in this order: 
12-lead Holter ECG, 12-lead standard ECG, VS, and PK blood draw.  
• Obtain VS 
• Perform symptom-directed PE, if applicable 
• Perform AE and SAE assessments 
• Obtain clinical labs before discharge 
• Obtain blood (plasma) PK samples at 24 h (±2 h) after dosing 
• Document ConMeds 
• Obtain 12-lead standard ECG at 24 h (± 2 h) after dosing (before discharge on Day 2) 
• Remove 12-lead Holter recorder on Day 2 at 24 h after dosing after last recording 
• Remind women of childbearing potential on the avoidance of pregnancy 
• Remind male and female subjects on the use of appropriate contraception 
• Remind male subjects to refrain from sperm donation  
• Remind subjects to abstain from prohibited medications, alcohol, marijuana, and illegal 
drugs 
• Remind subjects to abstain from rigorous physical activity 
• Instruct on the next scheduled visit 
• Discharge subject from the CTU after review of clinical laboratory tests, ECGs, and other 
assessments by PI or authorized clinician 
7.5 
Outpatient period (Days 3-7 for each dosing period                           
(Overall, Days 3-7, 11-15, 19-23 and 27-31 for dosing periods 1, 2, 3 and 4, 
respectively) 
This will be a 5-day outpatient period between completion of treatment in the previous period 
and re-admission to the CTU for next dosing period except after Dose 4. Subjects will report to 
the CTU any new AEs/SAEs they have experienced, and medications they have used during the 
outpatient periods.  
7.6 
Final Visit (Day 32, 8 ±2 days after last dose in Dosing Period 4) 
• Obtain VS 
• Perform complete PE  


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• Obtain weight 
• Collect blood for serum β-HCG pregnancy test in all females 
• Perform AE and SAE assessments 
• Update ConMeds 
• Obtain 12-lead standard ECG with 10-sec rhythm strip 
• Obtain blood and urine for clinical laboratory tests  
• Remind male and female subjects on the avoidance of pregnancy 
• Remind female subjects to use appropriate contraception for 30 days after Final Visit 
• Remind male subjects to use appropriate contraception and refrain from sperm donation 
for 90 days after Final Visit 
• Discharge subject from the trial 
7.7 
Early Termination Visit (if needed) 
• Obtain VS 
• Perform complete PE  
• Perform AE and SAE assessments 
• Update ConMeds 
• Obtain 12-lead standard ECG with 10-sec rhythm strip 
• Obtain blood and urine for clinical laboratory tests  
• Collect blood for serum β-HCG pregnancy test in all females  
• Obtain blood PK sample if ET occurs within 24 h of dosing 
• Remind male and female subjects on the avoidance of pregnancy 
• Remind female subjects to use appropriate contraception for 30 days after ET 
• Remind male subjects to use appropriate contraception and refrain from sperm donation 
for 90 days after ET 
7.8 
Unscheduled Visit (if needed) 
A subject may return to the clinic for an unscheduled visit at any time. The following activities at 
a minimum will be performed:  
• 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 
• Obtain 12-lead standard ECG with 10-sec rhythm strip as needed for the evaluation of an 
AE 
• Remind 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 will 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 first study drug 
dosing and will be documented on the subject’s source documents and eCRF. Confirmation of 
eligibility will be performed before dosing on Day 1 of each dosing period. 
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 of 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 cardiovascular 
disorders, including MI and angina, cardiac arrhythmias including LQTS, syncope due to cardiac 
arrhythmias or unexplained, psychiatric illness, and substance abuse will be specifically 
solicited. Family history especially of sudden death will be obtained. The MH will be obtained at 
Screening Visit and updated upon admission to the CTU and before dosing on Day 1 in Period 1. 
After first study drug dosing, 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 after Dosing Period 4), or ET Visit, 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 in each dosing period on Day -1 in each inpatient period. If 
a complete PE was performed ≤7 days before first dosing, then an abbreviated PE will not be 
performed on Day -1 of the Dosing Period 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 in each dosing period before dosing on Day 1 and 
after dosing on Days 1 and 2, 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 of each dosing period and at Final Visit (Day 8 ±2 after Dose 4) or ET. 
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 5 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, and on Day 2 of each of the four dosing periods, and at Final Visit after 
Dose 4, or ET. On Day 1 of each dosing period, 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 Day 2, VS will be 
measured at 24 h (±2 h) after dosing. Acceptable ranges are shown in Appendix B. 
VS that are considered aberrant due to an error in measurement may be repeated. At 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 
12-lead Standard Electrocardiogram (ECG) 
A 12-lead standard ECG and 10-sec rhythm strip will be obtained at Screening Visit and on Day 
-1, Day 1 before and after dosing, Day 2 (24 ±2 h after dosing) in each treatment period, and 
Final Visit after Dose 4, or ET. On Day 1 of each dosing period, a 12-lead standard 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 
on 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 HEM and CHEM tests will be approximately 9 mL per sample (Appendix D). 
8.2.1 
Clinical Laboratory Evaluations (Hematology, Chemistry, and Urinalysis) 
Blood and urine samples for clinical laboratory tests will be collected at Screening Visit, on Day 
-1 of each dosing period (with the exception in the first dosing period if screening clinical labs 
were collected ≤7 days of Dose 1), on Day 2 of each dosing period, and Final Visit after Dose 4, 
or ET. Subjects must be fasting for > 4 h before any blood draw for clinical laboratory 
assessments. These tests will include: 
• HEM: Hgb, Hct, RBC count, platelet count, and WBC count with absolute differential 
count 
• 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, total carbon dioxide (CO2), magnesium 
• 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 of Treatment Period 1 should be in the 
normal reference range with acceptable exceptions, as shown below and in Appendix B: 
Elevated bilirubin due to documented Gilbert 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 two 
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 values that 
reach toxicity Grade 1 values are 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 after 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 to 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. 
8.2.2 
Viral Serology Testing 
Serological testing for HIV antibody, HBsAg, and HCV antibody 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. 
8.2.3 
Pregnancy Testing 
In all women, a serum β-HCG level will be measured at Screening Visit and on Day -1 of each 
dosing period; results must be negative for entry into each dosing period of the trial. Serum 
pregnancy test will also be performed at Final Visit, or ET. 
8.2.4 
Serum FSH Testing 
A serum FSH level for confirmation of post-menopausal status in female subjects will be 
measured at Screening Visit only.   
8.2.5 
Urine Toxicology Screening 
A urine toxicology screen will be performed at Screening Visit and on Day -1 to detect the 
presence of amphetamines, cocaine (and metabolite), barbiturates, benzodiazepines, opiates, 
MDMA, methadone, tetrahydrocannabinol, methamphetamines, tricyclic antidepressants 
(TCAs), 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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8.2.6 
Urine Alcohol Testing  
Detection of recent alcohol consumption in urine will be performed at Screening Visit and on 
Day -1 in each treatment period. Results must be negative for study eligibility.  
8.3 
Special Procedures and Assays 
8.3.1 
Continuous 24-h ECG Monitoring (Holter ECG Monitoring) 
ECGs for assessment of the primary endpoint will be obtained digitally during all four dosing 
periods using a continuous 12-lead Holter ECG digital recorder system. The continuous ECG 
recording will be started approximately 1 h before dosing on Day 1 of all dosing periods and will 
continue until 24 h after dosing (i.e., in the morning of Day 2). Three replicate ECG recordings 
will be extracted at the following timepoints in each dosing period: 45, 30, and 15 min before 
dosing (baseline) and 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 h after dosing for a total of 12 timepoints per 
subject per dosing period. The subject will be in a supine position for at least 10 min before 
recording an ECG and 5 min after the nominal timepoint for the ECG extractions from the Holter 
monitors. These timepoints will correspond to PK blood sampling for each dosing period, but 
ECGs will be obtained before the measurement of VS and collection of blood samples, to avoid 
the effect of stress on the ECG. The mean of pre-dose ECGs extracted on Day 1 of each dosing 
period will be used as baseline reference for results obtained after dosing. 
ECGs will be extracted from the Holter recordings over a 5-min period and used to measure 
ECG intervals. Digital QT, QTcF, PR, QRS, and RR intervals and HR will be determined by the 
Core ECG Lab. Digital ECGs will be read in accordance with the principles outlined in ICH E14 
Guidance for TQT studies.16  
The 12-lead Holter and ECG equipment will be supplied and supported by the VACR Phase 1 
CTU. All ECG data will be collected using a continuous 12-lead ECG digital recorder. The 
continuous 12-lead digital ECG data will be stored onto secure digital memory cards. ECGs to be 
analyzed will be collected at pre-determined timepoints (as indicated above and in Appendix A: 
Schedule of Study Procedures and Evaluations) and will be read centrally by IQVIA Cardiac 
Safety Services. 
The following principles will be followed in the IQVIA Cardiac Safety Services core laboratory: 
• Each extracted ECG will be analyzed by the cardiologist who will be blinded to subject 
identifiers, time, and treatment.  
• Electrocardiograms will be analyzed for PR, QRS, RR, and QT intervals using semi-
automated measurements and for morphological abnormalities including T and U waves 
manually by experienced cardiologists.  
• A limited number of skilled readers will be employed in the over-read process to control 
for variability in interpretation.  
• All ECGs from a single subject will be read together by the same reader.  


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• Consistent leads will be used for estimation of ECG intervals to the extent possible, with 
lead II as the primary lead. If technical issues prevent measurement in lead II, the QT will 
be measured in an alternative lead as per the core laboratory procedure.  
The following sections provide a brief description of ECG analysis methods utilized by the core 
laboratory. 
8.3.1.1 
TQT and ECG Extraction Technique 
Three replicate ECG recordings will be extracted at the indicated timepoints from each of the 
four dosing periods. For each timepoint, ECG extraction will typically be from the last 5 min of 
the period (at least 10 min) when the subject is maintained in a supine quiet position before the 
nominal timepoint (i.e., 25-30 min for the 0.5-h post-dosing timepoint and 55-60 min for the 1-h 
post-dosing timepoint). 
The ECG Core Lab will use Antares software to extract ECGs from the continuous 24-h Holter 
recordings after evaluating the complexes for sinus origin, heart rate stability criteria and the 
smallest noise score. During protocol-specified ECG extraction windows, three 10-sec digital 12-
lead ECG tracings will be extracted from continuous Holter recordings. The mean QT, QTcF, 
and RR values from each extracted replicate will be calculated, and the average of all mean 
values of primary ECG parameters from all replicate ECGs from a nominal timepoint will be 
used as the subject’s reportable value at that timepoint. 
The IQVIA Cardiac Safety Services will submit extracted ECG files in FDA-compliant HL 7 
XML to the FDA ECG warehouse. 
8.3.1.2 
T-wave Morphology Analysis and Measurement of PR and QRS Intervals 
Categorical T-wave morphology analysis will be performed manually in the three ECG replicates 
at each timepoint. Each fiducial point (onset of P-wave, onset of Q-wave, offset of S-wave, and 
offset of T-wave) will be electronically marked. 
The original ECG waveform (Table 2) and such annotations will be saved separately at the 
conclusion of the trial in Extensible Markup Language (XML) format for independent review 
and upload to the FDA ECG Warehouse. 
 
 


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Table 2: T-wave Morphology Categories (Assessed Manually) 
In addition to the T-wave categorical analysis, the presence of abnormal U waves will be noted. 
However, discrete U waves will be excluded from QT/QTc interval measurements. 
8.3.2 
Pharmacokinetics  
8.3.2.1 
Assay for Zoliflodacin 
Blood (plasma) samples for assay of zoliflodacin PK will be collected in K2EDTA tubes at the 
following study days and timepoints: On Day 1 within 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; and on Day 2 at 24 h (± 2 h) after dosing, or ET if occurs within 24 h of 
dosing. 
Blood samples will be obtained promptly after each corresponding Holter recording and 12-lead 
standard ECG timepoint and VS assessment. 
Sample collections will be scheduled for the nominal timepoint and actual collection times 
recorded in source documents.  
Plasma concentrations of zoliflodacin will be determined using a validated HPLC-MS/MS 
method. 
8.3.2.2 
Assays for Placebo and Moxifloxacin Samples  
Blood samples obtained during placebo dosing periods will not be analyzed. Blood samples 
obtained during moxifloxacin dosing periods will be stored and analyzed only for-cause.  
 
Category 
Description 
Normal T-wave  
Any T-wave not meeting any criterion below 
Flat T-waves  
T amplitude <1 mm (either positive or negative) including flat 
isoelectric line 
Notched T-wave (+)  Presence of notch(es) of at least 0.05 millivolt (mV) amplitude on 
ascending or descending arm of the positive T-wave 
 
Biphasic 
 
T-wave that contains a second component with an opposite phase that 
is at least 0.1 mV deep (both positive and negative/positive and 
polyphasic T-waves included) 
Normal T-wave (-) 
T amplitude that is negative, without biphasic T-wave or notches 
Notched T-wave (-)  
Presence of notch(es) of at least 0.05 mV amplitude on descending or 
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8.3.3 
Specimen Preparation, Handling, and Shipping 
8.3.3.1 
Instructions for Specimens Preparation, Handling, and Storage 
Details regarding the specimen preparation, handling, and storage are described in the protocol-
specific MOP. 
Blood samples left after all routine clinical laboratory testing and pharmacokinetic assays are 
completed will not be stored indefinitely or used for purposes other than those described. No 
genetic testing will be done on blood samples collected.  
8.3.3.2 
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 DMID-CMS at: 
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  
Plasma samples will then be provided by DMID-CMS to the bioanalytical lab, KCAS Inc., at:  
KCAS Bioanalytical Services  
c/o Marsha Luna, Senior Manager, PBI 
12400 Shawnee Mission Parkway 
Shawnee, KS 66216 
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 DMID of SAEs within 24 h of site awareness; 
• Provide detailed written reports, including necessary documentation requested by DMID 
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, causality, and severity of: 
1. Treatment-emergent SAEs occurring from time of first dose in dosing period 1 through 
Final Visit (Day 8 ±2 after last dose in dosing period 4), or ET; 
2. Clinical laboratory AEs occurring from time of first dose in dosing period 1 through Final 
Visit (Day 8 ±2 after last dose in dosing period 4), or ET; 
3. Non-serious, unsolicited treatment-emergent AEs occurring from time of first dose in 
dosing period 1 through Final Visit (Day 8 ±2 after last dose in dosing period 4), or ET. 
9.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters 
9.2.1 
Adverse Events 
Definitions 
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. 


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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. 
Any medical condition that is present at the time that the subject is screened will be considered a 
baseline finding and not reported as an AE. However, if the condition increases in severity or 
frequency at any time during the trial, it will be recorded as an AE. 
All AEs will 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. 
9.2.1.1.1 Relationship to Study Products 
AEs and SAEs will 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 
• Not Related: There is not a reasonable possibility that the study drug caused the AE/SAE 
The investigator will 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. 
9.2.1.2 
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 
and relationship to the study drug, date of resolution of the event, seriousness, and outcome. 
All AEs will be documented from the time of study drug dosing through 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 
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. 
*An AE is considered “life-threatening” if, in the view of either the investigator or DMID, 
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. 
9.2.3 
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 determine 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 after dosing 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 they deteriorate after study drug dosing. For 
abnormalities noted from the time of first 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 Grade 1 abnormalities, will be evaluated by the CTU clinician and reported as 
Grade 1 abnormalities if clinically significant. If not clinically significant, these will not be 
considered laboratory AEs and thus will not be graded but will be recorded in the source 
document and followed-up clinically at the discretion of the CTU clinician. Abnormal laboratory 


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values, performed as part of HEM, CHEM, 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 menses 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 or ET Visit 
Any AE that meets a protocol-defined serious criterion will be submitted immediately (within 
24 h of site awareness) on an SAE report form to DMID PVG: 
 
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 will also be entered into 
AdvantageEDCSM. Please see the protocol-specific MOP for details regarding this procedure. 


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Other supporting documentation of the SAE may be requested by DMID PVG and will be 
provided as soon as possible. 
The CTU will copy the ISM on SAE reports provided to the DMID PVG. The DMID Medical 
Monitor (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 subject safety and 
protocol conduct. 
At any time after completion of the trial, if the Site PI or appropriate sub-investigator becomes 
aware of an SAE that is suspected to be related to study drug, 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 DMID 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 DMID determines that the information qualifies for 
reporting as specified in 21 CFR Part 312.32. DMID will also notify FDA of any unexpected fatal 
AE or suspected life-threatening AE as soon as possible, but in no case later than 7 calendar days 
after DMID’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 request. 
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 will be reported; if the overdose is 
associated with an AE, then the AE will also be reported. In the event of an overdose of study 
drug, the investigator will use clinical judgment in treating the overdose and contact the DMID 
MM. The investigator will 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. 


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9.3.4 
Reporting of Pregnancy 
Pregnancies that occur in female subjects during the trial 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 Final Visit. A male subject who participates in 
the trial and whose female partner becomes pregnant from the time of first dosing to 90 days after 
Final 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 
document and eCRF. 
9.5 
Halting Rules 
9.5.1 
Study Halting Criteria 
9.5.1.1 
Halting Criteria for Zoliflodacin and Placebo Periods 
Study dosing of zoliflodacin or placebo will be temporary halted, and a review of available safety 
data will be conducted by the SMC if any of the following occur after dosing:  
1. Death of a subject following dosing regardless of relatedness to the study drug; 
2. One subject with a non-fatal SAE that is considered related to the study drug by the study PI 
or authorized physician (listed in FDA Form 1572); 
3. Two or more subjects experience a QTcF >500 msec or ≥60 msec above baseline, based on 
readings from at least two standard 12-lead ECGs after study drug administration; 
4. 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; 
Note: VS abnormalities will be considered part of a systemic disorder or an organ-specific condition, as described 
in Appendix C: Adverse Events Toxicity Grading Criteria 


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, in order to be included among the Study Halting Criteria.  
5. One subject experiences a symptomatic ventricular tachyarrhythmia with or without QTcF 
prolongation after study drug administration; 
6. An overall pattern of symptomatic, clinical non-serious events 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 a subject in the trial. 
9.5.1.2 
Halting Criteria for Moxifloxacin Periods 
Study dosing of moxifloxacin will be temporary halted, and a review of available safety data will 
be conducted by the SMC if any of the following occur after dosing: 
1. Death of a subject following dosing regardless of relatedness to moxifloxacin;  
2. One subject with a non-fatal SAE that is considered related to moxifloxacin by the study PI or 
authorized physician (listed in FDA Form 1572); 
3. Three or more subjects with a Grade 3 systemic AE coded in the same organ system that is 
considered related to moxifloxacin by the study PI or authorized clinician.  
Note: VS abnormalities will be considered part of a systemic disorder or an organ specific condition, as described 
in Appendix C: Adverse Events Toxicity Grading Criteria 
, in order to be included among the Study Halting Criteria. 
9.6 
Safety Oversight 
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 will 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 
Site PI, ISM, or DMID MM 
• Scheduled meeting 


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o The SMC will review cumulative, unblinded interim safety data when available after 
database lock 
Procedures for SMC reviews/meetings will be defined in the SMC charter. The SMC will review 
safety data and advise on resumption or stopping of a temporary halted trial, and safety 
monitoring in future clinical trials with zoliflodacin.  


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10 
CLINICAL MONITORING 
10.1 
Site Monitoring Plan 
Site monitoring will be conducted to ensure that human subject protections, study and laboratory 
procedures, study intervention administration, and data collection processes are of high quality 
and meet DMID, 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, subjects’ source documents, eCRFs, ICFs, clinical and laboratory 
reports, and protocol and GCP compliance. Site monitors will have access to the CTU, 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 
The trial will evaluate the following hypotheses: 
a. Zoliflodacin administered at 2-g or 4-g doses causes a prolongation of the QTcF interval 
that exceeds the criteria in the ICH Guidance E14.16  
(A negative effect is defined in ICH Guidance E14 as “one in which the upper bound of the 
one-sided 95% confidence interval (CI) for the largest time-matched mean effect of the drug 
on the QTcF interval is <10 msec.”) 
b. The trial has the sensitivity to detect an effect on QTcF of regulatory concern, as produced 
by moxifloxacin. 
 
(Assay sensitivity will be demonstrated if, for at least one individual timepoint between 1h 
and 4h after administration of moxifloxacin, the lower bound of the one-sided 95% CI for 
ΔΔQTcF, is >5 msec.) 
11.2 
Sample Size Considerations 
Enrollment of 72 subjects would provide at least 84% power to conclude a negative effect, given 
that up to 16 subjects may withdraw early prior to beginning to replace subjects (at least 56 
subjects evaluable), and assuming a standard deviation of ΔΔQTcF of 7 msec and an underlying 
effect of 5 msec. 
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 advise on safety 
monitoring in future clinical trials of zoliflodacin. If criteria for halting the trial (as listed in 
Section 9.5.1) are met, 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 
unblinded statistician may present data in a closed session of an SMC meeting. 
11.4 
Final Analysis Plan 
The ICH Guidance E9 (Statistical Principles for Clinical Trials) will be followed for all statistical 
content.24 Summaries of frequencies and percentages will be presented for categorical data, and 
summary statistics such as minimum, median, mean, SD, and maximum values will be presented 
for continuous data. Details of safety, QTcF, other ECG interval measurements (QT, PR, QRS, 
RR and HR [based on RR measurements]), T-wave changes, ECG morphology, and PK and 


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PK/PD data analyses and presentations will be described in the Statistical Analysis Plan (SAP) 
and accompanying Tables, Listings, and Figures (TLF) templates. The SAP for safety and PK 
data will be prepared and finalized by the DCC before final data lock. The SAP for Holter ECG 
data will be prepared by IQVIA Cardiac Safety Services (CSS) and appended to the SAP. 
Analyses included in the clinical study report (CSR) will be performed by the DCC and CSS after 
final data lock. Any change from originally planned statistical analyses will be reported in the 
CSR.   
11.4.1 
Analysis Populations 
All subjects who received at least one dose of study drug (zoliflodacin, placebo, or moxifloxacin) 
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. If any subjects are found to be noncompliant with respect to dosing or have 
incomplete data, a decision to include them in the analysis will be made on a case-by-case basis.  
The PD analysis population will include all subjects who provide evaluable Holter ECG data from 
at least one study treatment, without protocol deviations potentially impacting the ECG intervals. 
Exclusions from the PD analysis population due to protocol deviations will be decided before 
unblinding. Subjects must have at least one ∆∆QTcF value defined for inclusion in the PD 
analysis population.   
The PD and PK analysis population will include all subjects who provide both evaluable Holter 
ECG and zoliflodacin PK data for the relevant study treatment. The PK/QTcF population will be 
the subset of subjects included in both the PD analysis population and the PK analysis population. 
Additionally, for the concentration-QTcF analysis, time-matched zoliflodacin concentrations 
corresponding to the ECG assessments will also be necessary. 
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. 


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11.4.3 
Safety Analysis 
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, SD, median, minimum, and maximum) for clinical 
laboratory data, 12-lead standard ECG and Holter 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 (with the 
exception of Holter ECG, see below). For change-from-screening summaries, subjects with an 
undefined change from screening, due to missing data, will be excluded. Clinical significance of 
abnormalities will be indicated in the listings. 
11.4.4 
PK Analysis  
PK parameters will be estimated for zoliflodacin by noncompartmental methods using version 8.0 
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 
• 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. 


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The results will be listed by subject, and summarized with descriptive statistics including: n, 
mean, SD, coefficient of variation, median, minimum, maximum, geometric mean, and geometric 
SD.  
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. 
11.4.6 
Analysis of Continuous ECG Parameters (Pharmacodynamics) 
11.4.6.1 
ECG Analysis and Interpretation 
The ∆∆QTcF, calculated as differences between time-matched mean change-from-baseline QTcF 
values for active treatment relative to placebo, will be evaluated to quantify the QTcF 
prolongation of the active treatments. The median of the three Holter ECG QTcF interval 
measurements at 45, 30, and 15 min before each dosing will be regarded as baseline for the 
respective period. 
QTcF corrections will be calculated using Fridericia’s formula: 
• QTcF=QT/RR0.33 
The primary variable will be the change-from-baseline QTcF (∆QTcF). Other endpoints to be 
evaluated include HR (bpm; calculated from RR interval measurements), PR (msec), QRS (msec), 
RR (msec), and cardiac abnormalities (morphologies, rhythm, and conduction).   
All statistical analyses and reporting of digital ECG data will be conducted on the mean of the 
replicate intervals within a timepoint. Descriptive statistics including two-sided 90% CI will be 
generated for observed, change-from-baseline, and time-matched placebo-corrected change-from-
baseline ECG intervals. 
11.4.6.2 
Primary Analysis: QTcF Effect 
The primary hypothesis to be tested is that following administration of zoliflodacin 2 g and 4 g, 
the upper bound of the one-sided 95% CI of treatment effect on ∆∆QTcF is ≥10 msec for at least 
one of the ECG assessments, against the alternative hypothesis that all mean effects are <10 msec. 
The primary analyses will be conducted to evaluate the effects of zoliflodacin 2 g and 4 g on 
cardiac repolarization as measured by ∆QTcF relative to placebo. Analysis will be performed 
using a linear mixed model with ∆∆QTcF as the dependent variable, with baseline QTcF, 
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effects, and subject nested within sequence as random effects. At each of the 9 post-baseline 
timepoints and for each zoliflodacin dose, a one-sided 95% CI for the treatment effect on 
∆∆QTcF will be estimated using least square means. There will be 18 CIs, one for each 
combination of zoliflodacin dose and timepoint. A negative effect of 2 g or 4 g zoliflodacin will 
be concluded if the maximum of the 18 one-sided 95% CI upper bound is <10 msec. No 
adjustment will be made for multiplicity, since it is not required under intersection-union testing, 
as planned for the trial. No subgroup analyses are planned. 
11.4.6.3 
Secondary Analyses: Non-QTc Intervals 
Non-QTc intervals (PR, QRS, and RR intervals) and HR (estimated from measurement of RR 
intervals) will be tabulated at each timepoint for each treatment group and the mean ± SD, 
median, 95% CI, minimum, and maximum values will be shown. Comparisons among treatment 
groups will be done using linear mixed effects models.  
Categorical analysis of PR, QRS, and RR intervals will also be performed. The following criteria 
will be used to specify noteworthy non-QTc intervals (PR, QRS, and RR intervals) and HR 
(derived from RR intervals) and the number of subjects and number of timepoints will be 
tabulated for each treatment group and may be compared statistically: 
• 
PR change-from-baseline >25% resulting in PR >200 msec  
• 
QRS change-from-baseline >25% resulting in QRS >120 msec 
• 
HR change-from-baseline >25% decrease resulting in HR <50 bpm 
• 
HR change-from-baseline >25% increase resulting in HR >100 bpm 
11.4.6.4 
Assay Sensitivity 
Another secondary hypothesis is that a moderate increase in QTcF with administration of the 
positive control moxifloxacin 400 mg is detectable in this trial.   
The model as described in the primary analyses will be repeated with the moxifloxacin treatment 
for assay sensitivity evaluation. The 1, 2, 3, and 4 h timepoints will be evaluated for assay 
sensitivity. Type I error (familywise error rate) will be controlled at an overall level of 5% by 
using a prespecified multiplicity adjustment. Assay sensitivity will be demonstrated if the lower 
bound of one-sided 95% CI (bounds will vary based on multiplicity adjustment) for treatment 
effect on ∆∆QTcF in at least one timepoint is >5 msec. In addition, two-sided 90% CIs will be 
obtained for the treatment effect on ∆∆QTcF at every timepoint and displayed graphically. 
11.4.6.5 
Categorical Analyses 
QTcF intervals will be categorized and tabulated for each treatment. The following criteria will be 
used to specify noteworthy QTcF intervals:  
• QTcF >450 msec  
• QTcF >480 msec  


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• QTcF >500 msec  
• QTcF increase ≥30 msec from baseline 
• QTcF increase ≥60 msec from baseline 
The number and percent of subjects in each category will be calculated. Comparisons across 
treatments may be conducted if sufficient counts are observed.  
11.4.6.6 
Cardiac Abnormalities: 
The morphological waveform analysis of the ECG data for TQT evaluations at each timepoint 
will be utilized for the summary of new onset cardiac abnormalities for each treatment. Results 
will be summarized in frequency tables with counts and percentages for both number of subjects 
and number of timepoints. 
11.4.7 
Concentration-QTcF Modeling 
Concentration-QTcF modeling will be utilized to characterize the exposure-QTcF relationship for 
zoliflodacin.25,26 Initially, linear or non-linear mixed-effect models will be fit to ∆∆QTcF values 
for only the zoliflodacin arms. More complex models will be employed if simpler models provide 
inadequate model fit. Hysteresis effects will be examined and may be utilized to characterize the 
delayed effects if observed. Estimates of the mean prolongation at the geometric mean 
zoliflodacin Cmax for the zoliflodacin 2-g and 4-g doses will be made from the final exposure 
response model with corresponding two-sided 90% CIs.   
Detailed analysis plans will be documented in the SAP. Results of the concentration-QTcF 
evaluations will be reported in the CSR. 


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12 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
The CTU 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 CTU will permit authorized representatives of 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 CTU. 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 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 DMID, 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 CTU for clarification and resolution. 


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14 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
14.1 
Ethical Standard 
The PI will ensure that the trial 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 associated ICFs by an 
appropriate IRB/EC listed on the FWA. Any amendments to the protocol or consent materials will 
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 DMID will 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 will be obtained before any protocol-specified procedures or interventions are 
carried out, and in accordance with 21 CFR 50.25 and 45 CFR 46. Information will 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 will 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 will also be informed of alternative procedures that may be available, and the 
important potential benefits and risks of these available alternative procedures. Subjects will 
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 will 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 will 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. Subjects will 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, will coerce or unduly influence a subject to participate 
or continue to participate in the trial. The extent of the confidentiality of the subjects’ records will 
be defined, and subjects will be informed that applicable data protection legislation will be 
followed. Subjects will be informed that the monitor(s), auditor(s), IRB, DMID, 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 subject’s confidentiality, 
to the extent permitted by applicable laws and regulations, and that, by signing a written ICF, the 
subject is authorizing such access. Subjects will 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 will 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 will be kept 
on file by the investigator for possible inspection by regulatory authorities and/or DMID and 
regulatory compliance persons. The subject will receive a copy of the signed and dated written 
ICF and any other written information provided to the subjects and will 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 aged <18 years will be excluded from participation because insufficient data are 
available in adults to judge potential risk in children, and as a Phase 1 trial, there is no known 
benefit.   
Neither women nor minorities will be routinely excluded from participation in the trial. Subjects 
will be recruited without regard to gender or race. It is expected that race and gender distributions 
in the trial 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 effects 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 
DMID and its 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 data will be released to any unauthorized third 
party without prior written approval from DMID. 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 subject; or (4) study results which may be 
published as described in Section 16. 
The study monitors or other authorized representatives of DMID may inspect all documents and 
records required to be maintained by the Site 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 
Certificate of Confidentiality 
To protect privacy, we have received a Certificate of Confidentiality.  With this Certificate, the 
researchers cannot be forced to release information that may identify the research subject, even by 
a court subpoena, in any federal, state, or local civil, criminal, administrative, legislative, or other 
proceedings.  The researchers will use the Certificate to resist any demands for information that 
would identify the subject, except as explained below. 


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The Certificate cannot be used to resist a demand for information from personnel of the United 
States Government that is used for auditing or evaluation of federally funded projects, like this 
study, or for information that must be released in order to meet the requirements of the Federal 
Food and Drug Administration (FDA). 
A Certificate of Confidentiality does not prevent the subject from voluntarily releasing 
information about themselves or their involvement in this research.  If any person or agency 
obtains a written consent to receive research information, then the researchers may not use the 
Certificate to withhold that information.   
The Certificate of Confidentiality does not prevent the researchers from reporting without the 
subject’s consent, information that would identify the subject as a participant in the research 
project regarding matters that must be legally reported including: child and elder abuse, sexual 
abuse, or wanting to harm themselves or others.   
The release of individual private information or specimens for other research will only occur if 
consent was obtained from the individual to whom the information, document, or biospecimen 
pertains, or for the purposes of other research that is in compliance with applicable Federal 
regulations governing the protection of human subjects in research. 
14.7 
Study Discontinuation 
DMID has the right to terminate the trial or the CTU’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 
• 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 will 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 will be consistent with the source documents or the discrepancies will 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 will be reviewed by the clinical team and data entry 
staff, who will ensure that they are accurate and complete. AEs will 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 CTU under the supervision of 
the Site PI. During the trial, the investigator will 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 study 
personnel.  
ECG data captured by 12-lead Holter monitors will be transmitted to the ECG Core Lab. QT, 
QTcF, and other ECG interval measurements and ECG interpretations will be performed at the 
ECG Core Lab using validated protocols. ECG data management is provided by IQVIA Cardiac 
Safety Services. 


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15.3 
Types of Data 
Data for the trial will include clinical safety assessments, laboratory safety assessments, 12-lead 
standard ECGs, Holter ECG interval measurements and waveform assessments, and PK 
parameters. 
15.4 
Timing/Reports 
A final CSR will be prepared after all safety, 12-lead standard ECG, 12-lead Holter ECG, and PK 
data are available. See Section 9.6.2 for additional reporting requirements.  
15.5 
Study Records Retention 
Study files and ICFs will 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 will be retained for a longer period, 
however, if required by local regulations. No records will be destroyed without the written 
consent of DMID, if applicable. It is DMID’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 CTU staff. Corrective actions for protocol deviations are to be developed by 
the CTU 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 will be promptly reported to 
DMID via DCC’s AdvantageEDCSM. 
All protocol deviations, as defined above, will be addressed in subject source documents. A 
completed copy of the DMID Protocol Deviation Form will be maintained in the regulatory file, 
as well as in the subject's source document. Protocol deviations will be sent to the local IRB/EC 


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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 study, the lead Principal Investigator is expected to publish the 
results of this research in a scientific journal. All investigators funded by the NIH must submit or 
have submitted for them to the National Library of Medicine’s PubMed Central 
(http://www.ncbi.nlm.nih.gov/pmc/) an electronic version of their final, peer-reviewed 
manuscripts upon acceptance for publication, to be made publicly available no later than 12 
months after the official date of publication. The NIH Public Access Policy ensures the public has 
access to the published results of NIH funded research.  It requires investigators to submit final 
peer-reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed 
Central upon acceptance for publication. Further, the policy stipulates that these papers must be 
accessible to the public on PubMed Central no later than 12 months after publication. 
 
Refer to: 
• NIH Public Access Policy, http://publicaccess.nih.gov/  
• NIH Office of Extramural Research (OER) Grants and Funding, 
http://grants.nih.gov/grants/oer.htm  
 
As of January 2018, all clinical trials supported by the NIH must be registered on 
ClinicalTrials.gov, no later than 21 days after the enrollment of the first subject. Results of all 
clinical trials supported by the NIH, generally, need to be submitted no later than 12 months 
following the primary completion date. A delay of up to 2 years is available for trials that meet 
certain criteria and have applied for certification of delayed posting. As part of the result posting, 
a copy of this protocol (and its amendments) and a copy of the Statistical Analysis Plan will be 
posted on ClincialTrials.gov. For this trial the responsible party is DMID/NIAID/NIH, which will 
register the trial and post results.   
 
Refer to: 
• Public Law 110-85, Section 801, Clinical Trial Databases 
• 42CFR11 
• NIH NOT-OD-16-149 
 
 


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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 2 Jan 2018) 
 
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 2 Jan 2018) 
 
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 2 Jan 2018) 
 
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 2 Jan 2018)  
 
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; 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; 
59(1):467-74. 
  
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; 60(1):621-623. 
 


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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 27 July 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. Coumel P, Maison-Blanche P. Heart rate variability and QT interval: their relationships with the 
cardiac frequency. In Aubert AE, Ector H, Stroobandt R (eds.), 1994. Cardiac Pacing and 
Electrophysiology. Dordrecht: Kluwer Academic Publishers, pp. 63-71. 
 
15. Lecocq B, Lecocq V, Jaillon P. Physiologic relation between cardiac cycle and QT duration in 
healthy volunteers. Am J Cardiol 1989; 64(8):481-6. 
 
16. 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/Guidances/U
CM073153.pdf (accessed 27 July 2017) 
 
17. Woosley RL, Heise CW and Romero KA. www.Crediblemds.org, QTDrug Lists, Accessions Date 
19 December 2017, AZCERT, Inc., 1822 Innovation Park Drive, Oro Valley, AZ 85755. 
 
18. Moxifloxacin hydrochloride [package insert]. Available at:  
https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=71b02da1-3175-1db8-
192a-c0a8a6cd98a5&type=display   
(Accessed 25 May 2018) 
 
19. Florian et al. Population Pharmacokinetic and Concentration-QTc Models for 
Moxifloxacin: Pooled Analysis of 20 TQT studies. J Clin Pharmacol 2011; 51:1152. 
 
20. Bloomfield DM, et al (2008).  The Effect of Moxifloxacin on QTc and Implications for the Design 
of Thorough QT Studies. Clin Pharmacol Therapeut 2008; 84:475-80. 
 
21. Darpo B. The thorough QT/QTc study 4 years after the implementation of the ICH E14 guidance. 
Br J Pharmacol. 2010; 159(1):49-57. 
 
22. Bolon MK. The newer fluoroquinolones. Infect Dis Clin North Am 2009; 23(4):1027-51. 
 
23. U.S. Medical Eligibility Criteria for Contraceptive Use, 2016. CDC MMWR 2016; 65(3):1-108. 
 
24. Guidance for Industry. E9 Statistical Principles for Clinical Trials. FDA, September 1998. 
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm0
73137.pdf (accessed 27 July 2017) 
 
25.  Garnett, CE, et al. Concentration-QT Relationships Play a Key Role in the Evaluation of 
Proarrhythmic Risk during Regulatory Review. J Clin Pharmacol 2008; 48:13-18. 


