Conditions: Gonorrhoea
Keywords: ETX0914 Plasma Pharmacokinetic Safety Tolerability Zoliflodacin
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 8
Healthy volunteers: yes

Brief summary:
The trial is to evaluate the pharmacokinetics and safety profiles of the single-dose of zoliflodacin in eight healthy male or female subjects ages 18 to 45 years inclusive. All subjects will be dosed in the morning of Day 1 in a staggered fashion with a minimum of several minutes apart. Each subject will receive a single 4g dose of zoliflodacin (2 x 2 g sachets of zoliflodacin) after at least an 8-h fast, which will continue for at least 4 h after dosing. Consumption of water will be permitted during the fasting period. Subjects will be monitored as inpatients in the Clinical Trial Unit (CTU) up to Day 4 and at the Final Visit (Day 8 ± 2). Study duration is approximately 4 weeks with subject participation duration up to 10 days (from dosing to final visit). The primary objective of this study is to evaluate the plasma PK of zoliflodacin after administration of a single 4-g oral dose under fasting conditions.

Detailed description:
The trial will be performed as an open-label, non-randomized, single-dose design in eight healthy male or female subjects ages 18 to 45 years inclusive to evaluate the pharmacokinetics and safety profiles of the zoliflodacin formulation. All subjects will be dosed in the morning of Day 1 in a staggered fashion with a minimum of several minutes apart. Each subject will receive a single 4g dose of zoliflodacin (2 x 2 g sachets of zoliflodacin) after at least an 8-h fast, which will continue for at least 4 h after dosing. Consumption of water will be permitted during the fasting period. Subjects will be monitored as inpatients in the Clinical Trial Unit (CTU) up to Day 4 and at the Final Visit (Day 8 ± 2). Study duration is approximately 4 weeks with subject participation duration up to 10 days (from dosing to final visit). The primary objective of this study is to evaluate the plasma PK of zoliflodacin after administration of a single 4-g oral dose under fasting conditions. The secondary objective is to evaluate the safety and tolerability of a single 4-g oral dose of zoliflodacin.

Arms:
arm 1: 4 g (2 sachets of 2 g) of zoliflodacin orally in the morning of Day 1 after 8 hours of fasting, n=8

Interventions: intervention 1: AZD0914
Intervention descriptions: intervention 1: Zoliflodacin (also known as AZD0914 and ETX0914), is a spiropyrimidinetrione antibacterial agent

Protocol document:
Prot_000.pdf: 
 
 
A Phase 1 Clinical Trial to Evaluate the Plasma Pharmacokinetics, Safety, 
and Tolerability of a Single Oral Dose of Zoliflodacin in Healthy Male and 
Female Subjects 
 
DMID Protocol Number: 16-0118 
 
 
DMID Funding Mechanism: Phase 1 Clinical Trial Unit 
 
 
Pharmaceutical Support Provided by: Entasis Therapeutics 
 
 
IND Sponsor: Division of Microbiology and Infectious Diseases, National 
Institute of Allergy and Infectious Diseases, National Institutes of Health 
 
 
Site Principal Investigator: Barbara Lomeli, MD 
 
 
DMID Clinical Project Manager: Meg Gordon, RN 
 
 
DMID Medical Officer: Rick Fairhurst, MD, PhD 
 
 
DMID Medical Monitor: Soju Chang, MD 
 
 
Version Number: 2.0 
 
 
25 January 2018 
 
 


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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5 
STUDY ENROLLMENT AND WITHDRAWAL 
Only subjects who meet all inclusion criteria and none of the exclusion criteria will be eligible 
for enrollment into the trial. No exemptions are granted on Inclusion/Exclusion Criteria in DMID 
sponsored trials. 
Eight healthy male and female subjects, aged 18 to 45 years inclusive, will be enrolled in a single 
cohort. Up to two alternates will be recruited. 
5.1 
Subject Inclusion Criteria 
All must be answered YES for the subject to be eligible for study participation: 
1) Informed consent form (ICF) understood and signed before initiating any study 
procedures 
2) Healthy male or female, as assessed by the authorized site clinician (listed on FDA Form 
1572)  
3) Willingness to comply with and be available for all protocol procedures including 
inpatient confinement for about 4 days and availability for follow-up for the duration of 
the trial 
4) Aged 18 to 45 years inclusive on the day of study drug dosing 
5) Body Mass Index (BMI) ≥18.5 and ≤30 kg/m2 and weight ≥50 kg (110 lbs.) and 
≤100 kg (220 lbs.) 
6) In female subjects of childbearing potential, a negative serum pregnancy test at Screening 
Visit and on Day -1 
• Note: A woman is considered of childbearing potential unless post-menopausal (≥ 1 
year without menses without other known or suspected cause and with a FSH level in 
the menopausal range), or surgically sterilized (hysterectomy, salpingectomy, 
oophorectomy or tubal ligation/occlusion) 
7) If female, not pregnant, not breast feeding, and not planning on becoming pregnant 
during the trial and for 30 days after study participation 
8) Females of childbearing potential and males agree to use acceptable contraception for the 
duration of the trial and for 30 days (females) or 90 days (males) after final study visit 
• Note: A highly effective method of birth control is defined as one with a low failure 
rate (i.e., less than 1 percent per year) according to the CDC criteria.15 These include 
progestin implants, intrauterine devices (IUDs), surgical (hysterectomy, 
salpingectomy, oophorectomy or tubal ligation/occlusion; vasectomy), or abstinence. 


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Use of methods with higher failure rate (such as progestin injectables, combined oral 
hormonal contraceptives, condoms, and diaphragms) will not be acceptable when 
used alone, but they could be considered if used in combination with another method 
(e.g., a female using combined oral contraceptives if her male partner is sterile, or if 
she and her non-sterile male partner use a double-barrier method), after consultation 
with the DMID Medical Officer. 
9) Male subjects must agree to refrain from sperm donation for the duration of the trial and 
for 90 days after Final Visit 
10) Laboratory tests, as outlined in Section 8.2.1.1, are in the normal reference range with 
acceptable exceptions as noted in Section 8.2.1.1 and Appendix B  
11) VS, as outlined in Section 8.1.6, are within the acceptable range per Appendix B 
12) Has adequate venous access for blood collection  
13) Urine drug screen is negative for tested substances (see Section 8.2.1.5) 
14) Alcohol test (breathalyzer) is negative 
15) Willing to abstain from alcohol consumption for 2 days before Day -1 and during the trial 
5.2 
Subject Exclusion Criteria 
All must be answered NO for the subject to be eligible for study participation: 
1) History of a chronic medical or surgical condition that would interfere with the accurate 
assessment of the trial’s objectives or increase the subject’s risk profile 
• Note: Chronic medical conditions include: diabetes mellitus; asthma requiring use of 
medication in the year before screening; autoimmune disorder such as lupus 
erythematosus, Wegener’s, rheumatoid arthritis, thyroid disease; cardiovascular 
disease, including coronary artery disease or cerebrovascular disease, or surgery; 
syncope related to cardiac arrhythmia or unexplained; chronic hypertension; 
malignancy except low-grade (squamous and basal cell) skin cancer thought to be 
cured; chronic renal, hepatic, pulmonary, or endocrine disease, myopathy, or 
neuropathy; gastrointestinal or biliary surgery. 
2) History of hypersensitivity or severe allergic reaction of any type to medications, bee 
stings, food, or environmental factors 
• Note: Severe allergic reaction is defined as any of the following: anaphylaxis, 
urticaria, or angioedema 
 
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4) A marked baseline prolongation of ECG intervals, or HR <45 bpm or >100 bpm on ECG 
measurements 
• Note: The following are considered prolonged ECG intervals: QTc/QTcF >449 msec 
in males and females; PR >209 msec; and QRS >110 msec 
5) Clinically significant abnormal ECG results 
Note: Clinically significant abnormal ECG results include: complete left or right 
bundle branch block; other ventricular conduction block; 2nd degree or 3rd degree 
atrioventricular (AV) block; sustained atrial or ventricular arrhythmia; two premature 
ventricular contractions in a row; pattern of ST elevation felt consistent with cardiac 
ischemia; evidence of a previous myocardial infarction (MI), left ventricular 
hypertrophy (LVH), or more than minor non-specific ST-T wave changes; or any 
condition deemed clinically significant by a study investigator. 
6) Abnormal renal function  
Note: Normal renal function is defined as normal creatinine [per criteria in Appendix B] 
and normal estimated glomerular filtration rate (eGFR) [i.e., >80.0 mL/min] values 
according to Cockroft-Gault. 
7) Positive serology results for HIV, HBsAg, or HCV 
8) Febrile illness with temperature >37.6°C for <7 days before dosing 
9) Donated whole blood or blood products within 60 days before dosing, or plans to donate 
before Final Visit (Day 8 ± 2) 
•  Note: Blood products include RBCs, WBCs, platelets, and plasma 
10) Known allergic reactions to any of the study drug components present in the formulation 
or in its processing, as listed in the IB 
11) Treatment with another investigational product within 30 days of dosing or 5 half-lives or 
twice the duration of the biological effect of the study drug (whichever is longer)  
• Note: Investigational products include a drug, vaccine, biologic, device or blood 
product 
12) Active drug or alcohol use, abuse, or dependence within 12 months before Screening 
Visit that, in the opinion of the investigator, would interfere with adherence to study 
requirements 
13) Use of any prescription medication within 30 days before dosing or planned use during 
the study period except as noted below and approved by the designated study clinician 
• Note 1: Prohibited medications include moderate or strong CYP3A4 inducers (per 
Section 6.9); antibiotics; injectable or oral antidiabetic drugs; anti-lipid drugs; 


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immunosuppressive agents; immune modulators; oral corticosteroids; anti-neoplastic 
agents; any vaccine (licensed or investigational) except licensed influenza vaccine 
during the flu season, which is allowed 7 days before or after dosing. 
• Note 2: Allowed medications include: oral contraceptives; H1 antihistamines; 
topical/ intranasal corticosteroids; nonsteroidal anti-inflammatory drugs [NSAIDS]; 
licensed influenza vaccine during the flu season, 7 days before or after dosing. 
14) Use of any non-prescription medication, herbal preparation, or nutritional supplement 
within 15 days before dosing or planned use during the study unless approved by the 
study clinician 
• Note: Exceptions: St. John’s wart is not allowed within 30 days of dosing, vitamins 
and OTC medications taken for a brief period (<48 h) for the treatment of common 
symptoms (such as headache, indigestion, muscle pain) may be allowed as approved 
by the designated study clinician. 
 
15) Intake of caffeinated beverages or food within 72 h before dosing or a history of high 
caffeine consumption (e.g., in the last 4 months drinking >5 cups of coffee/day) 
16) Smoking or use of tobacco or nicotine-containing products within 15 days before dosing 
17) Engagement in strenuous exercise within 15 days before dosing (e.g., marathon running, 
long distance cycling, weight lifting) and during the study period 
18) Any specific behavioral or clinical condition that in the judgment of the investigator 
precludes participation because it could affect compliance with study procedures or 
subject safety 
19) Plans to enroll or is already enrolled in another clinical trial that could interfere with 
safety assessment of the study drug at any time during the study period 
• Note: Includes trials that have a study intervention such as a drug, biologic, or 
device. 
20) Is a study site employee or staff member who is paid entirely or partially by the 
OCRR/NIAID contract for the DMID-funded trial 
• Note: Site employees or staff include the PIs, sub-investigators, or staff who are 
supervised by the PI or sub-investigators. 


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


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


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


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The clinical supplies storage area at the site must be monitored by the site staff for temperature 
consistency with the acceptable storage temperature range specified in this protocol or in the 
study drug label. Documentation of temperature monitoring should be maintained. Further 
details are described in the MOP. 
6.2 
Dosage, Preparation, and Administration of Study Intervention/ 
Investigational Product 
All subjects will receive a single 4-g PO dose (2 sachets of 2 g) of zoliflodacin in the morning of 
Day 1 in a staggered fashion several minutes apart. 
The study drug will be inspected for damage, contamination, discoloration, or particulate matter 
before use. Any study drug that fails inspection should be quarantined at 2-8°C (35.6-46.4°F) 
and labeled ‘Do Not Use’ until further notice. The Site PI or responsible person should 
immediately contact the DMID Product Support Team at 
DMIDProductSupportTeam@niaid.nih.gov and DMID Clinical Project Manager (CPM) for 
further instructions before administering any additional study drug. Based on the information 
collected, DMID and/or Entasis will determine whether the affected study drug can be used. If it 
cannot be used, the site will receive specific instructions on how to return it to DMID CMS or 
destroy it on site. 
A detailed procedure will be described in the MOP.  
Eligible subjects who provide informed consent, undergo screening procedures, and qualify, 
meeting all inclusion and none of the exclusion criteria for the trial, will receive a single 4-g dose 
(2 sachets of 2 g of zoliflodacin reconstituted on the same day and administered in a total of 
 
) orally after an overnight fast. The dose will be administered in a standardized 
cup as described in the MOP. After the 
 of zoliflodacin is administered, an additional 
 
will be added to the same cup and consumed by the subject to chase the initial 
dose. Dosing should be completed within 5 minutes after each study product suspension. After 
dosing, subjects will continue to fast for an additional 4 h while water is allowed ad lib. 
Refer to the protocol-specific MOP for detailed information on the preparation and administration 
of zoliflodacin. 
6.3 
Modification of Study Intervention/Investigational Product for a 
Subject 
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6.3.1  Overdose 
An overdose is defined as a dose greater than the high-dose level evaluated in the trial. All 
overdoses should be reported; if the overdose is associated with an AE, then the AE should also 
be reported. In the event of an overdose of zoliflodacin, the investigator should use clinical 
judgment in treating the overdose and contact the DMID Medical Monitor (MM). The 
investigator should refer to the relevant document(s) for detailed information regarding 
warnings, precautions, contraindications, AEs, and other significant data pertaining to 
zoliflodacin. Such documentation may include but not be limited to the IB. 
6.4 
Accountability Procedures for the Study Intervention/Investigational 
Product(s)  
The Site PI is responsible for the distribution and disposition of the study drug, and has ultimate 
responsibility for accountability. The Site PI may delegate this responsibility to the Site RP. If 
delegated, the Site RP will be responsible for maintaining complete records and documentation 
of the study drug’s receipt, accountability, dispensation, temperature monitoring, storage 
conditions, and final disposition. 
All study drugs, whether administered or not, must be documented on the appropriate study drug 
accountability record or dispensing log. Used and unused zoliflodacin sachets will be retained 
until monitored and released for disposition per DMID requirements.  
Upon completion of the trial and after the final monitoring visit, any remaining unused study 
drug will either be returned or destroyed appropriately at the clinical site as per sponsor 
requirements and instructions, or in accordance with disposition plans. 
6.5 
 Assessment of Subject Compliance with Study Intervention/ 
Investigational Product/Device  
Since each dose of zoliflodacin will be administered by site personnel, subject compliance is not 
anticipated to be an issue. Complete information regarding any partial or interrupted dosing will 
be documented. Subjects unable to ingest the full amount of the initial 
 of study drug 
suspension or who vomit within 24 h after dosing will be withdrawn from the study and replaced 
(See Section 5.3.3 and 5.3.4). Subjects who do not ingest the content of the second 
 study 
drug suspension will not be withdrawn from the study. 
6.6 
Prior and  Concomitant Medications/Treatments 
Medications include the following: prescription drugs, birth control hormonal preparations, non-
prescription medication, herbs, vitamins, nutritional supplements, and illicit and recreational 


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substances. Medications taken before or after dosing will be reported as Prior Medications or 
Concomitant Medications (ConMeds), respectively. 
Prior prescription medication information will be recorded at Screening Visit and, except for 
hormonal contraceptives, should not be taken for 30 days before dosing or during the study 
period.  
Zoliflodacin should not be co-administered in subjects using strong (i.e. avasimibe, 
carbamazepine, phenytoin, rifampin, and St. John's wort) or moderate (i.e. efavirenz, bosentan, 
etravirine, modafinil, and nafcillin) inducers of CYP3A4. These drugs should not be taken for 30 
days before dosing and during the study period. 
A vaccine should not be received within 30 days before dosing or before the end of the trial, 
except for licensed influenza vaccine during the flu season, which may be administered up to 7 
days before or after dosing.  
Non-prescription medications, herbs, vitamins, and nutritional supplements should not be taken 
within 15 days before dosing. OTC medications taken for a brief period (<48 h) for the treatment 
of common symptoms (such as headache, indigestion, muscle pain) may be allowed as approved 
by the designated study clinician. 
Allowed medications include: oral contraceptives; H1 antihistamines; topical/ intranasal 
corticosteroids; nonsteroidal anti-inflammatory drugs (NSAIDS); licensed influenza vaccine 
during the flu season, 7 days before or after dosing.  
Blood/blood products (RBCs, WBCs, platelets, and plasma) should not be donated within 60 
days of dosing or received before Final Visit. 
Following dosing, each new concomitant medication and changes to existing medications will be 
recorded. Subjects will be required not to utilize non-study medication during the trial except 
those deemed necessary by the Site PI or sub-investigator. 
Any drug (e.g., non-prescription medications, herbal supplements, vitamins, or prescription 
medications) or vaccine or blood/blood products used by the subject during the trial will be 
recorded in the subject’s source documents and on the appropriate electronic case report form 
(eCRF), and the PI or authorized study clinician (listed on FDA Form 1572) will note whether 
the use was medically indicated and immediately necessary. Any use of medications not 
authorized by the study PI or authorized clinician will be recorded as a deviation.  
 