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26. Salvy, V. et al. Update on the Evaluation of New Drugs for the Effect of Cardiac Repolarization in 
Humans in Early Drug Development. British J Pharmacol 2010; 159:34-48. 
 


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18 
APPENDICES


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Appendix A: Schedule of Study Procedures and Evaluations 
Table 3: Schedule of Events 
Study Visit 
Screening1 
Inpatient Periods 1-4 
Outpatient 
Periods 1-4 
Final Visit 
(after Dose 4) 
Unscheduled 
Early 
Termination 
Check-
in 
Dosing 
Follow-up 
Study Day / Assessments 
-21 to -2 
-1 
1 
2 
3 - 7 
8 (± 2) 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria2 
X 
X 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Medical history update 
 
X 
 
 
 
 
 
 
Prior and ConMeds 3 
X 
X 
X 
X 
X 
X 
X 
X 
Complete PE4 
X 
 
 
 
 
X 
 
X 
Abbreviated PE5 
 
X 
 
 
 
 
 
 
Symptom-directed PE6 
 
 
X 
X 
 
 
X 
 
Height, weight, BMI7 
X 
 
 
 
 
 
 
 
Weight 
 
X 
 
 
 
X 
 
X 
Vital signs8 
X 
X 
X 
X 
 
X 
X 
X 
Clinical labs (HEM, CHEM, 
UA)9 
X 
X 
 
X 
 
X 
X 
X 
Viral serology10 
X 
 
 
 
 
 
 
 
Serum pregnancy test11 
X 
X 
 
 
 
X 
 
X 
Serum FSH level11 
X 
 
 
 
 
 
 
 
Urine toxicology 
X 
X 
 
 
 
 
 
 
Alcohol urine test 
X 
X 
 
 
 
 
 
 
12-lead standard ECG12 
X 
X 
X 
X 
 
X 
X 
X 
Continuous Holter ECG13  
 
 
X 
X 
 
 
 
 
Randomization14 
 
 
X 
 
 
 
 
 
Study drug dosing 
 
 
X 
 
 
 
 
 


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Study Visit 
Screening1 
Inpatient Periods 1-4 
Outpatient 
Periods 1-4 
Final Visit 
(after Dose 4) 
Unscheduled 
Early 
Termination 
Check-
in 
Dosing 
Follow-up 
Study Day / Assessments 
-21 to -2 
-1 
1 
2 
3 - 7 
8 (± 2) 
 
 
PK samples15 
 
 
X 
X 
 
 
 
X 
Counsel on use of 
appropriate contraception 
and avoidance of pregnancy16 
X 
 
 
X 
 
X 
X 
X 
Counsel to avoid use of 
prohibited medications, 
alcohol, marijuana and illicit 
drugs 
X 
 
 
X 
 
 
 
 
Counsel to avoid rigorous 
physical activity 
X 
X 
 
X 
 
 
 
 
AE and SAE review17 
 
 
X 
X 
X 
X 
X 
X 
Admit to CTU 
 
X 
 
 
 
 
 
 
Discharge from CTU 
 
 
 
X 
 
 
 
 
Discharge from trial 
 
 
 
 
 
X 
 
 
 
1. 
Screening is completed within 21 days before study drug dosing and may require more than one visit. 
2. 
Inclusion/Exclusion criteria at Screening and on Day -1 and Day 1 before dosing in Dosing Period 1 to determine eligibility for enrollment and 
randomization. I/E criteria will be confirmed before each subsequent dosing period.   
3. 
Prior Medications include prescription during the period 30 days before first dosing and non-prescription drugs, herbs, vitamins, and nutritional 
supplements taken during the period 15 days before first dosing. ConMeds include those taken after dosing. (See Section 6.6) for prohibited medications 
and exclusions). 
4. 
Complete PE (except genital, breast, and rectal exams): at Screening, and Final Visit, or ET. 
5. 
Abbreviated PE: on Day -1 (not performed if the complete PE was performed ≤7 days from this visit) in each inpatient period. 
6. 
Symptom-directed PE: on Day 1 (pre-dose and post-dose) and Day 2 in each dosing period to evaluate new symptoms before dosing and AEs after 
dosing. 
7. 
BMI is calculated as wt (kg) / ht (m2). 
8. 
VS (BP, HR, RR, T): at Screening; on Days -1, 1, and 2 in each dosing period; and at Final Visit after Dose 4, or ET. On Day 1 of each dosing period, VS at 
baseline (within 1 h before dosing) and at 1 h (±10 min), 2 h (±10 min), and 4 h (±10 min) after dosing. 
9. 
Clinical laboratory testing with a 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, 


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bicarbonate (CO2), magnesium); and dipstick UA (blood, protein, glucose): at Screening, Day -1, and Day 2, or ET. Clinical labs may not be repeated before 
Dose 1 if screening labs were completed ≤7 days before dosing. Clinical labs may be obtained at an unscheduled visit as indicated for work up of an AE. 
10. Viral serology (HIV1/2 test, HBsAg, HCV antibody): at Screening. 
11. Serum pregnancy test in all women at Screening and within 24 h before each dosing period, and at the Final Visit, or ET. FSH only at Screening in post-
menopausal women. 
12. 12-lead standard ECG with 10-sec rhythm strip: at Screening, 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], Day 2 (24 h ±2 h) or ET. At an Unscheduled Visit, a 12-lead standard ECG will be done only if needed for the evaluation of an AE. 
13. Continuous Holter ECG recorded from 1 h before dosing to 24 h after dosing in each dosing period. ECGs are extracted (three replicates per timepoint) before 
dosing (at 45, 30, and 15 min before dosing) and at 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 24 h after dosing in each dosing period.  
14. Eligible subjects are randomized to a treatment sequence on Day 1 before receiving Dose 1. Randomization confirmed at each dosing period.  
15. 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), and 24 h (±2 h) after dosing in each dosing period, or ET if it occurs within 24 h of dosing. 
16. Female subjects to use appropriate contraception and avoid pregnancy for 30 days after Final Visit or ET. Male subjects to use appropriate contraception and 
avoid donating sperm for 90 days after Final Visit or ET. 
17. Collect all AEs from the time of dosing in Dosing Period 1 through Final Visit after Dose 4. Follow up AEs and SAEs to resolution or stabilization in 
the clinical judgment of the study investigator.  


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Appendix B: Acceptable Ranges of Screening Laboratory and Vital 
Sign Measurements  
Table 4: Acceptable Ranges of Screening Laboratory and Vital Sign Measurements – 
Hematology and Chemistry 
HEMATOLOGY AND CHEMISTRY  
 
Lab test name 
Reference 
range 
Acceptable 
lower limit 
Acceptable 
upper limit 
Lab unit 
Hemoglobin (Hgb), male 
 13.2 - 17.1 
13.0 
18.5 
g/dL 
Hemoglobin (Hgb), female 
11.7 – 15.5 
11.3 
16.5 
g/dL 
Hematocrit (Hct), male 
 38.5 – 50.0 
38.5 
54 
% 
Hematocrit (Hct), female 
 35 - 45 
35 
49 
% 
White blood cell count (WBC) 
 3,800 – 10,800  
3,500 
11,500 
cells/µL 
Neutrophil count 
 1,500 – 7,800 
1,200 
8,500 
cells/µL 
Lymphocyte count 
 850 – 3,900 
800 
5,000 
cells/µL 
Monocyte count 
200 - 950 
0 
1,100 
cells/µL 
Eosinophil count 
150 - 500 
0 
600 
cells/µL 
Basophil count 
0-200 
0 
300 
cells/µL 
Platelet count 
 140 - 400 
125 
475 
103/µL 
Sodium 
 135 - 146 
132 
148 
mmol/L 
Potassium 
3.5 - 5.3  
3.3 
5.5 
mmol/L 
CO2 (Bicarbonate) 
 20 - 32 
19 
33 
mmol/L 
Chloride 
98 -110  
94 
115 
mmol/L 
Calcium  
 8.6 - 10.3 
8.0 
11.0 
mg/dL 
Magnesium 
 1.5 - 2.5 
1.1 
2.8 
mg/dL 
Blood urea nitrogen (BUN) 
7 – 25  
0 
28 
mg/dL 
Glucose, fasting  
 65 - 99 
50 
115 
mg/dL 
Serum creatinine, male  
0.6 – 1.35 
0.5 
1.45 
mg/dL 
Serum creatinine, female 
0.5 – 1.10 
0.4 
1.2 
mg/dL 
Direct bilirubin 
0.0-0.2  
0 
0.4 
mg/dL 
Total bilirubin  
0.2 – 1.2  
0 
1.4 
mg/dL 
Total protein 
6.1 - 8.1 
5.8 
8.6 
g/dL 
Albumin 
 3.6 – 5.1 
3.2 
6.0 
g/dL 
Aspartate transferase (AST), male 
 10 - 40 
0 
45 
U/L 
Aspartate transferase (AST), female 
10 - 30 
0 
35 
U/L 
Alanine transferase (ALT), male 
9 - 46 
0 
52 
U/L 
Alanine transferase (ALT), female 
5 - 32 
0 
38 
U/L 
Alkaline phosphatase, males 
 40 - 115 
0 
150 
U/L 
Alkaline phosphatase ,females 
33 – 115 
0 
150 
U/L 
Hepatitis B surface antigen (HBsAg) 
non-reactive 
non-reactive 
non-reactive 
 n/a 
Hepatitis C antibody (HCVAb) 
non-reactive 
non-reactive 
non-reactive 
 n/as 
HIV-1/ HIV-2 antibody 
non-reactive 
non-reactive 
non-reactive 
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Serum β-HCG (females only) 
negative 
negative 
negative 
 n/a 
FSH (post-menopausal females 
only) 
23 – 116.3 
23 
116.3 
mIU/mL 
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. These 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 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 will 
be provided or the 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 values that reach 
toxicity Grade 1 values are allowable. 
f. 
Serum chloride and albumin values above the ULN are 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 
Table 5: Acceptable Ranges of Screening Laboratory and Vital Sign Measurements – 
Urinalysis 
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) 
0-2 
0 
6 
/field 
Bacteria 
none 
few 
b 
/field 
Hyaline casts 
none 
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 
Table 6: Acceptable Ranges of Screening Laboratory and Vital Sign Measurements – 
Vital Signs 
 
Measurement 
Lower limit 
Upper limit 
Lab unit 
Systolic BP 
90 
150 
mmHg 
Diastolic BP 
40 
90 
mmHg 
Pulse rate 
45 
100 
bpm 
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 CTU will refer to the 
“Guide for Estimating Severity Grade” located above. 
• Criteria are generally grouped by body system. 
Some protocols may have additional protocol specific grading criteria, which will supersede 
the use of these tables for specified criteria. 
 
 


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Table 7: Toxicity Grading Tables – Clinical AEs 
Note: Isolated/individual abnormalities of VS would not be considered toward halting criteria. Abnormalities of VS will be 
described as “increased X” or “decreased X” (X = HR, BP, RR, 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 will 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 VS that are either secondary to systemic or organ-specific clinical syndrome or 
primary disorders will be coded in the appropriate SOC (e.g., "cardiac disorders", respiratory disorders", "immunological 
disorders", etc.). These abnormalities will be considered in determining whether stopping criteria have been met. 
 
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 
• 
Baseline >60 
OR, if 
• 
Baseline <60 
 
• 50-54  
OR, if Baseline <60,  
• 45-50  
 
• 45-49  
OR,  if baseline <60,  
• 
40-44  
 
• <45  
OR,  if baseline <60 
• <40  
As above 
Hypertension (systolic) 
- mmHg 
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) - mmHg 
91-95 
96-100 
>100 
As above 
 Hypotension (systolic) 
- mmHg  
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) 


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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 
 
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 


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Clinical AEs 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Comments 
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 OR 
angioedema OR 
anaphylaxis OR 
requires 
epinephrine 
 
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)  
 


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Clinical AEs 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Comments 
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) 
Require minimal or no 
treatment; does not 
interfere with the 
subject’s daily 
activities. 
 
Result in a low level of 
inconvenience or 
concern with 
therapeutic measures; 
may cause some 
interference with 
functioning. 
 
Interrupt a 
subject’s usual 
daily activity and 
may require 
systemic drug 
therapy or other 
treatment; are 
usually 
incapacitating 
 
 
 
 
 
 
 
 
 


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Table 8: Toxicity Grading Tables – Laboratory AEs 
Laboratory AEs 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Blood, serum, or plasma * 
Sodium decrease – mmol/L 
130 - 131 
125 –129 
<125 
Sodium increase – mmol/L 
149 - 150 
 151 – 153 
>153 
Potassium increase – mmol/L 
5.6  – 6.0 
6.1 – 6.4 
≥6.5 
Potassium decrease – mmol/L 
3.0 – 3.2  
2.5 – 2.9 
<2.5 
Bicarbonate (CO2) increase – mmol/L 
34 - 35 
36 - 37 
>37 
Bicarbonate (CO2) decrease – mmol/L 
17 - 18 
14 - 16 
<14 
Glucose decrease, fasting – mg/dL 
47 - 49 
45 –46 
<45 
Glucose increase, fasting – mg/dL 
116 – 125 
126 – 249 
≥250 
Glucose increase, non-fasting – mg/dL 
116 – 160 
161 – 249 
≥250 
Blood urea nitrogen – mg/dL 
25 - 27 
28 – 32 
>32 
Creatinine increase, male – mg/dL 
1.46 – 1.7 
1.71 – 2.3 
>2.3 
Creatinine increase, female – mg/dL 
1.21 – 1.5 
1.51 – 2.0 
>2.0 
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 
Total protein decrease – g/dL 
5.1 – 5.7 
4.6 – 5.0 
<4.6 
Albumin decrease – g/dL 
2.8 – 3.4 
2.5 – 2.7 
<2.5 
AST increase, male – U/L 
46 – 115 
116 – 220 
>220 
AST increase, female – U/L 
36 - 90 
91 - 175 
>175 
ALT increase, male – U/L 
53 – 115 
116 - 230 
>230 
ALT increase, female – U/L 
39 – 95 
96 – 190 
>190 
Alkaline phosphatase increase – U/L 
151 – 240 
241 – 360 
>360 
Total bilirubin (serum) increase – mg/dL 
(with other LFTs in the normal range) 
1.5 – 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)** 
1.5 – 1.7 
1.8 – 2.1 
>2.1 
Hemoglobin decrease, female – g/dL 
10.8 – 11.2 
9.4 – 10.7 
<9.4 
Hemoglobin decrease, male – g/dL 
11.8 – 12.9 
10.0 – 11.7 
<10.0 
WBC increase – cells/µL 
11,000 – 15,000 
15,001 – 20,000 
>20,000 
WBC decrease – cells/µL 
2,500 – 3,500 
1,500 – 2,499 
<1,500 
Neutrophils decrease – cells/µL 
1,200 – 1,499 
1,000 – 1,199 
<1,000 
Lymphocytes decrease – cells/µL 
750 – 849 
500 – 749 
<500 


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Laboratory AEs 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Monocytes increase – cells/µL 
1,101 – 2,000 
2,001 – 3000 
>3,000 
Eosinophils increase – cells/µL 
500 – 750 
751 – 1,500 
>1,500 
Basophils increase – cells/µL 
201 – 500 
501 – 800 
>800 
Platelets decrease – cells/µL 
120,000 – 124,000 
100,000 – 119,000 
<100,000 
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 
6-10 
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 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 CTU clinician and reported as Grade 1 abnormalities 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 CTU 
clinician.  
Note 3: Other laboratory parameters performed and reported as parted of the CBC, metabolic panel, and UA will 
be evaluated by the study clinician, recorded in the source document, reported as laboratory AEs if clinically 
significant, and graded according to the criteria in Section 9.2.1. 
Note 4: If the dipstick UA 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 dipstick UA or microscopic UA may be retested following cessation of 
menses.  
 


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Table 9: Toxicity Grading Tables – ECG 
 
ECG interval 
abnormality  
Grade 1 
Grade 2 
Grade 3 
QTcF interval 
prolonged (msec) 
Asymptomatic, QTcF 
450-479 msec  
Asymptomatic, QTcF 480-500 msec 
OR increase in interval 30-59 msec 
above baseline 
Asymptomatic, QTcF >500 msec 
OR increase in interval ≥60 msec 
above baseline 
PR interval 
prolonged (msec) 
210-250 msec 
>250 msec 
Type II 2nd degree AV block OR 
ventricular pause >3.0 sec 
 
Note: Events will be coded as SAEs if there are life-threatening associated symptoms or signs (arrhythmia, CHF, 
hypotension, syncope, TdP, etc.) 
Note: If a male subject was accepted into the trial with a QTcF value that overlaps with values used for grading 
Grade 1 QTcF prolongation, an AE will be reported if the QTcF value is higher than the baseline value 
 


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                                                                109 
 
Appendix D: Blood Volume Withdrawn During the Trial 
Table 10: Laboratory Samples and Estimated Total Blood Volume (mL)  
Study Periods 
 
Inpatient Periods 1 to 4 
Outpatient Periods 
1 - 4 
Dosing    Period 4 
ET 
 
Study Visit 
Screen 
Check-in 
 Dosing 
Follow-up 
Wash-out 
 
Final 
 
+Study Daya 
-21 to -2 
-1 
1 
2 
3-7 
 
8 (±2) 
 
+ 
 
 
 
 
 
 
 
HEMATOLOGY1 
4 
4 
 
4 
 
4 
4 
CHEMISTRY and serum β-HCG and FSH1 
5 
5 
 
5 
 
5 
5 
Viral Serology (HIV, HBsAg, HCV)1 
8.5 
 
 
 
 
 
 
PK3 
 
 
54 
6 
 
 
6 
Total volume/visit 
17.5 
9 
54 
15 
0 
9 
15 
Dosing periods multiplier 
1 
4 
4 
4 
 
1 
1 
Total volume (all dosing periods) 
17.5 
36 
216 
60 
0 
9 
15 
Cumulative total volume 
17.5 
53.5 
269.5 
329.5 
329.5 
338.5 
 
a Study Days shown correspond to days in each treatment period. For a view of the cumulative numbering of study days, please refer to Section 7. 
  
1 Clinical blood tests (HEM, CHEM) are drawn at Screening Visit, on Day -1, and on Day 2 in each treatment period, or ET.  Serum pregnancy test in all 
women at Screening and within 24 h before each dosing period, and at the Final Visit, or ET. FSH only at Screening in post-menopausal women. 
2 Viral serology tests are drawn at Screening.  


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3 PK serum samples are drawn on Day 1: 30 min before dosing and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 h after dosing in each dosing period, or ET if occurs within 
24 h of dosing. 


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Appendix E: A Partial List of Drugs Causing QTc Prolongation and 
Torsade de Pointes 
Table 11: A Partial List of Drugs Causing QTc Prolongation and Torsade de Pointes 
CATEGORY 
DRUG 
Anti-arrhythmic agents 
Amiodarone 
Disopyramide 
Dofetilide 
Dronedarone 
Flecainide 
Ibutilide 
Procainamide 
Quinidine 
Sotalol 
 
Anti-infective agents 
Azithromycin 
Ciprofloxacin 
Clarithromycin 
Erythromycin 
Levofloxacin 
Moxifloxacin 
 
Anti-malarial agents 
Chloroquine 
 
Anti-psychotic agents 
Chlorpromazine 
Droperidol 
Haloperidol 
Pimozide 
Thioridazine 
 
Anesthetics, General 
Propofol 
Sevoflurane 
 
Others 
Methadone 
Papaverine HCl 
 
Source: https://crediblemeds.org/ (accessed 19 December 2017) and Reference 17 

SAP_001.pdf: 
CLINICAL RESEARCH IN INFECTIOUS DISEASES 
 
 
 
STATISTICAL ANALYSIS PLAN 
for 
DMID Protocol: 16-0110 
 
A Phase 1, Randomized, Double-blinded, Four-period 
Crossover, Thorough QT/QTc (TQT) Clinical Trial to 
Evaluate the Effect of Zoliflodacin on Cardiac 
Repolarization in Healthy Male and Female Subjects 
 
NCT03613649 
 
Version 1.0 
 
DATE: 19-DEC-2018 
 
THIS COMMUNICATION IS PRIVILEGED AND CONFIDENTIAL  
 
 


Statistical Analysis Plan - DMID Protocol: 16-0110  
Version 1.0 
19DEC2018 
- ii - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
STUDY TITLE 
Protocol Number Code: 
DMID Protocol: 16-0110 
Development Phase: 
Phase 1 
Products: 
Zoliflodacin 
Zoliflodacin Placebo 
Moxifloxacin Hydrochloride 
Form/Route: 
Zoliflodacin and Zoliflodacin Placebo: Suspension / Oral 
Moxifloxacin Hydrochloride: Tablet / Oral 
Indication Studied: 
Neisseria gonorrhoeae 
Sponsor: 
Division of Microbiology and Infectious Diseases (DMID) 
National Institute of Allergy and Infectious Diseases (NIAID) 
National Institutes of Health (NIH) 
Clinical Trial Initiation Date: 
04SEP2018 
Clinical Trial Completion Date: 
 
Date of the Analysis Plan: 
19DEC2018 
Version Number: 
1.0 
This study was performed in compliance with Good Clinical Practice. 
Information contained in this publication is the property of Division of Microbiology and Infectious Diseases and is confidential. This 
information may not be disclosed to third parties without written authorization from Division of Microbiology and Infectious Diseases. This 
report may not be reproduced, stored in a retrieval system or transmitted in any form or by any means - electronic, mechanical, recording or 
otherwise - without the prior authorization from Division of Microbiology and Infectious Diseases. This document must be returned to Division 
of Microbiology and Infectious Diseases upon request. 
 


Statistical Analysis Plan - DMID Protocol: 16-0110  
Version 1.0 
19DEC2018 
- iii - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
TABLE OF CONTENTS 
STUDY TITLE ............................................................................................................................... II 
TABLE OF CONTENTS ...............................................................................................................III 
LIST OF ABBREVIATIONS ....................................................................................................... VI 
1. 
PREFACE .....................................................................................................................1 
2. 
INTRODUCTION ........................................................................................................2 
2.1. 
Purpose of the Analyses ................................................................................................2 
3. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................3 
3.1. 
Study Objectives ...........................................................................................................3 
3.2. 
Endpoints ......................................................................................................................3 
3.3. 
Study Definitions and Derived Variables .....................................................................4 
4. 
INVESTIGATIONAL PLAN .......................................................................................8 
4.1. 
Overall Study Design and Plan .....................................................................................8 
4.2. 
Discussion of Study Design, Including the Choice of Control Groups ........................9 
4.3. 
Selection of Study Population ......................................................................................9 
4.4. 
Treatments ..................................................................................................................13 
4.4.1. 
Treatments Administered ............................................................................................13 
4.4.2. 
Identity of Investigational Product(s) .........................................................................13 
4.4.3. 
Method of Assigning Subjects to Sequences (Randomization) ..................................14 
4.4.4. 
Selection of Doses in the Study ..................................................................................14 
4.4.5. 
Selection and Timing of Dose for Each Subject .........................................................14 
4.4.6. 
Blinding ......................................................................................................................14 
4.4.7. 
Prior and Concomitant Therapy ..................................................................................15 
4.4.8. 
Treatment Compliance ................................................................................................15 
4.5. 
Safety and PK Variables .............................................................................................15 
5. 
SAMPLE SIZE CONSIDERATIONS .......................................................................17 
6. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................18 
6.1. 
General Principles .......................................................................................................18 
6.2. 
Timing of Analyses .....................................................................................................18 
6.3. 
Analysis Populations ..................................................................................................18 
6.3.1. 
Safety Population ........................................................................................................18 


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6.3.2. 
PK Population and PK Analysis Subset .....................................................................18 
6.3.3. 
Holter ECG Analysis Population ................................................................................18 
6.3.4. 
Pharmacokinetic-ECG (PK-ECG) Analysis Population .............................................19 
6.4. 
Covariates and Subgroups ..........................................................................................19 
6.5. 
Missing Data ...............................................................................................................19 
6.6. 
Interim Analyses and Data Monitoring ......................................................................19 
6.7. 
Multicenter Studies .....................................................................................................19 
6.8. 
Multiple Comparisons/Multiplicity ............................................................................19 
7. 
STUDY SUBJECTS ...................................................................................................20 
7.1. 
Disposition of Subjects ...............................................................................................20 
7.2. 
Protocol Deviations ....................................................................................................20 
8. 
EFFICACY EVALUATION ......................................................................................21 
9. 
SAFETY EVALUATION ..........................................................................................22 
9.1. 
Demographic and Other Baseline Characteristics ......................................................22 
9.1.1. 
Prior and Concurrent Medical Conditions ..................................................................22 
9.1.2. 
Prior and Concomitant Medications ...........................................................................22 
9.2. 
Measurements of Treatment Compliance ...................................................................23 
9.3. 
Adverse Events ...........................................................................................................23 
9.3.1. 
Unsolicited Adverse Events ........................................................................................23 
9.4. 
Deaths, Serious Adverse Events and other Significant Adverse Events ....................23 
9.5. 
Birth Control and Pregnancies ....................................................................................24 
9.6. 
Clinical Laboratory Evaluations .................................................................................24 
9.7. 
Vital Signs and Physical Evaluations .........................................................................25 
9.8. 
12-Lead Standard ECG ...............................................................................................26 
9.9. 
Concomitant Medications ...........................................................................................27 
9.10. 
Tolerability .................................................................................................................27 
10. 
PHARMACOKINETICS ...........................................................................................28 
10.1. 
Missing Data and Imputations ....................................................................................28 
10.2. 
Tabular and Graphical Summaries of Zoliflodacin Concentration-Time 
Profiles ........................................................................................................................28 
10.3. 
Definition and Estimation of Individual NCA PK Parameters ...................................29 
10.4. 
Descriptive Statistics ..................................................................................................30 


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11. 
IMMUNOGENICITY ................................................................................................31 
12. 
OTHER ANALYSES .................................................................................................32 
13. 
REPORTING CONVENTIONS ................................................................................33 
14. 
TECHNICAL DETAILS ............................................................................................34 
15. 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY OR 
PLANNED ANALYSES ............................................................................................35 
16. 
REFERENCES ...........................................................................................................36 
17. 
LISTING OF TABLES, FIGURES, AND LISTINGS ..............................................37 
APPENDICES ...............................................................................................................................38 
APPENDIX 1. TABLE MOCK-UPS..........................................................................................39 
APPENDIX 2. FIGURE MOCK-UPS ........................................................................................90 
APPENDIX 3. LISTINGS MOCK-UPS ...................................................................................115 
 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AP 
Alkaline Phosphatase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Code 
AUC 
Area Under the Curve 
AUC(0-inf) 
AUC Extrapolated to Infinity 
AUC(0-last) 
AUC from Time of Dosing to Time of the Last Measured Concentration. 
AUC(0-t) 
AUC from Time of Dosing to Time t. 
AV 
Atrioventricular 
BMI 
Body Mass Index 
bpm 
Beat(s) per Minute 
BQL 
Below Quantification Limit 
BUN 
Blood Urea Nitrogen 
C 
Degree(s) Celsius 
CDC 
Centers for Disease Control and Prevention 
CI 
Confidence Interval 
CL/F 
Apparent Oral Clearance 
Clast 
Last Measured Concentration above the Lower Limit of Quantification 
Cmax 
Maximum Concentration 
CO2 
Total Carbon Dioxide 
CRF 
Case Report Form 
CS 
Clinically Significant 
CSR 
Clinical Study Report 
CTU 
Clinical Trials Unit 
CV 
Coefficient of Variation 
ΔΔQTcF 
Time-Matched, Placebo-Corrected, Baseline-Adjusted Mean QTcF Interval 
DCC 
Data Coordinating Center 
DMID 
Division of Microbiology and Infectious Diseases 
ECG 
Electrocardiogram 


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EDC 
Electronic Data Capture 
eGFR 
Estimated Glomerular Filtration Rate 
ET 
Early Termination 
FEV1 
Forced Expiratory Volume in One Second 
FDA 
United States Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
g 
Gram(s) 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
GM 
Geometric Mean 
GSD 
Geometric Standard Deviation 
h 
Hour(s) 
HBsAg 
Hepatitis B Surface Antigen 
hCG 
Human Chorionic Gonadotropin 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
HLGT 
High Level Group Term 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ISM 
Independent Safety Monitor 
IUD 
Intrauterine Device 
Ke 
Terminal Phase Elimination Rate Constant 
LLOQ 
Lower Limit of Quantification 
LQTS 
Long QT Syndrome 
LVH 
Left Ventricular Hypertrophy 
MedDRA 
Medical Dictionary for Regulatory Activities  
max 
Maximum Value 
min 
Minimum Value 
mg 
Milligram(s) 
MH 
Medical History 
MI 
Myocardial Infarction 


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mL 
Milliliter(s) 
MOP 
Manual of Procedures 
msec 
Millisecond(s) 
N 
Number (typically refers to subjects) 
NCA 
Noncompartmental Analysis 
NCS 
Not Clinically Significant 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
NSAID 
Nonsteroidal Anti-Inflammatory Drug 
OCRR 
Office of Clinical Research Resources 
ONR 
Outside Normal Range 
OTC 
Over-the-Counter 
PD 
Pharmacodynamic(s) 
PE 
Physical Examination 
PI 
Principle Investigator 
PK 
Pharmacokinetic(s) 
PT 
Preferred Term 
QTcF 
QT Interval of the ECG Corrected Using Fridericia’s Formula 
RBC 
Red Blood Cell 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDTM 
Standard Data Tabulation Model 
SMC 
Safety Monitoring Committee 
SOC  
System Organ Class 
t1/2 
Apparent Terminal Elimination Half-Life 
TdP 
Torsades de Pointes 
TFLs 
Tables, Figures, and Listings 
TIA 
Transient Ischemic Attack 
Tmax 
Time to Obtain Maximum Concentration (Cmax) 
TQT 
Thorough QT/QTc 


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Vz/F 
Apparent Volume of Distribution During Terminal Phase 
WBC 
White Blood Cell 
WHO 
World Health Organization 
 


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1. 
PREFACE 
The Statistical Analysis Plan (SAP) for “A Phase 1, Randomized, Double-Blinded, Four-Period Crossover, 
Thorough QT/QTc (TQT) Clinical Trial to Evaluate the Effect of Zoliflodacin on Cardiac Repolarization in 
Healthy Male and Female Subjects” (DMID Protocol 16-0110) describes and expands upon the statistical 
information presented in the protocol. This document describes all planned analyses and includes example 
tables, figures, and listings (TFLs) planned for all planned analyses. This SAP follows the International 
Council for Harmonisation (ICH) guidelines, including E9[1] and E14[2]. Within the TFL mock-ups 
(Appendices 1, 2, and 3), references to the clinical study report (CSR) sections are included. Any deviation 
from this SAP will be described and justified in the CSR. The main text of this SAP discusses analysis of 
safety and pharmacokinetic (PK) endpoints for the study. Analysis of Holter ECG endpoints is presented in 
the ECG SAP (Appendix 4). 


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2. 
INTRODUCTION 
Single 2 gram (g) and single 4 g doses of zoliflodacin were safe and well-tolerated in previous clinical trials. 
The 2 g dose has been selected as the therapeutic dose for further clinical testing of zoliflodacin. The 4 g dose 
was shown to result in drug exposures higher than the 2 g dose and should provide exposures that will be 
achieved in patients when used with other drugs that may interact with zoliflodacin. For this reason, the 4 g 
dose was selected as the supratherapeutic dose for this TQT trial. Placebo for zoliflodacin was selected to 
control for natural diurnal changes in the electrocardiogram (ECG). Moxifloxacin was selected as a positive 
comparator to evaluate assay sensitivity for QT interval of the ECG corrected using Fridericia’s formula 
(QTcF), as it predictably causes a mild prolongation of the QTcF interval but has a very low risk for inducing 
cardiac arrhythmias. 
2.1. 
Purpose of the Analyses 
The main text of this SAP discusses analysis of safety and pharmacokinetic (PK) endpoints for the study. 
Analyses of Holter ECG endpoints (including changes in QTcF and other ECG intervals, T-wave morphology 
and other ECG effects), as well as drug concentration-QTcF modeling are presented in the ECG SAP 
(Appendix 4). 


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3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Study Objectives 
Primary: 
• To evaluate the effect of zoliflodacin on the QTcF interval 
Secondary: 
• To evaluate the effects of zoliflodacin on other ECG parameters (PR, QRS, and RR intervals, and 
heart rate)  
• To evaluate the sensitivity of QTcF measurement using moxifloxacin 
• To evaluate the effect of zoliflodacin on T-wave morphology 
• To evaluate the PK of 2 g and 4 g oral zoliflodacin under fasting state 
• To evaluate the relationship between zoliflodacin PK and time-matched QTcF pharmacodynamics 
(PD) 
• To evaluate the safety and tolerability of 2 g and 4 g oral zoliflodacin 
3.2. 
Endpoints 
Primary: 
• The upper bound of the one-sided 95% confidence interval (CI) for the largest time-matched, 
placebo-corrected, baseline-adjusted mean QTcF interval (∆∆QTcF) collected in the 24 hour (h) 
period after 2 g and 4 g dose of zoliflodacin is <10 milliseconds (msec) 
Secondary: 
• Time-matched, placebo-corrected, baseline-adjusted non-QT intervals (PR, QRS and RR intervals) 
and heart rate collected in the 24 h period after 2 g and 4 g dose of zoliflodacin 
• The lower bound of the one-sided 95% CI of the ∆∆QTcF is >5 msec at one or more individual 
timepoints between 1 h and 4 h after a single dose of moxifloxacin 400 milligrams (mg)  
• Incidence of abnormal T-wave morphology using defined categories in the 24 h period after 2 g 
and 4 g dose of zoliflodacin 
• Single-dose plasma concentrations (and PK exposure parameters, such as maximum concentration 
[Cmax] and area under the curve [AUC]) of zoliflodacin collected up to 24 h after 2 g and 4 g dose 
of zoliflodacin 
• Relationship between plasma concentrations of zoliflodacin (and PK and exposure parameters, 
such as Cmax and AUC) and ∆∆QTcF up to 24 h after 2 g and 4 g dose of zoliflodacin 
• Occurrence of treatment-emergent serious adverse events (SAEs), other unsolicited treatment-
emergent adverse event (AEs), and changes from baseline in vital signs, clinical laboratory values, 
and ECG parameters following administration of zoliflodacin and moxifloxacin from time of 
dosing to Final Visit, or early termination (ET) Visit 


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3.3. 
Study Definitions and Derived Variables  
Dosing Periods 
Dosing period may be described numerically (1, 2, 3, or 4) or in terms of the treatment received during the 
period (2 g zoliflodacin, 4 g zoliflodacin, placebo, or 400 mg moxifloxacin). Analysis of safety endpoints will 
be performed by treatment received for the period, not by the period number. 
Period 1: From start of first Check-in day (Day -1) through the day before Check-in for the second dose, or 
ET Visit, whichever occurs first. 
Period 2: From start of second Check-in day through the day before Check-in for the third dose, or ET Visit, 
whichever occurs first. 
Period 3: From start of third Check-in day through the day before Check-in for the fourth dose, or ET Visit, 
whichever occurs first. 
Period 4: From start of fourth Check-in day through Final Visit, or ET Visit, whichever occurs first. 
Baseline 
Baseline is defined for safety analyses as follows. 
• Measurements prior to the first dose will not have a baseline defined. 
• Measurements after the first dose, and prior to the second dose (including Period 2 check-in and 
pre-dose measurements and early termination measurements after the first dose and prior to the 
second dose) will use the last measurement prior to the first dose as baseline.  
• Measurements after the second dose, and prior to the third dose (including Period 3 check-in and 
pre-dose measurements and early termination measurements after the second dose and prior to the 
third dose) will use the last measurement prior to the second dose as baseline.  
• Measurements after the third dose, and prior to the fourth dose (including Period 4 check-in and 
pre-dose measurements and early termination measurements after the third dose and prior to the 
fourth dose) will use the last measurement prior to the third dose as baseline.  
• Measurements after the fourth dose will use the last measurement prior to the fourth dose as 
baseline. 
• Measurements taken during the Final Visit will use the last measurement prior to the first dose as 
baseline for the analysis time points labeled “Final Visit” and will use the last measurement prior 
to the fourth dose as baseline for the analysis time points labeled “Follow-up”. Listings will show 
both of the two change from baseline values for Final Visit. The justification for including the 
Period 1 baseline for the Final Visit is to show overall changes (ideally absence of changes) over 
the course of the study. Grading of change from baseline will be based on the Period 1 baseline 
only. 
Treatment Associated with Records 
Treatment associated with post-dose records will always be the last type of treatment received before the 
(start) date or date-time associated with the record. AEs will be summarized by treatment and listings of all 
safety endpoints will include treatment, as it is defined here. 
Possible values of treatment, in order of presentation in the CSR, are: 2 g zoliflodacin, 4 g zoliflodacin, 
placebo, and 400 mg moxifloxacin. 


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Study Day and Day in Period 
Study Day and Day in Period will primarily be used in listings to refer to timing of assessments and events 
relative to first dosing (Study Day) or dose for the respective period (Day in Period). 
The day that the first dose of study product is received is considered Study Day 1 for each subject. The day 
prior to first dose is considered Study Day = -1, not Study Day = 0. 
The day that the dose of study product is received is considered Day in Period = 1 for each subject and each 
dosing period. The day prior to dosing for each period is considered Day in Period = -1, not Day in 
Period = 0.  
Treatment Sequence 
Each subject will receive one dose orally of each of four treatments, labeled A through D: 
• Treatment A: zoliflodacin 2 g 
• Treatment B: zoliflodacin 4 g 
• Treatment C: placebo 
• Treatment D: moxifloxacin 400 mg 
Each subject will be randomly allocated to one of 12 dosing sequences before dosing on Day 1, Dosing Period 
1, and receive a single dose of the preceding four study drugs on different days according to their randomly-
assigned dosing sequences. The 12 dosing sequences, in order that they will be presented in the report, are 
ABCD, ACDB, ADBC, BADC, BDCA, BCAD, CDAB, CABD, CBDA, DCBA, DBAC, and DACB. 
Sequences will be referred to using these labels in TFLs. The four-letter codes for sequence indicate the order 
that the treatments will be given to the subject. For example, sequence CABD indicates that the subject would 
receive placebo in period 1, 2 g zoliflodacin in period 2, 4 g zoliflodacin in period 3, and 400 mg 
moxifloxacin in period 4. 
Tolerability 
Tolerability of zoliflodacin will be defined as follows. Tolerability will be concluded for a subject unless any 
one of the following occurred after receiving zoliflodacin as the most recent non-placebo dose: 1) subject 
discontinued study drug due to an AE, 2) subject choose to withdraw from the study due to an AE at any time 
from first dose of zoliflodacin until end of study, or 3) subject was withdrawn from the study by the 
investigator due to an adverse event at any time from first dose of zoliflodacin until end of study. Withdrawal 
or discontinuation of study drug after moxifloxacin as the most recent dose will not lead to a conclusion that 
zoliflodacin was not tolerable. 
Visit and Time Point Names for Analysis of Safety and PK Endpoints 
Analyses of clinical laboratory results, vital signs, ECG, and PK will be performed by planned time point, 
expressed as time in h relative to the most recent dose, within period. Labels for each time point are shown in 
Table 1, including the order the time points will be shown in TFLs and abbreviated labels. The Max Severity 
Post-Baseline time point is a derived, conceptual time point used in tables displaying severity grading. All 
other time points refer to planned assessments per the protocol. 
The “Follow-up” analysis time points refer to either Check-In visits for the next period (for analysis of 
treatments given in Period 1, 2, or 3) or to the Final Visit with Pre-dose 4 as baseline. For each treatment, if 
the treatment was given in Period 1, Period 2, or Period 3, then the pre-dose vital signs and ECG 
measurements prior to the next dose will be summarized. Listings will use protocol time point names rather 


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than analysis time point names, e.g. “Check-in” rather than “Follow-up” and “Pre-dose” rather than “Pre-dose 
(Prior to Next Dose).” 
Table 1: 
Analysis Time Points for Safety and PK Endpoints 
Order 
Period 
Analysis Time 
Point 
Abbreviated 
Label 
Endpoints 
Baseline 
1 
1 
Check-In 
Day -1 
Clinical Laboratory Results, Vital Signs, ECG 
N/A 
2 
1 
Pre-dose 
0 h 
Vital Signs, ECG, PK 
N/A 
3 
1 
Max Severity Post-
Baseline 
N/A 
Clinical Laboratory Results, Vital Signs, and ECG Toxicity 
Grading 
N/A 
4 
1 
0.5 h Post-dose 
0.5 h 
PK 
N/A 
5 
1 
1 h Post-dose 
1 h 
Vital Signs, ECG, PK 
Pre-dose 1 
6 
1 
2 h Post-dose 
2 h 
Vital Signs, ECG, PK 
Pre-dose 1 
7 
1 
3 h Post-dose 
3 h 
PK 
N/A 
8 
1 
4 h Post-dose 
4 h 
Vital Signs, ECG, PK 
Pre-dose 1 
9 
1 
6 h Post-dose 
6 h 
PK 
N/A 
10 
1 
8 h Post-dose 
8 h 
PK 
N/A 
11 
1 
12 h Post-dose 
12 h 
PK 
N/A 
12 
1 
24 h Post-dose 
24 h 
Clinical Laboratory Results, Vital Signs, ECG, PK 
Pre-dose 1 
13 
2 
Follow-up 
FU 
Clinical Laboratory Results, Vital Signs, ECG 
Pre-dose 1 
14 
2 
Pre-dose (Prior to 
Next Dose) 
0 h 
Vital Signs, ECG 
Pre-dose 1 
14 
2 
Pre-dose 
0 h 
PK 
N/A 
15 
2 
Max Severity Post-
Baseline 
N/A 
Clinical Laboratory Results, Vital Signs, and ECG Toxicity 
Grading 
Pre-dose 2 
16 
2 
0.5 h Post-dose 
0.5 h 
PK 
N/A 
17 
2 
1 h Post-dose 
1 h 
Vital Signs, ECG, PK 
Pre-dose 2 
18 
2 
2 h Post-dose 
2 h 
Vital Signs, ECG, PK 
Pre-dose 2 
19 
2 
3 h Post-dose 
3 h 
PK 
N/A 
20 
2 
4 h Post-dose 
4 h 
Vital Signs, ECG, PK 
Pre-dose 2 
21 
2 
6 h Post-dose 
6 h 
PK 
N/A 
22 
2 
8 h Post-dose 
8 h 
PK 
N/A 
23 
2 
12 h Post-dose 
12 h 
PK 
N/A 
24 
2 
24 h Post-dose 
24 h 
Clinical Laboratory Results, Vital Signs, ECG, PK 
Pre-dose 2 
25 
3 
Follow-up 
FU 
Clinical Laboratory Results, Vital Signs, ECG 
Pre-dose 2 
26 
3 
Pre-dose (Prior to 
Next Dose) 
0 h 
Vital Signs, ECG 
Pre-dose 2 
26 
3 
Pre-dose 
0 h 
PK 
N/A 
27 
3 
Max Severity Post-
Baseline 
N/A 
Clinical Laboratory Results, Vital Signs, and ECG Toxicity 
Grading 
Pre-dose 3 
28 
3 
0.5 h Post-dose 
0.5 h 
PK 
N/A 
29 
3 
1 h Post-dose 
1 h 
Vital Signs, ECG, PK 
Pre-dose 3 


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Order 
Period 
Analysis Time 
Point 
Abbreviated 
Label 
Endpoints 
Baseline 
30 
3 
2 h Post-dose 
2 h 
Vital Signs, ECG, PK 
Pre-dose 3 
31 
3 
3 h Post-dose 
3 h 
PK 
N/A 
32 
3 
4 h Post-dose 
4 h 
Vital Signs, ECG, PK 
Pre-dose 3 
33 
3 
6 h Post-dose 
6 h 
PK 
N/A 
34 
3 
8 h Post-dose 
8 h 
PK 
N/A 
35 
3 
12 h Post-dose 
12 h 
PK 
N/A 
36 
3 
24 h Post-dose 
24 h 
Clinical Laboratory Results, Vital Signs, ECG, PK 
Pre-dose 3 
37 
4 
Follow-up 
FU 
Clinical Laboratory Results, Vital Signs, ECG 
Pre-dose 3 
38 
4 
Pre-dose (Prior to 
Next Dose) 
0 h 
Vital Signs, ECG 
Pre-dose 3 
38 
4 
Pre-dose 
0 h 
PK 
N/A 
39 
4 
Max Severity Post-
Baseline 
N/A 
Clinical Laboratory Results, Vital Signs, and ECG Toxicity 
Grading 
Pre-dose 4 
40 
4 
0.5 h Post-dose 
0.5 h 
PK 
N/A 
41 
4 
1 h Post-dose 
1 h 
Vital Signs, ECG, PK 
Pre-dose 4 
42 
4 
2 h Post-dose 
2 h 
Vital Signs, ECG, PK 
Pre-dose 4 
43 
4 
3 h Post-dose 
3 h 
PK 
N/A 
44 
4 
4 h Post-dose 
4 h 
Vital Signs, ECG, PK 
Pre-dose 4 
45 
4 
6 h Post-dose 
6 h 
PK 
N/A 
46 
4 
8 h Post-dose 
8 h 
PK 
N/A 
47 
4 
12 h Post-dose 
12 h 
PK 
N/A 
48 
4 
24 h Post-dose 
24 h 
Clinical Laboratory Results, Vital Signs, ECG, PK 
Pre-dose 4 
49 
4 
Follow-up 
FU 
Clinical Laboratory Results, Vital Signs, ECG 
Pre-dose 4 
50 
4 
Final Visit 
N/A 
Clinical Laboratory Results, Vital Signs, ECG 
Pre-dose 1 


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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design and Plan 
An overall schematic of study design is shown in Figure 1. The TQT study will be performed in a single 
center, the Vince & Associates Clinical Research, Inc., clinical trials unit (CTU), according to a randomized, 
double-blinded (except for the use of moxifloxacin), placebo-controlled, four-period, four-treatment, 
crossover design balanced with respect to first-order carryover effect in up to 72 healthy male or female 
subjects, aged 18 to 45 years inclusive, to evaluate the effect of zoliflodacin on QTcF and other ECG 
parameters, the correlation of the drug concentrations (and PK profile) with ∆∆QTcF, and the PK and safety 
profiles of zoliflodacin.  
Subjects who consent to participate will be enrolled in the trial if they meet all inclusion and no exclusion 
eligibility criteria. Laboratory assessments at Screening Visit will include routine clinical laboratory tests 
(chemistry, hematology, urinalysis), testing for viral serology (human immunodeficiency virus [HIV] 
antibody, Hepatitis B surface antigen [HBsAg], and Hepatitis C virus [HCV] antibody), drugs of abuse, and 
alcohol. Serum pregnancy testing will be done in all women and serum follicle stimulating hormone (FSH) 
levels will be measured only in post-menopausal women.  
Each subject will receive one dose orally of each of four treatments: 2 g zoliflodacin (investigational drug, 
therapeutic dose), 4 g zoliflodacin (investigational drug, supratherapeutic dose), placebo (for zoliflodacin), 
and 400 mg moxifloxacin (positive control comparator). Each subject will be randomly allocated to one of 12 
dosing sequences before dosing on Day 1, Dosing Period 1, and receive a single dose of the four study 
treatments on different days according to their randomly-assigned dosing sequence (see Section 3.3 for list of 
the 12 sequences).  
Six (6) of the planned 72 subjects will be included in each treatment sequence. The design is balanced for 
period and first-order carryover effects. 
Subjects will be dosed in the morning of Day 1 in each dosing period, in a staggered fashion at least several 
minutes apart, and will receive study drug at approximately the same time in each subsequent dosing period. 
Each treatment will be administered 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. Zoliflodacin or placebo will be 
reconstituted in 60 milliliters (mL) of tap water. After the cup containing the 60 mL of zoliflodacin or placebo 
suspension is taken, approximately 60 mL of tap water will be added to the cup (as a rinse) and consumed by 
the subject to chase the initial dose. Moxifloxacin will be administered orally with 120 mL of water.  
Safety assessments post-dosing will include vital signs, physical examination (PE), 12-lead standard ECG, 
and clinical laboratory tests including hematology, chemistry, and urinalysis. Treatment-emergent AEs and 
SAEs will be assessed from time of dosing to end of trial. 
Continuous 12-lead Holter ECGs will be performed on Day 1 starting approximately 1 h before dosing and 
lasting for 24 h after dosing. At timepoints for ECG extraction, subjects will be resting in the supine position 
for at least 10 minutes before and 5 minutes after the nominal time, without any ongoing stimulation (e.g., 
television). Three replicate ECGs will be extracted at each timepoint to measure ECG intervals and assess T-
wave morphologies. 
Plasma for PK analysis will be collected at scheduled timepoints that match timepoints for ECG extraction 
before and after dosing on Day 1 and through Day 2 in each period, or ET if it occurs within 24 h after dosing. 


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Subjects will be monitored as inpatients in the CTU up to 24 h after each dose (Day 2). They will then be 
discharged from the inpatient CTU and followed as outpatients for at least 5 days (Days 3-7) after dosing in 
Dosing Periods 1-3. The total time to wash-out of the previously-received study drug is at least 8 days. The 
Final Visit will be 8 ±2 days after the last dose. 
A safety monitoring committee (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 safety 
monitoring in subsequent clinical trials with zoliflodacin. If criteria for halting the trial are met in any dosing 
period, dosing will be suspended, and 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 principal investigator (PI), SMC, and DMID. 
4.2. 
Discussion of Study Design, Including the Choice of Control Groups 
The 4-period crossover design is consistent with recommendations made in the ICH E14[1] guidance. A 
crossover trial can be conducted since the half-life of zoliflodacin is approximately 6 h. A wash-out phase of 
at least 5 half-lives of the drug is generally recommended for crossover trials to minimize the risk of 
carryover. A washout of 3 days would be sufficient to meet the 5 half-lives criterion for both zoliflodacin and 
moxifloxacin, so the 8 days or more of washout specified in the protocol is expected to prevent a carryover 
effect of the study drug between treatments. 
The 4 g dose will be used as the supratherapeutic dose required by the ICH E14 Guidance for TQT studies. 
Exposures resulting from a 4 g dose of zoliflodacin were shown to be safe in previous studies. The 400 mg 
dose of moxifloxacin to be used is the highest dose recommended for use in the clinic and is commonly used 
as a positive control in TQT studies to ensure assay sensitivity for detecting potentially clinically significant 
changes in the QT/QTc interval. 
Placebo and both of the 2 zoliflodacin doses will be blinded. However, moxifloxacin treatment will not be 
blinded. Due to the 12 sequences included in the study design, knowledge of the moxifloxacin period does not 
provide information about what treatments are received in the other 3 periods. Furthermore, the 12 sequences 
included in the study are balanced for period and first-order carryover effects. 
4.3. 
Selection of Study Population 
Only subjects who meet all inclusion criteria and no exclusion criteria will be eligible for enrollment into the 
trial. No exemptions are granted on Inclusion/Exclusion Criteria in DMID-sponsored trials. 
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 authorized site clinician (listed on United State Food and Drug 
Administration [FDA] Form 1572)  
3. Willingness to comply with and be available for all protocol procedures, including inpatient 
confinement for 3 days in each dosing period and follow-up for the duration of the trial 
4. Aged 18 to 45 years inclusive on the day of first dosing 


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5. Body Mass Index (BMI) ≥18.5 and ≤30 kg/m2 and weight ≥50 kg (110 pounds) and ≤100 kg (220 
pounds) 
6. In all female subjects, whether of childbearing potential or post-menopausal by medical history (MH), 
a negative serum pregnancy test at Screening Visit and on Day -1 of each dosing period 
• Note: A woman is considered of childbearing potential unless post-menopausal (≥1 year without 
menses without other known or suspected cause and with an 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 to become pregnant during the trial and 
for 30 days after Final Visit 
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 Visit 
• Note: A highly effective method of birth control is defined as one with a low failure rate (i.e., <1% 
per year) according to Centers for Disease Control and Prevention (CDC) criteria. These include 
progestin implants, intrauterine devices (IUDs), surgical (hysterectomy, salpingectomy, 
oophorectomy, or tubal ligation/occlusion; vasectomy), or abstinence. 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 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 of the protocol, are in the normal reference range with 
acceptable exceptions as noted in Section 8.2.1 and Appendix B of the protocol  
11. Vital signs, as outlined in Section 8.1.6 of the protocol, are within the acceptable range per Appendix 
B of the protocol 
12. Has adequate venous access for blood collection  
13. Urine drug screen is negative for tested substances (see Section 8.2.5 of the protocol) 
14. Urine alcohol test is negative 
15. Willing to abstain from alcohol consumption for 2 days before Day -1 of Period 1 and for the duration 
of the trial 
Subject Exclusion Criteria 
All must be answered NO for the subject to be eligible for study participation: 
1. History of acute or chronic cardiovascular disease or surgery 
• Note: Conditions include: congestive heart failure; coronary artery disease (myocardial 
infarction, unstable angina); cerebrovascular disease (cerebrovascular accident or stroke or 
transient ischemic attack (TIA); chronic hypertension; or coronary revascularization surgery 
(coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) 


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2. History of cardiac arrhythmia or syncope related to cardiac arrhythmia or unexplained, or use of a 
cardiac pacemaker  
• Note: Conditions include: atrial fibrillation, atrial flutter, or non-sustained or sustained 
ventricular tachycardia); use of a cardiac pacemaker; personal or family history of Long QT 
Syndrome (LQTS); or family history of sudden death 
3. History of any other 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; 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 surgery including weight loss surgery or biliary surgery 
4. Major surgical interventions are not permitted within 4 weeks of first dosing and during the trial. 
Minor surgical interventions are not allowed within 2 weeks of first dosing and during the trial. 
5. 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 
6. Active allergic symptoms to seasonal and animal allergens that are moderate to severe, affect daily 
activity, and require continuous treatment   
7. A marked baseline prolongation of ECG intervals, or heart rate <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 
8. 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; any characteristics that would make QT assessment unreliable, including flat T waves; 
or any condition deemed clinically significant by a study investigator 
9. Abnormal renal function 
• Note: Normal renal function is defined as normal creatinine [per criteria in Appendix B of the 
protocol] and normal estimated glomerular filtration rate (eGFR) [i.e., >80.0 mL/minute] values 
according to Cockroft-Gault 
10. Positive serology results for HIV, HBsAg, or HCV 
11. Febrile illness with temperature ≥38.0 degrees Celsius (C) for <7 days before dosing in each treatment 
period 


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12. Donated whole blood or blood products within 60 days before first dosing, or plans to donate or 
receive before Final Visit (Day 8 ±2 after last dose in dosing period 4) 
• Note: Blood products include red blood cells (RBCs), white blood cells (WBCs), platelets, and 
plasma 
13. Known allergic reactions to fluoroquinolones or to components present in the formulation or 
processing of zoliflodacin and moxifloxacin 
14. Treatment with another investigational product within 30 days of first 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 
15. Active drug or alcohol binge consumption, abuse, or dependence within 12 months before Screening 
Visit that, in the opinion of the investigator, would interfere with adherence to study requirements 
16. Use of any prescription medication within 30 days before first dosing or planned use during the trial 
except as noted below and approved by the designated study clinician 
• Note 1: Prohibited medications include moderate or strong CYP3A4 inducers and other drugs 
with known risk for QT prolongation and Torsades de pointes (TdP); antibiotics; injectable or 
oral antidiabetic drugs; anti-lipid drugs; 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 up to 7 days before first dosing or 7 days 
after last dosing 
• Note 2: Allowed medications include: oral contraceptives; H1 antihistamines; all medications 
approved for control of intraocular pressure including topical ophthalmic non-selective β-
blockers, such as betaxolol, carteolol, levobunolol, metipranolol, and timolol; topical/ intranasal 
corticosteroids; nonsteroidal anti-inflammatory drugs (NSAIDS); licensed influenza vaccine 
during the flu season, 7 days before first dosing or 7 days after last dosing 
17. Use of non-prescription medications, vitamins, herbs, or nutritional supplements within 15 days before 
first dosing or planned use during the trial unless approved by the study clinician 
• Note 1: Intake of nutritional supplements, juice, and herbal preparations or other foods or 
beverages that may affect the various drug-metabolizing enzymes and transporters (e.g., 
grapefruit, grapefruit juice, grapefruit-containing beverages, apple or orange juice, vegetables 
from the mustard green family [e.g., kale, broccoli, watercress, collard greens, kohlrabi, Brussels 
sprouts, mustard], and charbroiled meats) within 7 days before dosing 
• Note 2: Exceptions: St. John’s wart is not allowed within 30 days of dosing; vitamins and over-
the-counter (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 
18. Intake of caffeinated beverages or food within 72 h before first dosing or a history of high caffeine 
consumption (e.g., in the last 4 months drinking >5 cups of coffee/day) 
19. Smoking or use of tobacco or nicotine-containing products within 30 days before first dosing 
20. Engagement in strenuous exercise within 15 days before first dosing (e.g., marathon running, long-
distance cycling, weight lifting) and during the trial 


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21. 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 
22. 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 trial 
• Note: Includes trials that have a study intervention such as a drug, biologic, or device 
23. Is a CTU employee or staff member who is paid entirely or partially by the Office of Clinical Research 
Resources (OCRR)/NIAID contract for the DMID-funded trial 
• Note: CTU employees or staff include the PIs, sub-investigators, or staff who are supervised by the 
PI or sub-investigators 
4.4. 
Treatments 
4.4.1. 
Treatments Administered  
Each subject will receive 1 dose of each of the 4 study treatments orally. The 4 study treatments are 2 g 
zoliflodacin (Treatment A), 4 g zoliflodacin (Treatment B), placebo for zoliflodacin (Treatment C), and 400 
mg moxifloxacin hydrochloride (Treatment D). The order that the treatments will be given depends on the 
sequence the subject was randomized to. 
As specified in the protocol, dosing, which includes ingestion of the entire 120 mL of tap water for any of the 
treatments (60 mL of zoliflodacin or placebo suspension and 60 mL of the rinse, or 120 mL for taking the 
moxifloxacin tablet), will be completed within 5 minutes of initial suspension for Treatment A, Treatment B, 
and Treatment C and within 5 minutes of start of ingestion for Treatment D. After dosing, subjects will 
continue to fast for an additional 4 h while water is allowed ad lib. 
4.4.2. 
Identity of Investigational Product(s) 
Treatment A: One sachet containing 2 g of zoliflodacin will be reconstituted in 60 mL of tap water by the 
unblinded pharmacist and dosed orally after an overnight fast. The dose will be administered as a mix-and-
drink solution in a standardized cup as described in the Manual of Procedures (MOP). After the cup 
containing 60 mL (suspension volume) of zoliflodacin is taken, approximately 60 mL (rinse volume) of tap 
water will be added to the cup and consumed by the subject to chase the initial dose. The second 60 mL 
volume is called ‘the rinse”. 
Treatment B: Two sachets containing 2 g of zoliflodacin each will be reconstituted in 60 mL of tap water by 
the unblinded pharmacist and dosed orally after an overnight fast. The dose will be administered as a mix-
and-drink solution in a standardized cup as described in the MOP. After the cup containing 60 mL 
(suspension volume) of zoliflodacin suspension is taken, approximately 60 mL (rinse volume) of tap water 
will be added to the cup and consumed by the subject to chase the initial dose.  The second 60 mL volume is 
called ‘the rinse”.  
Treatment C: A single dose of 4 g of placebo in powder form, whose quantity will match that in the 4 g dose 
of zoliflodacin, will be reconstituted in 60 mL of tap water by the unblinded pharmacist and dosed orally after 
an overnight fast. The dose will be administered as a mix-and-drink solution in a standardized cup as 
described in the MOP. After the cup containing 60 mL (suspension volume) of placebo is taken, 
approximately 60 mL (rinse volume) of tap water will be added to the cup and consumed by the subject to 
chase the initial dose. The second 60 mL volume is called ‘the rinse”.  


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Treatment D: A single, commercially-available, film-coated, 400 mg tablet of moxifloxacin hydrochloride 
will be administered orally with 120 mL of tap water. 
Additional details of the investigational products may be found in the protocol and MOP. 
4.4.3. 
 Method of Assigning Subjects to Sequences (Randomization) 
Seventy-two 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. 
Randomized sequence assignments will be generated by a statistician at the DCC for this study. 
Randomization will occur following admittance to the CTU and confirmation of eligibility. 
Subjects will be randomized to one of 12 treatment sequences (Section 3.3) with equal allocation 
(1:1:1:1:1:1:1:1:1:1:1:1). The randomization list will be generated centrally through the AdvantageEDCSM 
(Electronic Data Capture [EDC] System, Emmes) by the unblinded study biostatistician, and a list will be 
transferred to the unblinded study pharmacist before starting the study for the purpose of an emergency back-
up. 
Enrollment of subjects will be done online using the enrollment module of AdvantageEDC. The 
randomization code will be prepared by statisticians at the DCC and included in the enrollment module for 
this trial. AdvantageEDC will assign each subject to a treatment sequence after the demographic and 
eligibility data have been entered into the system. A designated individual at the participating site will be 
provided with a code list for emergency unblinding purposes, which will be kept in a secure place. 
Instructions for using the enrollment module are included in the AdvantageEDC User’s Guide. 
4.4.4. 
Selection of Doses in the Study 
See Section 2.2.2 of the protocol for rationale of dose selection. 
4.4.5. 
Selection and Timing of Dose for Each Subject 
Treatment sequences will be assigned by randomization. Subjects will fast for at least 8 h before dosing and 
4 h after dosing. The dosing interval between dosing periods will be at least 8 days to allow for adequate 
wash-out of drug before the next dose.  
If a subject has a Grade 3 AE judged related to study drug administration, this subject will be withdrawn from 
the study and will not receive subsequent dosing. For all other AEs, dosing may be delayed up to 14 days in 
order to follow the AE for downgrading or resolution according to the above. If the subject does not meet the 
criteria for dosing specified above in 14 days, this subject will be withdrawn from the study and will not 
receive subsequent dosing. 
4.4.6. 
Blinding 
Placebo and both of the 2 zoliflodacin doses will be blinded. However, moxifloxacin treatment will not be 
blinded. The DCC and study pharmacist will be unblinded to all treatments. The protocol contains no explicit 
provisions for emergency unblinding. According to DMID policy, the study medical monitor responds to 
requests for emergency unblinding and instructs the DCC to release treatment codes only if necessary to 
ensure that the subject receives appropriate clinical care. 


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4.4.7. 
Prior and Concomitant Therapy  
See Section 6.6 of the protocol for restrictions regarding prior and concomitant therapies.  
4.4.8. 
Treatment Compliance 
Each of the 4 treatments will be administered in the CTU. Start and end times of dosing will be recorded. 
Since each dose of zoliflodacin, placebo or moxifloxacin 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 60 mL zoliflodacin or placebo 
suspension or the moxifloxacin tablet, or who vomit up to 5 h after dosing with zoliflodacin, placebo or 
moxifloxacin will be withdrawn from data analysis for the period when the event occurred, but will not be 
withdrawn from the trial and may complete the remaining treatment periods in the assigned dosing sequence. 
Subjects who do not ingest the content of the second 60 mL (the rinse) will not be withdrawn from the trial. 
4.5. 
Safety and PK Variables 
The following section describes the safety and PK endpoints. Endpoints related to Holter ECG time points are 
described separately in the ECG SAP (Appendix 4). For a detailed schedule of procedures refer to Table 2. 
Refer to Section 3 for a list of the primary and secondary objectives and outcomes. 
Incidence, relatedness, and severity of treatment-emergent AEs and SAEs will be recorded from time of dose 
to Final Visit, or ET Visit.  
The following other safety parameters will be assessed for each dosing period and at the Final Visit or ET 
Visit:  
• Change from baseline in clinical safety laboratory parameters, as measured at the In-Patient 
Follow-up visit (the day after dosing), after a minimum 4 h fast. 
− Chemistry: Sodium, Potassium, Magnesium, Chloride, Total Carbon Dioxide (CO2), Glucose 
(Fasting), Blood Urea Nitrogen (BUN), Creatinine, Estimated Glomerular Filtration Rate 
(GFR), Total Protein, Albumin, Aspartate Aminotransferase (AST), Alanine Aminotransferase 
(ALT), Alkaline Phosphatase (AP), Total Bilirubin, and Direct Bilirubin 
− Hematology: Hemoglobin, Hematocrit, Erythrocytes, Leukocytes, Neutrophils (absolute 
count), Lymphocytes (absolute count), Monocytes (absolute count), Eosinophils (absolute 
count), Basophils (absolute count), and Platelets 
− Urinalysis: Glucose by Dipstick, Protein by Dipstick, Hemoglobin by Dipstick. If dipstick 
testing is abnormal, a complete urinalysis with microscopic evaluation will be performed. 
Urinalysis microscopic evaluation parameters that will be graded and summarized may include 
Erythrocytes by Microscopic Evaluation, Leukocytes by Microscopic Evaluation, and Bacteria 
by Microscopic Evaluation. 
• Change from baseline in vital signs parameters, as measured at 1 h (±10 minutes), 2 h (±10 
minutes), 4 h (±10 minutes), and 24 h (±2 h) after dosing.  
− Systolic Blood Pressure, Diastolic Blood Pressure, Heart Rate, Respiratory Rate, and 
Temperature 
• Change from baseline in 12-lead standard ECG with 10-sec rhythm strip parameters, as measured 
1 h (±10 minutes), 2 h (±10 minutes), 4 h (±10 minutes) and 24 h (±2 h) after dosing. 


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− Overall interpretation of standard 12-lead ECGs (normal, abnormal not clinically significant 
[NCS], or abnormal clinically significant [CS]), and the following parameters: PR Interval; 
QRS Duration, QT Interval; QTcF Interval, RR Interval, ECG Mean Ventricular Rate 
Glomerular filtration rate, as estimated by the Cockcroft-Gault equation, will entered directly into the clinical 
database. 
AEs will be graded for severity and relationship to study product, as described in Section 9.2 of the protocol 
v3.0. Adverse and serious adverse events are defined in Section 9.2 of protocol. Vital signs and ECG results 
will be graded according to toxicity scales in Table 3. Clinical laboratory results will be graded according to 
toxicity scales in Table 4. 
Blood (plasma) samples for PK analysis will be collected at the following time points for each dosing period: 
within 30 minutes before dosing, and at 0.5 h (±5 minutes), 1 h (±5 minutes), 2 h (±5 minutes), 3 h (±10 
minutes), 4 h (±10 minutes), 6 h (±10 minutes), 8 h (±15 minutes), 12 h (±15 minutes), and 24 h (±2 h) after 
dosing, or ET if it occurs within 24 h of dosing. Zoliflodacin concentrations will be measured from plasma 
samples by the bioanalytical laboratory. 


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5. 
SAMPLE SIZE CONSIDERATIONS 
Enrollment of 72 subjects would provide at least 84% power to conclude a negative effect, given that up to 16 
subjects may withdraw early prior to beginning to replace subjects (at least 56 subjects evaluable), and 
assuming a standard deviation (SD) of ΔΔQTcF of 7 msec and an underlying effect of 5 msec. 


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6. 
GENERAL STATISTICAL CONSIDERATIONS 
6.1. 
General Principles 
Safety, and PK will be summarized by treatment (see Section 3.3), with the order of treatments presented as: 
1) 2 g zoliflodacin, 2) 4 g zoliflodacin, 3) placebo, and 4) 400 mg moxifloxacin. Summaries of frequencies 
and percentages will be presented for categorical data, and summary statistics including the mean, median, 
SD, minimum value (min), and maximum value (max) will be presented for continuous demographic and 
safety data. The method of Wilson will be used for CIs of proportions for safety data. The safety population 
will be used for summaries of demographics and safety endpoints.  
Sort order of listings will be by parameter, followed by sequence, followed by subject ID, followed by date 
(or day) and time. If a listing will not follow this sort order, the sort order to be used can be found in 
Instruction text for the listing. The sort order of clinical laboratory, vital signs, and ECG parameters is 
described in Section 9.  
6.2. 
Timing of Analyses 
The final analysis will be performed after database lock. There are no planned interim analyses. 
6.3. 
Analysis Populations 
All analysis populations to be used in the final analysis are described below. Reasons for exclusion from each 
analysis population will be summarized by sequence in Table 8 and listed (Listing 4). Although there may be 
multiple reasons for exclusion from the PK population, only one reason will be counted when summarizing 
reasons for exclusion from analysis populations in the table. The order that reasons will be considered are the 
same as the order shown in the table shell. For example, if a subject was excluded from the PK Population and 
had insufficient concentration data to compute any PK parameters, the subject would be counted for exclusion 
from the PK analysis subset for reason of exclusion from the PK population only, because that reason appears 
in the table before the reason of insufficient concentration data. 
6.3.1. 
Safety Population 
All subjects who received at least one dose of study drug (zoliflodacin, placebo, or moxifloxacin) will be 
included in the safety population and analyzed as treated. 
6.3.2. 
PK Population and PK Analysis Subset 
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. If any subjects are found to 
be noncompliant with respect to dosing or have incomplete data, a decision to include them in the analysis 
will be made on a case-by-case basis.  
6.3.3. 
Holter ECG Analysis Population 
The Holter ECG Analysis Population will include all subjects who have received at least one dose of 
zoliflodacin, moxifloxacin or placebo, treatment, without protocol deviations potentially impacting the ECG 
intervals and have baseline ECGs and at least one post-dose ECG assessment. 


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6.3.4. 
Pharmacokinetic-ECG (PK-ECG) Analysis Population 
PK-ECG Analysis Population will be a subset of the Holter ECG Analysis Population and will include all 
subjects in the Holter ECG Analysis Population with at least one plasma concentration value in the 
zoliflodacin treatment with a corresponding Holter ECG measurement value at the same nominal timepoint. 
6.4. 
Covariates and Subgroups 
The protocol does not define any formal subgroup analyses. 
6.5. 
Missing Data 
No imputation of missing data is planned. 
6.6. 
Interim Analyses and Data Monitoring 
No interim analysis is planned. 
6.7. 
Multicenter Studies 
This is a single site study. 
6.8. 
Multiple Comparisons/Multiplicity 
Safety and PK analyses will not adjust for multiple comparisons. For multiplicity in the ECG analysis, see the 
ECG SAP (Appendix 4). 


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7. 
STUDY SUBJECTS 
7.1. 
Disposition of Subjects 
Screened subjects who were ineligible for enrollment in the study (screen failures) or eligible but not enrolled 
will be summarized by inclusion and exclusion criteria (Table 6). 
Subject disposition will be summarized by sequence (Table 7), showing the number of subjects by sequence 
who were screened, enrolled, dosed, completed sample collection, or completed follow up. Eligibility for each 
analysis population will be summarized by sequence (Table 8). 
A flow diagram will summarize screening, enrollment, and disposition of subjects by sequence, including 
number of subjects dosed, number of subject completing ECG follow-up, and reasons for early termination or 
discontinuation of study product (Figure 2). 
Subjects who terminated early from the study will be listed (Listing 1). Subjects who were excluded from an 
analysis population will be listed (Listing 4). 
7.2. 
Protocol Deviations 
A summary of protocol deviations will be presented by deviation category and deviation type (Table 5). This 
table will provide both the number of subjects and the number of deviations for each category. All subject-
specific protocol deviations and non-subject-specific protocol deviations will be listed (Listing 2 and 
Listing 3). 


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8. 
EFFICACY EVALUATION 
Not Applicable. For analysis of Holter ECG endpoints, see the ECG SAP (Appendix 4). 