6.7 
Subject Restrictions 
6.7.1 Physical Activity 
Subjects will be asked to refrain from rigorous physical activity 15 days before dosing and 
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6.7.2 Fluid and Food intake 
Subjects will be provided food and non-alcoholic beverages by the CTU during the inpatient 
period of the trial. Subjects will fast for at least 8 h before dosing and 4 h after dosing. For 
clinical laboratory blood draws, subjects will fast for at least 4 h. Otherwise, there will be no 
restrictions regarding food and fluid intake.  
6.7.3  Alcohol, Marijuana and Illicit Drugs 
Alcohol should not be used at least two days before administration of study drug and during the 
trial.  
Marijuana and illicit drugs are exclusionary if detected before dosing and prohibited during the 
trial. 
6.7.4 Other Restrictions 
Smoking or use of tobacco or nicotine-containing products is prohibited within 15 days before 
dosing and during the trial. Caffeinated beverages or foods containing caffeine are prohibited 
within 72 h before dosing and during the trial. 
 
 


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7 
STUDY SCHEDULE 
The Schedule of Study Procedures and Evaluations is included as Appendix A. 
7.1 
Recruitment 
The subject population will be recruited from the local to the site surrounding area utilizing the 
CTU subject database and IRB-approved advertisements and social media. IRB-approved, 
prescreen questionnaires will be used to determine if subjects meet study requirements before 
scheduling screening visits. 
7.2 
Screening Visit (Day -21 to Day -2) 
The following will be done within 21 days before study drug dosing: 
• Obtain informed consent 
• Assign a study ID number to subjects who consent to participate 
• Review inclusion/exclusion criteria to ensure the subject is eligible for enrollment 
• Record demographics including age, gender, race, and ethnicity 
• Obtain contact information 
• Obtain MH   
• Review history of prior medications, including all taken within 30 days 
• Perform complete PE (except genital, rectal, and breast exams) by licensed clinician 
listed on Form FDA 1572 
• Obtain height and weight, and calculate BMI (wt [kg] / ht [m2]) 
• Take VS (supine systolic and diastolic BP, HR, respiratory rate, and oral temperature) 
• Obtain blood and urine samples for clinical laboratory tests  
• Obtain blood samples for viral serology  
• Obtain serum for β-HCG pregnancy test from all women  
• Obtain serum for FSH level from only post-menopausal women  
• Obtain urine sample for toxicology  
• Perform breathalyzer test for alcohol use 
• Obtain a 12-lead ECG with 10-sec rhythm strip 
• Counsel on the avoidance of pregnancy for women of childbearing potential 
• Counsel both male and females on the use of contraception 
• Counsel on the avoidance of alcohol, marijuana, illicit drugs, and prohibited medications 
Subjects who meet the eligibility criteria will be contacted by site personnel and asked to return 
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Subjects who fail screening due to a medical condition or abnormal laboratory tests including 
pregnancy test and positive tests for hepatitis B, hepatitis C, and HIV will be informed of the 
findings and counseled to seek medical care for further evaluation and treatment. If subjects test 
positive for HIV, HBsAg, and/or HCV infection, they will be informed that test results may be 
reported to the local Health Authorities according to State or Local Law. 
7.3 
Enrollment/Baseline  
7.3.1 Admission Visit (Day -1, Unit Check-in) 
Subjects meeting all of the inclusion and none of the exclusion criteria at Screening Visit will 
check into the CTU on Day -1 and the following procedures will be performed: 
• Review inclusion/exclusion criteria to ensure the subject remains eligible for enrollment 
• Update MH 
• Update Prior Medications  
• Perform abbreviated PE (An abbreviated complete PE will be performed if the Screening 
PE was completed >7 days from dosing) 
• Obtain VS 
• Obtain weight 
• Obtain blood and urine samples for clinical laboratory tests (if screening samples were 
collected >7days from dosing) 
• For all women, a serum β-HCG pregnancy test will be done, and negative results 
confirmed before dosing 
• Obtain urine sample for toxicology  
• Perform breathalyzer test for alcohol use 
• Obtain 12-lead ECG with 10-sec rhythm strip 
 
Subjects who meet the eligibility criteria on Day -1 will be admitted to the CTU on the same day. 
The subject will fast at least 8 h before dosing, but will have access to water during that period. 
7.4 
Inpatient period (Days 1 to 4) 
7.4.1 Administration of Study Drug (Day 1) 
A subject will be enrolled in the trial and receive the study drug on Day 1 if he/she continues 
meeting the eligibility criteria by assessments performed before dosing 
 


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


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


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


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


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8.1.5 Physical Examination 
A complete PE – except genital, breast, and rectal exams – will be performed at Screening Visit  
and Final Visit (Day 8 ± 2), or ET, and will assess general appearance, HEENT, heart, lungs, 
abdomen, skin, musculoskeletal system, and lymph nodes, and include an abbreviated 
neurological exam. 
An abbreviated PE will be performed on Day -1 and Day 4. If a complete PE was performed ≤7 
days before dosing, then an abbreviated PE will not be performed on Day -1. An abbreviated PE 
differs from a complete PE in that the abdomen and neurological system are not evaluated.  
A symptom-directed PE will be performed before dosing on Day 1 and after dosing on Days 1, 2, 
and 3, to evaluate new symptoms or treatment-emergent AEs, respectively.  
Height and weight will be measured, and BMI calculated, at Screening Visit; only weight will be 
measured on Day -1 and at Final Visit (Day 8 ± 2). 
Refer to the protocol-specific MOP for further details. The findings of each examination will be 
recorded on the subject’s source documents and eCRF. Any new findings on examination or 
worsening of existing conditions after dosing are to be reported as AEs.  
8.1.6 Vital Signs 
VS including resting (measured after supine for at least 10 min) systolic and diastolic BP, HR, 
respiratory rate, and oral temperature will be measured at Screening Visit, on Day -1, before and 
after dosing on Day 1, on Days 2, 3, and 4, and at Final Visit, or ET. On Day 1, VS will be 
measured approximately 1 h before dosing, and 1 h (±10 min), 2 h (±10 min), and 4 h (±10 min) 
after dosing. On Days 2, 3, and 4, VS will be measured at 24 h (±2 h), 48 h (±2 h), and 72 h (±2 
h), respectively. Acceptable ranges are shown in Appendix B. 
VS that are considered aberrant due to an error in measurement may be repeated. During 
screening and after dosing, an abnormal VS measurement may be repeated twice more at rest, 
within 5 min of each other. If the second measurement is abnormal, it will be reported at the 
highest grade of the two measurements and the subject will be excluded (if at Screening Visit) or 
the event reported as an AE (if after dosing). If the second measurement is normal, a third 
measurement will be taken at least after 5 min at rest. If the third measurement is still normal, the 
subject is eligible (if at Screening Visit) or there is no AE (if after dosing); if it is abnormal, the 
subject will be excluded (if at Screening Visit) or an AE will be reported at the highest assessed 
grade (between first and third measurements) and graded for severity per Appendix C (if after 
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8.1.7 Electrocardiogram 
A 12-lead ECG and 10-sec rhythm strip will be obtained at Screening Visit and on Days -1, 1, 
and 4, or ET. On Day 1, a 12-lead ECG and 10-sec rhythm strip will be recorded within 1 h 
before dosing and 1 h (±10 min), 2 h (±10 min), and 4 h (±10 min) after dosing. The ECGs will 
be reviewed by the PI or a designated clinician (listed in FDA Form 1572). ECGs will be 
performed after the subject rests quietly in a supine position for at least 5 min. To be eligible for 
participation, the QT/QTcF interval must be normal, and there must be no clinically significant 
ECG abnormalities. If a question regarding ECG interpretation arises, the study investigators will 
have the ECG reviewed by a cardiologist. 
8.2 
Laboratory Evaluations 
Venipuncture schedule and blood volumes are shown in Appendix A and Appendix D. The 
blood volume for hematology and chemistry tests will be approximately 9 mL per sample 
(Appendix D). 
8.2.1 Clinical Laboratory Evaluations 
8.2.1.1 Screening and Safety Clinical Laboratory (Hematology, Chemistry, and 
Urinalysis) Tests 
Blood and urine samples for clinical laboratory tests will be collected at Screening Visit, and on 
Days -1 (if not collected ≤7 days of dosing) and 4, or ET. These tests will include: 
• Hematology (HEM): hemoglobin (Hgb), hematocrit (Hct), red blood cell (RBC) count, 
platelet count, and white blood cell (WBC) count with absolute differential count 
• Chemistry (CHEM): serum creatinine, with estimation of GFR, blood urea nitrogen 
(BUN), glucose (fasting at least 4 h), total bilirubin, direct bilirubin, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AP), 
total protein, albumin, sodium, chloride, potassium, bicarbonate (CO2), magnesium 
• Urinalysis (UA): Routine dipstick testing of clean-catch urine for blood, protein, and 
glucose; other coincidental tests will be recorded   
 Clinical laboratory tests at Screening Visit and Day -1 should be in the normal reference range 
with acceptable exceptions, as shown below and in Appendix B: 
Elevated bilirubin due to documented Gilbert’s syndrome that is Grade 1 is allowable, but Grade 
2 or higher is exclusionary. (To document a subject has Gilbert syndrome, a diagnosis from the 
medical record must be provided or the PI may make a ‘presumptive’ diagnosis of Gilbert 
syndrome in subjects with unconjugated hyperbilirubinemia on repeated testing (at least 2 
samples separated in time) who have otherwise normal serum ALT/AST and AP concentrations, 
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Elevated serum glucose, sodium, potassium, bicarbonate (CO2), total protein, and AP with a 
toxicity grade of 1 is allowable. 
Serum chloride and albumin above the upper limit of normal (ULN) is allowable. 
If UA by dipstick is not within acceptable ranges per Appendix B for blood, protein, or glucose, a 
complete UA with microscopic evaluation will be performed and the results will supersede those 
of the dipstick. Menstruating females failing inclusion criteria due to a positive urine dipstick or 
microscopic UA may be retested following cessation of menses. Do not exclude subjects with ≤6 
RBC/HPF. 
Laboratory values that are outside the range of eligibility but are thought to be due to an acute 
condition or due to collection or laboratory error may be repeated once.   
Laboratory values will be transferred in AdvantageEDCSM.  
Abnormal safety laboratory values after dosing will be graded per the Toxicity Table, Appendix 
C. Abnormal values within the acceptable range per Appendix B noted at screening or baseline 
will only be considered AEs if they deteriorate after study drug dosing. 
8.2.1.2 Viral Serology Testing 
Serological testing for HIV antibody, HCV antibody, and HBsAg will be performed at Screening 
Visit. These tests must be negative for study eligibility. In cases where a false-positive result is 
suspected, confirmatory testing (e.g., Polymerase Chain Reaction) may be performed. 
8.2.1.3 Pregnancy Testing 
In all women, a serum β-HCG level will be measured at Screening Visit and on Day -1; results 
must be negative for entry into the trial. Serum pregnancy test will also be performed at Final 
Visit, or ET. 
8.2.1.4 Serum FSH testing 
A serum FSH level for confirmation of post-menopausal status in female subjects will be 
measured at Screening Visit only.   
8.2.1.5 Urine Toxicology Screening 
A urine toxicology screen will be performed at Screening Visit and on Day -1 to detect the 
presence of amphetamines, cocaine, barbiturates, benzodiazepines, opiates, 
tetrahydrocannabinol, MDMA, methadone, TCA, oxycodone, and phencyclidine. Results must 
be negative for study eligibility. Urine creatinine will be measured as part of the profile to assess 
quality of collected sample.  


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


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


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


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


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


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


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


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11 
STATISTICAL CONSIDERATIONS 
11.1 Study Hypotheses 
There are no formal hypotheses being tested in this Phase 1 trial. The objectives of the trial are to 
obtain additional PK and safety data for a single 4-g oral dose of zoliflodacin. 
11.1.1 Study Objectives and Outcome Measures 
11.1.1.1 Study Objectives 
Primary Objective:  To evaluate the plasma PK of a single 4-g oral dose of zoliflodacin 
under fasting conditions  
Secondary Objective:  To evaluate the safety and tolerability of a single 4-g oral dose of 
zoliflodacin 
11.1.1.2 Study Outcome Measures 
Primary Endpoints:  Cmax, Tmax, AUC(0-last), and other PK parameters determined using 
plasma concentrations of zoliflodacin in blood samples collected on Day 1 [baseline (30 
min before dosing) and 0.5 h, 1 h , 2 h , 3 h , 4 h , 6 h , 8 h , and 12 h  after dosing], Day 2 
[24 h and 36 h after dosing], Day 3 [48 h after dosing], and Day 4 [72 h after dosing], or 
ET, and measured using a validated HPLC-MS/MS method 
Secondary Endpoints: 
• The occurrence of treatment-emergent SAEs from administration of zoliflodacin on 
Day 1 to Final Visit (Day 8 ± 2), or ET 
• The occurrence of unsolicited AEs from administration of zoliflodacin on Day 1 to 
Final Visit (Day 8 ± 2), or ET 
• The changes from baseline (up to 60 min before dosing) in VS following 
administration of zoliflodacin as measured on Day 1 [1 h, 2 h, and 4 h after dosing], 
Days 2, 3 and 4 [24 h, 48 h, and 72 h, respectively, after dosing], and Final Visit (Day 
8 ± 2) , or ET 
• The changes from baseline (tested on Day-1) in clinical laboratory test values 
following administration of zoliflodacin, as measured on Day 4 [72 h after dosing], or 
ET 
• The changes from baseline (up to 60 min before dosing) in ECG parameters 
following administration of zoliflodacin, as measured on Day 1 [1 h, 2 h, and 4 h after 
dosing] and Day 4 [72 h after dosing], or ET 


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11.2 Sample Size Considerations 
Since this is a pilot Phase 1, open-label trial with a single 4-g dose cohort of zoliflodacin, no 
formal sample size calculations based on testing a statistical hypothesis were constructed. Eight 
subjects will be enrolled and it is planned to have seven evaluable subjects given zoliflodacin. 
This sample size will provide sufficient information to estimate exposure to the 4-g dose of 
zoliflodacin and to assess its safety. 
11.3 Safety Review 
An SMC will be appointed to oversee the safe conduct of the trial. A scheduled SMC meeting 
will be held after all subjects complete the trial to review safety data, and advice on using the 4-g 
dose in a subsequent thorough QTc study. If criteria for halting the trial (as listed in Section 
9.5.1) are met during dosing on Day 1, an ad hoc SMC meeting will be held to review all 
available safety data and to make recommendations about the dosing of all further subjects in the 
trial. 
11.4 Final Analysis Plan 
The ICH/ FDA Guidance Document E9 (Statistical Principles for Clinical Trials) will be 
followed for all statistical content.16 For categorical data, summaries of frequencies and 
percentages will be presented. Summaries for continuous data will include minimum, median, 
mean, standard deviation, and maximum. Details of study analyses for safety and PK data and 
their presentation will be described in the Statistical Analysis Plan (SAP) and accompanying 
Tables, Listings and Figures (TLF) templates. The SAP will be prepared and finalized by the 
DCC prior to final data lock. Analyses included in the CSR will be performed by the DCC after 
final data lock. Any change from originally planned statistical analyses will be reported in the 
final clinical study report (CSR).   
11.4.1 Analysis Populations 
All subjects who received the study drug will be included in the safety population and analyzed 
as treated. The PK analysis population will consist of all subjects who received zoliflodacin and 
have at least one quantifiable post-dosing drug concentration measured. The PK analysis subset 
will be based on the PK population, which includes all subjects who completed the PK part of 
the trial without any protocol violations that would likely affect the PK results and who have 
evaluable plasma concentration data for zoliflodacin from whom at least a subset of the 
designated PK parameters can be determined.  


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


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


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12 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
The site will maintain appropriate medical and/or research records for the trial, in compliance 
with ICH E6 GCP, Section 4.9, and regulatory and institutional requirements for the protection 
of confidentiality of subjects. As part of participating in a DMID-sponsored, DMID-affiliated, or 
manufacturer-sponsored trial, the site will permit authorized representatives of the sponsor 
(DMID), to include Emmes (the DCC), DynPort Vaccine Company, LLC (DVC), and regulatory 
agencies to review (and, when required by applicable law, to copy) clinical records for the 
purposes of quality assurance reviews, audits, and evaluation of the study safety and progress. 
Forms for use as source documents will be derived from eCRFs and will be provided by the 
DCC and the Site. Additional source data are all information, original records of clinical 
findings, observations, or other activities in a clinical trial necessary for the reconstruction and 
evaluation of the trial. Examples of these original documents and data records include, but are 
not limited to, hospital records, clinical and office charts, laboratory notes, memoranda, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic negatives, 
microfilm or magnetic media, x-rays, ECG print-outs, and subject files and records kept at the 
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13 
QUALITY CONTROL AND QUALITY ASSURANCE 
Following a written DMID-accepted site quality management plan, the CTU is responsible for 
conducting routine quality assurance and quality control activities to internally monitor study 
progress and protocol compliance. The PI will provide direct access to the CTU, source 
data/documents, and reports for monitoring and auditing by the sponsor, and inspection by local 
and regulatory authorities. The PI will ensure all study personnel are appropriately trained and 
applicable documentations are maintained on site.  
The DCC will implement quality control procedures beginning with the data entry system and 
generate data quality control checks that will be run on the database. Any missing data or data 
anomalies will be communicated to the site(s) for clarification and resolution. 