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9. 
SAFETY EVALUATION 
All safety analyses will be presented using the safety population. Subjects will be grouped for summary 
statistics by Treatment, as defined in Section 3.3.  
When calculating the incidence of AEs (i.e., on a per subject basis), each subject will be counted once and any 
repetitions of unsolicited AEs within a subject (by treatment) will be ignored for events coded in the same 
category by the Medical Dictionary for Regulatory Activities (MedDRA®). The denominators for percent 
values will be indicated within the table or table header and denominators will consist of the maximal size of 
the safety population in the indicated observation period. Moreover, events thus summarized will be coded to 
the highest severity observed. If the time interval defined by the start date and end date of the AE overlaps 
more than 1 period, the AE will be associated with treatment immediately preceding the AE start date only, 
and the AE will be graded according to the maximum severity of the event at any time prior to the AE end 
date. Abnormal laboratory values or clinical findings measured after dosing will be reported using the toxicity 
scales in Table 3 and Table 4.  
All laboratory, vital signs, and ECG results obtained after the first dose that have programmable criteria 
described in the toxicity scales will be graded for the CSR according to the programmable criteria, and 
toxicity grades of mild, moderate, or severe will be indicated for the result in the listings. For criteria 
involving a change from baseline, the baseline to be used is described in Section 3.3. 
If a subject was accepted into the trial with a laboratory, vital signs, or ECG parameter value that overlaps 
with values used for grading Grade 1 laboratory abnormalities, the result will only be graded (mild or worse) 
if the post-dose measurement of the parameter is different (worse) than baseline. In other words, a result will 
be graded as mild, moderate, or severe if and only if it both meets the grading criteria in Table 3 or Table 4 
and is worse than baseline by any amount. 
9.1. 
Demographic and Other Baseline Characteristics 
Sex, ethnicity, and race of all subjects will be summarized by sequence (Table 9). Ethnicity will be 
categorized as “Hispanic or Latino,” “Not Hispanic or Latino,” “Unknown,” or “Not Reported.” In 
accordance with NIH reporting policy, subjects may self-designate as belonging to more than one race or may 
refuse to identify a race, the latter reflected in the case report form (CRF) as “No” to each racial option. Age, 
height, weight, and BMI will be summarized by sequence (Table 10). 
Individual subject listings will be presented for all demographic and baseline characteristics (Listing 5). Note 
that while weight may be measured once prior to the first dose, the height, weight, and BMI from the first 
screening visit will be considered the baseline values. 
9.1.1. 
Prior and Concurrent Medical Conditions 
All current illnesses and past pre-existing medical conditions will be coded using MedDRA dictionary version 
20.1 or higher. Summaries of subjects’ pre-existing medical conditions by MedDRA system organ class 
(SOC) will be presented by sequence and overall (Table 11). Individual subject listings will be presented for 
all medical conditions (Listing 6). 
9.1.2. 
 Prior and Concomitant Medications  
All medications will be coded using the current version of the World Health Organization (WHO) Drug 
dictionary (WHO Drug Dictionary Enhanced C3 September 1, 2018 or higher). The use of prior and 
concomitant medications taken during the study will be summarized by treatment and by Anatomical 
Therapeutic Code ATC 1 and ATC 2 (separately in Table 30 for prior medications and Table 31 for 


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concomitant medications). Individual subject listings will be presented for all prior and concomitant 
medications (separately in Listing 19 for prior medications and Listing 20 for concomitant medications). 
Drugs will be listed and summarized as prior medications when the end date for the medication is before the 
first dose of study product and listed and summarized as concomitant medications otherwise. 
9.2. 
Measurements of Treatment Compliance 
Date and time of each treatment will be included in Listing 7. 
9.3. 
Adverse Events 
When calculating the incidence of AEs (i.e., on a per subject basis) within a given AE class (MedDRA 
category), each subject will only be counted once for each treatment and any repetitions of AEs within a 
subject/treatment will be ignored. For each treatment received, the worst severity observed for the subject 
within the observation period and AE class will be reported. The denominators for percent values will be 
indicated within the table or table header and denominators will consist of the maximal size of the safety 
population in the indicated observation period. 
9.3.1. 
Unsolicited Adverse Events 
A brief overall summary of AEs by treatment will be shown (Table 12), including number of subjects with at 
least 1 AE of any severity, number of subjects with at least 1 related AE of any severity, and number of 
subjects with at least 1 SAE. 
AEs by subject will be presented in Listing 8. A subject listing of non-serious AEs of moderate or greater 
severity will be reported (Table 16).  
The following summaries for unsolicited AEs will be presented: 
• Tabularly, the total number of AEs and the number and proportion of subjects reporting at least 
one unsolicited AE, summarized by treatment, MedDRA SOC, HLGT, and PT (Table 13). 
Denominators for percentages are the number of subjects who received the treatment being 
summarized. 95% CIs (Wilson CIs) will be presented for proportions. 
• Tabularly, the number and proportion of subjects reporting at least one unsolicited AE, 
summarized by treatment, SOC, HLGT, PT, severity, and relatedness (Table 14). 
• Graphically, by treatment, bar charts of frequency of related serious and non-serious AEs by 
severity and MedDRA SOC (and overall for any SOC) (Figure 3, Figure 4, Figure 5, Figure 6, 
Figure 7). These figures describe the total number of occurrences of each event, including multiple 
occurrences per subject. 
• Graphically, by treatment, bar chart of incidence of related serious and non-serious AEs by 
severity and MedDRA SOC (and overall for any SOC) (Figure 8, Figure 9, Figure 10, Figure 11, 
Figure 12). These figures describe the number of subjects with an event (each subject counted once 
per SOC). 
9.4. 
Deaths, Serious Adverse Events and other Significant Adverse Events 
Individual data listings of deaths and serious AEs (Table 15) will be provided. The listing will include: subject 
ID, treatment, AE description, duration, reason reported as an SAE, severity, relationship to treatment, 


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alternate etiology if not related, action taken with study treatment, whether subject discontinued due to AE, 
outcome, MedDRA SOC, MedDRA HLGT, and MedDRA PT. 
9.5. 
Birth Control and Pregnancies 
An individual data listing of pregnancy reports will be provided (Listing 21, Listing 22, Listing 23, Listing 24, 
Listing 25) if a pregnancy occurs post dosing. 
Birth control method(s) will be listed for each subject with start date and end date (Listing 26). 
9.6. 
Clinical Laboratory Evaluations 
Toxicity grade criteria for laboratory results can be found in Table 4. 
Unplanned clinical laboratory evaluations will be listed, but excluded from tabular and graphical summaries, 
except when calculating the maximum severity post-baseline. 
Screening and safety clinical laboratory results (chemistry, hematology, and urinalysis) will be listed 
(Listing 9, Listing 10, Listing 11). Additionally, abnormal laboratory results (graded mild, moderate, or 
severe) will be listed in Table 17, Table 18, and Table 19. Measurements outside of the normal range, but not 
graded as mild, moderate, or severe, will be flagged as “ONR” (outside normal range) in the listings. 
Laboratory results will be summarized in tables and figures: 
• Tabularly, by parameter, treatment, time point, and toxicity grade (including maximum severity 
post-baseline) 
− Chemistry Parameters: Table 20 
− Hematology Parameters: Table 22 
− Urinalysis Parameters: Table 24 
• Tabularly, by summary statistics for change from baseline, reported by parameter, treatment, and 
time point 
− Chemistry Parameters: Table 21 
− Hematology Parameters: Table 23 
• Graphically, using box plots showing the change from baseline by parameter, treatment, and time 
point 
− Chemistry Parameters: Figure 13, Figure 14, Figure 15, Figure 16, Figure 17, Figure 18, 
Figure 19, Figure 20, Figure 21, Figure 22, Figure 23, Figure 24, Figure 25, Figure 26, 
Figure 27, Figure 28 
− Hematology Parameters: Figure 29, Figure 30, Figure 31, Figure 32, Figure 33, Figure 34, 
Figure 35, Figure 36, Figure 37, Figure 38 
The following parameters will be presented (in order): 
• Chemistry: Sodium, Potassium, Magnesium, Chloride, CO2, Glucose (Fasting), BUN, Creatinine, 
Estimated GFR, Total Protein, Albumin, AST, ALT, AP, Total Bilirubin, and Direct Bilirubin 
• Hematology: Hemoglobin, Hematocrit, Erythrocytes, Leukocytes; absolute counts of Neutrophils, 
Lymphocytes, Monocytes, Eosinophils, and Basophils; and Platelets 


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• Urinalysis: Glucose by Dipstick, Protein by Dipstick, Hemoglobin by Dipstick, Erythrocytes by 
Microscopic Evaluation, Leukocytes by Microscopic Evaluation, Bacteria by Microscopic 
Evaluation 
Only laboratory parameters reported as continuous values will be included in tables of summary statistics for 
change from baseline and in box plots for change from baseline. Because microscopic urinalysis evaluation is 
only performed in subjects with an abnormal urine dipstick result, urinalysis parameters assessed by 
microscopic evaluation will be excluded from tables of summary statistics for change from baseline and in 
box plots for change from baseline. However, urinalysis parameters assessed by microscopic evaluation will 
be included in summaries of toxicity grading, where the toxicity grade will be imputed as “Normal” for 
subjects where microscopic evaluation was not performed. 
Laboratory parameters that have grading criteria for both decreases (result lower than normal range and 
baseline measurement) and increases (result higher than normal range and baseline measurement) will be 
summarized separately by direction of change. For example, sodium will be summarized separately as 
“Sodium, Decrease” and “Sodium, Increase.” 
In tables summarizing toxicity grading, maximum severity observed for the parameter after dosing and within 
the same dosing period will be summarized (max severity post-baseline). Results of maximum severity for 
“Any Parameter” will be included for chemistry, hematology, and urinalysis laboratory results. For “Any 
Parameter” results, the maximum severity across all laboratory parameters in the respective category is 
summarized by time point, and from maximum severity post baseline.  
By protocol, up to one repeat of a planned clinical laboratory assessment is allowed (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.). If replicates for clinical laboratory results are present in the 
database, then only the second replicate will be summarized and reported. Replicates not used in the analysis 
will not be listed. 
Viral serology screening results (Listing 12), urine toxicology and alcohol screening results (Listing 13), and 
serum hCG (Human Chorionic Gonadotropin) pregnancy test results (Listing 14) will be listed. If FSH is 
measured for any subject during the study, FSH will be included in Listing 14. 
9.7. 
Vital Signs and Physical Evaluations 
Toxicity grade criteria for vital signs can be found in Table 3. Unplanned vital signs measurements will be 
listed, but excluded from tabular and graphical summaries, except when calculating the maximum severity 
post-baseline. 
Vital signs results will be listed (Listing 15). 
Vital signs results will be summarized in tables and figures: 
• Tabularly, by parameter, treatment, time point, and toxicity grade (including maximum severity 
post-baseline) (Table 25) 
• Tabularly, by summary statistics for change from baseline, reported by parameter, treatment, and 
time point (Table 26) 
• Graphically, using box plots showing the change from baseline by parameter, treatment, and time 
point (Figure 39, Figure 40, Figure 41, Figure 42, Figure 43) 


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The following parameters will be presented (in order): Systolic Blood Pressure, Diastolic Blood Pressure, 
Heart Rate, Respiratory Rate, and Temperature 
Vital signs parameters that have grading criteria for both decreases (result lower than normal range and 
baseline measurement) and increases (result higher than normal range and baseline measurement) will be 
summarized separately by direction of change. 
In tables summarizing toxicity grading, maximum severity observed for the parameter after dosing and within 
the same period will be summarized (max severity post-baseline). Results of maximum severity for “Any 
Parameter” will be included. For “Any Parameter” results, the maximum severity across all vital signs 
parameters is summarized by time point, and from maximum severity post baseline.  
The study protocol allows measurements of vital signs to be repeated in the case of an abnormal 
measurement. The following rules will be used to decide which measurement to include in summaries if more 
than one replicate was entered into the clinical database. 
• If the first replicate is normal, then it will be used for analysis 
• If the first replicate is abnormal, and the second replicate is also abnormal, then the first replicate 
will be used if has a severity equal to or greater to the second replicate, or the second replicate will 
be used if the second replicate has a higher severity than the first replicate. 
• If the first replicate is abnormal, the second replicate is normal, and a third replicate measurement 
was not performed, then the first replicate will be used in the analysis. 
• If the first replicate is abnormal, the second replicate is normal, and the third replicate is normal, 
then the second replicate will be used in the analysis. 
• If the first replicate is abnormal, the second replicate is normal, and the third replicate is abnormal, 
then the first replicate will be used if has a severity equal to or greater to the third replicate, or the 
third replicate will be used if the third replicate has a higher severity than the first replicate. 
Vital signs replicates not used in the analysis will not be listed. 
PE findings will be listed (Listing 16). 
9.8. 
12-Lead Standard ECG 
Toxicity grade criteria for 12-lead standard ECG parameters (PR and QTcF intervals) can be found in Table 3. 
12-lead standard ECG interval measurements (Listing 17), and overall interpretation and comments 
(Listing 18) will be listed. Unplanned 12-lead standard ECG measurements will be listed but excluded from 
tabular and graphical summaries. 
12-lead standard ECG results will be summarized in tables and figures: 
• Tabularly, 12-lead standard ECG change in overall interpretation from baseline will be shown by 
treatment and time point in Table 27. 
• Tabularly, by parameter, treatment, time point, and toxicity grade (including maximum severity 
post-baseline) (Table 28) 
• Tabularly, by summary statistics for change from baseline, reported by parameter, treatment, and 
time point (Table 29) 


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• Graphically, using box plots showing the change from baseline by parameter, treatment, and time 
point (Figure 44, Figure 45, Figure 46, Figure 47, Figure 48, Figure 49) 
The following parameters will be presented (in order): PR Interval; QRS Duration, QT Interval; QTcF 
Interval, RR Interval; ECG Mean Ventricular Rate. 
9.9. 
Concomitant Medications 
All medications will be coded using the current version of the WHO Drug dictionary. The use of prior and 
concomitant medications taken during the study will be summarized by Anatomical Therapeutic Code ATC 1 
and ATC 2 (separately in Table 30 for prior medications and Table 31 for concomitant medications). 
Individual subject listings will be presented for all prior and concomitant medications (separately in 
Listing 19 for prior medications and Listing 20 for concomitant medications). 
9.10. 
Tolerability 
Tolerability to zoliflodacin (see Section 3.3) will be summarized for all subjects in the safety population who 
have received a dose of zoliflodacin (Table 32). Each subcomponent of tolerability will be included in the 
summaries: 1) subject discontinued study drug due to an AE, 2) subject choose to withdraw from the study 
due to an AE at any time from first dose of zoliflodacin until end of study, or 3) subject was withdrawn from 
the study by the investigator due to an adverse event at any time from first dose of zoliflodacin until end of 
study. 


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10. 
PHARMACOKINETICS 
The PK Analysis Population and PK Analysis Subset are defined in Section 6.3. If there are subjects who do 
not have sufficient samples for a complete analysis, a modified analysis will be conducted in which some or 
all PK parameters may not be estimated for those subjects, but available PK concentrations will still be 
tabulated and graphed. 
Summaries of PK data across subjects will be performed using the PK Analysis Subset by treatment (dose of 
zoliflodacin). Zoliflodacin concentrations will be reported in units of ng/mL. Moxifloxacin concentrations 
will not be measured in this study. 
The below describes the basic tabular and graphical summaries of zoliflodacin PK data as well as the 
noncompartmental analysis (NCA). Analysis of zoliflodacin concentration and exposure data in the context of 
Holter ECG results is discussed in the ECG SAP. 
10.1. 
Missing Data and Imputations 
Analyte concentrations identified as laboratory errors will be indicated as such in the report and may be 
excluded from analyses. Time points below the lower limit of quantification (LLOQ; 1.00 ng/mL), referred to 
as below quantification limit (BQL), preceding the first PK concentration above the LLOQ will be imputed as 
0 for plotting and for all calculations including NCA and summary statistics. All other BQL values will be 
missing for analysis purposes. 
If the exact time of sample collection for PK is not recorded, the collection time will be imputed as the 
planned time for analysis. If the exact time is not known, but it is known that the sample was collected outside 
of the protocol defined time window for collection, then the time point may be excluded from analysis at the 
discretion of the PK analyst. Rationale for excluding results from analysis will be described in the CSR. 
Collection of plasma samples outside of the protocol defined time window for the time point will not result in 
exclusion of the sample result from NCA or, typically, exclusion from calculation of summary statistics for 
the respective time point. PK samples collected out of window will be evaluated on a case to case basis and in 
extreme cases may be excluded from concentration summary statistics and plots of mean concentration. 
Exclusion of time points, including the justification, will be stated clearly in the report. 
Missing data due to non-collection of samples will not be imputed. A geometric mean (GM) of concentrations 
will be treated as missing for sets of data points containing a BQL value. 
10.2. 
Tabular and Graphical Summaries of Zoliflodacin Concentration-Time Profiles 
Zoliflodacin concentrations in plasma will be listed by subject and dosing period with separate columns for 
concentrations reported by the lab and concentrations used for analysis (Listing 27). The listings will indicate 
both the nominal time, and actual time associated with the sample. All times will be in units of h. 
Zoliflodacin concentrations in plasma will be summarized by dose and time point (Table 33, Table 34) and 
plotted. 
• Individual profiles by zoliflodacin dose as linear plots (Figure 50, Figure 51, Figure 52, Figure 53, 
Figure 54, Figure 55, Figure 56, Figure 57) 
• Individual profiles by zoliflodacin dose as semi-logarithmic plots (Figure 58, Figure 59, Figure 60, 
Figure 61, Figure 62, Figure 63, Figure 64, Figure 65) 
• Figure 66  will plot GM concentration-time profiles by zoliflodacin dose as linear plots. 


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• Figure 67  will plot GM concentration-time profiles by zoliflodacin dose as semi-logarithmic plots. 
10.3. 
Definition and Estimation of Individual NCA PK Parameters 
PK parameters will be estimated through a NCA using Phoenix® WinNonlin® version 8.0 or later (Pharsight 
Corporation, Cary, NC). Actual post-dose time will be used for the estimation of PK parameters instead of 
nominal time. Individual PK parameter estimates will be listed (Listing 28).  
Phoenix WinNonlin® NCA will use the following settings to compute parameters from plasma PK data: 
• Linear Up Log Down calculation method 
• Uniform weighting 
• Oral dosing 
• Lambda Z Acceptance Criteria 
o Rsq_adjusted ≥ 0.80 
o Span ≥ 2.5 half-lives 
o Includes at least 3 timepoints after Tmax 
Cmax 
Cmax is defined as the maximum observed drug concentration observed in plasma over all PK sample 
concentrations. It will be obtained from the Cmax parameter calculated by WinNonlin®. If there is no 
measurable concentration in the subject’s PK profile, then Cmax will be missing for that subject. Cmax will be 
reported in units of ng/mL. 
Tmax 
Time of maximum plasma concentration (Tmax) is defined as the time at which the Cmax occurs. It will be 
obtained from the Tmax parameter calculated by WinNonlin®. If there is no measurable Cmax in the subject’s 
PK profile, then Tmax will be missing for that subject. Tmax will be reported in units of h. 
Ke 
The terminal phase elimination rate constant (Ke) is defined as the first-order rate constant describing the rate 
of decrease of drug concentration in the terminal phase (defined as the terminal region of the PK curve where 
drug concentration follows first-order elimination kinetics). Ke will be computed as the slope of a terminal 
region consisting of ≥3 successive points in the plot of log-transformed concentration data versus time. Ke 
will be estimated using uniform weighting.  
Time points used in the estimation of Ke will be initially selected using the WinNonlin® automatic algorithm. 
Manually chosen time points may be used at the discretion of the PK analyst after examination of the 
automatically chosen points in the context of the semi-log profile. The set of points chosen must contain only 
timepoints after Tmax, include at least 3 timepoints, and satisfy the Lambda Z Acceptance Criteria described 
above. Otherwise, the elimination rate constant and all derived parameters (apparent terminal elimination 
half-life [t1/2], AUC Extrapolated to Infinity [AUC(0-inf)], Apparent Oral Clearance [CL/F], and Apparent 
Volume of Distribution During Terminal Phase [Vz/F]) will be treated as missing. 
The range of concentrations used to estimate Ke for each profile will be inspected by the PK analyst, who may 
adjust the set of concentrations used to estimate Ke if deemed necessary, but manually selected ranges must 
satisfy the same acceptance criteria as those chosen automatically by the WinNonlin® algorithm. Sets of drug 


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concentrations used to calculate Ke will be indicated in Listing 27. This parameter will be obtained from the 
Lambda_z parameter calculated by WinNonlin®. Ke will be reported in units of /h. 
t1/2 
The half-life (t1/2) is defined as the time required for the drug concentration to decrease by a factor of one-half 
in the terminal phase. The t1/2 can be estimated as ln(2) / Ke. It will be obtained from the HL_Lambda_z 
parameter calculated by WinNonlin®. Half-life will be reported in units of h. 
AUC 
AUC(0-last) is defined as the area under the concentration-time curve from dosing (time 0) to the time of the last 
measured concentration. AUC(0-last) will be estimated using the Linear Up Log Down calculation method and 
obtained from the AUClast parameter calculated by WinNonlin®. 
AUC(0-t) (partial AUC) is defined as the area under the concentration-time curve from dosing (time 0) to time 
t. AUC(0-t) may be computed for one or more values of t, with specific values of t determined after observing 
the data. It may be determined that no partial AUCs are required for inclusion in the CSR. Specific times (t) 
AUC(0-t) will be estimated using the Linear Up Log Down calculation method. 
AUC(0-inf) is defined as the total area under the concentration-time curve from dosing (time 0) taken to the 
limit as the end time becomes arbitrarily large. AUC(0-inf) can be calculated by adding AUC(0-last) to an 
extrapolated value equal to the last measured concentration greater than the LLOQ divided by Ke: 
AUC(0−inf) = AUC(0−last) + Clast
Ke
, 
where Clast is the last measured concentration ≥ LLOQ. AUC(0-inf) will be obtained from the AUCINF_obs 
parameter calculated by WinNonlin®. If the amount extrapolated portion of AUC(0-inf) is >20%, the estimated 
AUC(0-inf) value will be flagged when listed in the report and will be excluded from statistical summaries of 
parameter estimates and downstream calculations. 
All AUCs will be reported in units of h*ng/mL. 
CL/F 
Apparent oral clearance (CL/F) can be computed as Dose/AUC(0-inf). It will be obtained from the Cl_F_obs 
parameter calculated by WinNonlin®. Clearance will be reported in units of L/h. 
Vz/F 
Apparent volume of distribution during terminal phase (Vz/F) after non-intravenous administration can be 
calculated as (CL/F)/ Ke. It will be obtained from the Vz_obs parameter in WinNonlin®. Volume will be 
reported in units of L. 
10.4. 
Descriptive Statistics 
Subject specific PK parameter estimates will be listed (Listing 28). PK Estimates will be summarized 
(Table 35, Table 36) by zoliflodacin dose. Summary statistics will include mean, SD, min, max, median, 
coefficient of variation as a percent (CV%), GM, and geometric SD (GSD). The individual ratio of exposure 
parameters (Cmax, AUC(0-last) and AUC(0-inf)) will be summarized by min, max, median, CV%, GM, and 95% 
CI (t-intervals using log-transformed parameters) (Table 37). 


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11. 
IMMUNOGENICITY 
Not applicable. 


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12. 
OTHER ANALYSES 
Not applicable. 


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13. 
REPORTING CONVENTIONS 
The number of decimal places reported for listings and certain summary statistics (min and max) of height, 
weight, and safety parameters (clinical safety laboratory results, vital signs, etc.) will match the number of 
decimal places reported by the CTU, while other summary statistics (mean, median, GM, GSD) will be 
reported to an additional decimal place. Drug concentrations, AUCs, and Cmax and their summary statistics 
will have the same number of significant digits as the drug concentrations reported by the bioanalytical 
laboratory. Ke will be reported to 3 decimal places. Other PK parameters will be reported to 1 decimal place. 
P-values ≥0.001 and ≤0.999 will be reported to 3 decimal places; p-values less than 0.001 will be reported as 
“<0.001.” Percentages (including CV) will be reported as whole numbers. 
Listings of individual subject data include a Subject ID column. The subject identifiers assigned by site staff 
are replaced throughout this report with the Standard Data Tabulation Model (SDTM) variable USUBJID to 
protect the confidentiality of those who volunteered to participate in this protocol. USUBJID has been created 
as a composite of the 3-letter EDC platform code followed by a numeric identifier assigned chronologically to 
enrolled subjects as well as screening failures across all sites and protocols in the EDC platform. Any data 
sharing activities will include the USUBJID and not the subject identifiers assigned at the site. 


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14. 
TECHNICAL DETAILS 
SAS version 9.4 or above or R versions 3.2 or above will be used to generate tables, figures, and listings. PK 
parameters will be estimated through a NCA using Phoenix® WinNonlin® version 8.0 or later (Pharsight 
Corporation, Cary, NC). 


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15. 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY OR 
PLANNED ANALYSES 
None to report. 


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16. 
REFERENCES 
1. International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use. Statistical Principles for Clinical Trials E9. 1998. 
2. International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use. The Clinical Evaluation of QT/QTc Interval Prolongation and 
Proarrhythmic Potential for Nonantiarrhythmic Drugs E14. 2005. 


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17. 
LISTING OF TABLES, FIGURES, AND LISTINGS  
Table, figure, and listing shells are presented in Appendices 1, 2, and 3. 
 


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APPENDICES 


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APPENDIX 1. TABLE MOCK-UPS 
LIST OF TABLES 
Table 1: 
Analysis Time Points for Safety and PK Endpoints .....................................................6 
Table 2: 
Schedule of Study Procedures ....................................................................................41 
Table 3: 
Toxicity Grading Tables – Clinical Adverse Events ..................................................43 
Table 4: 
Laboratory Adverse Event Grading Scale ..................................................................46 
Table 5: 
Distribution of Protocol Deviations by Category and Type .......................................48 
Table 6: 
Ineligibility Summary of Screen Failures ...................................................................50 
Table 7: 
Subject Disposition by Sequence................................................................................51 
Table 8: 
Analysis Population Exclusions by Sequence ............................................................52 
Table 9: 
Summary of Categorical Demographic and Baseline Characteristics by 
Sequence .....................................................................................................................54 
Table 10: Summary of Continuous Demographic and Baseline Characteristics by 
Sequence .....................................................................................................................55 
Table 11: Summary of Subjects with Pre-Existing Medical Conditions by MedDRA 
System Organ Class ....................................................................................................57 
Table 12: Overall Summary of Adverse Events by Treatment ...................................................58 
Table 13: Summary of Unsolicited Adverse Events by MedDRA System Organ Class, 
High Level Group Term, Preferred Term, and Treatment ..........................................59 
Table 14: Unsolicited Adverse Events by MedDRA System Organ Class and Preferred 
Term, Maximum Severity, Relationship, and Treatment ...........................................60 
Table 15: Listing of Serious Adverse Events .............................................................................61 
Table 16: Listing of Non-Serious, Unsolicited, Moderate or Severe Adverse Events ...............62 
Table 17: Listing of Abnormal Laboratory Results - Chemistry ................................................64 
Table 18: Listing of Abnormal Laboratory Results - Hematology .............................................65 
Table 19: Listing of Abnormal Laboratory Results - Urinalysis ................................................66 
Table 20: Chemistry Clinical Safety Laboratory Results by Parameter, Maximum 
Severity, Time Point, and Dosing Period ...................................................................67 
Table 21: Chemistry Clinical Safety Laboratory Results Change from Baseline – 
Summary Statistics by Parameter, Time Point, and Dosing Period ...........................69 
Table 22: Hematology Clinical Safety Laboratory Results by Parameter, Maximum 
Severity, Time Point, and Dosing Period ...................................................................70 
Table 23: Hematology Clinical Safety Laboratory Results Change from Baseline – 
Summary Statistics by Parameter, Time Point, and Dosing Period ...........................71 


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Table 24: Urinalysis Clinical Safety Laboratory Results by Parameter, Maximum 
Severity, Time Point, and Dosing Period ...................................................................72 
Table 25: Vital Signs Results by Parameter, Maximum Severity, Time Point, and 
Dosing Period .............................................................................................................73 
Table 26: Vital Signs Change from Baseline – Summary Statistics by Parameter, Time 
Point, and Dosing Period ............................................................................................75 
Table 27: 12-Lead Standard ECG Overall Interpretations, Post Dose Compared to 
Baseline .......................................................................................................................76 
Table 28: 12-Lead Standard ECG Results by Parameter, Maximum Severity, Time 
Point, and Dosing Period ............................................................................................78 
Table 29: 12-Lead Standard ECG Change from Baseline – Summary Statistics by 
Parameter, Time Point, and Dosing Period ................................................................81 
Table 30: Number and Percentage of Subjects with Prior Medications by WHO Drug 
Classification and Sequence .......................................................................................82 
Table 31: Number and Percentage of Subjects with Concomitant Medications by WHO 
Drug Classification and Treatment .............................................................................83 
Table 32: Assessment of Tolerability .........................................................................................84 
Table 33: Summary Statistics for Zoliflodacin Concentrations by Nominal Time, after 
Single 2 g Zoliflodacin Dose ......................................................................................85 
Table 34: Summary Statistics for Zoliflodacin Concentrations by Nominal Time, after 
Single 4 g Zoliflodacin Dose ......................................................................................86 
Table 35: Summary Statistics for Zoliflodacin PK Parameters, after Single 2 g 
Zoliflodacin Dose .......................................................................................................87 
Table 36: Summary Statistics for Zoliflodacin PK Parameters, after Single 4 g 
Zoliflodacin Dose .......................................................................................................88 
Table 37: Summary Statistics for Zoliflodacin Exposure Measure Ratios Comparing a 
Single 4 g Oral Dose to a Single 2 g Oral Dose .........................................................89 
 


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9.5.1 Efficacy/Immunogenicity and Safety Measurements Assessed and Flow Chart 
Table 2: 
Schedule of Study Procedures 
Study Visit 
Screening1 
Inpatient Periods 1-4 
Outpatient Periods 
1-4 
Final Visit 
(after Dose 4) 
Unscheduled 
Early 
Termination 
Check-in 
Dosing 
Follow-up 
Study Day / Assessments 
-21 to -2 
-1 
1 
2 
3 - 7 
8 (± 2) 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria2 
X 
X 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Medical history update 
 
X 
 
 
 
 
 
 
Prior and Concomitant Medications 3 
X 
X 
X 
X 
X 
X 
X 
X 
Complete PE4 
X 
 
 
 
 
X 
 
X 
Abbreviated PE5 
 
X 
 
 
 
 
 
 
Symptom-directed PE6 
 
 
X 
X 
 
 
X 
 
Height, weight, BMI7 
X 
 
 
 
 
 
 
 
Weight 
 
X 
 
 
 
X 
 
X 
Vital signs8 
X 
X 
X 
X 
 
X 
X 
X 
Clinical labs9 
X 
X 
 
X 
 
X 
X 
X 
Viral serology10 
X 
 
 
 
 
 
 
 
Serum pregnancy test11 
X 
X 
 
 
 
X 
 
X 
Serum FSH level11 
X 
 
 
 
 
 
 
 
Urine toxicology 
X 
X 
 
 
 
 
 
 
Alcohol urine test 
X 
X 
 
 
 
 
 
 
12-lead standard ECG12 
X 
X 
X 
X 
 
X 
X 
X 
Continuous Holter ECG13  
 
 
X 
X 
 
 
 
 
Randomization14 
 
 
X 
 
 
 
 
 
Study drug dosing 
 
 
X 
 
 
 
 
 
PK samples15 
 
 
X 
X 
 
 
 
X 
Counsel on use of appropriate contraception 
and avoidance of pregnancy16 
X 
 
 
X 
 
X 
X 
X 
Counsel to avoid use of prohibited medications, 
alcohol, marijuana and illicit drugs 
X 
 
 
X 
 
 
 
 
Counsel to avoid rigorous physical activity 
X 
X 
 
X 
 
 
 
 


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Study Visit 
Screening1 
Inpatient Periods 1-4 
Outpatient Periods 
1-4 
Final Visit 
(after Dose 4) 
Unscheduled 
Early 
Termination 
Check-in 
Dosing 
Follow-up 
Study Day / Assessments 
-21 to -2 
-1 
1 
2 
3 - 7 
8 (± 2) 
 
 
AE and SAE review17 
 
 
X 
X 
X 
X 
X 
X 
Admit to CTU 
 
X 
 
 
 
 
 
 
Discharge from CTU 
 
 
 
X 
 
 
 
 
Discharge from trial 
 
 
 
 
 
X 
 
 
1. 
Screening is completed within 21 days before study drug dosing and may require more than one visit. 
2. 
Inclusion/Exclusion criteria at Screening and on Day -1 and Day 1 before dosing in Dosing Period 1 to determine eligibility for enrollment and randomization. I/E criteria will be confirmed before 
each subsequent dosing period. 
3. 
Prior Medications include prescription during the period 30 days before first dosing and non-prescription drugs, herbs, vitamins, and nutritional supplements taken during the period 15 days before 
first dosing. ConMeds include those taken after dosing. (See Section 6.6 of Protocol) for prohibited medications and exclusions). 
4. 
Complete PE (except genital, breast, and rectal exams): at Screening, and Final Visit, or ET. 
5. 
Abbreviated PE: on Day -1 (not performed if the complete PE was performed ≤7 days from this visit) in each inpatient period. 
6. 
Symptom-directed PE: on Day 1 (pre-dose and post-dose) and Day 2 in each dosing period to evaluate new symptoms before dosing and AEs after dosing. 
7. 
BMI is calculated as weight in kg divided by height (in meters) squared. 
8. 
Vital signs at Screening; on Days -1, 1, and 2 in each dosing period; and at Final Visit after Dose 4, or ET. On Day 1 of each dosing period, VS at baseline (within 1 h before dosing) and at 1 h 
(±10 minutes), 2 h (±10 minutes), and 4 h (±10 minutes) after dosing. 
9. 
Clinical laboratory testing with a minimum 4-h fast. 
10. Viral serology (HIV1/2 test, HBsAg, HCV antibody): at Screening. 
11. Serum pregnancy test in all women at Screening and within 24 h before each dosing period, and at the Final Visit, or ET. FSH only at Screening in postmenopausal women. 
12. 12-lead standard ECG with 10-sec rhythm strip: at Screening, Day -1, Day 1 [within 1 h before dosing, and at 1 h (±10 minutes), 2 h (±10 minutes), and 4 h (±10 minutes) after dosing], Day 2 (24 
h ±2 h) or ET. At an Unscheduled Visit, a 12-lead standard ECG will be done only if needed for the evaluation of an AE. 
13. Continuous Holter ECG recorded from 1 h before dosing to 24 h after dosing in each dosing period. ECGs are extracted (three replicates per timepoint) before dosing (at 45, 30, and 15 minutes 
before dosing) and at 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 24 h after dosing in each dosing period. 
14. Eligible subjects are randomized to a treatment sequence on Day 1 before receiving Dose 1. Randomization confirmed at each dosing period. 
15. Blood (plasma) PK samples: within 30 minutes before dosing, and at 0.5 h (±5 minutes), 1 h (±5 minutes), 2 h (±5 minutes), 3 h (±10 minutes), 4 h (±10 minutes), 6 h (±10 minutes), 8 h (±15 
minutes), 12 h (±15 minutes), and 24 h (±2 h) after dosing in each dosing period, or ET if it occurs within 24 h of dosing. 
16. Female subjects to use appropriate contraception and avoid pregnancy for 30 days after Final Visit or ET. Male subjects to use appropriate contraception and avoid donating sperm for 90 days after 
Final Visit or ET. 
17. Collect all AEs from the time of dosing in Dosing Period 1 through Final Visit after Dose 4. Follow up AEs and SAEs to resolution or stabilization in the clinical judgment of the study investigator. 
 


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12.2.2 Displays of Adverse Events 
Table 3: 
Toxicity Grading Tables – Clinical Adverse Events 
Clinical  
AEs 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Vital Signs 
Fever - °C 
38.0-38.4 
38.5-38.9 
>38.9 
Fever - °F 
100.4-101.1 
101.2-102.0 
>102.0 
Tachycardia - bpm 
101-115 
116-130 
>130 or ventricular dysrhythmias 
Bradycardia - bpm 
50-54 OR 45-50 if 
baseline <60 
45-49 OR 40-44 if baseline 
<60 
<45 OR <40 if baseline <60 
Hypertension (systolic) - mmHg 
141-150 
151-160 
>160 
Hypertension (diastolic) - mmHg 
91-95 
96-100 
>100 
 Hypotension (systolic) - mmHg  
85-89 
80-84 
<80 
Tachypnea – breaths per minutes 
23-25 
26-30 
>30 
12-Lead Standard ECG 
QTcF interval prolonged (msec) 
Asymptomatic, QTcF 
450-479 msec 
Asymptomatic, QTcF 480-
500 msec OR increase in 
interval 30-59 msec above 
baseline 
Asymptomatic, QTcF >500 msec OR 
increase in interval ≥60 msec above baseline 
PR interval prolonged (msec) 
210-250 msec 
>250 msec 
Type II 2nd degree AV block OR ventricular 
pause >3.0 sec 
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; 
forced expiratory volume 
in one second (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) 
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 
Allergic Reaction  
Pruritus without rash 
Localized urticaria OR 
requires oral therapy 
Generalized urticaria OR angioedema OR 
anaphylaxis OR requires epinephrine 
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 


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Clinical  
AEs 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
All Other Conditions 
Illness or clinical AE (as defined 
according to applicable 
regulations) 
Require minimal or no 
treatment; does not 
interfere with the subject’s 
daily activities. 
Result in a low level of 
inconvenience or concern 
with therapeutic measures; 
may cause some 
interference with 
functioning. 
Interrupt a subject’s usual daily activity and 
may require systemic drug therapy or other 
treatment; are usually incapacitating 
 


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12.4.1 Individual Laboratory Measurements and Abnormal Laboratory Values 
Table 4: 
Laboratory Adverse Event Grading Scale 
Laboratory AEs 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Chemistry 
Sodium decrease – mmol/L 
130 - 131 
125 –129 
<125 
Sodium increase – mmol/L 
149 - 150 
151 – 153 
>153 
Potassium increase – mmol/L 
5.6  – 6.0 
6.1 – 6.4 
≥6.5 
Potassium decrease – mmol/L 
3.0 – 3.2 
2.5 – 2.9 
<2.5 
Bicarbonate (CO2) increase – mmol/L 
34 – 35 
36 – 37 
>37 
Bicarbonate (CO2) decrease – mmol/L 
17 - 18 
14 - 16 
<14 
Glucose decrease, fasting – mg/dL 
47 - 49 
45 –46 
<45 
Glucose increase, fasting – mg/dL 
116 – 125 
126 – 249 
≥250 
Glucose increase, non-fasting – mg/dL 
116 – 160 
161 – 249 
≥250 
Blood urea nitrogen – mg/dL 
25 - 27 
28 – 32 
>32 
Creatinine increase, male – mg/dL 
1.46 – 1.70 
1.71 – 2.30 
>2.30 
Creatinine increase, female – mg/dL 
1.21 – 1.50 
1.51 – 2.00 
>2.00 
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 
Total protein decrease – g/dL 
5.1 – 5.7 
4.6 – 5.0 
<4.6 
Albumin decrease – g/dL 
2.8 – 3.4 
2.5 – 2.7 
<2.5 
AST increase, male – U/L 
46 – 115 
116 – 220 
>220 
AST increase, female – U/L 
36 - 90 
91 - 175 
>175 
ALT increase, male – U/L 
53 – 115 
116 - 230 
>230 
ALT increase, female – U/L 
39 – 95 
96 – 190 
>190 
Alkaline phosphatase increase – U/L 
151 – 240 
241 – 360 
>360 
Total bilirubin (serum) increase – mg/dL 
(with other LFTs in the normal range) 
1.5 – 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)** 
1.5 – 1.7 
1.8 – 2.1 
>2.1 
Hematology 
Hemoglobin decrease, female – g/dL 
10.8 – 11.2 
9.4 – 10.7 
<9.4 
Hemoglobin decrease, male – g/dL 
11.8 – 12.9 
10.0 – 11.7 
<10.0 
WBC increase – cells/μL 
11,000 – 15,000 
15,001 – 20,000 
>20,000 
WBC decrease – cells/μL 
2,500 – 3,500 
1,500 – 2,499 
<1,500 
Neutrophils decrease – cells/μL 
1,200 – 1,499 
1,000 – 1,199 
<1,000 
Lymphocytes decrease – cells/μL 
750 – 849 
500 – 749 
<500 
Monocytes increase – cells/μL 
1,101 – 2,000 
2,001 – 3000 
>3,000 
Eosinophils increase – cells/μL 
500 – 750 
751 – 1,500 
>1,500 
Basophils increase – cells/μL 
201 – 500 
501 – 800 
>800 
Platelets decrease – cells/μL 
120,000 – 124,000 
100,000 – 119,000 
<100,000 


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Laboratory AEs 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Urinalysis 
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 
 


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10.2 
Protocol Deviations 
Table 5: 
Distribution of Protocol Deviations by Category and Type 
Category 
Deviation Type 
All Subjects 
(N=X) 
No. of 
Subj. 
No. of 
Dev. 
Eligibility/enrollment 
Any type 
 
 
 
Did not meet inclusion criterion 
x 
x 
 
Met exclusion criterion 
 
 
 
ICF not signed prior to study procedures 
 
 
 
Other 
 
 
Treatment administration schedule 
Any type 
 
 
 
Out of window visit 
 
 
 
Missed visit/visit not conducted 
 
 
 
Missed treatment administration 
 
 
 
Delayed treatment administration 
 
 
 
Other 
 
 
Follow-up visit schedule 
Any type 
 
 
 
Out of window visit 
 
 
 
Missed visit/visit not conducted 
 
 
 
Other 
 
 
Protocol procedure/assessment 
Any type 
 
 
 
Incorrect version of ICF signed 
 
 
 
Blood not collected 
 
 
 
Urine not collected 
 
 
 
Other specimen not collected 
 
 
 
Too few aliquots obtained 
 
 
 
Specimen result not obtained 
 
 
 
Required procedure not conducted 
 
 
 
Required procedure done incorrectly 
 
 
 
Required specimen collected out of window 
 
 
 
Required procedure done out of window 
 
 
 
Study product temperature excursion 
 
 
 
Specimen temperature excursion 
 
 
 
Other 
 
 
Treatment administration 
Any type 
 
 
 
Required procedure done incorrectly 
 
 
 
Study product temperature excursion 
 
 
 
Other 
 
 


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Category 
Deviation Type 
All Subjects 
(N=X) 
No. of 
Subj. 
No. of 
Dev. 
Blinding policy/procedure 
Any type 
 
 
 
Treatment unblinded 
 
 
 
Other 
 
 
 


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14.1 
Description of Study Subjects 
Table 6: 
Ineligibility Summary of Screen Failures 
[Implementation Note: Only inclusion and exclusion criteria resulting in at least 1 screen failure will be 
included in the table.] 
Inclusion/Exclusion Category 
Inclusion/Exclusion Criterion 
n (%) 
Any 
Number of subjects failing any eligibility criterion or eligible but not enrolled 
x 
Inclusion 
Any inclusion criterion 
x (x) 
 
[inclusion criterion 1] 
x (x) 
 
[inclusion criterion 2] 
x (x) 
Exclusion 
Any exclusion criterion 
x (x) 
 
[exclusion criterion 1] 
x (x) 
 
[exclusion criterion 2] 
x (x) 
Eligible but not Enrolled 
Any Reason 
x (x) 
 
[Reason 1] 
x (x) 
 
[Reason 2] 
x (x) 
Note: More than one criterion may be marked per subject. Denominator for percentages is the total number of screen failures. 
 


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Table 7: 
Subject Disposition by Sequence 
Subject 
Dispositiona 
ABCD 
(N=X) 
ACDB 
(N=X) 
ADBC 
(N=X) 
BADC 
(N=X) 
BDCA 
(N=X) 
BCAD 
(N=X) 
CDAB 
(N=X) 
CABD 
(N=X) 
CBDA 
(N=X) 
DCBA 
(N=X) 
DBAC 
(N=X) 
DACB 
(N=X) 
All 
Subjects 
(N=X) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Screened 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Enrolled/Randomized 
x (100) 
x (100) 
x (100) 
x (100) 
x (100) 
x (100) 
x (100) 
x (100) 
x (100) 
x (100) 
x (100) 
x (100) 
x (100) 
Dosing Period 1: Received Treatment 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Dosing Period 1: Completed 24 h of Holter ECG after Dose 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Dosing Period 2: Received Treatment 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Dosing Period 2: Completed 24 h of Holter ECG after Dose 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Dosing Period 3: Received Treatment 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Dosing Period 3: Completed 24 h of Holter ECG after Dose 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Dosing Period 4: Received Treatment 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Dosing Period 4: Completed 24 h of Holter ECG after Dose 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Completed Final Visit 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Note: N= number of subject randomized to each sequence. 
a Refer to Listing 16.2.1 for reasons subjects discontinued or terminated early. 
Treatment A = 2 g zoliflodacin; Treatment B = 4 g zoliflodacin; Treatment C = placebo; Treatment D = 400 mg moxifloxacin 
 


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Table 8: 
Analysis Population Exclusions by Sequence 
[Implementation Note: Although subjects may meet multiple criteria for exclusion, they will be counted under only one reason for exclusion in this table. 
Priority for assigning reasons for exclusions is consistent with the order in the table.] 
Analysis 
Populations 
Reason Subjects Excluded 
ABCD 
(N=X) 
ACDB 
(N=X) 
ADBC 
(N=X) 
BADC 
(N=X) 
BDCA 
(N=X) 
BCAD 
(N=X) 
CDAB 
(N=X) 
CABD 
(N=X) 
CBDA 
(N=X) 
DCBA 
(N=X) 
DBAC 
(N=X) 
DACB 
(N=X) 
All 
Subjects 
(N=X) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Safety Population 
Any reason 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
PK Population 
Any reason 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Did not receive zoliflodacin 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Incomplete dose of zoliflodacin 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
No quantifiable post-dose zoliflodacin 
concentration 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
PK Analysis Subset 
Any Reason 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Exclusion from PK Population 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Has protocol deviations that potentially 
impact PK 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
PK data insufficient to estimate any PK 
parameters 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Holter ECG Analysis 
Population 
Any Reason 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
No dose of zoliflodacin, moxifloxacin or 
placebo received 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Has protocol deviations that potentially 
impact the ECG intervals 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Does not have at least one baseline and 
at least one post-dose Holter ECG 
assessment 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Pharmacokinetic-
ECG (PK-ECG) 
Analysis Population 
Any Reason 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 


Statistical Analysis Plan - DMID Protocol: 16-0110  
Version 1.0 
19DEC2018 
- 53 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Analysis 
Populations 
Reason Subjects Excluded 
ABCD 
(N=X) 
ACDB 
(N=X) 
ADBC 
(N=X) 
BADC 
(N=X) 
BDCA 
(N=X) 
BCAD 
(N=X) 
CDAB 
(N=X) 
CABD 
(N=X) 
CBDA 
(N=X) 
DCBA 
(N=X) 
DBAC 
(N=X) 
DACB 
(N=X) 
All 
Subjects 
(N=X) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
Exclusion from Holter ECG Analysis 
Population 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Does not have at least one ECG and PK 
concentration at the same nominal time 
point 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Note: N= number of subject randomized to each sequence.  
Treatment A = 2 g zoliflodacin; Treatment B = 4 g zoliflodacin; Treatment C = placebo; Treatment D = 400 mg moxifloxacin 
 


Statistical Analysis Plan - DMID Protocol: 16-0110  
Version 1.0 
19DEC2018 
- 54 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
14.1.2 Demographic Data by Study Group 
Table 9: 
Summary of Categorical Demographic and Baseline Characteristics by Sequence 
Variable 
 
ABCD 
(N=X) 
ACDB 
(N=X) 
ADBC 
(N=X) 
BADC 
(N=X) 
BDCA 
(N=X) 
BCAD 
(N=X) 
CDAB 
(N=X) 
CABD 
(N=X) 
CBDA 
(N=X) 
DCBA 
(N=X) 
DBAC 
(N=X) 
DACB 
(N=X) 
All 
Subjects 
(N=X) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Sex  
Male 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Female 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Ethnicity  
Not Hispanic or Latino 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Hispanic or Latino 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Not Reported 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Unknown 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Race  
American Indian or Alaska Native 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Asian 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Native Hawaiian or Other Pacific Islander 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Black or African American 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
White 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Multi-Racial 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Unknown 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Note: N= number of subject randomized to each sequence  
Treatment A = 2 g zoliflodacin; Treatment B = 4 g zoliflodacin; Treatment C = placebo; Treatment D = 400 mg moxifloxacin 
 


Statistical Analysis Plan - DMID Protocol: 16-0110  
Version 1.0 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 10: 
Summary of Continuous Demographic and Baseline Characteristics by Sequence 
[Implementation Note: Height, Weight, and BMI values summarized will be from the initial screening visit for each subject.] 
Variable 
Statistic 
ABCD 
ACDB 
ADBC 
BADC 
BDCA 
BCAD 
CDAB 
CABD 
CBDA 
DCBA 
DBAC 
DACB 
All 
Subjects 
Age (years) 
N 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Mean 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Standard Deviation 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Median 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Minimum 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Maximum 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Height (cm) 
N 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Mean 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Standard Deviation 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Median 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Minimum 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Maximum 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Weight (kg) 
N 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Mean 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Standard Deviation 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Median 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Minimum 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Maximum 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
BMI (kg/m2) 
N 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Mean 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Standard Deviation 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Median 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 


Statistical Analysis Plan - DMID Protocol: 16-0110  
Version 1.0 
19DEC2018 
- 56 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Variable 
Statistic 
ABCD 
ACDB 
ADBC 
BADC 
BDCA 
BCAD 
CDAB 
CABD 
CBDA 
DCBA 
DBAC 
DACB 
All 
Subjects 
 
Minimum 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Maximum 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Note: N=Number of subjects in the Safety Population  
Treatment A = 2 g zoliflodacin; Treatment B = 4 g zoliflodacin; Treatment C = placebo; Treatment D = 400 mg moxifloxacin 
 


Statistical Analysis Plan - DMID Protocol: 16-0110  
Version 1.0 
19DEC2018 
- 57 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
14.1.3 Prior and Concurrent Medical Conditions 
Table 11: 
Summary of Subjects with Pre-Existing Medical Conditions by MedDRA System Organ Class 
MedDRA System Organ Class 
ABCD 
(N=X) 
ACDB 
(N=X) 
ADBC 
(N=X) 
BADC 
(N=X) 
BDCA 
(N=X) 
BCAD 
(N=X) 
CDAB 
(N=X) 
CABD 
(N=X) 
CBDA 
(N=X) 
DCBA 
(N=X) 
DBAC 
(N=X) 
DACB 
(N=X) 
All 
Subjects 
(N=X) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Any SOC 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
[SOC 1] 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
[SOC 2] 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Note: N= number of subject randomized to each sequence 
n = Number of subjects reporting medical history within the specified SOC. A subject is only counted once per SOC.  
Treatment A = 2 g zoliflodacin; Treatment B = 4 g zoliflodacin; Treatment C = placebo; Treatment D = 400 mg moxifloxacin 
 


Statistical Analysis Plan - DMID Protocol: 16-0110  
Version 1.0 
19DEC2018 
- 58 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
14.3 
Safety Data 
14.3.1 Displays of Adverse Events 
Table 12: 
Overall Summary of Adverse Events by Treatment 
 
2 g Zoliflodacin 
(N=X) 
4 g Zoliflodacin 
(N=X) 
Placebo 
(N=X) 
400 mg Moxifloxacin 
(N=X) 
Any Treatment 
(N=X) 
Subjectsa with 
n 
% 
n 
% 
n 
% 
n 
% 
N 
% 
At least one unsolicited adverse event 
x 
x 
x 
x 
x 
x 
x 
x 
X 
x 
At least one related unsolicited adverse event 
x 
x 
x 
x 
x 
x 
x 
x 
X 
x 
At least one Mild related unsolicited adverse event 
x 
x 
x 
x 
x 
x 
x 
x 
X 
x 
At least one Moderate related unsolicited adverse event 
x 
x 
x 
x 
x 
x 
x 
x 
X 
x 
At least one Severe related unsolicited adverse event 
x 
x 
x 
x 
x 
x 
x 
x 
X 
x 
At least one SAEb 
x 
x 
x 
x 
x 
x 
x 
x 
X 
x 
At least one related SAE 
x 
x 
x 
x 
x 
x 
x 
x 
X 
x 
At least one adverse event leading to early terminationc  
x 
x 
x 
x 
x 
x 
x 
x 
X 
x 
N= Number of subjects in the Safety Population given a dose of the respective treatment 
a Subjects are counted once for each category regardless of the number of events. 
b A listing of Serious Adverse Events is included in Table 15. 
c As reported on the Adverse Event eCRF. 
 


Statistical Analysis Plan - DMID Protocol: 16-0110  
Version 1.0 
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- 59 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
14.3.1.2 
Unsolicited Adverse Events 
Table 13: 
Summary of Unsolicited Adverse Events by MedDRA System Organ Class, High Level Group Term, Preferred Term, and 
Treatment 
MedDRA System Organ Class 
MedDRA High Level Group Term 
MedDRA Preferred Term 
Treatment 
N 
n 
% 
95% CI 
No. of Events 
Any SOC 
Any HLGT 
Any PT 
Any Treatment 
 
x 
xx 
xx, xx 
x 
 
 
 
2 g Zoliflodacin 
 
 
 
 
 
 
 
 
4 g Zoliflodacin 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
400 mg Moxifloxacin 
 
 
 
 
 
SOC 1 
Any HLGT 
Any PT 
Any Treatment 
 
 
 
 
 
 
 
 
2 g Zoliflodacin 
 
 
 
 
 
 
 
 
4 g Zoliflodacin 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
400 mg Moxifloxacin 
 
 
 
 
 
SOC 1 
HLGT 1 
Any PT 
Any Treatment 
 
 
 
 
 
 
 
 
2 g Zoliflodacin 
 
 
 
 
 
 
 
 
4 g Zoliflodacin 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
400 mg Moxifloxacin 
 
 
 
 
 
SOC 1 
HLGT 1 
PT 1 
Any Treatment 
 
 
 
 
 
 
 
 
2 g Zoliflodacin 
 
 
 
 
 
 
 
 
4 g Zoliflodacin 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
400 mg Moxifloxacin 
 
 
 
 
 
SOC 1 
HLGT 1 
PT 2 
Any Treatment 
 
 
 
 
 
 
 
 
2 g Zoliflodacin 
 
 
 
 
 
 
 
 
4 g Zoliflodacin 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
400 mg Moxifloxacin 
 
 
 
 
 
Note: N=Number of subjects in the Safety Population given a dose of the respective treatment. 
This table presents number and percentage of subjects. A subject is only counted once per PT / treatment. 


Statistical Analysis Plan - DMID Protocol: 16-0110  
Version 1.0 
19DEC2018 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 14: 
Unsolicited Adverse Events by MedDRA System Organ Class and Preferred Term, Maximum Severity, Relationship, and 
Treatment 
MedDRA 
System Organ 
Class 
MedDRA High 
Level Group 
Term 
MedDRA 
Preferred Term 
Severity 
2 g Zoliflodacin 
(N=X) 
4 g Zoliflodacin 
(N=X) 
Placebo 
(N=X) 
400 mg Moxifloxacin 
(N=X) 
Any Treatment 
(N=X) 
Related 
n (%) 
Not 
Related 
n (%) 
Related 
n (%) 
Not 
Related 
n (%) 
Related 
n (%) 
Not 
Related 
n (%) 
Related 
n (%) 
Not 
Related 
n (%) 
Related 
n (%) 
Not 
Related 
n (%) 
Any SOC 
Any HLGT 
Any PT 
Mild 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
 
 
Moderate 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
 
 
Severe 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
SOC 1 
Any HLGT 
Any PT 
Mild 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
 
 
Moderate 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
 
 
Severe 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
SOC 1 
HLGT 1 
Any PT 
Mild 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
 
 
Moderate 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
 
 
Severe 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
SOC 1 
HLGT 1 
PT 1 
Mild 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
 
 
Moderate 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
 
 
Severe 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
SOC 1 
HLGT 1 
PT 2 
Mild 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
 
 
Moderate 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
 
 
Severe 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Note: N= Number of subjects in the Safety Population given a dose of the respective treatment. 
 


Statistical Analysis Plan - DMID Protocol: 16-0110  
Version 1.0 
19DEC2018 
- 61 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
14.3.2 Listing of Deaths, Other Serious and Significant Adverse Events 
Table 15: 
Listing of Serious Adverse Events 
[Implementation Note: This listing is included in the table shells document, as it is included in the body of the CSR. If the event is ongoing (no stop 
date), indicate “ongoing” for the “Duration”. If more than one reason is selected for the reason reported as an SAE, list all reasons in the column, 
separated by a comma. In the “If Not Related, Alternate Etiology” column, merge the 2 data fields for collecting alternate etiology, separate by a colon. 
Listing is ordered by Subject ID, then by AE Number.] 
Adverse 
Event 
Treatment 
No. of 
Days Post 
Treatment 
(Duration) 
No. of 
Days Post 
Dose the 
Event 
Became 
Serious 
Reason 
Reported as 
an SAE 
Severity 
Relationship 
to Study 
Treatment, 
Alternative 
Etiology 
Action 
Taken with 
Study 
Treatment 
Subject 
Discontinued 
Due to AE 
Outcome 
MedDRA 
System 
Organ 
Class 
MedDRA 
High Level 
Group 
Term 
MedDRA 
Preferred 
Term 
Subject ID: PHU.00123, Period 2 of Sequence:BACD , AE Number:001 
Anaphylaxis 
2 g 
Zoliflodacin 
5 (1) 
5 
Hospitalization 
Severe 
Not Related, 
Flu Vaccine 
None 
Yes 
Resolved 
 
 
 
Comments: 
Subject ID: ,Period of Sequence: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
Treatment A = 2 g zoliflodacin; Treatment B = 4 g zoliflodacin; Treatment C = placebo; Treatment D = 400 mg moxifloxacin 
 
 


Statistical Analysis Plan - DMID Protocol: 16-0110  
Version 1.0 
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- 62 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 16: 
Listing of Non-Serious, Unsolicited, Moderate or Severe Adverse Events 
[Implementation Note: This listing is included in the tables document, as it is included in the body of the CSR. If the event is ongoing (no stop date), 
indicate “ongoing” in the “Duration” column. In the “If Not Related, Alternate Etiology” column, merge the 2 data fields for collecting alternate 
etiology, separate by a colon. Dosing Period will be given a treatment label (2 g Zoliflodacin, 4 g Zoliflodacin, Placebo, or 400 mg Moxifloxacin).] 
Adverse 
Event 
Treatment 
No. of Days 
Post 
Treatment 
(Duration) 
Severity 
Relationship 
to Study 
Treatment, 
Alternative 
Etiology 
Action Taken 
with Study 
Treatment 
Subject 
Discontinued 
Due to AE 
Outcome 
MedDRA 
System Organ 
Class 
MedDRA 
High Level 
Group Term 
MedDRA 
Preferred 
Term 
Subject ID: PHU.00123, Period 2 of Sequence:BACD , AE Number:001 
Headache 
2 g 
Zoliflodacin 
5 (1) 
Moderate 
Related 
… 
 
 
 
 
 
Comments: 
 
Subject ID: , Period _ of Sequence: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
Comments: 
Treatment A = 2 g zoliflodacin; Treatment B = 4 g zoliflodacin; Treatment C = placebo; Treatment D = 400 mg moxifloxacin 
 


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14.3.3 Narratives of Deaths, Other Serious and Significant Adverse Events 
(not included in SAP, but this is a placeholder for the CSR) 
 


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14.3.4 Abnormal Laboratory Value Listings (by Subject) 
Table 17: 
Listing of Abnormal Laboratory Results - Chemistry 
[Implementation Note: This listing is included in the table shells document, as it is included in the body of the CSR. This listing will contain abnormal 
laboratory results of mild, moderate, or severe severity. A complete listing of all laboratory results is included in the listings document. In the Laboratory 
Parameter column, indicate the units after the parameter, e.g., Hemoglobin (g/dL). This listing is not color-coded, but the severity should be included in 
parentheses after the result, e.g., 16.2 (mild).] 
Subject 
ID 
Sequence 
Sex 
Treatment 
Period 
Number 
Planned 
Time 
Point 
Study Day 
(Day in Period) 
Laboratory Parameter 
(Units) 
Result (Severity) 
Change from 
Baselinea 
Clinical 
Significance 
PHU.00123 
ABCD 
Male 
4 g zoliflodacin 
2 
24 h Post-
dose 
11 (2) 
Glucose (mg/dL) 
130 (Moderate) 
+40 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a For Final Visit, listings show change from baseline values using the last measurement prior to first dose as baseline. 
 
 


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Table 18: 
Listing of Abnormal Laboratory Results - Hematology 
[Implementation Note: This listing is included in the table shells document, as it is included in the body of the CSR. This listing will contain abnormal 
laboratory results of mild, moderate, or severe severity. A complete listing of all laboratory results is included in the listings document. In the Laboratory 
Parameter column, indicate the units after the parameter, e.g., Hemoglobin (g/dL). This listing is not color-coded, but the severity should be included in 
parentheses after the result, e.g., 16.2 (mild).] 
Subject 
ID 
Sequence 
Sex 
Treatment 
Period 
Number 
Planned 
Time 
Point 
Study Day 
(Day in Period) 
Laboratory Parameter 
(Units) 
Result (Severity) 
Change from 
Baselinea 
Clinical 
Significance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a For Final Visit, listings show change from baseline values using the last measurement prior to first dose as baseline. 
 
 


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Table 19: 
Listing of Abnormal Laboratory Results - Urinalysis 
[Implementation Note: This listing is included in the table shells document, as it is included in the body of the CSR. This listing will contain abnormal 
laboratory results of mild, moderate, or severe severity. A complete listing of all laboratory results is included in the listings document. In the Laboratory 
Parameter column, indicate the units after the parameter, e.g., Erythrocytes (/hpf). This listing is not color-coded, but the severity should be included in 
parentheses after the result, e.g., 16.2 (mild).] 
Subject 
ID 
Sequence 
Sex 
Treatment 
Period 
Number 
Planned 
Time Point 
Study Day (Day 
in Period) 
Laboratory Parameter 
(Units) 
Result (Severity) 
Clinical 
Significance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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14.3.5 Displays of Laboratory Results 
14.3.5.1 
Chemistry Results 
Table 20: 
Chemistry Clinical Safety Laboratory Results by Parameter, Maximum Severity, Time 
Point, and Dosing Period 
[Implementation Note: If there is not at least 1 Mild, Moderate, or Severe Event for Any Period, Max Severity 
Post-Baseline, then only the Any Period, Max Severity Post-Baseline row will be shown for the parameter.] 
Dosing Period 
Time Point 
N 
Mild 
Moderate 
Severe 
n 
% 
n 
% 
n 
% 
Chemistry - Any Parameter 
Any Period 
Max Severity Post-Baseline 
x 
x 
x 
x 
x 
x 
x 
 
24 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
Final Visitb 
x 
x 
x 
x 
x 
x 
x 
 2 g Zoliflodacin 
Max Severity Post-Baseline 
x 
x 
x 
x 
x 
x 
x 
  
24 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
Follow-upa 
x 
x 
x 
x 
x 
x 
x 
 4 g Zoliflodacin 
Max Severity Post-Baseline 
x 
x 
x 
x 
x 
x 
x 
 
24 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
Follow-upa 
x 
x 
x 
x 
x 
x 
x 
 Placebo 
Max Severity Post-Baseline 
x 
x 
x 
x 
x 
x 
x 
  
24 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
Follow-upa 
x 
x 
x 
x 
x 
x 
x 
 400 mg Moxifloxacin 
Max Severity Post-Baseline 
x 
x 
x 
x 
x 
x 
x 
  
24 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
Follow-upa 
x 
x 
x 
x 
x 
x 
x 
Chemistry – Sodium, Decrease 
Any Period 
Max Severity Post-Baseline 
x 
x 
x 
x 
x 
x 
x 
 
24 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
Final Visitb 
x 
x 
x 
x 
x 
x 
x 
 2 g Zoliflodacin 
Max Severity Post-Baseline 
x 
x 
x 
x 
x 
x 
x 
  
24 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
Follow-upa 
x 
x 
x 
x 
x 
x 
x 
 4 g Zoliflodacin 
Max Severity Post-Baseline 
x 
x 
x 
x 
x 
x 
x 
 
24 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
Follow-upa 
x 
x 
x 
x 
x 
x 
x 
 Placebo 
Max Severity Post-Baseline 
x 
x 
x 
x 
x 
x 
x 
  
24 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
Follow-upa 
x 
x 
x 
x 
x 
x 
x 


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Dosing Period 
Time Point 
N 
Mild 
Moderate 
Severe 
n 
% 
n 
% 
n 
% 
 400 mg Moxifloxacin 
Max Severity Post-Baseline 
x 
x 
x 
x 
x 
x 
x 
  
24 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
Follow-upa 
x 
x 
x 
x 
x 
x 
x 
Chemistry – Sodium, Decrease 
… 
 
 
 
 
 
 
 
 
Note: The “Max Severity Post-Baseline” rows indicate the maximum severity experienced by each subject at any time point post 
baseline within the period, including unscheduled assessments. N=Number of subjects in the Safety Population that had clinical 
safety labs measured at the respective visit.  
a The “Follow-up” analysis time points refer to either Check-In visits for the next period (for analysis of treatments given in 
Period 1, 2, or 3) or to the Final Visit with Pre-dose 4 as baseline. 
b The “Final Visit” analysis time point uses the last measurement prior to the first dose as baseline. 
 
 


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Table 21: 
Chemistry Clinical Safety Laboratory Results Change from Baseline – Summary 
Statistics by Parameter, Time Point, and Dosing Period 
Dosing Period 
Time Point 
N 
Mean 
SD 
Median 
Min, Max 
Chemistry, Sodium (mmol/L) 
2 g Zoliflodacin 
24 h Post-dose 
 
 
 
 
 
 
Follow-upa  
 
 
 
 
 
4 g Zoliflodacin 
24 h Post-dose 
 
 
 
 
 
 
Follow-upa 
 
 
 
 
 
Placebo 
24 h Post-dose 
 
 
 
 
 
 
Follow-upa 
 
 
 
 
 
 400 mg Moxifloxacin 
24 h Post-dose 
 
 
 
 
 
 
Follow-upa  
 
 
 
 
 
Dosing Period 4 
Final Visitb 
 
 
 
 
 
Chemistry, Potassium (mmol/L) 
2 g Zoliflodacin 
24 h Post-dose 
 
 
 
 
 
 
Follow-upa 
 
 
 
 
 
4 g Zoliflodacin 
24 h Post-dose 
 
 
 
 
 
 
Follow-upa 
 
 
 
 
 
Placebo 
24 h Post-dose 
 
 
 
 
 
 
Follow-upa 
 
 
 
 
 
 400 mg Moxifloxacin 
24 h Post-dose 
 
 
 
 
 
 
Follow-upa  
 
 
 
 
 
Dosing Period 4 
Final Visitb 
 
 
 
 
 
Chemistry, Chloride (mmol/L) 
… 
 
 
 
 
 
 
Note: N=Number of subjects in the Safety Population that had clinical safety labs measured at the respective visit. 
a The “Follow-up” analysis time points refer to either Check-In visits for the next period (for analysis of treatments given in Period 
1, 2, or 3) or to the Final Visit with Pre-dose 4 as baseline. 
b The “Final Visit” analysis time point uses the last measurement prior to the first dose as baseline. 
 
 


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14.3.5.2 
Hematology Results 
Table 22: 
Hematology Clinical Safety Laboratory Results by Parameter, Maximum Severity, Time 
Point, and Dosing Period 
This table will repeat Table 20 for Hematology parameters. 
 


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Table 23: 
Hematology Clinical Safety Laboratory Results Change from Baseline – Summary 
Statistics by Parameter, Time Point, and Dosing Period 
This table will repeat Table 21 for Hematology parameters. 
 
 


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14.3.5.3 
Urinalysis Results 
Table 24: 
Urinalysis Clinical Safety Laboratory Results by Parameter, Maximum Severity, Time 
Point, and Dosing Period 
This table will repeat Table 20 for Urinalysis parameters. 


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14.3.6 Displays of Vital Signs 
Table 25: 
Vital Signs Results by Parameter, Maximum Severity, Time Point, and Dosing Period 
[Implementation Note: If there is not at least 1 Mild, Moderate, or Severe Event for Any Period, Max Severity 
Post-Baseline, then only the Any Period, Max Severity Post-Baseline row will be shown for the parameter.
Dosing Period 
Time Point 
N 
Mild 
Moderate 
Severe 
n 
% 
n 
% 
n 
% 
Systolic Blood Pressure, Decrease 
Any Period 
Max Severity Post-Baseline 
x 
x 
x 
x 
x 
x 
x 
 
1 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
2 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
4 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
24 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
Follow-upa 
x 
x 
x 
x 
x 
x 
x 
 
Pre-dose (Prior to Next Dose) 
x 
x 
x 
x 
x 
x 
x 
 
Final Visitb 
x 
x 
x 
x 
x 
x 
x 
 2 g Zoliflodacin 
Max Severity Post-Baseline 
x 
x 
x 
x 
x 
x 
x 
  
1 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
2 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
4 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
24 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
Follow-upa 
x 
x 
x 
x 
x 
x 
x 
 
Pre-dose (Prior to Next Dose) 
x 
x 
x 
x 
x 
x 
x 
 4 g Zoliflodacin 
Max Severity Post-Baseline 
x 
x 
x 
x 
x 
x 
x 
 
1 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
2 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
4 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
24 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
Follow-upa 
x 
x 
x 
x 
x 
x 
x 
 
Pre-dose (Prior to Next Dose) 
x 
x 
x 
x 
x 
x 
x 
 Placebo 
Max Severity Post-Baseline 
x 
x 
x 
x 
x 
x 
x 
  
1 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
2 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
4 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
24 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
Follow-upa 
x 
x 
x 
x 
x 
x 
x 
 
Pre-dose (Prior to Next Dose) 
x 
x 
x 
x 
x 
x 
x 
 400 mg Moxifloxacin 
Max Severity Post-Baseline 
x 
x 
x 
x 
x 
x 
x 
  
1 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
2 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
4 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
24 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
Follow-upa 
x 
x 
x 
x 
x 
x 
x 
 
Pre-dose (Prior to Next Dose) 
x 
x 
x 
x 
x 
x 
x 


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Dosing Period 
Time Point 
N 
Mild 
Moderate 
Severe 
n 
% 
n 
% 
n 
% 
Systolic Blood Pressure, Increase 
… 
 
 
 
 
 
 
 
 
Note: The “Max Severity Post-Baseline” rows indicate the maximum severity experienced by each subject at any time point post 
baseline within the period, including unscheduled assessments. N=Number of subjects in the Safety Population that had vital 
signs measured at the respective time point.  
a The “Follow-up” analysis time points refer to either Check-In visits for the next period (for analysis of treatments given in 
Period 1, 2, or 3) or to the Final Visit with Pre-dose 4 as baseline. 
b The “Final Visit” analysis time point uses the last measurement prior to the first dose as baseline. 
 


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Table 26: 
Vital Signs Change from Baseline – Summary Statistics by Parameter, Time Point, and 
Dosing Period 
[Implementation Note: The following vital signs parameters will be summarized, in order: Systolic Blood 
Pressure, Diastolic Blood Pressure, Heart Rate, Respiration Rate, Temperature.] 
Dosing Period 
Time Point 
N 
Mean 
SD 
Median 
Min, Max 
Systolic Blood Pressure (mmHg) 
2 g Zoliflodacin 
1 h Post-dose 
x 
x 
x 
x 
x 
 
2 h Post-dose 
x 
x 
x 
x 
x 
 
4 h Post-dose 
x 
x 
x 
x 
x 
 
24 h Post-dose 
x 
x 
x 
x 
x 
 
Follow-upa 
x 
x 
x 
x 
x 
 
Pre-dose (Prior to Next 
Dose) 
x 
x 
x 
x 
x 
4 g Zoliflodacin 
1 h Post-dose 
x 
x 
x 
x 
x 
 
2 h Post-dose 
x 
x 
x 
x 
x 
 
4 h Post-dose 
x 
x 
x 
x 
x 
 
24 h Post-dose 
x 
x 
x 
x 
x 
 
Follow-upa 
x 
x 
x 
x 
x 
 
Pre-dose (Prior to Next 
Dose) 
x 
x 
x 
x 
x 
Placebo 
1 h Post-dose 
x 
x 
x 
x 
x 
  
2 h Post-dose 
x 
x 
x 
x 
x 
 
4 h Post-dose 
x 
x 
x 
x 
x 
 
24 h Post-dose 
x 
x 
x 
x 
x 
 
Follow-upa 
x 
x 
x 
x 
x 
 
Pre-dose (Prior to Next 
Dose) 
x 
x 
x 
x 
x 
400 mg Moxifloxacin 
1 h Post-dose 
x 
x 
x 
x 
x 
 
2 h Post-dose 
x 
x 
x 
x 
x 
 
4 h Post-dose 
x 
x 
x 
x 
x 
 
24 h Post-dose 
x 
x 
x 
x 
x 
 
Follow-upa 
x 
x 
x 
x 
x 
 
Pre-dose (Prior to Next 
Dose) 
x 
x 
x 
x 
x 
Dosing Period 4 
Final Visitb 
x 
x 
x 
x 
x 
Diastolic Blood Pressure (mmHg) 
… 
 
 
 
 
 
 
Note: N= Number of subjects in the Safety Population that had vital signs measured at the respective time point.  
a The “Follow-up” analysis time points refer to either Check-In visits for the next period (for analysis of treatments given in Period 
1, 2, or 3) or to the Final Visit with Pre-dose 4 as baseline. 
b The “Final Visit” analysis time point uses the last measurement prior to the first dose as baseline. 
 


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14.3.7 Displays of 12-Lead Standard Measurements 
Table 27: 
12-Lead Standard ECG Overall Interpretations, Post Dose Compared to Baseline 
Change from Baseline in ECG 
Interpretation 
2 g Zoliflodacin 
n (%) 
4 g Zoliflodacin 
n (%) 
Placebo 
n (%) 
400 mg Moxifloxacin 
n (%) 
Any Period 
n (%) 
1 h Post-dose 
 
N=X 
N=X 
N=X 
N=X 
N=X 
Normal at Both Times 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Normal to Abnormal, NCS 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Normal to Abnormal, CS 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Abnormal, NCS at Both Times 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Abnormal, NCS to Abnormal, CS 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Abnormal, NCS to Normal 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
2 h Post-dose 
 
N=X 
N=X 
N=X 
N=X 
N=X 
Normal at Both Times 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Normal to Abnormal, NCS 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Normal to Abnormal, CS 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Abnormal, NCS at Both Times 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Abnormal, NCS to Abnormal, CS 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Abnormal, NCS to Normal 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
4 h Post-dose 
 
N=X 
N=X 
N=X 
N=X 
N=X 
Normal at Both Times 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Normal to Abnormal, NCS 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Normal to Abnormal, CS 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Abnormal, NCS at Both Times 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Abnormal, NCS to Abnormal, CS 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Abnormal, NCS to Normal 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
24 h Post-dose 
 
N=X 
N=X 
N=X 
N=X 
N=X 
Normal at Both Times 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Normal to Abnormal, NCS 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Normal to Abnormal, CS 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Abnormal, NCS at Both Times 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Abnormal, NCS to Abnormal, CS 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Abnormal, NCS to Normal 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 


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Change from Baseline in ECG 
Interpretation 
2 g Zoliflodacin 
n (%) 
4 g Zoliflodacin 
n (%) 
Placebo 
n (%) 
400 mg Moxifloxacin 
n (%) 
Any Period 
n (%) 
Follow-upa 
 
N=X 
N=X 
N=X 
N=X 
N=X 
Normal at Both Times 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Normal to Abnormal, NCS 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Normal to Abnormal, CS 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Abnormal, NCS at Both Times 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Abnormal, NCS to Abnormal, CS 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Abnormal, NCS to Normal 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Pre-dose (Prior to Next Dose) 
 
N=X 
N=X 
N=X 
N=X 
N=X 
Normal at Both Times 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Normal to Abnormal, NCS 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Normal to Abnormal, CS 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Abnormal, NCS at Both Times 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Abnormal, NCS to Abnormal, CS 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Abnormal, NCS to Normal 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Final Visitb 
 
N=X 
N=X 
N=X 
N=X 
N=X 
Normal at Both Times 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Normal to Abnormal, NCS 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Normal to Abnormal, CS 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Abnormal, NCS at Both Times 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Abnormal, NCS to Abnormal, CS 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Abnormal, NCS to Normal 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Note: N = number of subjects in safety population with the ECG measurement at the respective time point.  
CS = clinically significant; NCS = not clinically significant.  
a The “Follow-up” analysis time points refer to either Check-In visits for the next period (for analysis of treatments given in Period 
1, 2, or 3) or to the Final Visit with Pre-dose 4 as baseline. 
b The “Final Visit” analysis time point uses the last measurement prior to the first dose as baseline. 
 