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


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


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


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


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


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


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


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


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


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18 
APPENDICES


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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89 
 
APPENDIX D: BLOOD VOLUME WITHDRAWN DURING THE TRIAL 
Laboratory Samples and Estimated Total Blood Volume (mL)  
 
Study visit 
SCREENING 
CHECK-
IN 
INPATIENT PERIOD 
FINAL 
Total volume 
Early term visit 
Study Day 
-21 to -2 
-1 
1 
2 
3 
4 
 
8 (±2) 
 
HEMATOLOGY 1 
4 
4 
 
 
 
4 
 
12 
4 
CHEMISTRY and serum β-
HCG, FSH, HIV, HBsAg, 
HCV 1 
5 
5 
 
 
 
5 
 
15 
5 
PK 2 
 
 
54 
12 
6 
6 
 
78 
6 
Total volume/visit 
9 
9 
54 
12 
6 
15 
0 
- 
15 
Cumulative total volume 
9 
18 
72 
84 
90 
105 
105 
105 
 
 
1 Clinical blood tests are drawn at Screening Visit, on Day-1, and on Day 4, or ET. 
2 PK serum samples are drawn on Day 1: 30 min before dosing and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 h after dosing, or ET. 
 

SAP_001.pdf: 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
CLINICAL RESEARCH IN INFECTIOUS DISEASES 
 
 
 
Clinical Pharmacokinetic Noncompartmental 
Data Analysis Plan 
 
 
For 
 
DMID Protocol: 16-0118 
Study Title: A Phase 1 Clinical Trial to Evaluate the Plasma 
Pharmacokinetics, Safety, and Tolerability of a Single Oral Dose of 
Zoliflodacin in Healthy Male and Female Subjects 
 
 
 
Version 1.0 
 
DATE: 03 April 2018 
 
 
 
 
 
 
Prepared and Distributed by: 
The Emmes Corporation 
Rockville, Maryland USA 
 
 
 
THIS COMMUNICATION IS PRIVILEGED AND CONFIDENTIAL 
 
 
 


The Emmes Corporation 
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TABLE OF CONTENTS 
ACRONYMS AND ABBREVIATIONS ......................................................................................III 
1. 
PREFACE .....................................................................................................................1 
2. 
CLINICAL STUDY METHODS ..............................................................................2 
2.1. 
Analysis Groups ............................................................................................................2 
2.2. 
Dose Administration .....................................................................................................2 
2.3. 
PK Sampling Schedule .................................................................................................2 
2.4. 
Analytical Methods .......................................................................................................2 
2.5. 
Collection of Pharmacodynamic or Clinical Endpoints ...............................................2 
3. 
PHARMACOKINETIC ANALYSIS METHODS ..................................................3 
3.1. 
Analysis Population and Handling of Missing Time Points .........................................3 
3.2. 
Demographic and Baseline Characteristics ..................................................................3 
3.3. 
Dosing and Pharmacokinetic Sampling Summary .......................................................3 
3.4. 
Definition and Estimation of Individual NCA PK Parameters .....................................4 
3.5. 
Descriptive Statistics ....................................................................................................6 
3.6. 
Reporting Conventions .................................................................................................6 
4. 
REFERENCES .............................................................................................................7 
5. 
LISTING OF PROPOSED TABLES, FIGURES, AND LISTINGS ...........................8 
6. 
APPENDICES ..............................................................................................................9 
APPENDIX 1. LIST OF PROPOSED PK TABLES ..................................................................10 
APPENDIX 2. LIST OF PROPOSED PK FIGURES ................................................................14 
APPENDIX 3. LIST OF PROPOSED PK LISTINGS ...............................................................19 
 
 
 


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ACRONYMS AND ABBREVIATIONS 
Standard acronyms and abbreviations are listed below. 
Abbreviation 
Definition 
AUC 
Area Under the Concentration-Time Curve 
AUC(0-last) 
AUC to the Last Measurable Concentration 
AUC(0-t) 
AUC from 0 to time t 
AUC(0-∞) 
AUC Extrapolated to Infinity 
BMI 
Body Mass Index 
BQL 
Below the Quantification Limit 
Clast 
Last Measurable Concentration (above the quantification limit) 
CL/F 
Apparent Oral Clearance 
cm 
Centimeter(s) 
Cmax 
Maximum Plasma Concentration 
CSR 
Clinical Study Report 
CV 
Coefficient of Variation 
EDC 
Electronic Data Capture 
g 
Gram(s) 
GM 
Geometric Mean 
GSD 
Geometric Standard Deviation 
h 
Hour(s) 
HPLC-
MS/MS 
High-Performance Liquid Chromatography with Tandem Mass 
Spectrometry 
Ke 
Terminal Phase Elimination Rate Constant 
kg 
Kilogram(s) 
L 
Liter(s) 
LLOQ 
Lower Limit of Quantification 
Max 
Maximum 
Min 
Minimum 
min 
Minute(s) 
mL 
Milliliter(s) 
NCA 
Noncompartmental Analysis 
ng 
Nanogram(s) 
PK 
Pharmacokinetic(s) 
SD 
Standard Deviation 
t1/2 
Apparent Terminal Elimination Half-Life 
Tlast 
Time of Last Measurable Concentration 
Tmax 
Time to Maximum Plasma Concentration (Cmax) 
Vz/F 
Apparent Volume of Distribution During Terminal Phase  


The Emmes Corporation 
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1. 
PREFACE 
DMID protocol 16-0118 is a Phase 1 study of zoliflodacin in healthy male and female subjects. The 
pharmacokinetics (PK)-related objectives of the study are: 
• To evaluate the plasma PK of zoliflodacin after administration of a single 4 g oral dose under fasting 
conditions 
This document reiterates key PK elements in the study design of DMID Protocol 16-0118 and thoroughly 
describes the presentations and summaries of PK data as well as the noncompartmental analysis (NCA) to be 
included in the PK Report and summarized in the clinical study report (CSR) for this protocol. Shells and 
mockups are given for all PK-related tables, figures, and listings planned for inclusion in the CSR and/or PK 
Report. At minimum, mean PK plots as well as listings and summaries of zoliflodacin concentrations and PK 
parameters will be included in the CSR, while all tables, figures, and listings described in this document will 
be included in the PK Report. 
 
 


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2. 
CLINICAL STUDY METHODS 
2.1. 
Analysis Groups  
This is a Phase 1, open-label clinical trial of a single 4 g oral dose of zoliflodacin after an overnight fast. 
Eight healthy subjects who consent to participate in the trial and meet the eligibility criteria will be enrolled 
into a single cohort. Stratification will not be used in this study.  All subjects will be analyzed in a single 
analysis group and no comparisons will be performed. 
2.2. 
Dose Administration 
Eligible subjects will receive a single 4 g dose (2 sachets of 2 g of zoliflodacin reconstituted on the same day 
and administered in a total of 
) orally after an overnight fast. The dose will be administered 
in a standardized cup. After the 
 of zoliflodacin is administered, an additional 
 will 
be added to the same cup and consumed by the subject to chase the initial dose. Both doses will be completed 
within a total of 5 min. After dosing, subjects will continue to fast for an additional 4 h while water is allowed 
ad lib. 
2.3. 
PK Sampling Schedule  
Blood (plasma) samples will be collected into K2EDTA tubes at the following time points: On Day 1 at 30 
min before dosing, and 0.5 h (±5 min), 1 h (±5 min), 2 h (±5 min), 3 h (±10 min), 4 h (±10 min), 6 h (±10 
min), 8 h (±15 min), and 12 h (±15 min) after dosing; on Day 2 at 24 h (± 2 h) and 36 h (± 2 h) after dosing; 
on Day 3 at 48 h (±2 h) after dosing; and on Day 4 at 72 h (±2 h) after dosing, or early termination.  
2.4. 
Analytical Methods 
Plasma concentrations of zoliflodacin will be determined using a validated HPLC-MS/MS method. The 
analysis will be performed by KCAS Bioanalytical Services. Details are included in the assay validation. For 
details of sample collection, processing, storage, transportation, and bioanalysis, see the protocol, MOP, and 
assay validation documents. 
2.5. 
Collection of Pharmacodynamic or Clinical Endpoints 
Not applicable. 


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3. 
PHARMACOKINETIC ANALYSIS METHODS 
3.1. 
Analysis Population and Handling of Missing Time Points 
All subjects who received the study drug and who have at least one measurable drug concentration post-
dosing will be included in the PK analysis population. Additionally, there will be a PK analysis subset, which 
includes all subjects who completed the PK part of the trial without any protocol violations or deviations that 
would likely affect the PK results and who have evaluable plasma concentration data for zoliflodacin from 
which at least the Cmax and Tmax can be determined (peak concentration and at least one decreased 
concentration after the peak observed). Zoliflodacin concentrations will be listed and shown graphically as 
individual profiles for all subjects in the PK analysis population, but concentration summary statistics, mean 
PK profiles, and NCA will use the PK analysis subset only. All enrolled subjects excluded from the PK 
analysis population or the PK analysis subset will be described in the PK Report, including reason for 
exclusion. 
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.  If a sample is collected more than 10 min outside of the protocol 
defined time window, the sample result will be excluded from calculation of summary statistics for the 
respective time point, as well as from plots of mean concentration. 
Values below the lower limit of quantification (LLOQ) will be referred to as below the quantification limit 
(BQL). BQL values that precede the first PK concentration above the LLOQ will be imputed as 0 for linear 
plots and for all calculations including NCA and summary statistics, but will be excluded from semi-
logarithmic plots. All other BQL values will be treated as missing for all analyses. 
Missing pre-dose PK samples will have concentrations imputed as 0 for analysis. All other missing PK 
sample concentrations will not be imputed for the NCA. A geometric mean (GM) of concentrations will be 
treated as missing for sets of data points containing an imputed 0 value due to a BQL value. 
3.2. 
Demographic and Baseline Characteristics 
Sex, race, age, weight, height, and body mass index (BMI) of subjects in the PK analysis population will be 
listed and summarized (PK Table 1, PK Listing 1). 
3.3. 
Dosing and Pharmacokinetic Sampling Summary 
Subject dose administration times will be presented (PK Listing 2). Cases that potentially affect the analysis 
will be discussed. 
Protocol deviations related to dosing or PK sampling will be listed (PK Listing 3) and summarized in the PK 
Report text. Deviations to be included in the PK Report include: 
• Treatment administration deviations 
• Blood specimen not collected 
• Plasma specimen result not obtained 
• Specimen temperature excursion 
• Required specimen collected out of window 
• Subject vomiting within 24 h of dose 


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• Subject ingestion of prohibited food or within the prohibited window after dosing 
• Any other deviation determined by the PK analyst to be potentially affect PK  
Drug plasma concentrations will be listed by subject (PK Listing 4), with nominal and actual time associated 
with the sample indicated (nominal time is defined as the time in h since the start time of the dose). Both 
laboratory reported concentration values, and modified concentration values used for analysis (for instance, 
imputation of 0 for a BQL value at baseline) will be included, as separate columns, in the listing. 
Plasma drug concentrations will also be summarized (PK Table 2) and plotted. PK Figure 1 and PK Figure 2 
will plot all individual subject plasma PK profiles, as linear and semi-logarithmic plots, respectively. Subject 
ID for each individual profile in these figures will be shown in a legend. GM plots of zoliflodacin PK profiles 
will be shown in PK Figure 3. Semi-log mean plots of zoliflodacin PK profiles will be shown in PK Figure 4. 
3.4. 
Definition and Estimation of Individual NCA PK Parameters 
PK parameters will be estimated through a NCA using version 8.0 or later of Phoenix® WinNonlin® 
(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 (PK Listing 5). 
Phoenix® WinNonlin® NCA will use the following settings to compute parameters from plasma PK data: 
• Linear Up Log Down calculation method 
• Uniform weighting 
• Extravascular dose 
• Plasma Model Type 
• Lambda Z Acceptance Criteria 
o Rsq_adjusted ≥ 0.80 
o Span ≥ 3.0 half-lives 
o Includes ≥ 3 timepoints after Tmax 
▪ In exceptional circumstances, the data at Te may be included in computation of Ke if deemed 
necessary and appropriate by the PK analyst. If data at Tmax is included in computation of Ke, 
the decision will be justified in the PK Report. 
Cmax 
Maximum plasma concentration (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. 
Clast 


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Last observed (quantifiable) plasma concentration (Clast), in units of ng/mL.  Clast will not be included in tables 
or listings, but is referred to in the definitions of other PK parameters.  
Tlast 
Time of Clast (Tlast) will be obtained from the Tlast parameter calculated by WinNonlin®. If there is no 
measurable concentration in the subject’s PK profile, then Tlast will be missing for that subject. Tlast 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.  
The set of points chosen must contain only timepoints after Tmax and satisfy the Lambda Z Acceptance 
Criteria described above. Otherwise, the elimination rate constant and all derived parameters (t1/2, AUC(0-∞), 
CL/F, 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.  Drug 
concentrations used to calculate Ke will be indicated in Listing 4.  This parameter will be obtained from the 
Lambda_z parameter calculated by WinNonlin®. Ke will be reported in units of 1/h. 
t½ 
The apparent terminal elimination half-life (t½) is defined as the time required for the drug concentration to 
decrease by a factor of one-half in the terminal phase. t½ can be estimated as ln(2) / Ke. It will be obtained 
from the HL_Lambda_z parameter calculated by WinNonlin®. t1/2 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 PK Report.  Specific 
times (t) AUC(0-t) will be estimated using the Linear Up Log Down calculation method. 
AUC(0-∞) 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-∞) 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−∞) = AUC(0−last) + Clast
Ke
. 
AUC(0-inf) will be obtained from the AUCINF_obs parameter calculated by WinNonlin®. If the amount 
extrapolated portion of AUC(0-∞) is >20%, the estimated AUC(0-∞) value will be flagged when listed in the 
report and will be excluded from statistical summaries of parameter estimates and downstream calculations.  


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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-∞). It will be obtained from the Cl_F_obs 
parameter calculated by WinNonlin®. If the amount extrapolated portion of AUC(0-∞) is >20%, the estimated 
CL/F value will be flagged when listed in the report and will be excluded from statistical summaries of 
parameter estimates and downstream calculations. 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®. If the amount 
extrapolated portion of AUC(0-∞) is >20%, the estimated Vz/F value will be flagged when listed in the report 
and will be excluded from statistical summaries of parameter estimates and downstream calculations. Volume 
will be reported in units of L. 
3.5. 
Descriptive Statistics 
Subject-specific PK parameter estimates will be listed (Listing 5). PK estimates will be summarized in PK 
Table 3. Summary statistics will include mean, standard deviation (SD), minimum, maximum, median, 
coefficient of variation as a percent (CV%), GM, and geometric standard deviation (GSD).  
3.6. 
Reporting Conventions 
P-values ≥0.001 and ≤0.999 will be reported to 3 decimal places; p-values <0.001 will be reported as 
“<0.001” The mean, SD, and other statistics will be reported to 1 significant figure greater than the original 
data. The minimum and maximum will use the same number of significant figures as the original data. 
Percentages will be reported to the nearest whole number; values >0 but <1% will be presented as “<1”; 
values >99% but <100% will be reported as >99%. AUCs will be reported as whole numbers.  t1/2, Tmax, CL, 
and Vz/F values will be reported to 1 decimal place. Ke will be reported to 3 decimal places. Cmax will be 
reported with the same number of significant digits as the measurement. Ratios, location shifts (defined as a 
difference in mean or median), and associated 95% confidence intervals will be reported to 1 decimal place. 
Listings of individual subject data include a Subject ID column. The subject identifiers assigned by site staff 
are replaced throughout this report with the 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 
Electronic Data Capture (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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4. 
REFERENCES 
1. European Medicines Agency. Guideline on the Investigation of Bioequivalence, January 2010. 
2. Food and Drug Administration. Guidance for Industry: Exposure-Response Relationships – Study 
Design, Data Analysis, and Regulatory Applications, April 2003. 
3. Food and Drug Administration. Guidance for Industry: Statistical Approaches to Establishing 
Bioequivalence, January 2001.  
4. Food and Drug Administration. Guidance for Industry: Bioavailability and Bioequivalence Studies for 
Orally Administered Drug Products – General Considerations, March 2003. 
5. Food and Drug Administration. Guidance for Industry: Pharmacokinetics in Subjects with Impaired 
Hepatic Function; Study Design, Data Analysis, and Impact on Dosing and Labeling, May 2003. 
6. Food and Drug Administration. Guidance for Industry: Pharmacokinetics in Subjects with Impaired 
Renal Function; Study Design, Data Analysis, and Impact on Dosing and Labeling, March 2010. 
7. Food and Drug Administration. Guidance for Industry: Bioanalytical Method Validation, May 2001. 
8. Food and Drug Administration. Guidance for Industry: Validation of Analytical Procedures and 
Methods Validation for Drugs and Biologics, July 2015. 
 