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Table 28: 
12-Lead Standard ECG Results by Parameter, Maximum Severity, Time Point, and 
Dosing Period 
[Implementation Note: If there is not at least 1 Mild, Moderate, or Severe Event for Any Period, Max Severity 
Post-Baseline, then only the Any Period, Max Severity Post-Baseline row will be shown for the parameter.] 
Dosing Period 
Time Point 
N 
Mild 
Moderate 
Severe 
n 
% 
n 
% 
n 
% 
PR Interval Prolongation 
Any Period 
Max Severity Post-Baseline 
x 
x 
x 
x 
x 
x 
x 
 
1 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
2 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
4 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
24 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
Follow-upa 
x 
x 
x 
x 
x 
x 
x 
 
Pre-dose (Prior to Next Dose) 
x 
x 
x 
x 
x 
x 
x 
 
Final Visitb 
x 
x 
x 
x 
x 
x 
x 
 2 g Zoliflodacin 
Max Severity Post-Baseline 
x 
x 
x 
x 
x 
x 
x 
  
1 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
2 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
4 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
24 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
Follow-upa 
x 
x 
x 
x 
x 
x 
x 
 
Pre-dose (Prior to Next Dose) 
x 
x 
x 
x 
x 
x 
x 
 4 g Zoliflodacin 
Max Severity Post-Baseline 
x 
x 
x 
x 
x 
x 
x 
 
1 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
2 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
4 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
24 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
Follow-upa 
x 
x 
x 
x 
x 
x 
x 
 
Pre-dose (Prior to Next Dose) 
x 
x 
x 
x 
x 
x 
x 
 Placebo 
Max Severity Post-Baseline 
x 
x 
x 
x 
x 
x 
x 
  
1 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
2 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
4 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
24 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
Follow-upa 
x 
x 
x 
x 
x 
x 
x 
 
Pre-dose (Prior to Next Dose) 
x 
x 
x 
x 
x 
x 
x 
 400 mg Moxifloxacin 
Max Severity Post-Baseline 
x 
x 
x 
x 
x 
x 
x 
  
1 h Post-dose 
x 
x 
x 
x 
x 
x 
x 


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Dosing Period 
Time Point 
N 
Mild 
Moderate 
Severe 
n 
% 
n 
% 
n 
% 
 
2 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
4 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
24 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
Follow-upa 
x 
x 
x 
x 
x 
x 
x 
 
Pre-dose (Prior to Next Dose) 
x 
x 
x 
x 
x 
x 
x 
QTcF Prolongation  
Any Period 
Max Severity Post-Baseline 
x 
x 
x 
x 
x 
x 
x 
 
1 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
2 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
4 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
24 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
Follow-upa 
x 
x 
x 
x 
x 
x 
x 
 
Pre-dose (Prior to Next Dose) 
x 
x 
x 
x 
x 
x 
x 
 
Final Visitb 
x 
x 
x 
x 
x 
x 
x 
 2 g Zoliflodacin 
Max Severity Post-Baseline 
x 
x 
x 
x 
x 
x 
x 
  
1 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
2 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
4 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
24 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
Follow-upa 
x 
x 
x 
x 
x 
x 
x 
 
Pre-dose (Prior to Next Dose) 
x 
x 
x 
x 
x 
x 
x 
 4 g Zoliflodacin 
Max Severity Post-Baseline 
x 
x 
x 
x 
x 
x 
x 
 
1 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
2 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
4 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
24 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
Follow-upa 
x 
x 
x 
x 
x 
x 
x 
 
Pre-dose (Prior to Next Dose) 
x 
x 
x 
x 
x 
x 
x 
 Placebo 
Max Severity Post-Baseline 
x 
x 
x 
x 
x 
x 
x 
  
1 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
2 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
4 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
24 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
Follow-upa 
x 
x 
x 
x 
x 
x 
x 
 
Pre-dose (Prior to Next Dose) 
x 
x 
x 
x 
x 
x 
x 


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Dosing Period 
Time Point 
N 
Mild 
Moderate 
Severe 
n 
% 
n 
% 
n 
% 
 400 mg Moxifloxacin 
Max Severity Post-Baseline 
x 
x 
x 
x 
x 
x 
x 
  
1 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
2 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
4 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
24 h Post-dose 
x 
x 
x 
x 
x 
x 
x 
 
Follow-upa 
x 
x 
x 
x 
x 
x 
x 
 
Pre-dose (Prior to Next Dose) 
x 
x 
x 
x 
x 
x 
x 
Note: The “Max Severity Post-Baseline” rows indicate the maximum severity experienced by each subject at any time point post 
baseline within the period, including unscheduled assessments. N = number of subjects in safety population with the ECG 
measurement at the respective time point.  
a The “Follow-up” analysis time points refer to either Check-In visits for the next period (for analysis of treatments given in 
Period 1, 2, or 3) or to the Final Visit with Pre-dose 4 as baseline. 
b The “Final Visit” analysis time point uses the last measurement prior to the first dose as baseline. 
 


Statistical Analysis Plan - DMID Protocol: 16-0110  
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Table 29: 
12-Lead Standard ECG Change from Baseline – Summary Statistics by Parameter, Time 
Point, and Dosing Period 
[Implementation Note: The following 12-lead standard ECG parameters will be summarized, in order:] 
Dosing Period 
Time Point 
N 
Mean 
SD 
Median 
Min, Max 
PR Interval (msec) 
2 g Zoliflodacin 
1 h Post-dose 
x 
x 
x 
x 
x 
 
2 h Post-dose 
x 
x 
x 
x 
x 
 
4 h Post-dose 
x 
x 
x 
x 
x 
 
24 h Post-dose 
x 
x 
x 
x 
x 
 
Follow-upa 
x 
x 
x 
x 
x 
 
Pre-dose (Prior to Next Dose) 
x 
x 
x 
x 
x 
4 g Zoliflodacin 
1 h Post-dose 
x 
x 
x 
x 
x 
 
2 h Post-dose 
x 
x 
x 
x 
x 
 
4 h Post-dose 
x 
x 
x 
x 
x 
 
24 h Post-dose 
x 
x 
x 
x 
x 
 
Follow-upa 
x 
x 
x 
x 
x 
 
Pre-dose (Prior to Next Dose) 
x 
x 
x 
x 
x 
Placebo 
1 h Post-dose 
x 
x 
x 
x 
x 
  
2 h Post-dose 
x 
x 
x 
x 
x 
 
4 h Post-dose 
x 
x 
x 
x 
x 
 
24 h Post-dose 
x 
x 
x 
x 
x 
 
Follow-upa 
x 
x 
x 
x 
x 
 
Pre-dose (Prior to Next Dose) 
x 
x 
x 
x 
x 
400 mg Moxifloxacin 
1 h Post-dose 
x 
x 
x 
x 
x 
 
2 h Post-dose 
x 
x 
x 
x 
x 
 
4 h Post-dose 
x 
x 
x 
x 
x 
 
24 h Post-dose 
x 
x 
x 
x 
x 
 
Follow-upa 
x 
x 
x 
x 
x 
 
Pre-dose (Prior to Next Dose) 
x 
x 
x 
x 
x 
Dosing Period 4 
Final Visitb 
x 
x 
x 
x 
x 
QRS Duration (msec) 
… 
 
 
 
 
 
 
Note: N= number of subjects in safety population with the ECG measurement at the respective time point.  
a The “Follow-up” analysis time points refer to either Check-In visits for the next period (for analysis of treatments given in Period 
1, 2, or 3) or to the Final Visit with Pre-dose 4 as baseline. 
b The “Final Visit” analysis time point uses the last measurement prior to the first dose as baseline. 
 
 


Statistical Analysis Plan - DMID Protocol: 16-0110  
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14.4 
Summary of Prior and Concomitant Medications 
Table 30: 
Number and Percentage of Subjects with Prior Medications by WHO Drug Classification and Sequence 
[Instruction: Include prior medications (medications with an end date prior to first dose) only.] 
WHO Drug Code 
Level 1, Anatomic Group 
WHO Drug Code 
Level 2, Therapeutic 
Subgroup 
ABCD 
(N=X) 
ACDB 
(N=X) 
ADBC 
(N=X) 
BADC 
(N=X) 
BDCA 
(N=X) 
BCAD 
(N=X) 
CDAB 
(N=X) 
CABD 
(N=X) 
CBDA 
(N=X) 
DCBA 
(N=X) 
DBAC 
(N=X) 
DACB 
(N=X) 
All 
Subjects 
(N=X) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Any Level 1 Codes 
Any Level 2 Codes 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
[ATC Level 1 - 1] 
Any [ATC 1 – 1] 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
[ATC 2 - 1] 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
[ATC 2 - 2] 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
[ATC 2 - 3] 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
[ATC Level 1 – 2] 
[ATC 2 - 1] 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
[ATC 2 - 2] 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
[ATC 2 - 3] 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Treatment A = 2 g zoliflodacin; Treatment B = 4 g zoliflodacin; Treatment C = placebo; Treatment D = 400 mg moxifloxacin 
 


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Table 31: 
Number and Percentage of Subjects with Concomitant Medications by WHO Drug Classification and Treatment 
[Instruction: Include concomitant medications (medications that are ongoing or that have an end date after first dose) only. The associated treatment for a 
concomitant medication should be the last treatment received prior to the start of the medication.] 
WHO Drug Code 
Level 1, Anatomic Group 
WHO Drug Code 
Level 2, Therapeutic Subgroup 
2 g 
Zoliflodacin 
(N=X) 
4 g 
Zoliflodacin 
(N=X) 
Placebo 
(N=X) 
400 mg 
Moxifloxacin 
(N=X) 
Any Treatment 
(N=X) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Any Level 1 Codes 
Any Level 2 Codes 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
[ATC Level 1 - 1] 
Any [ATC 1 – 1] 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
[ATC 2 - 1] 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
[ATC 2 - 2] 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
[ATC 2 - 3] 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
[ATC Level 1 – 2] 
[ATC 2 - 1] 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
[ATC 2 - 2] 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
[ATC 2 - 3] 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 


Statistical Analysis Plan - DMID Protocol: 16-0110  
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14.5 
Tolerability 
Table 32: 
Assessment of Tolerability 
 
All Subjects 
(N=X) 
n 
% 
Tolerability to zoliflodacin 
 
 
Subject did not discontinue study drug due to AE 
 
 
Subject did not choose to withdraw from the study due to an AE 
 
 
Subject was not withdrawn from the study due to an AE 
 
 
Note: Tolerability was concluded for a subject unless any one of the following occurred after receipt of a dose of zoliflodacin: 1) 
subject discontinued study drug due to an AE, 2) subject choose to withdraw from the study due to an AE at any time from first 
receipt of zoliflodacin until end of study, or 3) subject was withdrawn from the study by the investigator due to an adverse event 
at any time from first receipt of zoliflodacin until end of study 
N = Number of subjects in the Safety Population who received a dose of zoliflodacin 
 
 


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14.6 
Pharmacokinetics 
Table 33: 
Summary Statistics for Zoliflodacin Concentrations by Nominal Time, after Single 2 g 
Zoliflodacin Dose 
Subject ID 
Zoliflodacin Concentration (ng/mL) by Nominal Timea After Dose (h) 
0 
0.5 
1 
2 
3 
4 
6 
8 
12 
24 
PHU.00101 
x 
x 
x 
x 
x 
x 
X 
x 
x 
x 
PHU.00102 
x 
x 
x 
x 
x 
x 
X 
x 
x 
x 
PHU.00102 
x 
x 
x 
x 
x 
x 
X 
x 
x 
x 
… 
x 
x 
x 
x 
x 
x 
X 
x 
x 
x 
Statistics 
x 
x 
x 
x 
x 
x 
X 
x 
x 
x 
Nb 
x 
x 
x 
x 
x 
x 
X 
x 
x 
x 
Mean 
x 
x 
x 
x 
x 
x 
X 
x 
x 
x 
SD 
x 
x 
x 
x 
x 
x 
X 
x 
x 
x 
Min 
x 
x 
x 
x 
x 
x 
X 
x 
x 
x 
Median 
x 
x 
x 
x 
x 
x 
X 
x 
x 
x 
Max 
x 
x 
x 
x 
x 
x 
X 
x 
x 
x 
CV% 
x 
x 
x 
x 
x 
x 
X 
x 
x 
x 
GM 
x 
x 
x 
x 
x 
x 
X 
x 
x 
x 
GSD 
x 
x 
x 
x 
x 
x 
X 
x 
x 
x 
a Times are relative to time of dosing.  
b Number of data points used to compute the summary statistics. For calculation of summary statistics, BQL values were imputed 
as 0 if they did not come after a PK sample concentration that is above the LLOQ and treated as missing otherwise. 
 


Statistical Analysis Plan - DMID Protocol: 16-0110  
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Table 34: 
Summary Statistics for Zoliflodacin Concentrations by Nominal Time, after Single 4 g 
Zoliflodacin Dose 
This table will repeat Table 32 for zoliflodacin concentrations after a single 4 g zoliflodacin dose. 
 


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Table 35: 
Summary Statistics for Zoliflodacin PK Parameters, after Single 2 g Zoliflodacin Dose 
Statistic 
Cmax 
(ng/mL) 
Tmax 
(h) 
Tlast 
(h) 
AUC(0-last) 
(h*ng/mL) 
AUC(0-inf) 
(h*ng/mL) 
Ke 
(/h) 
t1/2 
(h) 
CL/F 
(L/h) 
Vz/F 
(L) 
N 
x 
x 
x 
x 
x 
X 
x 
x 
x 
Mean 
x 
x 
x 
x 
x 
X 
x 
x 
x 
SD 
x 
x 
x 
x 
x 
X 
x 
x 
x 
Min 
x 
x 
x 
x 
x 
X 
x 
x 
x 
Median 
x 
x 
x 
x 
x 
X 
x 
x 
x 
Max 
x 
x 
x 
x 
x 
X 
x 
x 
x 
CV% 
x 
x 
x 
x 
x 
X 
x 
x 
x 
GM 
x 
x 
x 
x 
x 
X 
x 
x 
x 
GSD 
x 
x 
x 
x 
x 
X 
x 
x 
x 
 


Statistical Analysis Plan - DMID Protocol: 16-0110  
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Table 36: 
Summary Statistics for Zoliflodacin PK Parameters, after Single 4 g Zoliflodacin Dose 
This table will repeat Table 34 for zoliflodacin PK parameters after a single 4 g zoliflodacin dose. 
 


Statistical Analysis Plan - DMID Protocol: 16-0110  
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Table 37: 
Summary Statistics for Zoliflodacin Exposure Measure Ratios Comparing a Single 4 g 
Oral Dose to a Single 2 g Oral Dose 
Statistic 
Cmax Ratio 
AUC(0-last) Ratio 
AUC(0-inf) Ratio 
N 
x 
X 
x 
Min 
x 
X 
x 
Median 
x 
X 
x 
Max 
x 
X 
x 
CV% 
x 
X 
x 
GM 
x 
X 
x 
95% CI 
(x, x) 
(x, x) 
(x, x) 
 
 


Statistical Analysis Plan - DMID Protocol: 16-0110  
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APPENDIX 2.  FIGURE MOCK-UPS 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................94 
Figure 2: 
Study Flow Diagram ...................................................................................................95 
Figure 3: 
Frequency of Related Adverse Events by MedDRA System Organ Class and 
Severity, Any Time after First Dose ...........................................................................96 
Figure 4: 
Frequency of Related Adverse Events by MedDRA System Organ Class and 
Severity, after 2 g Zoliflodacin and Prior to Next Dose .............................................97 
Figure 5: 
Frequency of Related Adverse Events by MedDRA System Organ Class and 
Severity, after 4 g Zoliflodacin and Prior to Next Dose .............................................97 
Figure 6: 
Frequency of Related Adverse Events by MedDRA System Organ Class and 
Severity, after Placebo and Prior to Next Dose ..........................................................97 
Figure 7: 
Frequency of Related Adverse Events by MedDRA System Organ Class and 
Severity, after 400 mg Moxifloxacin and Prior to Next Dose ....................................97 
Figure 8: 
Incidence of Related Adverse Events by MedDRA System Organ Class and 
Maximum Severity, Any Time after First Dose .........................................................98 
Figure 9: 
Incidence of Related Adverse Events by MedDRA System Organ Class and 
Severity, after 2 g Zoliflodacin and Prior to Next Dose .............................................99 
Figure 10: Incidence of Related Adverse Events by MedDRA System Organ Class and 
Severity, after 4 g Zoliflodacin and Prior to Next Dose .............................................99 
Figure 11: Incidence of Related Adverse Events by MedDRA System Organ Class and 
Severity, after Placebo and Prior to Next Dose ..........................................................99 
Figure 12: Incidence of Related Adverse Events by MedDRA System Organ Class and 
Severity, after 400 mg Moxifloxacin and Prior to Next Dose ....................................99 
Figure 13: Clinical Laboratory Results: Change from Baseline by Parameter, Dosing 
Period, and Time Point – Chemistry, Sodium ..........................................................100 
Figure 14: Clinical Laboratory Results: Change from Baseline by Parameter, Dosing 
Period, and Time Point – Chemistry, Potassium ......................................................101 
Figure 15: Clinical Laboratory Results: Change from Baseline by Parameter, Dosing 
Period, and Time Point – Chemistry, Magnesium ....................................................101 
Figure 16: Clinical Laboratory Results: Change from Baseline by Parameter, Dosing 
Period, and Time Point – Chemistry, Chloride.........................................................101 
Figure 17: Clinical Laboratory Results: Change from Baseline by Parameter, Dosing 
Period, and Time Point – Chemistry, CO2 ................................................................101 
Figure 18: Clinical Laboratory Results: Change from Baseline by Parameter, Dosing 
Period, and Time Point – Chemistry, Glucose (Fasting) ..........................................101 


Statistical Analysis Plan - DMID Protocol: 16-0110  
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Figure 19: Clinical Laboratory Results: Change from Baseline by Parameter, Dosing 
Period, and Time Point – Chemistry, BUN ..............................................................101 
Figure 20: Clinical Laboratory Results: Change from Baseline by Parameter, Dosing 
Period, and Time Point – Chemistry, Creatinine ......................................................101 
Figure 21: Clinical Laboratory Results: Change from Baseline by Parameter, Dosing 
Period, and Time Point – Chemistry, Estimated Glomerular Filtration Rate ...........101 
Figure 22: Clinical Laboratory Results: Change from Baseline by Parameter, Dosing 
Period, and Time Point – Chemistry, Total Protein..................................................102 
Figure 23: Clinical Laboratory Results: Change from Baseline by Parameter, Dosing 
Period, and Time Point – Chemistry, Albumin ........................................................102 
Figure 24: Clinical Laboratory Results: Change from Baseline by Parameter, Dosing 
Period, and Time Point – Chemistry, AST ...............................................................102 
Figure 25: Clinical Laboratory Results: Change from Baseline by Parameter, Dosing 
Period, and Time Point – Chemistry, ALT ...............................................................102 
Figure 26: Clinical Laboratory Results: Change from Baseline by Parameter, Dosing 
Period, and Time Point – Chemistry, AP .................................................................102 
Figure 27: Clinical Laboratory Results: Change from Baseline by Parameter, Dosing 
Period, and Time Point – Chemistry, Total Bilirubin ...............................................102 
Figure 28: Clinical Laboratory Results: Change from Baseline by Parameter, Dosing 
Period, and Time Point – Chemistry, Direct Bilirubin .............................................102 
Figure 29: Clinical Laboratory Results: Change from Baseline by Parameter, Dosing 
Period, and Time Point– Hematology, Hemoglobin ................................................103 
Figure 30: Clinical Laboratory Results: Change from Baseline by Parameter, Dosing 
Period, and Time Point– Hematology, Hematocrit ..................................................103 
Figure 31: Clinical Laboratory Results: Change from Baseline by Parameter, Dosing 
Period, and Time Point– Hematology, Erythrocytes ................................................103 
Figure 32: Clinical Laboratory Results: Change from Baseline by Parameter, Dosing 
Period, and Time Point– Hematology, Leukocytes ..................................................103 
Figure 33: Clinical Laboratory Results: Change from Baseline by Parameter, Dosing 
Period, and Time Point– Hematology, Neutrophils..................................................103 
Figure 34: Clinical Laboratory Results: Change from Baseline by Parameter, Dosing 
Period, and Time Point– Hematology, Lymphocytes ...............................................103 
Figure 35: Clinical Laboratory Results: Change from Baseline by Parameter, Dosing 
Period, and Time Point– Hematology, Monocytes ...................................................103 
Figure 36: Clinical Laboratory Results: Change from Baseline by Parameter, Dosing 
Period, and Time Point– Hematology, Eosinophils..................................................103 
Figure 37: Clinical Laboratory Results: Change from Baseline by Parameter, Dosing 
Period, and Time Point– Hematology, Basophils .....................................................104 


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Figure 38: Clinical Laboratory Results: Change from Baseline by Parameter, Dosing 
Period, and Time Point– Hematology, Platelets .......................................................104 
Figure 39: Vital Signs: Change from Baseline by Parameter, Dosing Period, and Time 
Point – Systolic Blood Pressure ................................................................................105 
Figure 40: Vital Signs: Change from Baseline by Parameter, Dosing Period, and Time 
Point – Diastolic Blood Pressure ..............................................................................106 
Figure 41: Vital Signs: Change from Baseline by Parameter, Dosing Period, and Time 
Point – Heart Rate .....................................................................................................106 
Figure 42: Vital Signs: Change from Baseline by Parameter, Dosing Period, and Time 
Point – Respiratory Rate ...........................................................................................106 
Figure 43: Vital Signs: Change from Baseline by Parameter, Dosing Period, and Time 
Point – Temperature .................................................................................................106 
Figure 44: 12-Lead Standard ECG: Change from Baseline by Parameter, Dosing 
Period, and Time Point – PR Interval .......................................................................107 
Figure 45: 12-Lead Standard ECG: Change from Baseline by Parameter, Dosing 
Period, and Time Point – QRS Duration ..................................................................108 
Figure 46: 12-Lead Standard ECG: Change from Baseline by Parameter, Dosing 
Period, and Time Point – QT Interval ......................................................................108 
Figure 47: 12-Lead Standard ECG: Change from Baseline by Parameter, Dosing 
Period, and Time Point – QTcF Interval ..................................................................108 
Figure 48: 12-Lead Standard ECG: Change from Baseline by Parameter, Dosing 
Period, and Time Point – RR Interval ......................................................................108 
Figure 49: 12-Lead Standard ECG: Change from Baseline by Parameter, Dosing 
Period, and Time Point – ECG Mean Ventricular Rate ............................................108 
Figure 50: Individual Profiles of Zoliflodacin Concentrations - Part 1 .....................................109 
Figure 51: Individual Profiles of Zoliflodacin Concentrations - Part 2 .....................................110 
Figure 52: Individual Profiles of Zoliflodacin Concentrations - Part 3 .....................................110 
Figure 53: Individual Profiles of Zoliflodacin Concentrations - Part 4 .....................................110 
Figure 54: Individual Profiles of Zoliflodacin Concentrations - Part 5 .....................................110 
Figure 55: Individual Profiles of Zoliflodacin Concentrations - Part 6 .....................................110 
Figure 56: Individual Profiles of Zoliflodacin Concentrations - Part 7 .....................................110 
Figure 57: Individual Profiles of Zoliflodacin Concentrations - Part 8 .....................................110 
Figure 58: Semi-log Individual Profiles of Zoliflodacin Concentrations - Part 1 ......................111 
Figure 59: Semi-log Individual Profiles of Zoliflodacin Concentrations - Part 2 ......................112 
Figure 60: Semi-log Individual Profiles of Zoliflodacin Concentrations - Part 3 ......................112 
Figure 61: Semi-log Individual Profiles of Zoliflodacin Concentrations - Part 4 ......................112 


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Figure 62: Semi-log Individual Profiles of Zoliflodacin Concentrations - Part 5 ......................112 
Figure 63: Semi-log Individual Profiles of Zoliflodacin Concentrations - Part 6 ......................112 
Figure 64: Semi-log Individual Profiles of Zoliflodacin Concentrations - Part 7 ......................112 
Figure 65: Semi-log Individual Profiles of Zoliflodacin Concentrations - Part 8 ......................112 
Figure 66: Mean Profiles of Zoliflodacin Concentrations by Dose ...........................................113 
Figure 67: Semi-log Mean Profiles of Zoliflodacin Concentrations by Dose ............................114 
 


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10.1 
Disposition of Subjects 
9.1 
Overall Study Design and Plan Description 
Figure 1: 
Study Design 
Screen
Washout between dosing
At least 8 days
Treatment
 Period 1
A
B
etc.
FINAL VISIT
8 + 2 days
After last dose
SCREENING
Up to 21 days
Before 1st dose
Treatment
 Period 2
B
C
etc.
Treatment
 Period 3
C
D
etc.
Treatment
 Period 4
D
A
etc.
Final Visit
Randomization 
Sequences*
ABCD
BCDA
etc.
RANDOMIZATION 
before dosing on
Day +1 of 
Treatment Period 1
 
 
NOTE: A, B, C, and D refer to each of the study treatments: Treatment A = 2 g zoliflodacin; Treatment B = 4 g zoliflodacin; 
Treatment C = placebo; Treatment D = 400 mg moxifloxacin. This is a four-treatment, four-period, crossover trial. Treatments and 
treatment sequences will be randomized using a 12-sequence design balanced for period and first-order carryover effects, and 
double-blinded, except for administration of moxifloxacin. Six subjects will be randomized to each treatment sequence. The 
schematic displays only two of the 12 sequences.  
* See Section 3.3 for details and a complete list of planned treatment sequences. 
 


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Figure 2: 
Study Flow Diagram 
[Implementation Note: In the SAP, include a blank diagram with the possible reasons why subjects may be excluded from analyses. The reasons for 
exclusion should be in line with the SAP text. If possible, indicate the analysis population in the CONSORT diagram. Order the reasons for exclusion by 
decending ‘N’or ‘n’]. 
The below mockup for the flow diagram is preliminary. The flow diagram will show the number of subjects screened and enrolled, the reasons for 
screening failures, the number of subjects completing each period by sequence, and reasons for early termination or exclusion from the primary analysis. 
 
 


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14.3.1.2 Unsolicited Adverse Events 
Figure 3: 
Frequency of Related Adverse Events by MedDRA System Organ Class and Severity, 
Any Time after First Dose 
[Implementation Note: This figure includes serious and non-serious unsolicited adverse events deemed related 
to study product. Instead of “Group A”, report figure will say “Any Time After First Dose” at the top of the 
figure. Figure will be repeated for each dose group. Note that this figure will present total counts of adverse 
events, and a subject may be represented by more than one count for the same type of adverse event.] 
 
 
 


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Figure 4: 
Frequency of Related Adverse Events by MedDRA System Organ Class and Severity, 
after 2 g Zoliflodacin and Prior to Next Dose 
This figure will repeat Figure 4 for AEs occurring after 2 g Zoliflodacin. 
 
Figure 5: 
Frequency of Related Adverse Events by MedDRA System Organ Class and Severity, 
after 4 g Zoliflodacin and Prior to Next Dose 
This figure will repeat Figure 4 for AEs occurring after 4 g Zoliflodacin. 
 
Figure 6: 
Frequency of Related Adverse Events by MedDRA System Organ Class and Severity, 
after Placebo and Prior to Next Dose 
This figure will repeat Figure 4 for AEs occurring after Placebo. 
 
Figure 7: 
Frequency of Related Adverse Events by MedDRA System Organ Class and Severity, 
after 400 mg Moxifloxacin and Prior to Next Dose 
This figure will repeat Figure 4 for AEs occurring after 400 mg Moxifloxacin  
 


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Figure 8: 
Incidence of Related Adverse Events by MedDRA System Organ Class and Maximum 
Severity, Any Time after First Dose 
[Implementation Note: This figure includes serious and non-serious unsolicited adverse events deemed related 
to study product. Instead of “Group A”, report figure will say “Any Time After First Dose” at the top of the 
figure. Figure will be repeated for each dose group. Note that this figure will present the number of subjects 
with types of adverse events, and a subject may not be counted more than once for the same type of adverse 
event, but will be counted only once for the maximum severity of the respective type.] 
 
 
 


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Figure 9: 
Incidence of Related Adverse Events by MedDRA System Organ Class and Severity, 
after 2 g Zoliflodacin and Prior to Next Dose 
This figure will repeat Figure 8 for AEs occurring after 2 g Zoliflodacin. 
 
Figure 10: 
Incidence of Related Adverse Events by MedDRA System Organ Class and Severity, 
after 4 g Zoliflodacin and Prior to Next Dose 
This figure will repeat Figure 8 for AEs occurring after 4 g Zoliflodacin. 
 
Figure 11: 
Incidence of Related Adverse Events by MedDRA System Organ Class and Severity, 
after Placebo and Prior to Next Dose 
This figure will repeat Figure 8 for AEs occurring after Placebo. 
 
Figure 12: 
Incidence of Related Adverse Events by MedDRA System Organ Class and Severity, 
after 400 mg Moxifloxacin and Prior to Next Dose 
This figure will repeat Figure 8 for AEs occurring after 400 mg Moxifloxacin. 
 


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14.3.5.1 Chemistry Results 
Figure 13: 
Clinical Laboratory Results: Change from Baseline by Parameter, Dosing Period, and 
Time Point – Chemistry, Sodium 
[Implementation Note: Figure in CSR should show Follow-up time points in addition to 24 h Post-dose time 
points. The x-axis labels should lead “24 h Post-dose” rather than “1 day Post-dose”.] 
 
 
 


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Figure 14: 
Clinical Laboratory Results: Change from Baseline by Parameter, Dosing Period, and 
Time Point – Chemistry, Potassium 
This figure will repeat Figure 13 for Chemistry, Potassium 
 
Figure 15: 
Clinical Laboratory Results: Change from Baseline by Parameter, Dosing Period, and 
Time Point – Chemistry, Magnesium 
This figure will repeat Figure 13 for Chemistry, Magnesium 
 
Figure 16: 
Clinical Laboratory Results: Change from Baseline by Parameter, Dosing Period, and 
Time Point – Chemistry, Chloride 
This figure will repeat Figure 13 for Chemistry, Chloride 
 
Figure 17: 
Clinical Laboratory Results: Change from Baseline by Parameter, Dosing Period, and 
Time Point – Chemistry, CO2 
This figure will repeat Figure 13 for Chemistry, CO2 
 
Figure 18: 
Clinical Laboratory Results: Change from Baseline by Parameter, Dosing Period, and 
Time Point – Chemistry, Glucose (Fasting) 
This figure will repeat Figure 13 for Chemistry, Glucose (Fasting) 
 
Figure 19: 
Clinical Laboratory Results: Change from Baseline by Parameter, Dosing Period, and 
Time Point – Chemistry, BUN 
This figure will repeat Figure 13 for Chemistry, BUN 
 
Figure 20: 
Clinical Laboratory Results: Change from Baseline by Parameter, Dosing Period, and 
Time Point – Chemistry, Creatinine 
This figure will repeat Figure 13 for Chemistry, Creatinine 
 
Figure 21: 
Clinical Laboratory Results: Change from Baseline by Parameter, Dosing Period, and 
Time Point – Chemistry, Estimated Glomerular Filtration Rate 
This figure will repeat Figure 13 for Chemistry, Estimated Glomerular Filtration Rate 
 


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Figure 22: 
Clinical Laboratory Results: Change from Baseline by Parameter, Dosing Period, and 
Time Point – Chemistry, Total Protein 
This figure will repeat Figure 13 for Chemistry, Total Protein 
 
Figure 23: 
Clinical Laboratory Results: Change from Baseline by Parameter, Dosing Period, and 
Time Point – Chemistry, Albumin 
This figure will repeat Figure 13 for Chemistry, Albumin 
 
Figure 24: 
Clinical Laboratory Results: Change from Baseline by Parameter, Dosing Period, and 
Time Point – Chemistry, AST 
This figure will repeat Figure 13 for Chemistry, AST 
 
Figure 25: 
Clinical Laboratory Results: Change from Baseline by Parameter, Dosing Period, and 
Time Point – Chemistry, ALT 
This figure will repeat Figure 13 for Chemistry, ALT 
 
Figure 26: 
Clinical Laboratory Results: Change from Baseline by Parameter, Dosing Period, and 
Time Point – Chemistry, AP 
This figure will repeat Figure 13 for Chemistry, Alkaline Phosphatase 
 
Figure 27: 
Clinical Laboratory Results: Change from Baseline by Parameter, Dosing Period, and 
Time Point – Chemistry, Total Bilirubin 
This figure will repeat Figure 13 for Chemistry, Total Bilirubin 
 
Figure 28: 
Clinical Laboratory Results: Change from Baseline by Parameter, Dosing Period, and 
Time Point – Chemistry, Direct Bilirubin 
This figure will repeat Figure 13 for Chemistry, Direct Bilirubin 
 
 


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14.3.5.2 
Hematology Results 
Figure 29: 
Clinical Laboratory Results: Change from Baseline by Parameter, Dosing Period, and 
Time Point– Hematology, Hemoglobin 
This figure will repeat Figure 13 for Hematology, Hemoglobin 
 
Figure 30: 
Clinical Laboratory Results: Change from Baseline by Parameter, Dosing Period, and 
Time Point– Hematology, Hematocrit 
This figure will repeat Figure 13 for Hematology, Hematocrit 
 
Figure 31: 
Clinical Laboratory Results: Change from Baseline by Parameter, Dosing Period, and 
Time Point– Hematology, Erythrocytes 
This figure will repeat Figure 13 for Hematology, Erythrocytes 
 
Figure 32: 
Clinical Laboratory Results: Change from Baseline by Parameter, Dosing Period, and 
Time Point– Hematology, Leukocytes 
This figure will repeat Figure 13 for Hematology, Leukocytes 
 
Figure 33: 
Clinical Laboratory Results: Change from Baseline by Parameter, Dosing Period, and 
Time Point– Hematology, Neutrophils 
This figure will repeat Figure 13 for Hematology, Neutrophils 
 
Figure 34: 
Clinical Laboratory Results: Change from Baseline by Parameter, Dosing Period, and 
Time Point– Hematology, Lymphocytes 
This figure will repeat Figure 13 for Hematology, Lymphocytes 
 
Figure 35: 
Clinical Laboratory Results: Change from Baseline by Parameter, Dosing Period, and 
Time Point– Hematology, Monocytes 
This figure will repeat Figure 13 for Hematology, Monocytes 
 
Figure 36: 
Clinical Laboratory Results: Change from Baseline by Parameter, Dosing Period, and 
Time Point– Hematology, Eosinophils 
This figure will repeat Figure 13 for Hematology, Eosinophils 


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Figure 37: 
Clinical Laboratory Results: Change from Baseline by Parameter, Dosing Period, and 
Time Point– Hematology, Basophils 
This figure will repeat Figure 13 for Hematology, Basophils 
 
Figure 38: 
Clinical Laboratory Results: Change from Baseline by Parameter, Dosing Period, and 
Time Point– Hematology, Platelets 
This figure will repeat Figure 13 for Hematology, Platelets 
 


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14.3.6 Displays of Vital Signs 
Figure 39: 
Vital Signs: Change from Baseline by Parameter, Dosing Period, and Time Point – 
Systolic Blood Pressure 
[Implementation Note: Figure in CSR should show “Follow-up” and “Pre-dose (Prior to Next Dose)” time 
points in addition to those shown in the mock-up.] 
 
 


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Figure 40: 
Vital Signs: Change from Baseline by Parameter, Dosing Period, and Time Point – 
Diastolic Blood Pressure 
This figure will repeat Figure 38 for Diastolic Blood Pressure 
 
Figure 41: 
Vital Signs: Change from Baseline by Parameter, Dosing Period, and Time Point – Heart 
Rate 
This figure will repeat Figure 38 for Heart Rate 
 
Figure 42: 
Vital Signs: Change from Baseline by Parameter, Dosing Period, and Time Point – 
Respiratory Rate 
This figure will repeat Figure 38 for Respiratory Rate 
 
Figure 43: 
Vital Signs: Change from Baseline by Parameter, Dosing Period, and Time Point – 
Temperature 
This figure will repeat Figure 38 for Temperature 
 


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14.3.7 Displays of ECG Measurements 
Figure 44: 
12-Lead Standard ECG: Change from Baseline by Parameter, Dosing Period, and Time 
Point – PR Interval 
[Implementation Note: Figure in CSR should show “Follow-up” and “Pre-dose (Prior to Next Dose)” time 
points in addition to those shown in the mock-up.] 
 
 


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Figure 45: 
12-Lead Standard ECG: Change from Baseline by Parameter, Dosing Period, and Time 
Point – QRS Duration 
This figure will repeat Figure 43 for QRS Duration 
 
Figure 46: 
12-Lead Standard ECG: Change from Baseline by Parameter, Dosing Period, and Time 
Point – QT Interval 
This figure will repeat Figure 43 for QT Interval 
 
Figure 47: 
12-Lead Standard ECG: Change from Baseline by Parameter, Dosing Period, and Time 
Point – QTcF Interval 
This figure will repeat Figure 43 for QTcF Interval 
 
Figure 48: 
12-Lead Standard ECG: Change from Baseline by Parameter, Dosing Period, and Time 
Point – RR Interval 
This figure will repeat Figure 43 for RR Interval 
 
Figure 49: 
12-Lead Standard ECG: Change from Baseline by Parameter, Dosing Period, and Time 
Point – ECG Mean Ventricular Rate 
This figure will repeat Figure 43 for ECG Mean Ventricular Rate 
 


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Figure 50: 
Individual Profiles of Zoliflodacin Concentrations - Part 1 
[Instruction: First 9 subjects (sorted by USUBJID) will go into Part 1. There are 8 figures of individual plots 
(72 subjects w/ 9 subjects per figure).] 
 
 


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Figure 51: 
Individual Profiles of Zoliflodacin Concentrations - Part 2  
This figure will repeat Figure 49 for 9 other subjects (in order of increasing USUBJID). 
 
Figure 52: 
Individual Profiles of Zoliflodacin Concentrations - Part 3  
This figure will repeat Figure 49 for 9 other subjects (in order of increasing USUBJID). 
 
Figure 53: 
Individual Profiles of Zoliflodacin Concentrations - Part 4  
This figure will repeat Figure 49 for 9 other subjects (in order of increasing USUBJID). 
 
Figure 54: 
Individual Profiles of Zoliflodacin Concentrations - Part 5  
This figure will repeat Figure 49 for 9 other subjects (in order of increasing USUBJID). 
 
Figure 55: 
Individual Profiles of Zoliflodacin Concentrations - Part 6  
This figure will repeat Figure 49 for 9 other subjects (in order of increasing USUBJID). 
 
Figure 56: 
Individual Profiles of Zoliflodacin Concentrations - Part 7  
This figure will repeat Figure 49 for 9 other subjects (in order of increasing USUBJID). 
 
Figure 57: 
Individual Profiles of Zoliflodacin Concentrations - Part 8  
This figure will repeat Figure 49 for 9 other subjects (in order of increasing USUBJID). 
 


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Figure 58: 
Semi-log Individual Profiles of Zoliflodacin Concentrations - Part 1 
[Instruction: First 9 subjects (sorted by USUBJID) will go into Part 1. There are 8 figures of individual plots 
(72 subjects w/ 9 subjects per figure).] 
 
 


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Figure 59: 
Semi-log Individual Profiles of Zoliflodacin Concentrations - Part 2  
This figure will repeat Figure 57 for 9 other subjects (in order of increasing USUBJID). 
 
Figure 60: 
Semi-log Individual Profiles of Zoliflodacin Concentrations - Part 3  
This figure will repeat Figure 57 for 9 other subjects (in order of increasing USUBJID). 
 