 
 


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5. 
LISTING OF PROPOSED TABLES, FIGURES, AND LISTINGS 
Proposed table, figure, and listing shells are presented in Appendices 1, 2, and 3. 


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6. 
APPENDICES 


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APPENDIX 1. 
LIST OF PROPOSED PK TABLES 
LIST OF PK TABLES 
PK Table 1: Summary of Demographic and Baseline Characteristics of Subjects 
Included in the PK Analysis Population .....................................................................11 
PK Table 2: Summary Statistics for Concentrations by Nominal Time .....................................12 
PK Table 3: Summary Statistics for PK Parameters ...................................................................13 


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PK Table 1: Summary of Demographic and Baseline Characteristics of Subjects Included in the PK 
Analysis Population 
Parameter 
PK Analysis Population  
(N=X) 
Sex – N (%) 
 
Male 
 
Female 
 
Age (years) 
 
Mean (SD) 
 
Median 
 
Min, Max 
 
Height (cm) 
 
Mean (SD) 
 
Median 
 
Min, Max 
 
Weight (kg) 
 
Mean (SD) 
 
Median 
 
Min, Max 
 
BMI (kg/m2) 
 
Mean (SD) 
 
Median 
 
Min, Max 
 
Race – N (%) 
 
American Indian or Alaska Native 
 
Asian 
 
Black or African American 
 
Native Hawaiian or other Pacific Islander 
 
White 
 
 


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PK Table 2: Summary Statistics for Concentrations by Nominal Time 
Subject ID 
Zoliflodacin Concentration (ng/mL) by Nominal Time1 After Dose (h) 
0 
0.5 
1 
2 
3 
4 
6 
8 
12 
24 
36 
48 
72 
99ZZZ001 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
99ZZZ002 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
99ZZZ003 
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 
Statistics 
 
 
 
 
 
 
 
 
 
 
 
 
 
N2 
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.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
SD 
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 
GM 
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 
(Min, Max) 
(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) 
1 Times are relative to time of dosing. 
2 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. 


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PK Table 3: Summary Statistics for PK Parameters 
Statistic 
Cmax 
(ng/mL) 
Tmax 
(h) 
Tlast 
(h) 
AUC(0-last)  
(h×ng/mL) 
AUC(0-∞) 
(h×ng/mL) 
Ke 
(1/h) 
t1/2 
(h) 
CL/F 
(L/h) 
Vz/F 
(L) 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
SD 
 
 
 
 
 
Min 
 
 
 
 
 
Median 
 
 
 
 
 
Max 
 
 
 
 
 
CV % 
 
 
 
 
 
GM 
 
 
 
 
 
GSD 
 
 
 
 
 
 
 
 
 


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APPENDIX 2. 
LIST OF PROPOSED PK FIGURES 
LIST OF PK FIGURES 
PK Figure 1: Concentration Profiles for All Subjects by Time ..................................................15 
PK Figure 2: Semi-log Concentration Profiles for All Subjects by Time ...................................16 
PK Figure 3: Mean Concentration by Nominal Time .................................................................17 
PK Figure 4: Mean Concentration by Nominal Time (Semi-Log) .............................................18 


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PK Figure 1: Concentration Profiles for All Subjects by Time 
 
 


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PK Figure 2: Semi-log Concentration Profiles for All Subjects by Time 
 
 


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PK Figure 3: Mean Concentration by Nominal Time 
 
Note: Error bars give ± 1 standard deviation. 
 


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PK Figure 4: Mean Concentration by Nominal Time (Semi-Log) 
 
 
 


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APPENDIX 3. 
LIST OF PROPOSED PK LISTINGS 
TABLE OF PK LISTINGS 
PK Listing 1: Subject Level Demographic and Baseline Characteristics ...................................20 
PK Listing 2: Zoliflodacin Dosing ..............................................................................................21 
PK Listing 3: Protocol Deviations Related to Dosing or PK Samples........................................22 
PK Listing 4: Subject Level Zoliflodacin Concentrations in Plasma..........................................23 
PK Listing 5: Subject-Specific Pharmacokinetic Parameters .....................................................24 


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PK Listing 1: Subject Level Demographic and Baseline Characteristics 
Subject ID  
Sex 
Race 
Age  
(years) 
Height  
(kg) 
Weight  
(cm) 
BMI 
(kg/m2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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PK Listing 2: Zoliflodacin Dosing 
Subject ID 
Dose (g) 
Start Date Dose 
Start Time of Dose 
End Time of Dose 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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PK Listing 3: Protocol Deviations Related to Dosing or PK Samples 
Subject 
ID 
DV 
Number 
Deviation 
Description 
Study 
Day 
Reason for 
Deviation 
Deviation 
Resulted 
in AE? 
Deviation 
Resulted in 
Subject 
Termination? 
Deviation 
Affected 
Product 
Stability? 
Specimen 
Type 
Affected 
Visit 
Number 
Deviation 
Category 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: This listing contains a subset of the protocol deviations in the clinical database relevant to the PK analysis 
 


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PK Listing 4: Subject Level Zoliflodacin Concentrations in Plasma 
Subject ID 
Nominal Time1 
(h) 
Actual Time1 
(h) 
Lab Reported Drug 
Concentration 
(ng/mL) 
Analysis Drug 
Concentration 
(ng/mL) 
Used in Ke 
Calculations 
Excluded 
from NCA 
Reason for 
Exclusion from 
NCA 
XXX.99999 
0 
0 
BQL 
0 
No 
No 
 
XXX.99999 
0.5 
0.5 
50.1 
50.1 
No 
No 
 
XXX.99999 
24 
24.0 
BQL 
missing 
No 
No 
 
1Times are relative to time of dose. For Actual Times, out-of-window times are indicated by an asterisk. 


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PK Listing 5: Subject-Specific Pharmacokinetic Parameters 
Subject ID 
Cmax 
(ng/mL) 
Tmax 
(h) 
Tlast 
(h) 
AUC(0-last)  
(h×ng/mL) 
AUC(0-∞) 
(h×ng/mL) 
t1/2 
(h) 
Ke 
(1/h) 
CL/F 
(L/h) 
Vz/F 
(L) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CLINICAL RESEARCH IN INFECTIOUS DISEASES 
 
 
 
STATISTICAL ANALYSIS PLAN 
for 
DMID Protocol: 16-0118 
 
Study Title: 
 
A Phase 1 Clinical Trial to Evaluate the Plasma 
Pharmacokinetics, Safety, and Tolerability of a Single Oral Dose 
of Zoliflodacin in Healthy Male and Female Subjects 
 
 
NCT03404167 
 
Version 1.0 
 
DATE: 03-APR-2018 
 
THIS COMMUNICATION IS PRIVILEGED AND CONFIDENTIAL  
 
 


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STUDY TITLE 
Protocol Number Code: 
DMID Protocol: 16-0118 
Development Phase: 
Phase 1 
Products: 
Zoliflodacin 
Form/Route: 
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: 
02 February 2018 
Clinical Trial Completion Date: 
 
Date of the Analysis Plan: 
03 April 2018 
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. 
 


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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 .....................................................................3 
4. 
INVESTIGATIONAL PLAN ....................................................................................4 
4.1. 
Overall Study Design and Plan .....................................................................................4 
4.2. 
Discussion of Study Design, Including the Choice of Control Groups ........................4 
4.3. 
Selection of Study Population ......................................................................................4 
4.4. 
Treatments ....................................................................................................................8 
4.4.1. 
Treatments Administered ..............................................................................................8 
4.4.2. 
Identity of Investigational Product(s) ...........................................................................8 
4.4.3. 
Method of Assigning Subjects to Treatment Groups (Randomization) .......................8 
4.4.4. 
Selection of Doses in the Study ....................................................................................8 
4.4.5. 
Selection and Timing of Dose for Each Subject ...........................................................8 
4.4.6. 
Blinding ........................................................................................................................8 
4.4.7. 
Prior and Concomitant Therapy ....................................................................................8 
4.4.8. 
Treatment Compliance ..................................................................................................9 
4.5. 
Efficacy and Safety Variables ......................................................................................9 
5. 
SAMPLE SIZE CONSIDERATIONS ....................................................................10 
6. 
GENERAL STATISTICAL CONSIDERATIONS ...............................................11 
6.1. 
General Principles .......................................................................................................11 
6.2. 
Timing of Analyses .....................................................................................................11 
6.3. 
Analysis Populations ..................................................................................................11 
6.3.1. 
Intention-to-Treat Analysis (ITT) Population ............................................................11 


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6.3.2. 
Full Analysis Population.............................................................................................11 
6.3.3. 
Modified Intention-to-Treat (mITT) Population ........................................................11 
6.3.4. 
Evaluable Population ..................................................................................................11 
6.3.5. 
Per Protocol Population ..............................................................................................11 
6.3.6. 
Safety Population ........................................................................................................11 
6.3.7. 
PK Population .............................................................................................................12 
6.3.8. 
Immunogenicity Population ........................................................................................12 
6.4. 
Covariates and Subgroups ..........................................................................................12 
6.5. 
Missing Data ...............................................................................................................12 
6.6. 
Interim Analyses and Data Monitoring ......................................................................12 
6.7. 
Multicenter Studies .....................................................................................................12 
6.8. 
Multiple Comparisons/Multiplicity ............................................................................12 
7. 
STUDY SUBJECTS ...................................................................................................13 
7.1. 
Disposition of Subjects ...............................................................................................13 
7.2. 
Protocol Deviations ....................................................................................................13 
8. 
EFFICACY EVALUATION ......................................................................................14 
8.1. 
Primary Efficacy Analysis ..........................................................................................14 
8.2. 
Secondary Efficacy Analyses .....................................................................................14 
8.3. 
Exploratory Efficacy Analyses ...................................................................................14 
9. 
SAFETY EVALUATION ..........................................................................................15 
9.1. 
Demographic and Other Baseline Characteristics ......................................................15 
9.1.1. 
Prior and Concurrent Medical Conditions ..................................................................15 
9.1.2. 
Prior and Concomitant Medications ...........................................................................15 
9.2. 
Measurements of Treatment Compliance ...................................................................15 
9.3. 
Adverse Events ...........................................................................................................16 
9.3.1. 
Solicited Events and Symptoms .................................................................................16 
9.3.2. 
Unsolicited Adverse Events ........................................................................................16 
9.4. 
Deaths, Serious Adverse Events and other Significant Adverse Events ....................16 
9.5. 
Pregnancies .................................................................................................................16 
9.6. 
Clinical Laboratory Evaluations .................................................................................17 
9.7. 
Vital Signs and Physical Evaluations .........................................................................18 


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9.8. 
Concomitant Medications ...........................................................................................19 
9.9. 
Other Safety Measures ................................................................................................19 
10. 
PHARMACOKINETICS ...........................................................................................20 
11. 
IMMUNOGENICITY ................................................................................................21 
12. 
OTHER ANALYSES .................................................................................................22 
13. 
REPORTING CONVENTIONS ................................................................................23 
14. 
TECHNICAL DETAILS ............................................................................................24 
15. 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY OR 
PLANNED ANALYSES ............................................................................................25 
16. 
REFERENCES ...........................................................................................................26 
17. 
LISTING OF TABLES, FIGURES, AND LISTINGS ..............................................27 
APPENDICES ...............................................................................................................................28 
APPENDIX 1. TABLE MOCK-UPS..........................................................................................29 
APPENDIX 2. FIGURE MOCK-UPS ........................................................................................90 
APPENDIX 3. LISTINGS MOCK-UPS ...................................................................................102 
APPENDIX 4. NONCOMPARTMENTAL ANALYSIS TEMPLATE ...................................127 
 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the Curve 
AUC(0-last) 
AUC to the Last Measurable Concentration 
AUC(0-∞) 
AUC Extrapolated to Infinity 
BMI 
Body Mass Index 
BQL 
Below Quantification Limit 
Cmax 
Maximum Plasma Concentration 
CDC 
Centers for Disease Control and Prevention 
CI 
Confidence Interval 
CL/F 
Clearance 
CSR 
Clinical Study Report 
CV 
Coefficient of Variation 
DMID 
Division of Microbiology and Infectious Diseases 
DNA 
Deoxyribonucleic Acid 
ECG 
Electrocardiograph 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ET 
Early Termination 
F 
Bioavailability 
FDA 
Food and Drug Administration 
FSH 
Follicle-Stimulating Hormone 
g 
Gram(s) 
GM 
Geometric Mean 
h 
Hour(s) 
HBsAg 
Hepatitis B Surface Antigen 
HCV 
Hepatitis C Virus 
HEENT 
Head, Eyes, Ears, Nose and Throat 
HIV 
Human Immunodeficiency Virus 


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HLGT 
Higher Level Group Term 
HPLC-MS/MS 
High-Performance Liquid Chromatography with Tandem Mass Spectrometry 
HR 
Heart Rate 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ITT 
Intention to Treat (Analysis) 
ke 
Elimination Rate Constant 
kg 
Kilogram(s) 
LLOQ 
Lower Limit of Quantification 
MedDRA 
Medical Dictionary for Regulatory Activities  
mg 
Milligram(s) 
MH 
Medical History 
min 
Minute(s) 
mITT 
Modified Intention to Treat (Analysis) 
mmHg 
Millimeters of Mercury 
msec 
Millisecond(s) 
N 
Number / Denominator (typically refers to subjects) 
n 
Number / Count / Numerator 
NCA 
Noncompartmental Analysis 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
ng 
Nanogram(s) 
OCRR 
Office of Clinical Research Resources 
PE 
Physical Examination 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
PT 
Preferred Term 
QTc 
Corrected QT Interval 
QTcF 
QT Interval with Fridericia Correction 
RBC 
Red Blood Cell 
sec 
Second(s) 


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SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SMC 
Safety Monitoring Committee 
SOC  
System Organ Class 
t1/2 
Terminal Elimination Half-Life 
Tmax 
Time of Maximum Plasma Concentration 
Vz/F 
Volume of Distribution 
VS 
Vital Sign(s) 
WBC 
White Blood Cell 
WHO 
World Health Organization 
 


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1. 
PREFACE 
The Statistical Analysis Plan (SAP) for “A Phase 1 Clinical Trial to Evaluate the Plasma Pharmacokinetics, 
Safety, and Tolerability of a Single Oral Dose of Zoliflodacin in Healthy Male and Female Subjects” 
(Division of Microbiology and Infectious Diseases (DMID) protocol 16-0118) describes and expands upon 
the statistical information presented in the protocol. 
This document describes all planned analyses and provides reasons and justifications for these analyses. It 
also includes sample tables, listings, and figures planned for the final analyses. Regarding the final analyses 
and Clinical Study Report (CSR), this SAP follows the International Conference on Harmonisation (ICH) of 
Technical Requirements for Registration of Pharmaceuticals for Human Use Guidelines, as indicated in Topic 
E3 (Structure and Content of Clinical Study Reports), and more generally is consistent with Topic E8 
(General Considerations for Clinical Trials) and Topic E9 (Statistical Principles for Clinical Trials). The 
structure and content of the SAP provides sufficient detail to meet the requirements identified by the Food and 
Drug Administration (FDA) and ICH, while all work planned and reported for this SAP will follow 
internationally accepted guidelines published by the American Statistical Association and the Royal Statistical 
Society for statistical practice. 
This document contains five sections: (1) a review of the study design, (2) general statistical considerations, 
(3) comprehensive statistical analysis methods for efficacy and safety outcomes, (4) planned statistical 
analyses for pharmacokinetic (PK) endpoints, and (5) a list of proposed tables and figures. Any deviation 
from this SAP will be described and justified in the CSR, as appropriate. The reader of this SAP is 
encouraged to also review the study protocol and manual of operating procedures for details on conduct of the 
study and the operational aspects of clinical assessments. 
 


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2. 
INTRODUCTION 
This Phase 1 trial is an open-label, non-randomized evaluation of the PK and safety profiles of a single 4-g 
oral dose of zoliflodacin [2 x 2 gram (g) sachets] in 8 healthy male or female subjects, aged 18-45 years.  
2.1. 
Purpose of the Analyses 
A single oral dose of zoliflodacin has been shown to be effective against uncomplicated gonorrhea caused by 
N. gonorrhoeae strains susceptible or resistant to currently available therapies. These findings supported the 
ongoing clinical development of zoliflodacin as a potential new therapeutic option for uncomplicated 
gonorrhea. A recently completed Phase 2 clinical trial suggests that zoliflodacin doses in the range of 2 g to 
3 g are therapeutic. In the current study, a 4-g dose of zoliflodacin, using a different formulation than in the 
prior PK studies, is given to 8 healthy subjects.  The purpose of analyses is to characterize the PK 
characteristics and safety profile of a 4-g dose of this formulation of zoliflodacin.  