Figure 61: 
Semi-log Individual Profiles of Zoliflodacin Concentrations - Part 4  
This figure will repeat Figure 57 for 9 other subjects (in order of increasing USUBJID). 
 
Figure 62: 
Semi-log Individual Profiles of Zoliflodacin Concentrations - Part 5  
This figure will repeat Figure 57 for 9 other subjects (in order of increasing USUBJID). 
 
Figure 63: 
Semi-log Individual Profiles of Zoliflodacin Concentrations - Part 6  
This figure will repeat Figure 57 for 9 other subjects (in order of increasing USUBJID). 
 
Figure 64: 
Semi-log Individual Profiles of Zoliflodacin Concentrations - Part 7  
This figure will repeat Figure 57 for 9 other subjects (in order of increasing USUBJID). 
 
Figure 65: 
Semi-log Individual Profiles of Zoliflodacin Concentrations - Part 8  
This figure will repeat Figure 57 for 9 other subjects (in order of increasing USUBJID). 
 


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Figure 66: 
Mean Profiles of Zoliflodacin Concentrations by Dose 
 
 


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Figure 67: 
Semi-log Mean Profiles of Zoliflodacin Concentrations by Dose 
 
 


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APPENDIX 3. LISTINGS MOCK-UPS 
LIST OF LISTINGS 
Listing 1: 16.2.1 Early Terminations or Discontinued Subjects ...............................................117 
Listing 2: 16.2.2.1: Subject-Specific Protocol Deviations ........................................................118 
Listing 3: 16.2.2.2: Non-Subject-Specific Protocol Deviations ................................................119 
Listing 4: 16.2.3: Subjects Excluded from Analysis Populations .............................................120 
Listing 5: 16.2.4.1: Demographic Data .....................................................................................121 
Listing 6: 16.2.4.2: Pre-Existing and Concurrent Medical Conditions .....................................122 
Listing 7: Treatments Administered ..........................................................................................123 
Listing 8: Unsolicited Adverse Events ......................................................................................124 
Listing 9: Clinical Laboratory Results – Chemistry .................................................................125 
Listing 10: Clinical Laboratory Results – Hematology ..............................................................126 
Listing 11: Clinical Laboratory Results – Urinalysis ..................................................................127 
Listing 12: Screening Laboratory Results – Serology ................................................................128 
Listing 13: Laboratory Results – Urine Toxicology and Alcohol Testing ..................................129 
Listing 14: Laboratory Results – Serum hCG Pregnancy Tests .................................................130 
Listing 15: Vital Signs ................................................................................................................131 
Listing 16: Physical Exam Findings ...........................................................................................132 
Listing 17: Listing of 12-Lead Standard ECG Interval Measurements ......................................133 
Listing 18: Listing of 12-Lead Standard ECG Overall Interpretation and Comments ...............134 
Listing 19: Prior Medications ......................................................................................................135 
Listing 20: Concomitant Medications .........................................................................................136 
Listing 21: Pregnancy Reports – Maternal Information .............................................................137 
Listing 22: Pregnancy Reports – Gravida and Para ....................................................................138 
Listing 23: Pregnancy Reports – Live Birth Outcomes ..............................................................139 
Listing 24: Pregnancy Reports – Still Birth Outcomes ...............................................................139 
Listing 25: Pregnancy Reports – Spontaneous, Elective, or Therapeutic Abortion 
Outcomes ..................................................................................................................139 
Listing 26: Birth Control Listing.................................................................................................140 
Listing 27: Subject Level Zoliflodacin Concentrations in Plasma ..............................................141 
Listing 28: Subject-Specific Zoliflodacin PK Parameters ..........................................................142 


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16.1.6 Listing of Subjects Receiving Investigational Product 
(not included in SAP, but this is a placeholder for the CSR) 
 


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16.2 
Database Listings by Subject 
16.2.1 Discontinued Subjects 
Listing 1: 
16.2.1 Early Terminations or Discontinued Subjects 
[Implementation Note: Category will be either “Early Termination” or “Treatment Discontinuation.” In the “Reason” column, concatenate any “specify” 
fields, including AE number and DV number. In the CSR, Subject ID should be USUBJID (not PATID) for purposes of de-identification. Sort order: 
Sequence, Subject ID, alphabetically by Category (in the case a subject both terminates early and discontinues treatment).] 
Sequence 
Subject ID 
Category 
Reason for Early Termination or Treatment Discontinuation 
Last Treatment Prior to 
Termination or 
Discontinuation 
Period Number 
Study Day (Day 
in Period) 
 
 
 
 
 
 
Treatment A = 2 g zoliflodacin; Treatment B = 4 g zoliflodacin; Treatment C = placebo; Treatment D = 400 mg moxifloxacin 
 
 


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16.2.2 Protocol Deviations 
Listing 2: 
16.2.2.1: Subject-Specific Protocol Deviations 
[Implementation Note: In the “Deviation” column, concatenate any and all “specify” fields (including visit number, etc.). If “Reason for Deviation” is 
“Other,” concatenate “specify” field, separate by a colon, e.g., “Other: Subject refusal.” In the CSR, Subject ID should be USUBJID (not PATID) for 
purposes of de-identification. Sort order: Sequence, Subject ID, DV Number.] 
Sequence 
Subject ID 
DV Number 
Deviation 
Deviation 
Category 
Study Day 
Reason for 
Deviation 
Deviation 
Resulted 
in AE? 
Deviation Resulted 
in Subject 
Termination? 
Deviation 
Affected 
Product 
Stability? 
Deviation 
Resolution 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A = 2 g zoliflodacin; Treatment B = 4 g zoliflodacin; Treatment C = placebo; Treatment D = 400 mg moxifloxacin 
 
 


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Listing 3: 
16.2.2.2: Non-Subject-Specific Protocol Deviations 
[Implementation Note: In the “Deviation” column, concatenate any and all “specify” fields (including visit number, etc.). If “Reason for Deviation” is 
“Other,” concatenate “specify” field, separate by a colon, e.g., “Other: Subject refusal.” Sort order: Site, Start Date.] 
Site 
Start Date  
Deviation 
End Date 
Reason for 
Deviation 
Deviation 
Resulted in 
Subject 
Termination? 
Deviation 
Affected 
Product 
Stability? 
Deviation 
Category 
Deviation 
Resolution 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.3 Subjects Excluded from Analysis 
Listing 4: 
16.2.3: Subjects Excluded from Analysis Populations 
[Implementation Note: This data in this listing should be congruent with the “Analysis Populations by Sequence” table. The reasons included here should 
match the SAP text that describes who will be excluded from analyses.] 
Sequence 
Subject ID 
Analyses in which 
Subject is Included 
Analyses from which  
Subject is Excluded 
Results Available? 
Reason Subject Excluded 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: “Yes” in the “Results available” column indicates that available data were removed from the analysis. “No” indicates that no data were available for inclusion in the analysis.  
Treatment A = 2 g zoliflodacin; Treatment B = 4 g zoliflodacin; Treatment C = placebo; Treatment D = 400 mg moxifloxacin 
 
 


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16.2.4 Demographic Data 
Listing 5: 
16.2.4.1: Demographic Data 
[Implementation Note: If a subject is multi-racial, in “Race” column, note “Multiple: (list races, separated by a comma).” 
In the CSR, Subject ID should be USUBJID (not PATID) for purposes of de-identification.] Sort order: Sequence, Subject ID. Height, weight, and BMI 
are from (first) screening visit. 
Height, weight, and BMI included in this listing will be from the initial screening visit.] 
Sequence 
 Subject ID 
Sex 
Age 
(years) 
Ethnicity 
Race 
Height 
(cm) 
Weight 
(kg) 
BMI 
(kg/m2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A = 2 g zoliflodacin; Treatment B = 4 g zoliflodacin; Treatment C = placebo; Treatment D = 400 mg moxifloxacin 
 
 


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Listing 6: 
16.2.4.2: Pre-Existing and Concurrent Medical Conditions 
[Implementation Note: “Condition Start Day” and “Condition End Day” are relative to enrollment. Rather than use exact study days, categorize as 
follows: 
Condition Start Day 
• 5 years prior to enrollment 
• 1-5 years prior to enrollment 
• 1-12 months prior to enrollment 
• Within 1 month of enrollment 
Condition End Day 
• See “Condition Start Day” categories if condition ended prior to enrollment 
• During study 
• Ongoing] 
Sequence 
 Subject ID 
MH Number 
Medical History Term 
Condition Start Day  
Condition End Day 
MedDRA System Organ Class 
MedDRA Preferred Term 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A = 2 g zoliflodacin; Treatment B = 4 g zoliflodacin; Treatment C = placebo; Treatment D = 400 mg moxifloxacin 
 
 


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Listing 7: 
Treatments Administered 
[Implementation Note: Listing will be sorted by sequence, Subject ID, and Study Day.] 
Sequence 
Subject ID 
Treatment 
Study Day 
Date 
Start Time of Dose 
End Time of Dose 
ABCD 
PHU.0123 
2 g Zoliflodacin 
1 
ddMMMyyyy 
hh:mm 
hh:mm 
ABCD 
PHU.0123 
4 g Zoliflodacin 
10 
ddMMMyyyy 
hh:mm 
hh:mm 
ABCD 
PHU.0123 
Placebo 
19 
ddMMMyyyy 
hh:mm 
hh:mm 
ABCD 
PHU.0123 
400 mg Moxifloxacin 
28 
ddMMMyyyy 
hh:mm 
hh:mm 
Treatment A = 2 g zoliflodacin; Treatment B = 4 g zoliflodacin; Treatment C = placebo; Treatment D = 400 mg moxifloxacin 
 


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16.2.7 Adverse Events 
Listing 8: 
Unsolicited Adverse Events 
[Implementation Note: If the event is ongoing (no stop date), indicate “ongoing” in the “Duration” column. In the “If Not Related, Alternate Etiology” 
column, merge the 2 data fields for collecting alternate etiology, separate by a colon. This listing includes all unsolicited adverse events. Add columns 
for MedDRA HLT or LLT depending on halting criteria or other study needs. In the CSR, Subject ID should be USUBJID (not PATID) for purposes of 
de-identification. Sort order: Sequence, Subject ID, Associated with Dose No., No. of Days Post Treatment. If the table will be multi-page, move the 
footnote/explanation to the footer so that it repeats for each page of the table.] 
Adverse 
Event 
Treatment 
No. of Days 
Post 
Treatment 
(Duration) 
Severity 
SAE? 
Relationship 
to Study 
Treatment, 
Alternative 
Etiology 
Action 
Taken with 
Study 
Treatment 
Subject 
Discontinued 
Due to AE 
Outcome 
MedDRA 
System 
Organ Class 
MedDRA 
High Level 
Group Term 
MedDRA 
Preferred 
Term 
Sequence: , Subject ID: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
 
 
 
 
 
 
 
 
 
 
 
 
Sequence: , Subject ID: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
Note: For additional details about SAEs, see Table: xx.  
Treatment A = 2 g zoliflodacin; Treatment B = 4 g zoliflodacin; Treatment C = placebo; Treatment D = 400 mg moxifloxacin 
 
 


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16.2.8 Individual Laboratory Measurements 
Listing 9: 
Clinical Laboratory Results – Chemistry 
[Implementation Note: These listings (for hematology, chemistry, and urinalysis) include all laboratory results, scheduled and unscheduled, including 
screening. These listings are not color-coded, but the severity should be included in parentheses after the result for abnormal results, e.g., 16.2 (Mild). 
The “extra” fields that are completed for abnormal results are not included in this listing; they are included in the listing of abnormal laboratory results 
that is included in the table shells document. In the CSR, Subject ID should be USUBJID (not PATID) for purposes of de-identification. Sort order: 
Sequence, Subject ID, and Planned Time Point. Measurements outside of the normal range, but not graded as mild, moderate, or severe, will be flagged 
as “ONR” in the listings.] 
Sequence 
Subject ID 
Period 
Number 
Treatment 
Time Point 
Study Day 
(Day in 
Period) 
Sex 
Laboratory 
Parameter (Units) 
Result (Severity 
Grade) 
Change from 
Baselinea 
Reference 
Range  
Clinical 
Significance 
ABCD 
PHU.0123 
1 
2 g Zoliflodacin 
24 h Post-
dose 
2 (2) 
Male 
Sodium (mEq/L) 
149 (Mild) 
+5 
135-146 
No 
ABCD 
PHU.0123 
2 
2 g Zoliflodacin 
Follow-up 
8 (-1) 
Male 
Sodium (mEq/L) 
134 (ONR) 
-10 
135-146 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A = 2 g zoliflodacin; Treatment B = 4 g zoliflodacin; Treatment C = placebo; Treatment D = 400 mg moxifloxacin  
a For Final Visit, change from baseline values using the last measurement prior to first dose as baseline, followed by change from baseline using the Period 4 baseline in parentheses. 
 
 


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Listing 10: 
Clinical Laboratory Results – Hematology 
Sequence 
Subject ID 
Period 
Number 
Treatment 
Time 
Point 
Study Day 
(Day in 
Period) 
Sex 
Laboratory 
Parameter (Units) 
Result (Severity 
Grade) 
Change from 
Baselinea 
Reference 
Range  
Clinical 
Significance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A = 2 g zoliflodacin; Treatment B = 4 g zoliflodacin; Treatment C = placebo; Treatment D = 400 mg moxifloxacin  
a For Final Visit, change from baseline values using the last measurement prior to first dose as baseline, followed by change from baseline using the Period 4 baseline in parentheses. 
 
 


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Listing 11: 
Clinical Laboratory Results – Urinalysis 
Sequence 
Subject ID 
Period 
Number 
Treatment 
Time 
Point 
Study Day (Day 
in Period) 
Sex 
Laboratory 
Parameter (Units) 
Result (Severity Grade) 
Reference 
Range  
Clinical 
Significance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A = 2 g zoliflodacin; Treatment B = 4 g zoliflodacin; Treatment C = placebo; Treatment D = 400 mg moxifloxacin  
 


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Listing 12: 
Screening Laboratory Results – Serology 
Sequence 
Subject ID 
Visit 
HIV Antibodies 
HCV Antibodies 
HBsAg 
ABCD 
PHU.0123 
Screening 
Negative 
Negative 
Negative 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A = 2 g zoliflodacin; Treatment B = 4 g zoliflodacin; Treatment C = placebo; Treatment D = 400 mg moxifloxacin 
 


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Listing 13: 
Laboratory Results – Urine Toxicology and Alcohol Testing 
[Instruction: Update columns as necessary to reflect urine toxicology tests present in the final clinical database.] 
Sequence 
Subject ID 
Visit 
Amphetamines 
Barbiturates Benzodiazepines Benzoylecgonine Cannabinoids 
Opiates 
Phencyclidine 
Methadone 
Alcohol 
ABCD 
PHU.00123 
Screening 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
ABCD 
PHU.00123 
Unscheduled 
(Day 2) 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A = 2 g zoliflodacin; Treatment B = 4 g zoliflodacin; Treatment C = placebo; Treatment D = 400 mg moxifloxacin 
 
 


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Listing 14: 
Laboratory Results – Serum hCG Pregnancy Tests  
[Instruction: If collected for any subject in the study, serum FSH will be included in this table.] 
Sequence 
Subject ID 
Visit 
Actual Study Day 
Serum hCG Result 
ABCD 
PHU.0123 
Screening 
-15 
Negative 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A = 2 g zoliflodacin; Treatment B = 4 g zoliflodacin; Treatment C = placebo; Treatment D = 400 mg moxifloxacin 
 
 


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16.2.9 Vital Signs and Physical Exam Findings 
Listing 15: 
Vital Signs 
Sequence 
Subject ID 
Treatment 
Period Number 
Time Point 
Study Day 
(Day in 
Period) 
Time  
(hh:mm) 
Parameter (units) 
Result 
(Severity) 
Change from 
Baselinea 
ABCD 
PHU.00123 
2 g 
Zoliflodacin 
1 
1 h Post-dose 
2 (2) 
hh:mm 
Systolic Blood 
Pressure (mmHg) 
142 (Mild) 
+10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A = 2 g zoliflodacin; Treatment B = 4 g zoliflodacin; Treatment C = placebo; Treatment D = 400 mg moxifloxacin  
a For Final Visit, change from baseline values using the last measurement prior to first dose as baseline, followed by change from baseline using the Period 4 baseline in parentheses. 
 


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Listing 16: 
Physical Exam Findings 
[Implementation Note: This listing includes all physical exam findings, scheduled and unscheduled. If a subject does not have any findings upon 
examination, they will not be included in this listing. If reported as an AE, display “Yes” with the AE Number in parentheses, e.g., “Yes (7)”. In the 
CSR, Subject ID should be USUBJID (not PATID) for purposes of de-identification.] Sort order: Sequence, Subject ID, Period Number, Study Day.] 
Sequence 
Subject ID 
Treatment 
Period 
Number 
Study Day 
(Day in 
Period) 
Body System 
Abnormal Finding 
Reported as an AE? 
(AE Description; Number) 
ABCD 
PHU.0123 
2 g 
Zoliflodacin 
1 
2 (2) 
SKIN 
MACULAR RASH ON SHOULDERS 
Yes (Rash; 001) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A = 2 g zoliflodacin; Treatment B = 4 g zoliflodacin; Treatment C = placebo; Treatment D = 400 mg moxifloxacin 
 
 


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Listing 17: 
Listing of 12-Lead Standard ECG Interval Measurements  
Sequence 
Subject ID 
Treatment 
Period Number 
Time Point 
Study Day 
(Day in 
Period) 
Time  
(hh:mm) 
Parameter (units) 
Result 
(Severity) 
Change from 
Baselinea 
ABCD 
PHU.0123 
2 g 
Zoliflodacin 
1 
1 h Post-dose 
2 (2) 
hh:mm 
QTcF 
455 (Mild) 
25 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A = 2 g zoliflodacin; Treatment B = 4 g zoliflodacin; Treatment C = placebo; Treatment D = 400 mg moxifloxacin  
a For Final Visit, change from baseline values using the last measurement prior to first dose as baseline, followed by change from baseline using the Period 4 baseline in parentheses. 
 
 


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Listing 18: 
Listing of 12-Lead Standard ECG Overall Interpretation and Comments 
Sequence 
Subject ID 
Treatment 
Period Number 
Time Point 
Study Day (Day 
in Period) 
Time  
(hh:mm) 
Interpretation 
Comments 
ABCD 
PHU.0123 
2 g 
Zoliflodacin 
1 
1 h Post-dose 
2 (2) 
hh:mm 
Abnormal NCS 
Sinus Bradycardia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A = 2 g zoliflodacin; Treatment B = 4 g zoliflodacin; Treatment C = placebo; Treatment D = 400 mg moxifloxacin 
 
 


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16.2.10 
Prior and Concomitant Medications 
Listing 19: 
Prior Medications 
[Instruction: Include prior medications (medications with an end date prior to dosing) only. Listing will be sorted by Sequence, then by Subject ID, and 
then by CM Number. Medication start and end Days are relative to enrollment (Day 1). If start date is more than 30 days before enrollment then 
categorize as: 1-12 months prior to enrollment, 1-5 years prior to enrollment, or >5 years prior to enrollment.] 
Sequence 
Subject ID 
CM Number 
Medication 
Medication Start Day 
Medication End Day 
Indication 
Taken for a condition on 
Medical History? 
(MH Description; Number) 
ATC Level 1  
(ATC Level 2) 
ABCD 
PHU.0123 
001 
BENADRYL 
1-12 months prior to 
enrollment 
1-12 months prior to 
enrollment 
ITCHING 
No 
DERMATOLOGICALS 
(ANTIPRURITICS, INCL. 
ANTIHISTAMINES, 
ANESTHETICS, ETC.) 
 
 
 
 
 
 
 
 
 
Treatment A = 2 g zoliflodacin; Treatment B = 4 g zoliflodacin; Treatment C = placebo; Treatment D = 400 mg moxifloxacin 
 
 


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Listing 20: 
Concomitant Medications 
[Instruction: Include concomitant medications (medications that are ongoing or that have an end date after dosing) only. Listing will be sorted by 
Sequence, then by Subject ID, and then by CM Number. Medication start and end Days are relative to enrollment (Day 1). If start date is more than 30 
days before enrollment then categorize as: 1-12 months prior to enrollment, 1-5 years prior to enrollment, or >5 years prior to enrollment. If ongoing, 
display “Ongoing” in End Day column. The Treatment (Sequence) column should show the most recent treatment prior to the medication start day, with 
the sequence randomized to in parentheses. If the Medication Start Day is the same day zoliflodacin, moxifloxacin, or placebo is administered, then the 
Treatment will be the study product administered on the Medication Start Day.] 
Treatment 
(Sequence) 
Subject ID 
CM 
Number 
Medication 
Medication Start 
Day 
Medication End 
Day 
Indication 
Taken for an AE? 
(AE Description; 
Number) 
Taken for a condition 
on Medical History? 
(MH Description; 
Number) 
ATC Level 1  
(ATC Level 2) 
2 g 
zoliflodacin 
(ABCD) 
PHU.0123 
001 
BENADRYL 
2 
2 
ITCHING 
Yes (MACULAR 
RASH; 001) 
No 
DERMATOLOGICALS 
(ANTIPRURITICS, 
INCL. 
ANTIHISTAMINES, 
ANESTHETICS, ETC.) 
 
 
 
 
 
 
 
 
 
 
Treatment A = 2 g zoliflodacin; Treatment B = 4 g zoliflodacin; Treatment C = placebo; Treatment D = 400 mg moxifloxacin 
 


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16.2.11 Pregnancy Reports 
Listing 21: 
Pregnancy Reports – Maternal Information 
[Implementation Note: Only include the “Pregnancy Number” column if a subject has more than 1 pregnancy. Date of Conception will be calculated 
based on estimated delivery date. BMI will be calculated based on pre-pregnancy height and weight. Mother’s weight gain will be calculated based on 
pre-pregnancy weight and end of pregnancy weight. If a major congenital anomaly with previous pregnancy, display “Yes” and the text from the 
“specify” field, separated by a colon. If any substance use is reported, include a listing of substance use. If autopsy revealed an alternate etiology, display 
“Yes” and the text from the “specify” field, separated by a colon. If abnormality in product of conception, display “Yes” and the text from the “specify” 
field, separated by a colon. In the CSR, Subject ID should be USUBJID (not PATID) for purposes of de-identification. Sort order: Sequence, Subject ID, 
Pregnancy Number.] 
Sequence  
Subject 
ID  
Pregnancy 
Number 
Study Day 
Corresponding 
to Estimated 
Date of 
Conception 
Source of 
Maternal 
Information 
Pregnancy 
Status 
Mother’s 
Pre-
Pregnancy 
BMI 
Mother’s 
Weight 
Gain 
During 
Pregnancy 
Tobacco, 
Alcohol, or 
Drug Use 
During 
Pregnancy? 
Medications 
During 
Pregnancy? 
Maternal 
Complications 
During 
Pregnancy? 
Maternal 
Complications 
During Labor, 
Delivery, or 
Post-Partum? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Maternal Complications are included in the Adverse Event listing. Medications taken during pregnancy are included in the Concomitant Medications Listing. 
Treatment A = 2 g zoliflodacin; Treatment B = 4 g zoliflodacin; Treatment C = placebo; Treatment D = 400 mg moxifloxacin 
 


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Listing 22: 
Pregnancy Reports – Gravida and Para 
 
 
 
Live Births 
 
 
 
 
 
Subject 
ID 
Pregnancy 
Number 
Gravida 
Extremely 
PBa 
Very 
Early 
PBa 
Early 
PBa 
Late 
PBa 
Early 
TBb 
Full 
TBb 
Late 
TBb 
Post 
TBb 
Still 
Births 
Spontaneous 
Abortion/ 
Miscarriage 
Elective 
Abortions 
Therapeutic 
Abortions 
Major 
Congenital 
Anomaly 
with 
Previous 
Pregnancy? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Gravida includes the current pregnancy, para events do not. 
a Preterm Birth 
b Term Birth 
Extremely PB: < 25 weeks 
Very Early PB:  25 0/7 - 31 6/7 weeks 
Early PB: 32 0/7 - 33 6/7 weeks 
Late PB: 34 0/7 - 36 6/7 weeks 
Early TB: 37 0/7 - 38 6/7 weeks 
Full TB: 39 0/7 - 40 6/7 weeks 
Late TB: 41 0/7 - 41 6/7 weeks 
Post TB: > 42 0/7 weeks 
 


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Listing 23: 
Pregnancy Reports – Live Birth Outcomes 
Subject 
ID 
Pregnancy 
Number 
Fetus 
Number 
Pregnancy 
Outcome 
(for this 
Fetus) 
Fetal 
Distress 
During 
Labor and 
Delivery? 
Delivery 
Method 
Gestational 
Age at Live 
Birth  
Size for 
Gestational 
Age 
Apgar 
Score, 1 
minute 
Apgar 
Score, 5 
minutes 
Cord pH 
Congenital 
Anomalies? 
Illnesses/ 
Hospitalizations 
within 1 Month of 
Birth? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Congenital Anomalies are included in the Adverse Event listing. 
Listing 24: 
Pregnancy Reports – Still Birth Outcomes 
Subject 
ID 
Date of 
Initial 
Report 
Fetus 
Number 
Pregnancy 
Outcome 
(for this 
Fetus) 
Fetal Distress 
During 
Labor and 
Delivery? 
Delivery 
Method 
Gestational 
Age at Still 
Birth 
Size for 
Gestational 
Age 
Cord pH 
Congenital 
Anomalies? 
Autopsy 
Performed? 
If Autopsy, Etiology 
for Still Birth 
Identified? 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 25: 
Pregnancy Reports – Spontaneous, Elective, or Therapeutic Abortion Outcomes 
Subject 
ID 
Date of Initial 
Report 
Fetus Number 
Pregnancy Outcome 
(for this Fetus) 
Gestational Age at 
Termination 
Abnormality in Product of Conception? 
Reason for Therapeutic 
Abortion 
 
 
 
 
 
 
 
 


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Listing 26: 
Birth Control Listing 
[Instruction: Listing will be sorted by Sequence, then by Subject ID, and then by CM Number. Birth control start and end Days are relative to first dose 
(Day 1). If start date is more than 30 days before enrollment then categorize as: 1-12 months prior to enrollment, 1-5 years prior to enrollment, or >5 
years prior to enrollment. If ongoing, display “Ongoing” in End Day column. Multiple forms of birth control for a single subject will be listed on 
separate rows.] 
Sequence 
Subject ID 
Sex 
Child Bearing 
Potential 
Birth Control 
Method 
Birth Control Start 
Day 
Birth Control End 
Day 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A = 2 g zoliflodacin; Treatment B = 4 g zoliflodacin; Treatment C = placebo; Treatment D = 400 mg moxifloxacin 


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Listing 27: 
Subject Level Zoliflodacin Concentrations in Plasma 
Subject ID 
Zoliflodacin 
Dose 
(g) 
Nominal 
Timea 
(h) 
Actual Timea 
(h) 
Concentration as Reported in 
the Bioanalytical Reportb 
(ng/mL) 
Concentration as 
Used in Phoenix 
(ng/mL) 
Used in Ke 
Calculations 
PHU.00101 
2 
0 
0 
BQL 
0 
 
PHU.00101 
2 
0.5 
0.5 
x 
x 
 
PHU.00101 
2 
1 
1 
x 
x 
 
PHU.00101 
2 
2 
2 
x 
x 
 
 
 
 
 
 
 
 
a Times are relative to time of dose. For Actual Times, out-of-window times are indicated by an asterisk. 
b <Bioanalytical report will be referenced here> 
 


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Listing 28: 
Subject-Specific Zoliflodacin PK Parameters 
Subject ID 
Zoliflodacin 
Dose 
(g) 
Cmax 
(ng/mL) 
Tmax 
(h) 
Tlast 
(h) 
AUC(0-last) 
(h*ng/mL) 
AUC(0-inf) 
(h*ng/mL) 
t1/2 
(h) 
Ke 
(/h) 
CL/F 
(L/h) 
Vz/F 
(L) 
PHU.00101 
2 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PHU.00101 
4 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PHU.00102 
2 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PHU.00102 
4 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 


ECG STATISTICAL ANALYSIS PLAN 
 
 
DMID 16-0110 
 
 
 
 
 
 
 
 
      DynPort Vaccine Company, LLC 
____________________________________________________________________________________________________________________________________________________________ 
Document: 
DMID 16-0110_ECG_SAP_18Sep2018  
Authors: 
Pramod Kadam\Pooja Hingorani 
Version: 
Final 
Page 1 of  24 
 
 Version Date: 
18Sep2018 
 
 
 
 
 
ECG STATISTICAL ANALYSIS PLAN 
 
 
 
Protocol Number: DMID 16-0110 
 
 
A Phase 1, Randomized, Double-blinded, Four-period 
Crossover, Thorough QT/QTc (TQT) Clinical Trial to 
Evaluate the Effect of Zoliflodacin on Cardiac 
Repolarization in Healthy Male and Female Subjects 
 
 
 
 
Version:  Final 
Date:  18 Sep 2018 
 
 
 
 
 
 
 
 
 
 
 
Authors: 
 
         Pramod Kadam\Pooja Hingorani 
IQVIA Reviewer: 
                 
Dr. Dilip Karnad 
DynPort Vaccine Company, LLC Reviewer: Dr. George Saviolakis 
  
 
 


ECG STATISTICAL ANALYSIS PLAN 
 
 
DMID 16-0110 
 
 
 
 
 
 
 
 
      DynPort Vaccine Company, LLC 
____________________________________________________________________________________________________________________________________________________________ 
Document: 
DMID 16-0110_ECG_SAP_18Sep2018  
Authors: 
Pramod Kadam\Pooja Hingorani 
Version: 
Final 
Page 2 of  24 
 
 Version Date: 
18Sep2018 
 
 
 
 
SIGNATURE PAGE 
This statement confirms that the Report Writing team of Cardiac Safety Services, IQVIA and 
DynPort Vaccine Company, LLC have reviewed the ECG Statistical Analysis Plan for the Study 
DMID 16-0110.  
 
 
Study No.:  
 
 
DMID 16-0110 
 
Study Title:  
A Phase 1, Randomized, Double-blinded, Four-period Crossover, 
Thorough QT/QTc (TQT) Clinical Trial to Evaluate the Effect of 
Zoliflodacin on Cardiac Repolarization in Healthy Male and 
Female Subjects 
 
Report writing group:  
IQVIA  
Natraj by Rustomjee, 602 A, 6th Floor,  
194, MV Road, Near Western Express Highway Metro Station 
 
Mumbai - 400 069, India  
 
 
Sponsor:  
 
 
DynPort Vaccine Company, LLC  
110 Thomas Johnson Drive, Suite 200  
Frederick, MD 21702, USA  
 
 
 
 


ECG STATISTICAL ANALYSIS PLAN 
 
 
DMID 16-0110 
 
 
 
 
 
 
 
 
      DynPort Vaccine Company, LLC 
____________________________________________________________________________________________________________________________________________________________ 
Document: 
DMID 16-0110_ECG_SAP_18Sep2018  
Authors: 
Pramod Kadam\Pooja Hingorani 
Version: 
Final 
Page 3 of  24 
 
 Version Date: 
18Sep2018 
 
 
 
The signatures on this page indicate review and authorization of this document. 
For IQVIA: 
 
Name: 
Pramod Kadam  
 
 
Title: 
Biostatistician II 
 
 
(Sig.): 
 
 
 
 
Date: 
 
 
 
Name: 
Pooja Hingorani 
 
 
Title: 
Sr Medical Writer  
 
 
(Sig.): 
 
 
 
 
Date: 
 
 
 
 
Name: 
Dilip Karnad 
 
 
Title: 
Head, Research and Reports 
 
 
(Sig.): 
 
 
 
 
Date: 
 
 
 
 
For DynPort Vaccine Company, LLC: 
Name: 
George Saviolakis 
 
Title: 
Medical Director 
 
 
(Sig.): 
 
 
 
 
Date: 
 
 
 
 
 
 
 


ECG STATISTICAL ANALYSIS PLAN 
 
 
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____________________________________________________________________________________________________________________________________________________________ 
Document: 
DMID 16-0110_ECG_SAP_18Sep2018  
Authors: 
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Version: 
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 Version Date: 
18Sep2018 
 
 
 
 
TABLE OF CONTENTS 
MODIFICATION HISTORY ......................................................................................... 5 
ABBREVIATIONS AND DEFINITIONS ..................................................................... 8 
1. 
INTRODUCTION ............................................................................................... 11 
2. 
STUDY OBJECTIVES AND OUTCOME MEASURES ................................... 11 
2.1. 
STUDY OBJECTIVES ............................................................................................. 11 
2.1.1. 
Primary objective .................................................................................... 11 
2.1.2. 
Secondary objective ................................................................................ 11 
2.2. 
STUDY OUTCOME MEASURES.............................................................................. 11 
2.2.1. 
Primary outcome measure ...................................................................... 11 
2.2.2. 
Secondary outcome measures ................................................................. 11 
3. 
STUDY DESIGN................................................................................................. 12 
3.1. 
OVERVIEW OF HOLTER ECG DATA COLLECTION IN THE STUDY .......................... 14 
4. 
ANALYSIS POPULATIONS RELATED TO EXPERT ECG REPORT .......... 14 
5. 
STATISTICAL ANALYSIS METHODS ........................................................... 15 
5.1. 
GENERAL STATISTICAL CONSIDERATIONS FOR CARDIAC SAFETY EVALUATION ... 15 
5.2. 
TREATMENTS FOR CARDIAC SAFETY EVALUATION .............................................. 16 
5.3. 
STUDY HOLTER ECG TIMEPOINTS ...................................................................... 16 
5.4. 
ANALYSIS OF CENTRAL TENDENCY (BY-TIMEPOINT ANALYSIS) ......................... 17 
5.4.1. 
Categorical analysis ............................................................................... 19 
5.4.2. 
Analysis of ECG morphological abnormalities ...................................... 20 
5.5. 
PHARMACOKINETIC-QTCF ANALYSIS ................................................................. 21 
5.5.1. 
Hysteresis effect check ............................................................................ 21 
5.5.2. 
Testing for linearity: ............................................................................... 22 
5.5.3. 
Model selection: ...................................................................................... 22 
5.6. 
GRAPHICAL ANALYSIS ......................................................................................... 23 
6. 
REFERENCES .................................................................................................... 23 
 
 
 


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Modification History 
Unique 
Identifie
r for this 
Version 
Date of the 
Document 
Version 
Section number and text from 
previous version 
Section number and text 
in new version 
Draft 01 
16JUL2018 
Not Applicable – First Version 
 
Draft 02 
13AUG2018 
1. Inserting throughout text the 
appropriate references to 
TLFs #s 
Wherever applicable in this 
document 
2. Reviewer from Sponsor 
added 
Signature page 
3. Review abbreviations in 
Final and delete/add as 
needed. 
Updated the abbreviation 
list 
4. In the entire document 
wherever applicable, when 
the abbreviation is used for 
the first time, it is now 
spelled out.   
As per review comments 
5. Global comment ‘Remove 
hyphen in DMID-16-0110’ 
Updated wherever 
applicable in this document 
6. Global comment ‘Postdose’ 
added hyphen ‘post-dose’ 
throughout the document 
Updated wherever 
applicable in this document 
as per reviewer’s comment 
7. Section 2.2 – Study Outcome 
measures 
Updated as per study 
protocol text 
8. Section 3 – Study design 
Updated as per study 
protocol text and review 
comments 
9. Section 4 – Reworded 
‘Analysis Set’ to ‘Analysis 
Population’ 
As per review comments 
10. Section 5 – reworded 
‘average’ to ‘mean’ 
As per review comments 


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11. Added ‘Calculated from RR’ 
in parenthesis to Heart rate in 
Section 5 and in the rest of 
the document 
As per review comments 
12. Added analysis for RR 
As per review comments 
13. Added analysis for QTcB  
As per sponsor discussion 
and as per ICH E14 
guidance. 
14. Deleted ‘groups’ where 
‘Treatment groups’ appeared 
in the text 
As per review comments 
15. Section 5 onwards – changed 
2-sided 90% confidence 
intervals to one-sided 95% 
confidence intervals 
As per review comments 
16. Section 5.3 – Added Baseline 
to be determined for each 
period separately.  reworded 
‘average’ to ‘mean’ 
As per review comments 
17. Section 5.3 – Table 3 – 
Added Day 2 to Day1 Hour 
24 timepoint 
As per review comments 
18. Section 5.4.1 –  Added QTcB 
for categorical outlier 
analysis.  
As per sponsor discussion 
and as per ICH E14 
guidance. 
19. Section 5.4.2 – Clarified the 
baseline considered for 
treatment emergent 
morphological abnormalities 
Based on review comments 
20. Section 5.5 title changed 
from ‘Concentration-QTcF 
analysis’ to ‘Pharmacokinetic 
– QTcF Analysis’ 
As per review comments 
21. Section 5.5 deleted ‘its 
metabolites (if available)’  
As per review comments – 
no metabolites data 
available 


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22. Added section numbering to 
methods of Concentration 
QTcF analysis 
As per review comments 
23. Test of linearity section – 
Corrected ΔQTcF to 
ΔΔQTcF 
As per reviewer’s 
observation 
Final 
18SEP2018 
Accepted minor edit 
comments throughout the 
document 
As per Sponsor’s comments 
Added reference of the 
scientific white paper  
As per Sponsor’s comments 
Modified the SAS code in 
section 5.4  
As per IQVIA reviewer’s 
input 


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Abbreviations and Definitions 
 