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3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Study Objectives 
Primary Objective: 
• To evaluate the plasma PK of zoliflodacin after administration of a single 4-g oral dose under 
fasting conditions 
Secondary Objective: 
• To evaluate the safety and tolerability of a single 4-g oral dose of zoliflodacin 
3.2. 
Endpoints 
Primary Endpoints: 
• Cmax, Tmax, area under the curve (AUC) until last measurable concentration (AUC(0-last)), and other 
PK parameters for zoliflodacin determined using plasma concentrations of zoliflodacin in blood 
samples collected on Day 1 [baseline (30 min before dosing) and 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 
and 12 h after dosing], Day 2 [24 h and 36 h after dosing], Day 3 [48 h after dosing], and Day 4 
[72 h after dosing], or early termination (ET), and measured using a validated high performance 
liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method 
Secondary Endpoints: 
• The occurrence of treatment-emergent serious adverse events (SAEs) from administration of 
zoliflodacin on Day 1 to Final Visit (Day 8 ± 2), or ET 
• The occurrence of unsolicited treatment-emergent adverse events (AEs) from administration of 
zoliflodacin on Day 1 to Final Visit (Day 8 ± 2), or ET 
• The changes from baseline (up to 60 min before dosing) in vital signs (VS) following 
administration of zoliflodacin, as measured on Day 1 [1 h, 2 h, and 4 h after dosing], Days 2, 3, 
and 4 [24 h, 48 h, and 72 h, respectively, after dosing], and Final Visit (Day 8 ± 2), or ET 
• The changes from baseline (Day -1) in clinical laboratory values following administration of 
zoliflodacin, as measured on Day 4, or ET 
• The changes from baseline (up to 60 min before dosing) in electrocardiograph (ECG) parameters 
following administration of zoliflodacin, as measured on Day 1 [1 h, 2 h, and 4 h after dosing] and 
Day 4 [72 h after dosing], or ET 
3.3. 
Study Definitions and Derived Variables  
The baseline value will be defined as the last value obtained prior to the dosing with zoliflodacin. 


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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design and Plan 
The trial will be performed as an open-label, non-randomized, single-dose design in 8 healthy male or female 
subjects to evaluate the PK and safety profiles of the zoliflodacin formulation. Zoliflodacin is presented as 
granules for oral suspension, 50 % weight(wt)/wt, packaged in a single sachet. Each subject will receive a 
single 4g dose of zoliflodacin (2 sachets of 2 g of zoliflodacin reconstituted on the same day and administered 
in a total of 
) orally after an overnight fast. After the 
 of zoliflodacin is administered, 
an additional 
 should be added to the same cup and consumed by the subject to chase the 
initial dose. Ingestion of the content of both the initial 
 volume and the 
 wash should be 
completed within 5 min. All subjects will be dosed in the morning of Day 1 in a staggered fashion with a 
minimum of several minutes apart. There is no placebo used in this study. 
Subjects will participate in the study for approximately 4 weeks, including a 3-week screening period, a 4-day 
inpatient stay with dosing on Day 1, and a 1-week follow-up period after study product administration. The 
last follow-up visit is scheduled on Day 8. Safety oversight will be conducted by a Safety Monitoring 
Committee (SMC), which is an independent group of experts that monitors subject safety and advises DMID. 
The SMC will review safety data and advise on using the 4-g dose of zoliflodacin in a subsequent thorough 
QT study. 
4.2. 
Discussion of Study Design, Including the Choice of Control Groups 
Zoliflodacin is a spiropyrimidinetrione antibacterial drug, which inhibits bacterial Deoxyribonucleic acid 
(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.5,6  
Regulatory guidance ICH/FDA E14 has emphasized the need to obtain robust data on the effect of new 
chemical entities on ECG parameters, focusing on cardiac repolarization as measured by the corrected QT 
interval (QTc).6 To obtain these data, the potential of a single therapeutic dose and a single supratherapeutic 
dose of the study drug to prolong cardiac repolarization is measured. 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.5,7,8 The current trial will further 
characterize the PK and safety profiles of the 4-g dose of a new zoliflodacin formulation. This dose could 
result in drug exposures that are multiples of the proposed 2-g therapeutic dose and meet the requirements for 
a supratherapeutic dose. Since the main objective is to characterize the PK of zoliflodacin, this study does not 
use a control group. 
4.3. 
Selection of Study Population 
Only subjects who meet all of the inclusion and none of the exclusion criteria will be eligible for enrollment 
into this study. No exemptions are granted on Inclusion/Exclusion Criteria in DMID-sponsored studies. 
Eight healthy male and female subjects, aged 18-45 years inclusive, will be enrolled in a single cohort. Up to 
two alternates will be recruited. 


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Inclusion Criteria 
All must be answered YES for the subject to be eligible for study participation: 
1. Informed consent form (ICF) understood and signed before initiating any study procedures 
2. Healthy male or female, as assessed by the authorized site clinician (listed on FDA Form 1572)  
3. Willingness to comply with and be available for all protocol procedures including inpatient 
confinement for about 4 days and availability for follow-up for the duration of the trial 
4. Aged 18 to 45 years inclusive on the day of study drug dosing 
5. Body Mass Index (BMI) ≥18.5 and ≤30 kg/m2 and weight ≥50 kg (110 lbs.) and ≤100 kg (220 lbs.) 
6. In female subjects of childbearing potential, a negative serum pregnancy test at Screening Visit and on 
Day -1 
• Note: A woman is considered of childbearing potential unless post-menopausal (≥ 1 year without 
menses without other known or suspected cause and with a Follicle-stimulating hormone (FSH) 
level in the menopausal range), or surgically sterilized (hysterectomy, salpingectomy, 
oophorectomy or tubal ligation/occlusion) 
7. If female, not pregnant, not breast feeding, and not planning on becoming pregnant during the trial and 
for 30 days after study participation 
8. Females of childbearing potential and males agree to use acceptable contraception for the duration of 
the trial and for 30 days (females) or 90 days (males) after final study visit 
• Note: A highly effective method of birth control is defined as one with a low failure rate (i.e., less 
than 1 percent per year) according to the 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 must agree to refrain from sperm donation for the duration of the trial and for 90 days 
after final study visit 
10. Laboratory tests, as outlined in Section 8.2.1.1 of the protocol, are in the normal reference range with 
acceptable exceptions as noted in Section 8.2.1.1 and Appendix B of the protocol  
11. VS, 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 8.2.1.5 of the protocol) 
14. Alcohol test (breathalyzer) is negative 
15. Willing to abstain from alcohol consumption for 2 days before Day -1 and during the trial 


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Exclusion Criteria 
All must be answered NO for the subject to be eligible for study participation: 
1. History of a chronic medical or surgical condition that would interfere with the accurate assessment of 
the trial’s objectives or increase the subject’s risk profile 
Note: Chronic medical conditions include: diabetes mellitus; asthma requiring use of medication in 
the year before screening; autoimmune disorder such as lupus erythematosus, Wegener’s, rheumatoid 
arthritis, thyroid disease; cardiovascular disease, including coronary artery disease or 
cerebrovascular disease, or surgery; syncope related to cardiac arrhythmia or unexplained; chronic 
hypertension; malignancy except low-grade (squamous and basal cell) skin cancer thought to be 
cured; chronic renal, hepatic, pulmonary, or endocrine disease, myopathy, or neuropathy; 
gastrointestinal or biliary surgery. 
2. History of hypersensitivity or severe allergic reaction of any type to medications, bee stings, food, or 
environmental factors 
Note: Severe allergic reaction is defined as any of the following: anaphylaxis, urticaria, or 
angioedema 
3. Active allergic symptoms to seasonal and animal allergens that require treatment   
4. A marked baseline prolongation of ECG intervals, or heart rate (HR) <45 bpm or >100 bpm on ECG 
measurements 
Note: The following are considered prolonged ECG intervals: QTc/QTcF >449 msec in males and 
females; PR >209 msec; and QRS >110 msec 
5. Clinically significant abnormal ECG results 
Note: Clinically significant abnormal ECG results include: complete left or right bundle branch 
block; other ventricular conduction block; 2nd degree or 3rd degree atrioventricular (AV) block; 
sustained atrial or ventricular arrhythmia; two premature ventricular contractions in a row; pattern 
of ST elevation felt consistent with cardiac ischemia; evidence of a previous myocardial infarction 
(MI), left ventricular hypertrophy (LVH), or more than minor non-specific ST-T wave changes; or any 
condition deemed clinically significant by a study investigator. 
6. Abnormal renal function  
Note: Normal renal function is defined as normal creatinine [per criteria in Appendix B of the 
protocol] and normal estimated glomerular filtration rate (eGFR) [i.e., >80.0 mL/min] values 
according to Cockroft-Gault. 
7. Positive serology results for Human Immunodeficiency Virus (HIV), Hepatitis B Surface Antigen 
(HBsAg), or Hepatitis C Virus (HCV) 
8. Febrile illness with temperature >37.6 °C for <7 days before dosing 
9. Donated whole blood or blood products within 60 days before dosing, or plans to donate before Final 
Visit (Day 8 ± 2) 
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10. Known allergic reactions to any of the study drug components present in the formulation or in its 
processing, as listed in the Investigator’s Brochure (IB) 
11. Treatment with another investigational product within 30 days of dosing or 5 half-lives or twice the 
duration of the biological effect of the study drug (whichever is longer)  
Note: Investigational products include a drug, vaccine, biologic, device or blood product 
12. Active drug or alcohol use, abuse, or dependence within 12 months before Screening Visit that, in the 
opinion of the investigator, would interfere with adherence to study requirements 
13. Use of any prescription medication within 30 days before dosing or planned use during the study 
period except as noted below and approved by the designated study clinician 
Note 1: Prohibited medications include moderate or strong CYP3A4 inducers (per Section 6.9); 
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 7 days 
before or after dosing. 
Note 2: Allowed medications include: oral contraceptives; H1 antihistamines; topical/ intranasal 
corticosteroids; nonsteroidal anti-inflammatory drugs [NSAIDS]; licensed influenza vaccine during 
the flu season, 7 days before or after dosing. 
14. Use of any non-prescription medication, herbal preparation, or nutritional supplement within 15 days 
before dosing or planned use during the study unless approved by the study clinician 
Note: Exceptions: St. John’s wart is not allowed within 30 days of dosing, vitamins and OTC 
medications taken for a brief period (<48 h) for the treatment of common symptoms (such as 
headache, indigestion, muscle pain) may be allowed as approved by the designated study clinician. 
15. Intake of caffeinated beverages or food within 72 h before dosing or a history of high caffeine 
consumption (e.g., in the last 4 months drinking >5 cups of coffee/day) 
16. Smoking or use of tobacco or nicotine-containing products within 15 days before dosing 
17. Engagement in strenuous exercise within 15 days before dosing (e.g., marathon running, long distance 
cycling, weight lifting) and during the study period 
18. Any specific behavioral or clinical condition that in the judgment of the investigator precludes 
participation because it could affect compliance with study procedures or subject safety 
19. Plans to enroll or is already enrolled in another clinical trial that could interfere with safety assessment 
of the study drug at any time during the study period 
Note: Includes trials that have a study intervention such as a drug, biologic, or device. 
20. Is a study site employee or staff member who is paid entirely or partially by the Office of Clinical 
Research Resources (OCRR)/NIAID contract for the DMID-funded trial 
Note: Site employees or staff include the Principal Investigators (PIs), sub-investigators, or staff who 
are supervised by the PI or sub-investigators. 


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4.4. 
Treatments 
4.4.1. 
Treatments Administered  
Zoliflodacin is a spiropyrimidinetrione antibacterial agent, with a novel mode of action. It is a first-in-class 
oral gyrase inhibitor being developed for treatment of uncomplicated gonococcal infection, including cases 
caused by isolates with resistance to currently available treatments. A single oral dose of zoliflodacin has been 
shown to be effective against uncomplicated gonorrhea caused by N. gonorrhoeae strains susceptible or 
resistant to currently available therapies. These findings supported the ongoing clinical development of 
zoliflodacin as a potential new therapeutic option for uncomplicated gonorrhea. 
4.4.2. 
Identity of Investigational Product(s) 
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, co-formulated with 
 
. 
4.4.3. 
Method of Assigning Subjects to Treatment Groups (Randomization) 
This is a single arm trial. All subjects will receive a single 4 g oral dose of zoliflodacin. 
4.4.4. 
Selection of Doses in the Study 
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.1,2,3 The current trial will further characterize the PK and safety profiles of the 4-g dose of a new 
zoliflodacin formulation. This dose could result in drug exposures that are multiples of the proposed 2-g 
therapeutic dose and meet the requirements for a supratherapeutic dose according to the ICH/FDA E14 
Guidance for thorough QTc studies.4 
4.4.5. 
Selection and Timing of Dose for Each Subject 
Eligible subjects will receive a single 4-g dose (2 sachets of 2 g of zoliflodacin reconstituted on the same day 
and administered in a total of 
) orally after an overnight fast. After the 
 of 
zoliflodacin is administered, an additional 
 will be added to the same cup and consumed by 
the subject to chase the initial dose. Ingestion of the content of both the initial 
 volume and the 
 
 should be completed within 5 min. After dosing, subjects will continue to fast for an additional 4 h 
while water is allowed ad lib. All subjects will receive zoliflodacin in the morning of Day 1 in a staggered 
fashion several minutes apart. 
4.4.6. 
Blinding 
This is an open-label study, no blinding procedures are required. 
4.4.7. 
Prior and Concomitant Therapy  
Concomitant medications include the following: prescription drugs, birth control hormonal preparations, non-
prescription medication, herbs, vitamins, nutritional supplements, and illicit and recreational substances. Any 
of these taken before or after dosing will be reported as Prior Medications or Concomitant Medications, 
respectively. 


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Prior prescription medication information will be recorded at Screening Visit and, except for hormonal 
contraceptives, should not be taken for 30 days before dosing or during the study period.  
Zoliflodacin should not be co-administered in subjects using strong (i.e., avasimibe, carbamazepine, 
phenytoin, rifampin, and St. John's wort) or moderate (i.e. efavirenz, bosentan, etravirine, modafinil, and 
nafcillin) inducers of CYP3A4. These drugs should not be taken for 30 days before dosing and during the 
study period. 
A vaccine should not be received within 30 days before dosing or before the end of the trial, except for 
licensed influenza vaccine during the flu season, which may be administered up to 7 days before or after 
dosing.  
Non-prescription medications, herbs, vitamins, and nutritional supplements should not be taken within 15 
days before dosing. OTC medications taken for a brief period (<48 h) for the treatment of common symptoms 
(such as headache, indigestion, muscle pain) may be allowed as approved by the designated study clinician. 
Allowed medications include: oral contraceptives; H1 antihistamines; topical/ intranasal corticosteroids; 
nonsteroidal anti-inflammatory drugs (NSAIDS); licensed influenza vaccine during the flu season, 7 days 
before or after dosing.  
Blood/blood products (RBCs, WBCs, platelets, and plasma) should not be donated within 60 days of dosing 
or received before Final Visit. 
Following dosing, each new concomitant medication and changes to existing medications will be recorded. 
Subjects will be required not to utilize non-study medication during the trial except those deemed necessary 
by the Site PI or sub-investigator. 
Any drug (e.g., non-prescription medications, herbal supplements, vitamins, or prescription medications) or 
vaccine or blood/blood products used by the subject during the trial will be recorded in the subject’s source 
documents and on the appropriate electronic case report form (eCRF), and the PI or authorized study clinician 
(listed on FDA Form 1572) will note whether the use was medically indicated and immediately necessary. 
Any use of medications not authorized by the study PI or authorized clinician will be recorded as a deviation. 
4.4.8. 
Treatment Compliance 
All subjects will receive a single 4 g dose of zoliflodacin administered in the clinic. Dates and times of 
administration will be recorded by site personnel. Complete information regarding any partial or interrupted 
dosing will be documented. 
4.5. 
Efficacy and Safety Variables 
As this study is a Phase I clinical trial in healthy adult subjects, there will be no assessment of drug efficacy. 
Safety endpoints are briefly listed below. For a detailed schedule of activities, refer to Appendix A of the 
protocol. For a complete list of primary and secondary objectives and outcomes, refer to Section 3 of the SAP. 
Safety will be assessed by the timing, frequency, relatedness to study drug, and severity of:  
1. Treatment-emergent SAEs occurring from dosing through Final Visit (Day 8 ± 2), or ET 
2. Clinical laboratory AEs occurring from dosing through Final Visit (Day 8 ± 2), or ET 
3. Non-serious, unsolicited treatment-emergent AEs occurring from dosing through Final Visit (Day 8 ± 
2), or ET. 
Details of the study safety parameters can be found in the protocol. 


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5. 
SAMPLE SIZE CONSIDERATIONS 
Since this is a pilot Phase 1, open-label trial with a single 4-g dose cohort of zoliflodacin, no formal sample 
size calculations based on testing a statistical hypothesis were constructed. Eight subjects will be enrolled, and 
it is planned to have seven evaluable subjects given zoliflodacin. This sample size will provide sufficient 
information to estimate exposure to the 4-g dose of zoliflodacin and to assess its safety. 


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6. 
GENERAL STATISTICAL CONSIDERATIONS 
6.1. 
General Principles 
Tabulations will be used extensively to summarize the data. Summary statistics for continuous data will 
include the mean, median, standard deviation, and range (minimum and maximum values). Summary 
statistics for discrete data will include counts and percentages, contingency tables, and associated confidence 
intervals (CIs). Denominators will be shown for all percentages (as N=X). When 95% CIs are given for a 
binary variable, Wilson Score CIs will be used. Parameters will be summarized overall and not by any 
subgroup. 
In general, all data will be listed, sorted by subject ID, and when appropriate, by visit number within subject. 
The total population size relevant to specific tables or to columns or rows within tables will be displayed. 
Listings of individual subject data include a Subject ID column. The subject identifiers assigned by site staff 
are replaced throughout this report with the 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 
Electronic Data Capture (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. 
6.2. 
Timing of Analyses 
The final analysis will be performed after database lock. 
6.3. 
Analysis Populations 
A tabular listing of all subjects, visits, and observations excluded from the analysis of PK data will be 
provided in the CSR (Listing 4). 
6.3.1. 
Intention-to-Treat Analysis (ITT) Population 
Not applicable. 
6.3.2. 
Full Analysis Population 
Not applicable. 
6.3.3. 
Modified Intention-to-Treat (mITT) Population 
Not applicable. 
6.3.4. 
Evaluable Population 
Not applicable. 
6.3.5. 
Per Protocol Population 
Not applicable. 
6.3.6. 
Safety Population 
All subjects who received the study drug will be included in the safety population and analyzed as treated. 


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6.3.7. 
PK Population 
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. 
6.3.8. 
Immunogenicity Population 
Not applicable. 
6.4. 
Covariates and Subgroups 
The protocol does not define any formal subgroup analyses, and the study is not adequately powered to 
perform subgroup analyses. 
6.5. 
Missing Data 
All attempts will be made to collect all data per protocol. Clinical labs will not be collected for Day -1 if 
collected ≤7 days of dosing. Therefore, missing clinical laboratory results on Day -1 only will be imputed 
using last observation carried forward when results with 7 days prior to dosing are available. Missing clinical 
laboratory results on Day 4 or “Day 4 or ET” will not be imputed. Missing pre-dose PK samples will have 
concentrations imputed as BQL (below quantification limit). No other 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. 
6.6. 
Interim Analyses and Data Monitoring 
There are no planned interim analyses for this study. 
An SMC will review all the safety data to Day 8 or ET in the study cohort. If any of the predefined objective 
criteria for halting the study, listed in Section 9.5.1 of the protocol, are met, a SMC ad hoc meeting will be 
held to review all available safety data (see Section 9.6.2 of the protocol for more details). 
6.7. 
Multicenter Studies 
Not applicable. This is a single site study. 
6.8. 
Multiple Comparisons/Multiplicity 
This is a small Phase 1 first-in-human study with multiple primary endpoints. The primary endpoints are 
descriptive rather than hypothesis tests, no adjustments for multiple testing are planned. 


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7. 
STUDY SUBJECTS 
7.1. 
Disposition of Subjects 
Screened subjects who were ineligible for enrollment in the study will be summarized by inclusion and 
exclusion criteria in Table 7, and enrolled subjects who were ineligible for inclusion in the analysis 
populations will be presented by reason for subject exclusion in Table 6.  
Subject disposition will be summarized (Table 5), showing the number of subjects who screened, enrolled, 
dosed, completed sample collection, and completed follow-up. Subjects who terminated early from the study 
will be listed (Listing 1). Subjects who were excluded from the PK population, then PK analysis subset, or 
safety population will be listed, including reason for exclusion (Listing 4). 
7.2. 
Protocol Deviations 
A summary of protocol deviations will be presented by the deviation category and reason in Table 2. 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, respectively). 
 


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8. 
EFFICACY EVALUATION 
There are no efficacy endpoints for this trial 
8.1. 
Primary Efficacy Analysis 
Not applicable. 
8.2. 
Secondary Efficacy Analyses 
Not applicable. 
8.3. 
Exploratory Efficacy Analyses 
Not applicable. 


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9. 
SAFETY EVALUATION 
All safety analyses will be presented using the safety population. When calculating the incidence of AEs (i.e., 
on a per subject basis), each subject will be counted once and any repetitions of AEs within a subject will be 
ignored for events coded in the same category by the Medical Dictionary for Regulatory 
Activities (MedDRA); the denominator will be the total safety population size. Moreover, events thus 
summarized will be coded to the highest severity observed per toxicity tables (Table 3 and Table 4).   
9.1. 
Demographic and Other Baseline Characteristics 
Sex, ethnicity, and race of all subjects will be summarized (Table 8). Ethnicity will be categorized as 
“Hispanic or Latino,” or “Not Hispanic or Latino,” or “Unknown/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 eCRF as “No” to each racial option. Age (in years), height (in m), weight (in 
kg), and BMI (in kg/m2) will be summarized (Table 9). 
Individual subject listings will be presented for all demographic and baseline characteristics (Listing 5). 
9.1.1. 
Prior and Concurrent Medical Conditions 
Medical history (MH) including all current illnesses and past pre-existing medical conditions will be 
MedDRA 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 (Table 10). Individual subject 
listings including medical history term, condition start and end day, SOC, and PT will be presented for all 
medical conditions (Listing 6). Surgeries, and the underlying illness indicating the surgery, were collected as 
separate medical history terms, and will be reported as separate rows in the listing. 
9.1.2. 
 Prior and Concomitant Medications  
All medications will be coded using the current version of the World Health Organization (WHO) Drug 
dictionary. The use of prior and concomitant medications taken during the study will be summarized by 
Anatomical Therapeutic Chemical (ATC) classification codes ATC 1 and ATC 2 (separately in Table 117 for 
prior medications and Table 118 for concomitant medications). Individual subject listings will be presented 
for all prior and concomitant medications (separately in Listing 18 for prior medications and Listing 19 for 
concomitant medications).  
9.2. 
Measurements of Treatment Compliance 
All subjects were to receive a single 4 g dose of zoliflodacin administered in the clinic. The dates and times of 
administration are listed for each subject in Listing 7. Subjects unable to ingest the full amount of the initial 
 of study drug suspension or who vomit within 24 h after dosing will be withdrawn from the study and 
replaced (See Section 5.3.3 and 5.3.4 of the protocol). Subjects who do not ingest the content of the second 
 of study drug suspension will not be withdrawn from the study. Subjects who received any amount of 
the study drug but withdraw from the trial will be encouraged to continue follow-up (with subjects’ consent) 
for safety assessments and PK sample collection. 
Subjects receiving the full initial 
 suspension and the full 
 wash (
) will 
be reported in Listing 7 as receiving “4 g” of the drug. Subjects receiving an incomplete dose will be reported 
in Listing 7 as receiving “<4 g” of the drug.   


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9.3. 
Adverse Events 
When calculating the incidence of AEs within each category (i.e., on a per subject basis), each subject will 
only be counted once and any repetitions of AEs within a subject will be ignored; the denominator will be the 
total safety population size. When multiple AEs of different severities are observed for a subject within a 
category, the worst severity will be tabulated for calculations of incidence. All reported AEs will be included 
in the summaries and analyses. 
9.3.1. 
Solicited Events and Symptoms 
There are no solicited symptoms or AEs in this trial. 
9.3.2. 
Unsolicited Adverse Events 
The proportion of subjects reporting at least one unsolicited AE after dosing and prior to Day 8 or ET will be 
summarized by MedDRA SOC, higher level group term (HLGT), and preferred term (PT). A 95% Wilson 
Score CI will be presented for each MedDRA SOC, HLGT, and PT. Tables, figures, and listings of AEs will 
include clinical laboratory AEs and ECG AEs. 
AEs by subject will be presented in Listing 8. Additionally, moderate and severe non-serious AEs will be 
listed in Table 15. 
A brief overall summary of AEs will be given in Table 11. The following summaries for unsolicited AEs will 
be presented by MedDRA SOC, HLGT, and PT: 
• Frequency (number and percent of subjects with an AE of mild severity or greater, with 95% 
Wilson Score intervals) and number of AE, regardless of severity or relationship to study product 
(Table 12) 
• Frequency of AEs by severity and relationship to study product (Table 13); 
• Bar chart of frequency of related AEs by severity and MedDRA SOC (Figure 2). This figure 
describes the total number of occurrences of each AE, including multiple occurrences per subject. 
• Bar chart of incidence of serious and non-serious AEs by maximum severity and MedDRA SOC 
(Figure 1). This figure describes the number and percent of subjects with an AE. 
9.4. 
Deaths, Serious Adverse Events and other Significant Adverse Events 
Individual data listings of deaths and Serious AEs (Table 14) will be provided. The listing will include: 
Subject ID, AE Description, Duration, Reason Reported as an SAE, Severity, Relationship to Treatment, 
Alternate Etiology if not Related, Outcome, MedDRA SOC, and MedDRA PT. 
9.5. 
Pregnancies 
A female subject who participates in the trial and becomes pregnant will be asked to inform study personnel 
of a pregnancy occurring 30 days after the final study visit. A male subject who participates in the trial and 
whose female partner becomes pregnant 90 days after the final study visit will be asked to inform study 
personnel of the pregnancy. For all reported pregnancies, subjects will be asked to provide pregnancy 
outcome upon delivery or pregnancy termination to the clinical trial unit.  


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An individual data listing of pregnancy reports will be provided in Listing 21, Listing 22, Listing 23, Listing 
24, and Listing25 if a pregnancy occurs post dosing. A by-subject list of birth control methods can be found in 
Listing 20. 
9.6. 
Clinical Laboratory Evaluations 
Toxicity grade criteria can be found in Table 3 and Table 4. Unscheduled or repeated follow-up tests for 
medical or safety reasons will be listed but excluded from tabular and graphical summaries. 
Clinical labs will not be collected for Day -1 if collected ≤7 days of dosing. In all cases, the most recent result 
in the database prior to dosing will be used as baseline. Missing clinical laboratory results on Day 4 or ET will 
not be imputed. If multiple Day -1 results exist for a subject, the latest result prior to dosing will be regarded 
as the baseline value.  
All clinical laboratory results (chemistry, hematology, and urinalysis) will be listed (Listing 9, Listing 10, and 
Listing 11). Other laboratory results (viral serology, pregnancy tests, and confirmation of menopause) will be 
listed separately (Listing 12). Toxicology results will be shown in Listing 13 and Breathalyzer results will be 
shown in Listing 14. Abnormal laboratory results will be listed in Table 16, Table 17, and Table 18. 
Chemistry laboratory results will be summarized by parameter and severity (including maximum severity 
post-baseline) regardless of relatedness (Table 19, Table 20, Table 21, Table 22, Table 23, Table 24, Table 25, 
Table 26, Table 27, Table 28, Table 29, Table 30 and Table 31) and additionally the frequency of related 
laboratory toxicities will be summarized by parameter and severity (including maximum severity post-
baseline; Table 32, Table 33, Table 34, Table 35, Table 36, Table 37, Table 38, Table 39, Table 40, Table 41, 
Table 42, Table 43, and Table 44). Summary statistics will be reported by parameter and scheduled visit, 
including change from baseline (Table 45, Table 46, Table 47, Table 48, Table 49, Table 50, Table 51, Table 
52, Table 53, Table 54, Table 55, Table 56, Table 57, Table 58, and Table 59). Individual line plots showing 
the laboratory result over time will be shown by chemistry parameter (Figure 3, Figure 4, Figure 5, Figure 6, 
Figure 7, Figure 8, Figure 9, Figure 10, Figure 11, Figure 12, Figure 13, Figure 14, Figure 15, Figure 16 and 
Figure 17). Subjects will not be labeled in the line plots, as the purpose of the figures is to give an overall 
trend of trajectory. The following chemistry parameters will be included in summaries of severity: sodium, 
potassium, bicarbonate, glucose, blood urea nitrogen, creatinine, protein, albumin, aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), alkaline phosphatase, and bilirubin. The following chemistry 
parameters will be included in tables of summary statistics and in graphical plots: sodium, potassium, 
magnesium, chloride, bicarbonate, glucose, blood urea nitrogen, creatinine, protein, albumin, AST, ALT, 
alkaline phosphatase, bilirubin, and direct bilirubin. 
Hematology laboratory results will be summarized by parameter and severity (including maximum severity 
post-baseline) regardless of relatedness (Table 60, Table 61, Table 62, Table 63, Table 64, Table 65, Table 66, 
Table 67 and Table 68) and additionally the frequency of related laboratory toxicities will be summarized by 
parameter and severity (including maximum severity post-baseline; Table 69, Table 70, Table 71, Table 72, 
Table 73, Table 74, Table 75, Table 76 and Table 77). Summary statistics will be reported by parameter and 
scheduled visit, including change from baseline (Table 78, Table 79, Table 80, Table 81, Table 82, Table 83, 
Table 84, Table 85, Table 86, and Table 87). Individual line plots showing the laboratory result over time will 
be shown by hematology parameter (Figure 18, Figure 19, Figure 20, Figure 21, Figure 22, Figure 23, 
Figure 24, Figure 25, Figure 26, and Figure 27). Subjects will not be labeled in the line plots, as the purpose 
of the figures is to give an overall trend of trajectory. The following hematology parameters will be included 
in summaries of severity: hemoglobin, leukocytes, neutrophils, lymphocytes, monocytes, eosinophils, 
basophils, and platelets. The following hematology parameters will be included in tables of summary statistics 


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and in graphical plots: hemoglobin, hematocrit, erythrocytes, leukocytes, neutrophils, lymphocytes, 
monocytes, eosinophils, basophils, and platelets. 
Urinalysis laboratory results will be summarized by parameter (protein, glucose, and hemoglobin) and 
severity (including maximum severity post-baseline) regardless of relatedness (Table 88, Table 89, Table 90, 
and Table 91) and additionally the frequency of related laboratory toxicities will be summarized by parameter 
and severity (including maximum severity post-baseline; Table 92, Table 93, Table 94, and Table 95). 
Because urinalysis parameters are not continuous (except for microscopy follow-up parameters in the event of 
abnormal urine), no tables of summary statistics or line plots will be produced for urinalysis results. If 
performed, results of microscopy follow-up tests to abnormal urine dipstick tests will be included in listings 
of urinalysis results. 
In tables of severity, maximum severity observed for the parameter after dosing will be summarized. Tables 
of maximum severity for “Any Parameter” will be included for chemistry, hematology, and urinalysis 
laboratory results. In these tables, the maximum severity across all laboratory results in the respective 
category is summarized by visit, and from maximum severity post baseline. Ordinarily, only the maximum 
severity event will be counted in the summary tables. For instance, if subject has a mild decrease and a 
moderate increase observed post-dose, they will be counted once as a moderate increase for maximum 
severity post-baseline. In the exceptional case that a subject has an increase and a decrease of equal maximum 
severity, they will be counted twice for maximum severity post baseline, once for an increase and once for a 
decrease. 
9.7. 
Vital Signs and Physical Evaluations 
VS measurements include systolic blood pressure, diastolic blood pressure, pulse rate, respiratory rate, and 
oral temperature. VS will be assessed within 60 min of dosing (baseline), 1 h (±10 min), 2 h (±10 min), and 
4 h (±10 min) after dosing, and at Day 2, Day 3, Day 4, and Day 8 or ET. VS will be tabulated by parameter, 
severity grading, and visit (Table 96, Table 97, Table 98, Table 99, Table 100, and Table 101) and listed 
(Listing 15). Additionally, descriptive statistics, including mean, standard deviation, median, minimum and 
maximum will be presented to summarize VS at baseline and post-dose and will also present change from 
baseline (Table 102, Table 103, Table 104, Table 105 and Table 106). For each vital sign, individual line plots 
showing the vital sign over time will be shown by parameter (Figure 28, Figure 29, Figure 30, Figure 31 and 
Figure 32). Subjects will not be labeled in the line plots, as the purpose of the figures is to give an overall 
trend of trajectory.  
In tables of severity, maximum severity observed for the parameter after dosing will be summarized. Tables 
of maximum severity for “Any Parameter” will be included for VS results. In these tables, the maximum 
severity across all VS is summarized by visit, and from maximum severity post baseline. Ordinarily, only the 
maximum severity event will be counted in the summary tables. For instance, if subject has a mild decrease 
and a moderate increase observed post-dose, they will be counted once as a moderate increase for maximum 
severity post-baseline. In the exceptional case that a subject has an increase and a decrease of equal maximum 
severity, they will be counted twice for maximum severity post baseline, once for an increase and once for a 
decrease. 
A complete physical examination (PE), except genital, rectal and breast exams, will be conducted at 
Screening and at Day 8 (± 2) or ET. This examination will assess general appearance, HEENT (head, eyes, 
ears, nose and throat), heart, lungs, abdomen, skin, musculoskeletal system, and lymph nodes, and include an 
abbreviated neurological exam. An abbreviated PE will be performed on Day -1 (unless a complete PE was 
performed < 7 days before dosing) and Day 4. An abbreviated PE differs from a complete PE in that the 


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abdomen and neurological system are not evaluated. A symptom-directed PE will be performed before dosing 
on Day 1 and after dosing on Days 1, 2, and 3, to evaluate new symptoms or treatment-emergent AEs, 
respectively. Results of physical examinations, scheduled and unscheduled, will be presented in Listing 16. 
9.8. 
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 ATC 1 and ATC 2 (separately in 
Table 117 for prior medications and Table 118 for concomitant medications). Individual subject listings will 
be presented for all prior and concomitant medications (separately in Listing 18 for prior medications and 
Listing 19 for concomitant medications). 
9.9. 
Other Safety Measures 
A 12-lead ECG and 10-sec rhythm strip will be obtained at Screening Visit and on Days -1, 1, and 4 (72 h ± 
2 h post dose), or ET. On Day 1, a 12-lead ECG and 10-sec rhythm strip will be recorded within 1 h before 
dosing and 1 h (±10 min), 2 h (±10 min), and 4 h (±10 min) after dosing. ECG change in overall interpretation 
from baseline will be shown by study visit in Table 107. For PR interval and QT intervals with Fridericia 
correction (QTcF), ECG results will be tabulated by parameter, severity grading, and visit (Table 108 and 
Table 109). Summary statistics of ECG results, including change from baseline, will be reported by parameter 
(PR interval, QRS duration, QT interval, QTcF interval, RR interval, and ECG mean ventricular rate) in 
tabular form by study visit (Table 110, Table 111, Table 112, Table 113, Table 114, and Table 115) and will 
be shown graphically as line plots by visit (Figure 33, Figure 34, Figure 35, Figure 36, Figure 37, Figure 38, 
and Figure 39). Subjects will not be labeled in the line plots, as the purpose of the figures is to give an overall 
trend of trajectory. Line plots of change from baseline will be shown for QTcF intervals (Figure 37) but 
change from baseline will not be shown graphically for other ECG parameters. Frequency of QTcF 
prolongation (between 30 and <60 msec or ≥60 msec) will be given by post-dose visit (Table 116). Individual 
data listings of ECG results (interpretation, PR interval, QRS duration, QT interval, QTcF interval, RR 
interval, and ECG mean ventricular rate) will be presented (Listing 17). 