Abbreviation or specialist 
term 
Explanation  
AE 
Adverse event 
AIC 
Akaike Information Criterion  
ANCOVA 
Analysis of covariance 
AUC 
Area under the curve 
AV 
Atrioventricular 
β2 
Model-predicted estimates of slope 
bpm 
Beats per minute 
CI 
Confidence interval 
Cmax 
Maximum plasma concentration 
CS 
Compound symmetry 
CSS 
Cardiac Safety Services, IQVIA 
CTU 
Clinical trial unit 
CV 
Coefficient of variation 
DDFM 
Denominator degrees of freedom method 
DMID 
Division of Microbiology and Infectious Diseases 
ECG 
Electrocardiogram 
Emax 
Nonlinear model frequently used in dose–response analyses 
ET 
Early termination 
g 
Gram 
h 
Hour 
HR 
Heart rate 
Hz 
Hertz 
ICH 
International Council for Harmonization 
LCL 
Lower confidence limit 
LOESS 
Locally-weighted scatterplot smoothing 
LS 
Least square 


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Abbreviation or specialist 
term 
Explanation  
LVH 
Left ventricular hypertrophy 
Max 
Maximum 
mg 
Milligram 
MI 
Myocardial infarction 
Min 
Minimum 
msec 
Milliseconds 
N 
Number of observations 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PO 
Oral  
PR interval 
Interval from onset of P-wave to the onset of the QRS 
complex 
QRS 
Duration from the start of the Q-wave to the end of the S-
wave 
QT interval 
Interval from onset of the Q-wave to the end of the T-wave 
QTc 
Corrected QT interval 
QTcB 
QT interval corrected by Bazett’s formula 
QTcF 
QT interval corrected by Fridericia’s formula 
∆QTcF 
Change-from-baseline QTcF value 
∆∆QTcF 
Placebo-corrected change from baseline QTcF value 
RR 
Interval from the peak of the R wave of a QRS complex to 
the peak of the R wave of the next QRS complex  
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SE 
Standard error 
TQT 
Thorough QT/QTc 
Tmax 
Time to maximum plasma concentration 
T-wave 
ECG wave indicative of ventricular repolarization 


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Abbreviation or specialist 
term 
Explanation  
UCL 
Upper confidence limit 
UN  
Unstructured covariance 
VS 
Vital signs 
 
 
 


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1. Introduction 
This Electrocardiogram (ECG) Statistical Analysis Plan (SAP) for the DMID 16-0110 study, for 
preparing the Expert ECG Report, is based on Clinical Trial Protocol Version 1.0 dated 
18 Jun 2018 for the DMID 16-0110 study.1 
 
2. Study Objectives and Outcome Measures  
2.1. 
Study Objectives 
2.1.1. Primary objective 
 To evaluate the effect of zoliflodacin on the corrected QT interval of the ECG using 
Fridericia’s formula (QTcF). 
2.1.2. Secondary objective 
 To evaluate the effects of zoliflodacin on other ECG parameters [PR, QRS, and RR 
intervals, and heart rate (HR)]  
 To evaluate the sensitivity of QTcF measurement using moxifloxacin  
 To evaluate the effect of zoliflodacin on T-wave morphology  
 To evaluate the pharmacokinetics (PK) of 2 grams (g) and 4 g oral zoliflodacin under 
fasting state  
 To evaluate the relationship between zoliflodacin PK and time-matched QTcF 
pharmacodynamics (PD)  
 To evaluate the safety and tolerability of 2 g and 4 g oral zoliflodacin 
2.2. 
Study Outcome Measures 
2.2.1. Primary outcome measure 
 The upper bound of the one-sided 95% confidence interval (CI) for the largest 
time-matched, placebo-corrected, baseline-adjusted mean QTcF interval (ΔΔQTcF) 
collected in the 24 hour (h) post-dosing period after 2 g and 4 g dose of zoliflodacin is 
<10 milliseconds (msec) 
2.2.2. Secondary outcome measures 
 Time-matched, placebo-corrected, baseline-adjusted non-QT intervals (PR, QRS, and 
RR intervals) and HR collected in the 24 h period after 2 g and 4 g dose of 
zoliflodacin 
 The lower bound of the one-sided 95% CI of the ∆∆QTcF is >5 msec at one or more 
individual timepoints between 1 h and 4 h after a single dose of moxifloxacin 400 mg.  
 Incidence of abnormal T-wave morphology using defined categories in the 24 h 
period after 2 g and 4 g dose of zoliflodacin 


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 Single-dose plasma concentrations (and PK exposure parameters, such as Cmax and 
AUC) of zoliflodacin collected up to 24 h after 2 g and 4 g dose of zoliflodacin 
 Relationship between plasma concentrations of zoliflodacin (and PK exposure 
parameters, such as Cmax and AUC) and ΔΔQTcF up to 24 h after 2 g and 4 g dose of 
zoliflodacin 
 Occurrence of treatment-emergent serious adverse events (SAEs), other unsolicited 
treatment-emergent adverse events (AEs), and changes from baseline in vital signs 
(VS), clinical laboratory values, and ECG parameters following administration of 
zoliflodacin and moxifloxacin from time of dosing to Final Visit, or Early 
Termination (ET) Visit 
 
3. Study Design 
This TQT study is being performed in a single center, the Vince & Associates Clinical Research, 
Inc., clinical trial unit (CTU). The study has a randomized, double-blinded (except for the use of 
moxifloxacin), placebo-controlled, four-period, four-treatment, crossover design which is 
balanced for period and first-order carryover effects with 72 healthy subjects (male or female), 
aged 18 to 45 years inclusive. In this study, the ECG and PK data from these subjects will be 
used to evaluate the effect of zoliflodacin on QTcF and other ECG parameters, the correlation of 
drug concentration (and PK profile) with ΔΔQTcF, and the PK and safety profiles of the new 
zoliflodacin formulation. 
Each subject will receive one oral dose of each of four treatments, labeled A through D: 
• Treatment A: zoliflodacin 2 g orally (PO) (investigational drug, therapeutic dose) 
• Treatment B: zoliflodacin 4 g PO (investigational drug, supratherapeutic dose) 
• Treatment C: placebo PO (for zoliflodacin) 
• Treatment D: moxifloxacin 400 mg PO (positive control comparator) 
Each subject will be randomly allocated to one of 12 dosing sequences before dosing on Day 1, 
Dosing Period 1. Each subject will receive a single dose of the following four study drugs on 
different days according to their randomly-assigned dosing sequence, as follows: 
 
 


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Table 1: Dosing sequences for randomization 
ABCD 
ACDB 
ADBC 
 DCBA 
BADC 
BDCA 
BCAD 
 DBAC 
CDAB 
CABD 
CBDA 
 DACB 
Six of the planned 72 subjects are to be included in each treatment sequence. The design is 
balanced for period and first-order carryover effects. 
Subjects will be dosed on the morning of Day 1 in each dosing period, in a staggered fashion at 
least several minutes apart, and will receive study drug at approximately the same time in each 
subsequent dosing period. Each treatment will be administered after at least an 8-hour fast 
period, which will continue for at least 4 h after dosing. Zoliflodacin or placebo will be 
reconstituted in 60 mL of tap water. After the cup containing the 60 mL of zoliflodacin or 
placebo is taken, approximately 60 mL of tap water will be added to the cup and consumed by 
the subject to chase the initial dose. Moxifloxacin will be administered orally with 120 mL of 
water. 
Continuous 12-lead Holter ECGs will be recorded on Day 1 and Day 2 of each dosing period 
starting approximately 1 h before dosing and lasting 25 h. At timepoints for Holter ECG 
extraction, subjects will rest in the supine position for at least 10 minutes before and 5 minutes 
after the nominal time, without any ongoing stimulation (e.g., television). Three replicate ECGs 
will be extracted at each timepoint for ECG interval measurement and assessment of T-wave 
morphology. 
Plasma for PK analysis will be collected at scheduled timepoints that match the timepoints for 
ECG extraction before and after dosing on Day 1 and through Day 2, or ET if it occurs within 
24 h after dosing. 
Subjects are to be monitored as inpatients in the CTU up to 24 h after each dose (Day 2). They 
will be discharged from the CTU and followed up as outpatients for at least 5 days (Days 3-7) 
after dosing in Dosing Periods 1-3. The total time to wash-out of the previously-received study 
drug is at least 8 days. The Final Visit will be 8±2 days after the last dose. 
Subjects will be excluded if they have any of the following cardiac criteria: 
 History of acute or chronic cardiovascular disease or surgery 
 History of cardiac arrhythmia or syncope related to cardiac arrhythmia or unexplained, or 
use of a cardiac pacemaker 
 A marked baseline prolongation of ECG intervals QTc/QTcF >449 msec in males and 
females; PR >209 msec; and QRS >110 msec, or HR <45 bpm or >100 bpm on ECG 
measurements.  
 Clinically significant abnormal ECG results including: 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 


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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; any characteristics that would make 
QT assessment unreliable, including flat T-waves; or any condition deemed clinically 
significant by a study investigator. 
3.1. 
 Overview of Holter ECG Data Collection in the Study 
ECGs will be recorded during all four dosing periods using high resolution (1000 Hz) 12-lead 
Holter ECG equipment.  
The continuous ECG recording will start approximately 1 h before dosing on Day 1 of all dosing 
periods and continue until 24 h after dosing (i.e., in the morning of Day 2). Three replicate ECG 
recordings will be extracted at the following timepoints in each dosing period: 45, 30, and 15 
minutes before dosing (baseline) and 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 h after dosing for a total of 
12 timepoints per subject per dosing period. The subject will be in a supine position for at least 
10 minutes before recording an ECG at the nominal timepoint for the ECG extractions from the 
Holter monitors. These timepoints are to correspond to the PK blood sampling timepoints for 
each dosing period with ECGs being obtained before the measurement of VS and collection of 
blood samples, to avoid the effect of stress on the ECG. The mean of pre-dose ECGs extracted 
on Day 1 of each dosing period will be used as the baseline reference for comparison with 
post-dose ECGs. 
The primary objective and primary outcome measure in this study is based on QTcF values. 
However, the ICH-E14 guidance acknowledges that all formulae make assumptions about the 
nature of the QT-HR relationship that may not apply to those with disease or taking drugs. The 
ICH-E14 guidance, therefore, suggests that uncorrected QT and RR interval data, HR data, as 
well as QT interval data corrected using Bazett’s (QTcB) and Fridericia’s (QTcF) corrections 
should be submitted in all applications, in addition to QT interval data corrected using any other 
formulae.2 Thus, this analysis plan also includes statistical analysis of QTcF, QTcB, HR 
(calculated from RR), RR interval, QT interval, PR interval and the QRS duration. 
4. Analysis Populations related to Expert ECG Report 
Holter ECG Analysis Population: The Holter ECG Analysis Population will include all 
subjects who have received at least one dose of zoliflodacin, moxifloxacin, or placebo, treatment, 
without protocol deviations potentially impacting the ECG intervals and have baseline ECGs and 
at least one post-dose ECG assessment. 
PK Analysis Population: The PK Analysis Population will include all subjects who have 
received at least one dose of zoliflodacin and have at least one measured zoliflodacin 
concentration at a scheduled post-dose PK timepoint without major protocol deviations. Subjects 
will be analyzed according to the actual treatment they receive.  
PK-ECG Analysis Population: The PK-ECG Analysis Population will be a sub-set of the 
Holter ECG Analysis Population and will include all subjects in the Holter ECG Analysis 


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Population with at least one plasma concentration value in the zoliflodacin treatment period with 
a corresponding Holter ECG measurement value at the same nominal timepoint.  
5. Statistical Analysis Methods 
This section describes the statistical analysis methods for the Holter ECG data from the 
DMID 16-0110 study. 
5.1. 
General Statistical Considerations for Cardiac Safety Evaluation 
 ECG parameter measurements and morphological abnormalities from the central ECG 
laboratory interpretation will be evaluated in this analysis 
 Continuous ECG data (QTcF, QTcB, HR [calculated from RR], RR, QT, PR, and QRS) 
will be described using the following descriptive statistics: number of subjects, mean, 
standard deviation (SD), median, coefficient of variation (CV), minimum, maximum, 
standard error (SE) and one-sided 95% CI. For a timepoint where N ≤3 for a treatment 
period, only median, minimum and maximum values will be provided. Frequencies and 
percentages will be used for summarizing categorical outlier values. For calculation of 
mean of ECG parameter values across replicates at each timepoint, the value will be 
rounded to nearest whole number in the derived dataset (Refer to DMID 16-
0110_ECG_Table shells: Tables 3 and 4; DMID 16-0110_ECG_Listing shells: Listings 1 
to 7).  
 Continuous ECG data will be assumed to be normally distributed. Test of normality will 
not be performed. 
 One-sided 95% CIs will be calculated for absolute and change from baseline values and 
provided in the report (Refer to DMID 16-0110_ECG_Table shells: Tables 3 and 4; 
DMID 16-0110_ECG_Listing shells: Listings 1 to 7).   
 Repeated measures mixed effects modeling will be used to estimate the placebo-corrected 
effect of study drug(s) on the ECG parameters (Refer to DMID 16-0110_ECG_Table 
shells: Table 6).  
 Additional visit windowing will not be performed as this will have already been done 
prior to database lock.  
 Presentation of results – decimal places and significant digits (Refer to Table 2) 
Table 2  
Presentation of results – decimal places  
ECG Reporting Precision 
Descriptive Summaries 
 
Minimum, Maximum 
Recorded decimal places 
Mean, Median 
Recorded decimal places + 1 
Standard Deviation, Standard Error 
Recorded decimal places + 2 
Inferential Statistics 
 
LS Mean, Difference in LS Means 
Recorded decimal places + 1 
CIs corresponding to LS Means and Difference in LS Means 
Recorded decimal places + 2 


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Listings 
Recorded decimal places 
PK Reporting Precision 
Mean (arithmetic and geometric), Median 
Recorded decimal places + 1 
Listings 
Recorded decimal places 
 
5.2. 
Treatments for Cardiac Safety Evaluation 
The DMID 16-0110 study includes four treatments: 
Each subject received one dose of each of four treatments, labeled A through D: 
• Treatment A: zoliflodacin 2 g PO (investigational drug, therapeutic dose) 
• Treatment B: zoliflodacin 4 g PO (investigational drug, supratherapeutic dose) 
• Treatment C: placebo PO (for zoliflodacin) 
• Treatment D: moxifloxacin 400 mg PO (positive control comparator) 
Subject disposition for Holter ECG analysis population (number of subjects enrolled, completed, 
discontinued, and present in Holter ECG analysis population) will be presented. In addition, 
subject and ECG disposition for Holter ECG analysis population (number of subjects, expected 
number of ECGs, ECGs extracted and missing ECGs) will be summarized for each timepoint 
and all treatments. 
5.3. 
Study Holter ECG Timepoints 
At each study timepoint, the mean value of an ECG parameter from all available replicate ECGs 
recorded at that timepoint (maximum of 3 replicates) for an individual subject will be considered 
as the value of the ECG parameter at the nominal timepoint for the subject. 
Baseline: Baseline will be determined separately for each dosing period. Mean of triplicate 
ECGs recorded at 3 pre-dose assessments (mean of 9 ECGs) on Day 1 (i.e. D1PRE45MIN, 
D1PRE30MIN and D1PRE15MIN) of each treatment period will be considered as baseline for 
the corresponding treatment period. 
Holter ECG analysis timepoints for the study are as follows: 
Table 3: Holter ECG Timepoints as per Visit code poster and Visit codes used in ECG 
database 
No. 
Timepoints as per Visit code poster 
Visit Codes in ECG 
database 
1 
Period 1 Day 1 Predose 45 minutes 
P1D1PRE45MIN 
2 
Period 1 Day 1 Predose 30 minutes 
P1D1PRE30MIN 
3 
Period 1 Day 1 Predose 15 minutes 
P1D1PRE15MIN 
4 
Period 1 Day 1 Post dose 0.5 hours 
P1D1H0.5 
5 
Period 1 Day 1 Post dose 1 hour 
P1D1H1 
6 
Period 1 Day 1 Post dose 2 hour 
P1D1H2 
7 
Period 1 Day 1 Post dose 3 hour 
P1D1H3 
8 
Period 1 Day 1 Post dose 4 hour 
P1D1H4 
9 
Period 1 Day 1 Post dose 6 hour 
P1D1H6 


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No. 
Timepoints as per Visit code poster 
Visit Codes in ECG 
database 
10 
Period 1 Day 1 Post dose 8 hour 
P1D1H8 
11 
Period 1 Day 1 Post dose 12 hour 
P1D1H12 
12 
Period 1 Day 1 Post dose 24 hour (Day 2) 
P1D1H24 
 
 
 
13 
Period 2 Day 1 Predose 45 minutes 
P2D1PRE45MIN 
14 
Period 2 Day 1 Predose 30 minutes 
P2D1PRE30MIN 
15 
Period 2 Day 1 Predose 15 minutes 
P2D1PRE15MIN 
16 
Period 2 Day 1 Post dose 0.5 hours 
P2D1H0.5 
17 
Period 2 Day 1 Post dose 1 hour 
P2D1H1 
18 
Period 2 Day 1 Post dose 2 hour 
P2D1H2 
19 
Period 2 Day 1 Post dose 3 hour 
P2D1H3 
20 
Period 2 Day 1 Post dose 4 hour 
P2D1H4 
21 
Period 2 Day 1 Post dose 6 hour 
P2D1H6 
22 
Period 2 Day 1 Post dose 8 hour 
P2D1H8 
23 
Period 2 Day 1 Post dose 12 hour 
P2D1H12 
24 
Period 2 Day 1 Post dose 24 hour (Day 2) 
P2D1H24 
 
 
 
25 
Period 3 Day 1 Predose 45 minutes 
P3D1PRE45MIN 
26 
Period 3 Day 1 Predose 30 minutes 
P3D1PRE30MIN 
27 
Period 3 Day 1 Predose 15 minutes 
P3D1PRE15MIN 
28 
Period 3 Day 1 Post dose 0.5 hours 
P3D1H0.5 
29 
Period 3 Day 1 Post dose 1 hour 
P3D1H1 
30 
Period 3 Day 1 Post dose 2 hour 
P3D1H2 
31 
Period 3 Day 1 Post dose 3 hour 
P3D1H3 
32 
Period 3 Day 1 Post dose 4 hour 
P3D1H4 
33 
Period 3 Day 1 Post dose 6 hour 
P3D1H6 
34 
Period 3 Day 1 Post dose 8 hour 
P3D1H8 
35 
Period 3 Day 1 Post dose 12 hour 
P3D1H12 
36 
Period 3 Day 1 Post dose 24 hour (Day 2) 
P3D1H24 
 
 
 
37 
Period 4 Day 1 Predose 45 minutes 
P4D1PRE45MIN 
38 
Period 4 Day 1 Predose 30 minutes 
P4D1PRE30MIN 
39 
Period 4 Day 1 Predose 15 minutes 
P4D1PRE15MIN 
40 
Period 4 Day 1 Post dose 0.5 hours 
P4D1H0.5 
41 
Period 4 Day 1 Post dose 1 hour 
P4D1H1 
42 
Period 4 Day 1 Post dose 2 hour 
P4D1H2 
43 
Period 4 Day 1 Post dose 3 hour 
P4D1H3 
44 
Period 4 Day 1 Post dose 4 hour 
P4D1H4 
45 
Period 4 Day 1 Post dose 6 hour 
P4D1H6 
46 
Period 4 Day 1 Post dose 8 hour 
P4D1H8 
47 
Period 4 Day 1 Post dose 12 hour 
P4D1H12 
48 
Period 4 Day 1 Post dose 24 hour (Day 2) 
P4D1H24 
 
5.4. 
Analysis of Central Tendency (By-timepoint Analysis) 
By-timepoint analysis will be performed using Holter ECG data from subjects in the Holter ECG 
Analysis Population. Absolute values, change-from-baseline and time-matched, placebo-
corrected, change-from-baseline values for each ECG parameter will be considered for this 
analysis (Refer to DMID 16-0110_ECG_Table shells: Tables 3, 4 and 5; 
DMID 16-0110_ECG_Listing shells: Listings 1 to 7; DMID 16-0110_ECG_Figure shells: Figure 
1 to 56). Change-from-baseline QTcF (∆QTcF) values (and other ECG parameters QTcB, HR 


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[calculated from RR], RR, QT, PR and QRS duration values) will be calculated by subtracting 
the mean value of replicate ECGs at baseline from the mean value of replicate ECGs at post-dose 
timepoints.   
Time-matched, placebo-corrected, change from baseline in QTcF interval (∆∆QTcF) values (and 
other ECG parameters QTcB, HR [calculated from RR], RR, QT, PR and QRS duration values) 
will be calculated as differences between time-matched change-from-baseline QTcF values for 
active treatment minus time-matched change-from-baseline QTcF values for placebo for each 
subject (Refer to DMID 16-0110_ECG_Table shells: Table 5; DMID 16-0110_ECG_Listing 
shells: Listings 1 to 7). 
As a primary analysis, a repeated measurement analysis on ∆∆QTcF values will be performed at 
each post-dose timepoint using analysis of covariance (ANCOVA) (Refer to 
DMID 16-0110_ECG_Table shells: Table 6; DMID 16-0110_ECG_Figure shells: Figure 57). 
Unless otherwise specified, a restricted maximum likelihood based, linear mixed effect model 
will be used. Model will include ∆∆QTcF as the dependent variable. Baseline QTcF value as 
continuous covariate and sequence, period, treatment, nominal timepoint (as categorical) and 
interactions of timepoint with treatment will be treated as fixed effects. The model will also 
include subject nested within sequence as a random effect. SAS PROC MIXED will be used to 
perform the analysis. 
At each of the 9 post-dose timepoints and for each zoliflodacin dose, a one-sided 95% CI for the 
treatment effect on ΔΔQTcF will be estimated using least square (LS) means. There will be 18 
CIs, one for each combination of zoliflodacin dose and timepoint. A negative effect of 2 g or 4 g 
zoliflodacin will be concluded if the maximum of the 18 one-sided 95% CI upper bounds is 
<10 msec. No adjustment will be made for multiplicity. 
SAS code will be similar to: 
PROC MIXED; 
 
CLASS TREATMENT PERIOD SEQUENCE TIME SUBJ; 
 
MODEL 
ΔΔQTCF 
= 
TREATMENT 
PERIOD 
SEQUENCE 
TIME 
BASELINE_QTCF        
TIME*TREATMENT; 
 
RANDOM SUBJECT(SEQUENCE); 
 
REPEATED TIME / SUBJ=SUBJ(PERIOD) TYPE=CS; 
 
LSMEANS TIME*TREATMENT / ALPHA=0.1; 
 RUN; 
In the above model, treatment will be Zoliflodacin 2 g and Zoliflodacin 4 g. 
Similar ANCOVA models will also be done for QTcB, HR (calculated from RR), RR, QT, PR 
and QRS as secondary analyses (Refer to DMID 16-0110_ECG_Table shells: Table 6; DMID 
16-0110_ECG_Figure shells: Figure 57 to 63).  
The analysis will also be presented in graphs. For each of the 2 active treatments, all 9 
confidence intervals (corresponding to the 9 post-dose timepoints) will be presented on one 
graph. The change from baseline (ΔQTcF) and placebo-corrected change from baseline QTcF 
(ΔΔQTcF) will be presented separately (Refer to DMID 16-0110_ECG_Figure shells: Figure 57 
to 63).  


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Assay sensitivity (i.e., the ability to detect small increases from baseline QTcF duration) will be 
established by comparing the time-matched placebo-corrected change from baseline in QTcF in 
the moxifloxacin at the following 4 timepoints, i.e., 1, 2, 3, and 4 hours post-dose. The model as 
described in the primary analyses will be used. If the lower bound of one-sided 95% CI for 
treatment effect on ΔΔQTcF in at least one timepoint is >5 msec, it will be concluded that the 
assay is sensitive to small increases in baseline QTcF duration. Multiplicity adjustment will be 
done using the Bonferroni correction method. Since 4 timepoints and overall two-sided alpha of 
0.1 are included in the analysis, two-sided alpha will be set to 0.1/4 = 0.025 in the model (Refer 
to DMID 16-0110_ECG_Figure shells: Figures 64 and 65). 
  
PROC MIXED; 
 
CLASS PERIOD SEQUENCE TIME SUBJ; 
 
MODEL ΔΔQTCF = PERIOD SEQUENCE TIME BASELINE_QTCF; 
 
RANDOM SUBJECT(SEQUENCE); 
 
REPEATED TIME / SUBJ=SUBJ(PERIOD) TYPE=CS; 
 
LSMEANS TIME / ALPHA=0.025; 
 RUN; 
In addition, using the above linear mixed effects model, least squares mean estimates of ΔΔQTcF 
and their one-sided 95% CIs for moxifloxacin will be obtained for the treatment effect at all 
post-dose timepoints without multiplicity correction and displayed graphically to demonstrate the 
time course of the moxifloxacin effect. 
Descriptive statistics (number of subjects, mean, SD, median, CV, minimum, maximum, SE and 
one-sided 95% CI) will be used to summarize the ECG parameters for each timepoint and for 
each treatment. For those visits with N ≤3, only median, maximum, and minimum values will be 
provided. These will be provided for absolute values and change from baseline values for all 4 
treatments. Time-matched, placebo-corrected, change from baseline values will be provided for 
the 2 g zoliflodacin, 4 g zoliflodacin, and moxifloxacin for QTcF, QTcB, HR (calculated from 
RR), RR, QT interval, PR interval, and QRS duration. 
Descriptive statistics will also be shown graphically with the x-axis showing the nominal time 
and the y-axis showing the mean change from baseline and its one-sided 95% CI for each of the 
ECG intervals parameters separately (i.e., QTcF, QTcB, HR, RR, QT, PR and QRS) for each of 
the treatment periods. 
5.4.1. 
Categorical analysis 
Categorical outlier analysis will supplement the central tendency analysis by determining if there 
were individual subjects who had an exaggerated effect on any ECG interval that were not 
revealed in a mean change from baseline central tendency analysis.  
ECG parameter values from individual post-dose replicate ECGs at each timepoint (not mean or 
median of all replicates) will be considered separately for categorical outlier analysis.  
Results of categorical outlier analysis will be presented as number and percentage of subjects in 
each treatment. Results will be tabulated by individual treatment. If a subject has more than one 
categorical outlier value for a parameter at a timepoint, then the subject will be counted only 


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once for that timepoint. Statistical tests for comparison between treatment arms will not be 
performed.   
For outlier analysis, the baseline value for each participant is defined as mean of 3 pre-dose 
assessments (9 ECGs) on Day 1 (i.e. D1PRE45MIN, D1PRE30MIN and D1PRE15MIN) of the 
corresponding treatment period.  
ECG parameters namely QT/QTc will be flagged as normal, abnormal insignificant or 
significant, based on the pre-approved study specific ECG abnormality criteria based on ICH 
E14 guidance.2 
The categorical outlier values for QTcF, QTcB, HR, PR, and QRS parameters (Refer to DMID 
16-0110_ECG_Table shells: Table 9; DMID 16-0110_ECG_Listing shells: Listings 8 to 13) for 
the individual subjects in each dose cohort will be summarized as follows: 
1. QTcF and QTcB will be categorized using the following study-specific criteria: 
 QTc >450 msec to 480 msec 
 QTc >480 msec to 500 msec 
 QTc >500 msec 
 QTc increase from baseline ≥30 msec to <60 msec  
 QTc increase from baseline ≥60 msec  
2. Uncorrected QT will be categorized for >500 msec. 
3. Categorical outliers for HR (calculated from RR) will be categorized based on the 
following criteria: 
 HR change-from-baseline >25% decrease resulting in HR <50 bpm 
 HR change-from-baseline >25% increase resulting in HR >100 bpm   
4.  Categorical outliers for PR and QRS parameters will be categorized for the following 
criteria: 
 PR change-from-baseline >25% resulting in PR >200 msec  
 QRS change-from-baseline >25% resulting in QRS >120 msec 
5.4.2. 
Analysis of ECG morphological abnormalities 
The ECG morphological abnormalities will be presented in terms of the number and percentage 
of subjects in each treatment with changes from baseline that represent the appearance or the 
worsening of the morphological abnormality. The ECG morphological abnormalities will be 
summarized by treatment using the number and percentage of subjects within each treatment 
based on incidence rates. The denominator for the percentage will be the number of evaluable 
subjects in each treatment.  


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Abnormalities present in any one or more of the baseline timepoint replicate ECGs recorded for 
a particular period will be considered to be present at baseline for post-dose ECGs from that 
specific period. 
If a subject has an ECG morphological abnormality in more than one replicate ECG of a study 
timepoint, the subject will be counted only once for that timepoint.  
Morphological abnormalities will be summarized by treatment and by timepoint using the 
number and percentage of subjects within each treatment. No statistical test of significance will 
be applied. Treatment emergent morphological ECG abnormalities and their significance will be 
discussed in detail in the report.  
T-wave morphology abnormalities will be presented separately in terms of the number and 
percentage of subjects in each treatment. The T-wave morphology abnormalities will be 
summarized by the T-wave morphology categories for abnormal T-waves such as flat T-waves, 
biphasic T-waves, and notched T-waves, as stated in section 8.3.1.2 of the protocol1 (Refer to 
DMID 16-0110_ECG_Table shells: Tables 10 and 11; DMID 16-0110_ECG_Listing shells: 
Listings 14 and 15).  
5.5. 
Pharmacokinetic-QTcF Analysis 
PK-QTcF analysis will be performed using individual PK and ΔΔQTcF data from all timepoints 
from all subjects regardless of dose of zoliflodacin, in the PK-ECG Analysis Population. Time-
matched plasma concentration of zoliflodacin and corresponding ΔΔQTcF data will be used to 
quantify the relationship between exposure and response (ΔΔQTcF). Moxifloxacin will not be 
included in this analysis. A linear or nonlinear mixed effects modeling approach will be used to 
quantify the relationship between plasma concentration of zoliflodacin and ΔΔQTcF (Refer to 
DMID 16-0110_ECG_Table shells: Tables 12 to 15; DMID 16-0110_ECG_Listing shells: 
Listings 16 and 17; DMID 16-0110_ECG_Figure shells: Figure 66 to 71). 
5.5.1. Hysteresis effect check 
To assess if there is a time dependency (a hysteresis effect) between zoliflodacin concentration 
and ΔΔQTcF visually, zoliflodacin concentration and ΔΔQTcF will be plotted vs. timepoint in a 
single plot and visually inspected for a difference between Tmax for concentration and Tmax for 
ΔΔQTcF. In addition, a scatter plot of mean ΔΔQTcF and mean plasma zoliflodacin 
concentration values from all subjects at each timepoint will be plotted using different colors and 
symbols for the 2 g and 4 g dose groups and the points connected in temporal sequence. If there 
is a unique value of ΔΔQTcF for each value of concentration, even as time evolves, the plot 
suggests no hysteresis. If plot shows that the value of ΔΔQTcF for a given value of concentration 
differs as time evolves, and the values of ΔΔQTcF observed before Tmax consistently differ from 
the values observed at a similar concentration at a timepoint after Tmax this would suggest 
presence of hysteresis (Refer to DMID 16-0110_ECG_Figure shells: Figures 66 and 67). If 
hysteresis is present, a PK model with an additional effect compartment will be used.4 In this 
case, the concentration in the effect compartment (Ce) will be calculated and used in the model 
instead of the original concentration. 


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5.5.2. Testing for linearity: 
A potential non-linear relationship between zoliflodacin concentration and ΔΔQTcF will be 
assessed visually and statistically (Refer to DMID 16-0110_ECG_Table shells: Table 12 and 13; 
DMID 16-0110_ECG_Figure shells: Figure 69). 
In the visual approach, a scatter plot of ΔΔQTcF versus zoliflodacin plasma concentration for all 
timepoints will be generated and the locally weighted scatterplot smoothing (LOESS) and its 
one-sided 95% CI will be plotted and inspected for nonlinearity.3 A PK-PD model with ΔΔQTcF 
as the dependent variable and zoliflodacin concentration and quadratic term of zoliflodacin 
concentration as independent variables will be performed using PROC MIXED with slope of 
concentration and quadratic term of concentration and intercept as subject-specific random 
effects.4  
If there is no clear indication of nonlinearity based on visual inspection of the ΔΔQTcF vs. 
concentration plot, or the quadratic term for concentration is non-significant at a two-sided alpha 
level of 0.05, a linear mixed effects modeling approach will be used.4 If there is an indication of 
a nonlinear relationship, a nonlinear mixed effect modeling approach will be examined. Akaike 
Information Criterion (AIC) of linear and different nonlinear mixed effect models including log-
linear and Emax will be calculated. The model with the least AIC will be considered as the final 
model for concentration-effect modelling.4 
5.5.3. Model selection: 
The selection of the PK-PD model for evaluating zoliflodacin concentration and ΔΔQTcF will 
follow the assessment of hysteresis and non-linearity.5 If there is no evidence of hysteresis and 
no indication of nonlinearity, linear mixed effects modeling approach will be used to quantify the 
relationship between zoliflodacin plasma concentration and ΔΔQTcF. 
The model will include ΔΔQTcF as the dependent variable, with zoliflodacin concentration as 
fixed effects and intercept and slope as subject-specific random effects. Unstructured covariance 
(UN) structures will be used and denominator degrees of freedom method (DDFM) will be set to 
Kenward-Roger.6 The subject-specific slope random effect will be dropped from the model or 
concentration values will be rescaled if the model fails to converge. 
Model-predicted parameter estimates (model-predicted estimates of slope {β2}, SE of β2, 
p-values (for slope {β2} and overall model fit), predicted ΔΔQTcF and its upper bound of the 
one-sided 95% confidence limit at geometric mean Cmax [separately for zoliflodacin 2 g PO and 
zoliflodacin 4 g PO]) will be calculated (Refer to DMID 16-0110_ECG_Table shells: Tables 14 
and 15; DMID 16-0110_ECG_Listing shells: Listings 16 and 17; DMID 16-0110_ECG_Figure 
shells: Figure 70). 
The model derived relationship between concentration of zoliflodacin and ΔΔQTcF will be 
validated by calculating the mean ΔΔQTcF and its one-sided 95% CIs for each decile of 
concentration values in the 2 g and 4 g zoliflodacin treatments.3 The mean ΔΔQTcF and its one-
sided 95% CIs for each decile of concentration values in the 2 g and 4 g zoliflodacin treatment 
will then be plotted at the corresponding median concentration value in each decile (Refer to 
DMID 16-0110_ECG_Figure shells: Figure 71). 


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5.6. 
Graphical Analysis  
The actual values, the change-from-baseline and time-matched, placebo-corrected, change from 
baseline in ECG parameters will also be presented in a graphical manner. For each treatment, 
mean value of actual values at each timepoint with one-sided 95% CIs as error bars will be 
plotted for each treatment for QTcF. For timepoints with less than 5 subjects ‘Range’ will be 
plotted instead of 95% CI. Similar plots will be prepared for QTcB, HR (calculated from RR), 
RR, QT, PR and QRS parameters for absolute values and the change-from-baseline QTcF, HR 
(calculated from RR), QT, PR and QRS (Refer to DMID 16-0110_Figure shells: Figure 1 to 56). 
For placebo-corrected, change from baseline in ECG parameters, least square means at each 
timepoint with one-sided 95% CIs as error bars will be plotted for each treatment. The graphs for 
ECG parameter values will be separated by treatment in the same plot (Refer to DMID 16-
0110_ECG_Figure shells: Figures 57 to 63). 
For the time course of moxifloxacin, one-sided 95% CIs (unadjusted and adjusted for 
multiplicity) will be obtained for the moxifloxacin effect on ΔΔQTcF at every timepoint using a 
linear mixed effects ANCOVA model and displayed graphically (Refer to DMID 16-
0110_ECG_Figure shells: Figures 64 and 65). 
Mean and 95% CI of ΔΔQTcF and concentration of zoliflodacin will be plotted in the 
zoliflodacin treatment period by timepoints (Refer to DMID 16-0110_ECG_Figure shells: 
Figures 66 and 67). 
A scatterplot of individual values of ΔΔQTcF versus plasma concentration of zoliflodacin from 
all subjects from all timepoints will be prepared and the LOESS curve will be plotted (Refer to 
DMID 16-0110_ECG_Figure shells: Figure 69). 
Individual ΔΔQTcF and plasma concentration of zoliflodacin for all subjects from all visits will 
be plotted and the model-based (including zoliflodacin plasma concentration as independent 
covariate) population mean prediction line for ΔΔQTcF and its one-sided 95% CI will be plotted 
(Refer to DMID 16-0110_ECG_Figure shells: Figure 70).  
The mean ΔΔQTcF and its one-sided 95% CIs for each decile of concentration values in the 2 g 
and 4 g zoliflodacin treatment periods will be plotted at the corresponding median concentration 
value in each decile (Refer to DMID 16-0110_ECG_Figure shells: Figure 71). 
 
6. References 
1. Clinical Trial Protocol DMID 016-0110 (version 1.0, Dated 18 Jun 2018)  
2. ICH Harmonized Tripartite Guideline E14 (2005). The clinical evaluation of QT/QTc 
interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs. 
Available at: 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidanc
es/ucm073153.pdf. Accessed on:18 September 2018 


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3. Tornøe CW, Garnett CE, Wang Y, Florian J, Li M, Gobburu JV. Creation of a knowledge 
management system for QT analyses. J Clin. Pharmacol. 2011;51:1035-42. 
4. Darpo B, Benson C, Dota C et al. Results from the IQ-CSRC prospective study support 
replacement of the thorough QT study by QT assessment in the early clinical phase. Clin 
Pharmacol Ther. 2015;97:326-35.  
5. Garnett C, Bonate PL, Dang Q, et al. Scientific white paper on concentration-QTc 
modeling. J Pharmacokinet Pharmacodyn. 2018; 45:383-397. 
6. Garnett CE, Beasley N, Bhattaram VA, et al. Concentration-QT relationships play a key 
role in the evaluation of proarrhythmic risk during regulatory review. J. Clin. Pharmacol. 
2008;48;13.