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10. 
PHARMACOKINETICS 
The PK analysis plan is described in the PK SAP. The summary from the PK Report and key tables, figures 
and listings (concentrations, parameters, and mean time-concentration profiles) will be included in the CSR.   
 


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11. 
IMMUNOGENICITY 
There are no immunogenicity endpoints in this trial. 


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12. 
OTHER ANALYSES 
There are no other analyses in this trial. 


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13. 
REPORTING CONVENTIONS 
P-values ≥0.001 and ≤0.999 will be reported to 3 decimal places; p-values <0.001 will be reported as 
“<0.001”; p-values >0.999 will be reported as “> 0.999“. All summary statistics besides the minimum value 
and maximum value will be reported to 1 decimal place greater than the original data. The minimum and 
maximum will use the same number of decimal places as the original data. Proportions will be presented as 2 
decimal places; proportions >0 but <0.01 will be presented as “<0.01”. Percentages will be reported to the 
nearest whole number; percentages >0 but <1% will be presented as “<1”.  
 


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14. 
TECHNICAL DETAILS 
SAS version 9.4 or above or R version 3.2 or above will be used to generate tables, figures, and listings.   


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15. 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY OR 
PLANNED ANALYSES 
No changes. 


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16. 
REFERENCES 
 
1. Investigator’s Brochure. Product Name, Zoliflodacin (Research number ETX0914), Edition Number 3, 
18 September 2017 
 
2. A Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD0914 (Phase 1 study). 
ClinicalTrials.gov Identifier: NCT01929629. 
https://clinicaltrials.gov/ct2/show/NCT01929629?term=AZD0914&rank=3 (accessed 27July 2017). 
 
3. 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 
 
4. 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/UCM
073153.pdf (Accessed on 27 July 2017) 
 
5. Basarab GS, Kern GH, McNulty J, et al. Responding to the challenge of untreatable gonorrhea: 
ETX0914, a first-in-class agent with a distinct mechanism-of-action against bacterial Type II 
topoisomerases. Sci Rep. 2015 Jul 14;5:11827 
 
6. Huband MD, Bradford PA, Otterson LG, et al. In vitro antibacterial activity of AZD0914, a new 
spiropyrimidinetrione DNA gyrase/topoisomerase inhibitor with potent activity against Gram-positive, 
fastidious Gram-Negative, and atypical bacteria. Antimicrob Agents Chemother. 2015 Jan; 59(1): 467-
74. 
 
7. Centers for Disease Control and Prevention, (CDC). CDC Fact Sheet: STD Trends in the United 
States: 2011 National Data for Chlamydia, Gonorrhea, and Syphilis, 2013. Available at: 
http://www.cdc.gov/std/stats11/trends-2011.pdf  (accessed on 10 July 2014) 
 
8. Centers for Disease Control and Prevention (CDC). Antibiotic Resistance Threats in the United States, 
2013. Available at: http://www.cdc.gov/drugresistance/threatreport-2013/pdf/ar-threats-2013-508.pdf 
(accessed on 10 July 2014) 


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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: 
Study Design ...............................................................................................................35 
Table 2: 
Distribution of Protocol Deviations by Category, and Type ......................................37 
Table 3: 
Toxicity Grading Scale ...............................................................................................38 
Table 4: 
Laboratory Adverse Event Grading Scale ..................................................................41 
Table 5:  
Subject Disposition .....................................................................................................43 
Table 6: 
Analysis Populations ..................................................................................................44 
Table 7: 
Ineligibility Summary of Screen Failures ...................................................................45 
Table 8: 
Summary of Categorical Demographic and Baseline Characteristics ........................48 
Table 9: 
Summary of Continuous Demographic and Baseline Characteristics ........................49 
Table 10: Summary of Subjects with Pre-Existing Medical Conditions by MedDRA 
System Organ Class ....................................................................................................50 
Table 11: Overall Summary of Adverse Events .........................................................................51 
Table 12: Summary of Unsolicited Adverse Events by MedDRA System Organ Class, 
Higher Level Group Term, and Preferred Term .........................................................53 
Table 13: Unsolicited Adverse Events by MedDRA System Organ Class, Higher Level 
Group Term, Preferred Term, Maximum Severity, and Relationship ........................54 
Table 14: Listing of Serious Adverse Events .............................................................................55 
Table 15: Listing of Non-Serious, Unsolicited, Moderate or Severe Adverse Events ...............56 
Table 16: Listing of Abnormal Laboratory Results - Chemistry ................................................58 
Table 17: Listing of Abnormal Laboratory Results - Hematology .............................................59 
Table 18: Listing of Abnormal Laboratory Results - Urinalysis ................................................60 
Table 19:  Chemistry Laboratory Results by Severity and Time Point – Any Chemistry 
Parameter ....................................................................................................................61 
Table 20: Chemistry Laboratory Results by Severity and Time Point – Sodium .......................62 
Table 21: Chemistry Laboratory Results by Severity and Time Point – Potassium ...................63 
Table 22: Chemistry Laboratory Results by Severity and Time Point – Bicarbonate ................63 
Table 23: Chemistry Laboratory Results by Severity and Time Point – Glucose ......................63 
Table 24: Chemistry Laboratory Results by Severity and Time Point – Blood Urea 
Nitrogen ......................................................................................................................64 
Table 25: Chemistry Laboratory Results by Severity and Time Point – Creatinine ..................64 
Table 26: Chemistry Laboratory Results by Severity and Time Point – Protein ........................64 


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Table 27: Chemistry Laboratory Results by Severity and Time Point – Albumin .....................64 
Table 28: Chemistry Laboratory Results by Severity and Time Point – Aspartate 
Aminotransferase ........................................................................................................64 
Table 29: Chemistry Laboratory Results by Severity and Time Point – Alanine 
Aminotransferase ........................................................................................................64 
Table 30: Chemistry Laboratory Results by Severity and Time Point – Alkaline 
Phosphatase .................................................................................................................64 
Table 31:  Chemistry Laboratory Results by Severity and Time Point – Bilirubin .....................65 
Table 32 
Chemistry Abnormal Laboratory Results Related to Study Treatment by 
Severity and Time Point – Any Chemistry Parameter ................................................66 
Table 33:  Chemistry Abnormal Laboratory Results Related to Study Treatment by 
Severity and Time Point – Sodium .............................................................................66 
Table 34:  Chemistry Abnormal Laboratory Results Related to Study Treatment by 
Severity and Time Point – Potassium .........................................................................67 
Table 35:  Chemistry Abnormal Laboratory Results Related to Study Treatment by 
Severity and Time Point – Bicarbonate ......................................................................67 
Table 36: Chemistry Abnormal Laboratory Results Related to Study Treatment by 
Severity and Time Point – Glucose ............................................................................67 
Table 37:  Chemistry Abnormal Laboratory Results Related to Study Treatment by 
Severity and Time Point – Blood Urea Nitrogen ........................................................67 
Table 38:  Chemistry Abnormal Laboratory Results Related to Study Treatment by 
Severity and Time Point – Creatinine .........................................................................67 
Table 39: Chemistry Abnormal Laboratory Results Related to Study Treatment by 
Severity and Time Point – Protein ..............................................................................68 
Table 40: Chemistry Abnormal Laboratory Results Related to Study Treatment by 
Severity and Time Point – Albumin ...........................................................................68 
Table 41:  Chemistry Abnormal Laboratory Results Related to Study Treatment by 
Severity and Time Point – Aspartate Aminotransferase .............................................68 
Table 42:  Chemistry Abnormal Laboratory Results Related to Study Treatment by 
Severity and Time Point – Alanine Aminotransferase ...............................................68 
Table 43:  Chemistry Abnormal Laboratory Results Related to Study Treatment by 
Severity and Time Point – Alkaline Phosphatase .......................................................68 
Table 44:  Chemistry Abnormal Laboratory Results Related to Study Treatment by 
Severity and Time Point – Bilirubin ...........................................................................68 
Table 45:  Chemistry Laboratory Summary Statistics by Time Point – Sodium 
(mmol/L) .....................................................................................................................69 
Table 46:  Chemistry Laboratory Summary Statistics by Time Point – Potassium 
(mmol/L) .....................................................................................................................69 


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Table 47:  Chemistry Laboratory Summary Statistics by Time Point – Magnesium 
(mg/dL) .......................................................................................................................69 
Table 48:  Chemistry Laboratory Summary Statistics by Time Point – Chloride 
(mmol/L) .....................................................................................................................69 
Table 49:  Chemistry Laboratory Summary Statistics by Time Point – Bicarbonate 
(mmol/L) .....................................................................................................................69 
Table 50:  Chemistry Laboratory Summary Statistics by Time Point – Glucose (mg/dL) ..........69 
Table 51:  Chemistry Laboratory Summary Statistics by Time Point – Blood Urea 
Nitrogen (mg/dL) ........................................................................................................70 
Table 52:  Chemistry Laboratory Summary Statistics by Time Point – Creatinine 
(mg/dL) .......................................................................................................................70 
Table 53:  Chemistry Laboratory Summary Statistics by Time Point – Protein (g/dL) ..............70 
Table 54:  Chemistry Laboratory Summary Statistics by Time Point – Albumin (g/dL)............70 
Table 55: Chemistry Laboratory Summary Statistics by Time Point – Aspartate 
Aminotransferase (U/L) ..............................................................................................70 
Table 56: Chemistry Laboratory Summary Statistics by Time Point – Alanine 
Aminotransferase (U/L) ..............................................................................................70 
Table 57: Chemistry Laboratory Summary Statistics by Time Point – Alkaline 
Phosphatase (U/L) ......................................................................................................70 
Table 58: Chemistry Laboratory Summary Statistics by Time Point – Bilirubin 
(mg/dL) .......................................................................................................................71 
Table 59:  Chemistry Laboratory Summary Statistics by Time Point – Direct Bilirubin 
(mg/dL) .......................................................................................................................71 
Table 60:  Hematology Laboratory Results by Severity and Time Point – Any 
Hematology Parameter ...............................................................................................72 
Table 61:  Hematology Laboratory Results by Severity and Time Point – Hemoglobin ............72 
Table 62:  Hematology Laboratory Results by Severity and Time Point – Leukocytes ..............72 
Table 63:  Hematology Laboratory Results by Severity and Time Point – Neutrophils .............72 
Table 64:  Hematology Laboratory Results by Severity and Time Point – Lymphocytes ..........72 
Table 65:  Hematology Laboratory Results by Severity and Time Point – Monocytes ..............72 
Table 66:  Hematology Laboratory Results by Severity and Time Point – Eosinophils .............72 
Table 67:  Hematology Laboratory Results by Severity and Time Point – Basophils ................73 
Table 68:  Hematology Laboratory Results by Severity and Time Point – Platelets ..................73 
Table 69:  Hematology Abnormal Laboratory Results Related to Study Treatment by 
Severity and Time Point – Any Hematology Parameter ............................................74 


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Table 70:  Hematology Abnormal Laboratory Results Related to Study Treatment by 
Severity and Time Point – Hemoglobin .....................................................................74 
Table 71:  Hematology Abnormal Laboratory Results Related to Study Treatment by 
Severity and Time Point – Leukocytes .......................................................................74 
Table 72:  Hematology Abnormal Laboratory Results Related to Study Treatment by 
Severity and Time Point – Neutrophils ......................................................................74 
Table 73:  Hematology Abnormal Laboratory Results Related to Study Treatment by 
Severity and Time Point – Lymphocytes ....................................................................74 
Table 74:  Hematology Abnormal Laboratory Results Related to Study Treatment by 
Severity and Time Point – Monocytes ........................................................................74 
Table 75:  Hematology Abnormal Laboratory Results Related to Study Treatment by 
Severity and Time Point – Eosinophils ......................................................................74 
Table 76:  Hematology Abnormal Laboratory Results Related to Study Treatment by 
Severity and Time Point – Basophils..........................................................................75 
Table 77:  Hematology Abnormal Laboratory Results Related to Study Treatment by 
Severity and Time Point – Platelets ............................................................................75 
Table 78:  Hematology Laboratory Summary Statistics by Time Point – Hemoglobin 
(g/dL) ..........................................................................................................................76 
Table 79:  Hematology Laboratory Summary Statistics by Time Point – Hematocrit (%) .........76 
Table 80:  Hematology Laboratory Summary Statistics by Time Point – Erythrocytes 
(10^12/L) ....................................................................................................................76 
Table 81:  Hematology Laboratory Summary Statistics by Time Point – Leukocytes 
(10^9/L) ......................................................................................................................76 
Table 82:  Hematology Laboratory Summary Statistics by Time Point – Neutrophils 
(10^9/L) ......................................................................................................................76 
Table 83:  Hematology Laboratory Summary Statistics by Time Point – Lymphocytes 
(10^9/L) ......................................................................................................................76 
Table 84:  Hematology Laboratory Summary Statistics by Time Point – Monocytes 
(10^9/L) ......................................................................................................................76 
Table 85:  Hematology Laboratory Summary Statistics by Time Point – Eosinophils 
(10^9/L) ......................................................................................................................77 
Table 86:  Hematology Laboratory Summary Statistics by Time Point – Basophils 
(10^9/L) ......................................................................................................................77 
Table 87:  Hematology Laboratory Summary Statistics by Time Point – Platelets 
(10^9/L) ......................................................................................................................77 
Table 88:  Urinalysis Laboratory Results by Severity and Time Point – Any Urinalysis 
Parameter ....................................................................................................................78 
Table 89:  Urinalysis Laboratory Results by Severity and Time Point – Protein ........................78 


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Table 90:  Urinalysis Laboratory Results by Severity and Time Point – Glucose ......................78 
Table 91:  Urinalysis Laboratory Results by Severity and Time Point – Hemoglobin ...............78 
Table 92:  Urinalysis Abnormal Laboratory Results Related to Study Treatment by 
Severity and Time Point – Any Urinalysis Parameter ................................................79 
Table 93:  Urinalysis Abnormal Laboratory Results Related to Study Treatment by 
Severity and Time Point – Protein ..............................................................................79 
Table 94:  Urinalysis Abnormal Laboratory Results Related to Study Treatment by 
Severity and Time Point – Glucose ............................................................................79 
Table 95:  Urinalysis Abnormal Laboratory Results Related to Study Treatment by 
Severity and Time Point – Hemoglobin .....................................................................79 
Table 96: Vital Signs by Assessment, Maximum Severity, and Time Point – Any 
Assessment .................................................................................................................80 
Table 97: Vital Signs by Assessment, Maximum Severity, and Time Point – Systolic 
Blood Pressure ............................................................................................................80 
Table 98: Vital Signs by Assessment, Maximum Severity, and Time Point – Diastolic 
Blood Pressure ............................................................................................................80 
Table 99: Vital Signs by Assessment, Maximum Severity, and Time Point – Pulse Rate .........80 
Table 100: Vital Signs by Assessment, Maximum Severity, and Time Point – 
Respiratory Rate .........................................................................................................80 
Table 101: Vital Signs by Assessment, Maximum Severity, and Time Point –
Temperature ................................................................................................................80 
Table 102: Vital Signs Summary Statistics by Assessment and Time Point – Systolic 
Blood Pressure (mmHg) .............................................................................................81 
Table 103: Vital Signs Summary Statistics by Assessment and Time Point – Diastolic 
Blood Pressure (mmHg) .............................................................................................82 
Table 104: Vital Signs Summary Statistics by Assessment and Time Point – Pulse Rate 
(beats/min) ..................................................................................................................82 
Table 105: Vital Signs Summary Statistics by Assessment and Time Point – Respiratory 
Rate (breaths/min) ......................................................................................................82 
Table 106: Vital Signs Summary Statistics by Assessment and Time Point –
Temperature (C) ..........................................................................................................82 
Table 107: ECG Overall Interpretations, Post Dose Compared to Baseline ................................83 
Table 108: ECG by Parameter, Maximum Severity, and Time Point – PR Interval, 
Aggregate ....................................................................................................................84 
Table 109: ECG by Parameter, Maximum Severity, and Time Point – QTcF Interval, 
Aggregate ....................................................................................................................84 


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Table 110: ECG Summary Statistics by Parameter and Time Point – PR Interval, 
Aggregate (msec) ........................................................................................................85 
Table 111: ECG Summary Statistics by Parameter and Time Point – QRS Duration, 
Aggregate (msec) ........................................................................................................85 
Table 112: ECG Summary Statistics by Parameter and Time Point – QT Interval, 
Aggregate (msec) ........................................................................................................85 
Table 113: ECG Summary Statistics by Parameter and Time Point – QTcF Interval, 
Aggregate (msec) ........................................................................................................85 
Table 114: ECG Summary Statistics by Parameter and Time Point – RR Interval, 
Aggregate (msec) ........................................................................................................86 
Table 115: ECG Summary Statistics by Parameter and Time Point – ECG Mean 
Ventricular Rate (msec) ..............................................................................................86 
Table 116: ECG Measurements, Frequency of QTcF Prolongation .............................................87 
Table 117: Number and Percentage of Subjects with Prior Medications by WHO Drug 
Classification ..............................................................................................................88 
Table 118: Number and Percentage of Subjects with Concomitant Medications by WHO 
Drug Classification .....................................................................................................89 


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9.5.1 Overall Study Design and Plan Description  
Table 1: 
Study Design 
9.5.1 Safety Measurements Assessed and Flow Chart 
Study Visit 
Screening 1 
Check-in 
Inpatient Period 
Final Visit 
Unscheduled 
Early 
termination 
Dosing 
Follow Up 
Study Day / Assessments 
-21 to -2 
-1 
1 
2 
3 
4 
8 (± 2) 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Medical history update 
 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and ConMeds  2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete PE 3 
X 
 
 
 
 
 
X 
 
X 
Abbreviated PE 4 
 
X 
 
 
 
X 
 
 
 
Symptom-directed PE 5 
 
 
X 
X 
X 
 
 
X 
 
Height, weight, BMI 6 
X 
 
 
 
 
 
 
 
 
Weight 
 
X 
 
 
 
 
X 
 
 
Vital signs 7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical labs (hematology, 
chemistry, urinalysis) 8 
X 
X 
 
 
 
X 
 
X 
X 
Viral serology 9 
X 
 
 
 
 
 
 
 
 
Serum pregnancy test 
X13 
X 
 
 
 
 
X 
 
X 
Serum FSH level 
X13 
 
 
 
 
 
 
 
 
Urine toxicology 
X 
X 
 
 
 
 
 
 
 
Alcohol breathalyzer test 
X 
X 
 
 
 
 
 
 
 
12-lead ECG 10 
X 
X 
X 
 
 
X 
 
 
X 
Study drug dosing 
 
 
X 
 
 
 
 
 
 
PK samples 11 
 
 
X 
X 
X 
X 
 
 
X 
Counsel on use of contraception 
and avoidance of pregnancy14 
X 
 
 
 
 
X 
X 
 
X 
Counsel to avoid use of prohibited 
medications, alcohol, marijuana 
and illicit drugs 
X 
X 
 
 
 
X 
X 
 
 
Interim medical history 
 
 
X 
X 
X 
X 
X 
X 
X 


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


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10.2 
Protocol Deviations 
Table 2: 
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 
 
 
 
Stool not collected 
 
 
 
Other specimen not collected 
 
 
 
Too few aliquots obtained 
 
 
 
Specimen result not obtained 
 
 
 
Required procedure not conducted 
 
 
 
Required procedure done incorrectly 
 
 
 
Study product temperature excursion 
 
 
 
Specimen temperature excursion 
 
 
 
Other 
 
 
Treatment administration 
Any type 
 
 
 
Required procedure done incorrectly 
 
 
 
Study product temperature excursion 
 
 
 
Other 
 
 
N = number of subjects enrolled. 


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12.2.2 Displays of Adverse Events 
Table 3: 
Toxicity Grading Scale 
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 of the protocol) 
Bradycardia - bpm 
50-54 OR 45-50 if baseline 
<60 
45-49 OR 40-44 if 
baseline <60 
<45 OR <40 if 
baseline <60 
as above 
Hypertension (systolic) - 
mm Hg 
141-150 
151-160 
>160 
Assume awake, and in 
supine position for 5 min at 
rest; for AE, measurements 
on same arm at least 3 
times with 2 concordant 
results (Section 8.1.6 of the 
protocol) 
Hypertension (diastolic) - 
mm Hg 
91-95 
96-100 
>100 
As above 
Hypotension (systolic) - 
mm Hg 
85-89 
80-84 
<80 
As above 
Tachypnea – breaths per 
min 
23-25 
26-30 
>30 
Assume awake and in 
supine position for 5 min at 
rest; for AE, measurements 
at least 3 times with 2 
concordant results (Section 
8.1.6 of the protocol) 
Note: Isolated/individual abnormalities of vital signs would not be considered toward halting criteria. Abnormalities of vital signs should be 
described as “increase X” or “decrease X” (X = heart rate, blood pressure, respiratory rate, temperature) if asymptomatic, transient and not 
associated with a systemic or organ-specific disorder, and coded by MedDRA within the System Organ Class (SOC) “Investigations.” These 
abnormalities should be graded per criteria in Appendix C of the protocol, but not considered in determining whether study stopping criteria 
have been met. On the other hand, abnormalities of vital signs that are either secondary to systemic or organ-specific clinical syndrome or 
primary disorders should be coded in the appropriate SOC (e.g., "cardiac disorders", respiratory disorders", "immunological disorders", etc.). 
These abnormalities should be considered in determining whether stopping criteria have been met. 
 
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 
 


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


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


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


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Laboratory AEs 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Glucose 
1+ 
2+ 
>2+ 
Blood (dipstick) 
1+ 
2+ 
>2+ 
Blood (microscopic) - RBCs per HPF 
6-10 
11-50 
>50 and/or gross blood 
WBC (microscopic) – WBC per HPF 
5-10 
11-50 
>50 
Bacteria (microscopic) 
few 
moderate 
Many 
* Institutional normal reference ranges and allowable ranges at screening are provided in Appendix B of the protocol. 
**ALT, males: >216 U/mL; ALT, females: >132 U/mL; AST, male or female: >126 U/mL) 
Note 1: If a subject was accepted into the trial with a laboratory value of an analyte that overlaps with values used for grading Grade 1 (mild) 
laboratory abnormalities, an AE will be reported if the on-study value of the same analyte is different (worse) from the baseline. 
Note 2: Safety laboratory results that are abnormal according to the local laboratory reference range, but not considered a Grade 1 
abnormality, will be evaluated by the study site clinician and reported as Grade 1 abnormality if clinically significant. If not clinically 
significant, these will not be considered laboratory AEs and will thus not be graded, but will be recorded in the source document and followed-
up clinically at the discretion of the study site clinician.  
Note 3: Other laboratory parameters performed and reported as parted of the complete blood count, metabolic panel and urinalysis will be 
evaluated by the study physician, recorded in the source document, and reported as laboratory AEs if clinically significant, and graded 
according to the criteria in Section 9.2.1 of the protocol. 
Note 4: If US by dipstick is abnormal, a microscopic urinalysis will be performed and the results will supersede the results of the dipstick 
urinalysis. 
Note 5: Menstruating females with a positive urine dipstick or microscopic urinalysis  may be retested following cessation of menses. 
 
ECG interval abnormality  
Grade 1 
Grade 2 
Grade 3 
QT/QTc interval (Fridericia’s correction) 
prolonged (msec) 
Asymptomatic, QTc 450-
479 msec, OR increase in 
interval <30 msec above 
baseline 
 
Asymptomatic, QTc 480-
499 msec OR increase in 
interval 30-59 msec above 
baseline 
Asymptomatic, QTc ≥500 
msec OR increase in interval 
≥60 msec above baseline 
PR interval prolonged - sec 
0.21-0.25 sec 
>0.25 sec 
Type II 2nd degree AV block 
OR ventricular pause >3.0 sec 
Note: The events will be coded as SAE if there are life-threatening associated symptoms or signs (arrhythmia, CHF, hypotension, syncope, 
torsade’s de pointes, etc.) 
Note: If a male subject was accepted into the trial with a QT/QTc value that overlaps with values used for grading Grade 1 (mild) QT/QTc 
prolongation, an AE will be reported if the on-study value of the QT/QTc is higher than the baseline 
 
 


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14.1 
Description of Study Subjects 
14.1.1 Disposition of Subjects 
Table 5:  
Subject Disposition 
Subject 
Disposition  
All Subjects 
(N=X) 
n 
% 
Screened 
x 
-- 
Enrolled 
x 
100 
Received Treatment 
x 
Xx 
Completed Final Blood Draw 
 
 
Completed Follow-up (Study Day 8) 
 
 
Early Termination a 
 
 
Discontinued Study Product 
 
 
Note: N = number of subjects enrolled 
a Refer to Listing 1 for reasons subjects discontinued or terminated early. 
 
 


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Table 6: 
Analysis Populations  
Analysis Populations 
Reason Subjects Excluded 
All Subjects 
(N=X) 
% 
N 
Safety Population 
Subject not dosed 
x 
Xx 
PK Analysis Population 
Any Reason 
 
 
 
Subject not dosed 
 
 
 
No measurable PK concentration 
 
 
PK Subset 
Any Reason 
 
 
 
Subject not dosed 
 
 
 
Disqualifying protocol deviation 
 
 
 
No measurable PK concentration 
 
 
Note: N = number of subjects enrolled 
 


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Table 7: 
Ineligibility Summary of Screen Failures 
Inclusion/Exclusion Category 
Inclusion/Exclusion Criterion 
na 
%b 
Inclusion and Exclusion 
Number of subjects failing any eligibility criterion 
X 
100 
Inclusion 
Any inclusion criterion 
X 
xx 
 
Informed consent form (ICF) understood and signed before initiating any study 
procedures 
X 
xx 
 
Healthy male or female, as assessed by the authorized site clinician 
X 
xx 
 
Willingness to comply with and be available for all protocol procedures including 
inpatient confinement for about 4 days and availability for follow-up for the 
duration of the trial 
X 
xx 
 
Aged 18 to 45 years inclusive on the day of study drug dosing 
X 
xx 
 
BMI ≥18.5 and ≤30 kg/m2 and weight ≥50 kg (110 lbs.) and ≤100 kg (220 lbs.) 
X 
xx 
 
In female subjects of childbearing potential, a negative serum pregnancy test at 
Screening Visit and on Day -1 
X 
xx 
 
If female, not pregnant, not breast feeding, and not planning on becoming pregnant 
during the trial and for 30 days after study participation 
X 
xx 
 
Females of childbearing potential and males agree to use acceptable contraception 
for the duration of the trial and for 30 days (females) or 90 days (males) after final 
study visit 
X 
xx 
 
Male subjects must agree to refrain from sperm donation for the duration of the 
trial and for 90 days after Final Visit 
x 
xx 
 
Laboratory tests, as outlined in Section 8.2.1.1 of the protocol, are in the normal 
reference range with acceptable exceptions as noted in Section 8.2.1.1 and 
Appendix B of the protocol 
x 
xx 
 
VS, as outlined in Section 8.1.6 of the protocol, are within the acceptable range per 
Appendix B of the protocol 
x 
xx 
 
Has adequate venous access for blood collection 
x 
xx 
 
Urine drug screen is negative for tested substances 
x 
xx 
 
Alcohol test (breathalyzer) is negative 
x 
xx 
 
Willing to abstain from alcohol consumption for 2 days before Day -1 and during 
the trial 
x 
xx 


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Inclusion/Exclusion Category 
Inclusion/Exclusion Criterion 
na 
%b 
Exclusion 
Any exclusion criterion 
x 
xx 
 
History of a chronic medical or surgical condition that would interfere with the 
accurate assessment of the trial’s objectives or increase the subject’s risk profile 
x 
xx 
 
History of hypersensitivity or severe allergic reaction of any type to medications, 
bee stings, food, or environmental factors 
x 
xx 
 
Active allergic symptoms to seasonal and animal allergens that require treatment   
x 
xx 
 
A marked baseline prolongation of ECG intervals, or HR <45 bpm or >100 bpm on 
ECG measurements 
x 
xx 
 
Clinically significant abnormal ECG results 
x 
xx 
 
Abnormal renal function 
x 
xx 
 
Positive serology results for HIV, HBsAg, or HCV 
x 
xx 
 
Febrile illness with temperature >37.6°C for <7 days before dosing 
x 
xx 
 
Donated whole blood or blood products within 60 days before dosing, or plans to 
donate before Final Visit (Day 8 ± 2) 
x 
xx 
 
Known allergic reactions to any of the study drug components present in the 
formulation or in its processing, as listed in the IB 
x 
xx 
 
Treatment with another investigational product within 30 days of dosing or 5 half-
lives or twice the duration of the biological effect of the study drug (whichever is 
longer) 
x 
xx 
 
Active drug or alcohol use, abuse, or dependence within 12 months before 
Screening Visit that, in the opinion of the investigator, would interfere with 
adherence to study requirements 
x 
xx 
 
Use of any prescription medication within 30 days before dosing or planned use 
during the study period except as noted below and approved by the designated 
study clinician 
x 
xx 
 
Use of any non-prescription medication, herbal preparation, or nutritional 
supplement within 15 days before dosing or planned use during the study unless 
approved by the study clinician 
x 
xx 
 
Intake of caffeinated beverages or food within 72 h before dosing or a history of 
high caffeine consumption (e.g., in the last 4 months drinking >5 cups of 
coffee/day) 
x 
xx 
 
Smoking or use of tobacco or nicotine-containing products within 15 days before 
dosing 
x 
xx 


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Inclusion/Exclusion Category 
Inclusion/Exclusion Criterion 
na 
%b 
 
Engagement in strenuous exercise within 15 days before dosing (e.g., marathon 
running, long distance cycling, weight lifting) and during the study period 
x 
xx 
 
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 
x 
xx 
 
Plans to enroll or is already enrolled in another clinical trial that could interfere 
with safety assessment of the study drug at any time during the study period 
x 
xx 
 
Is a study site employee or staff member who is paid entirely or partially by the 
OCRR/NIAID contract for the DMID-funded trial 
x 
xx 
a More than one criterion may be marked per subject. 
b Denominator for percentages is the total number of screen failures. 
 
 


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14.1.2 Demographic Data by Study Group 
Table 8: 
Summary of Categorical Demographic and Baseline Characteristics 
Variable 
Characteristic 
All Subjects 
(N=X) 
n 
% 
Sex  
Male 
x 
xx 
 
Female 
 
 
Ethnicity  
Not Hispanic or Latino 
x 
xx 
 
Hispanic or Latino 
 
 
 
Not Reported 
 
 
 
Unknown 
 
 
Race  
American Indian or Alaska Native 
x 
Xx 
 
Asian 
 
 
 
Native Hawaiian or Other Pacific Islander 
 
 
 
Black or African American 
 
 
 
White 
 
 
 
Multi-Racial 
 
 
 
Unknown 
 
 
Note: N = number of subjects enrolled. 
 
 


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Table 9: 
Summary of Continuous Demographic and Baseline Characteristics 
Variable 
Statistic 
All Subjects 
(N=X) 
Age 
Mean 
x.x 
 
Standard Deviation 
x.x 
 
Median 
x.x 
 
Minimum 
x 
 
Maximum 
x 
Height 
Mean 
x.x 
 
Standard Deviation 
x.x 
 
Median 
x.x 
 
Minimum 
x 
 
Maximum 
x 
Weight 
Mean 
x.x 
 
Standard Deviation 
x.x 
 
Median 
x.x 
 
Minimum 
x 
 
Maximum 
x 
BMI 
Mean 
x.x 
 
Standard Deviation 
x.x 
 
Median 
x.x 
 
Minimum 
x 
 
Maximum 
x 
Note: N = number of subjects enrolled 
 
 


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14.1.3 
Prior and Concurrent Medical Conditions 
Table 10: 
Summary of Subjects with Pre-Existing Medical Conditions by MedDRA System Organ 
Class 
MedDRA System Organ Class 
All Subjects 
(N=X) 
n 
% 
Any SOC 
x 
xx 
[SOC 1] 
 
 
[SOC 2] 
 
 
 
 
 
Note: N = number of subjects in safety population; n = Number of subjects reporting medical history within the specified SOC. A subject is only 
counted once per SOC. 
 
 


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14.3 
Safety Data 
14.3.1 Displays of Adverse Events 
Table 11: 
Overall Summary of Adverse Events 
 
Frequency of Event in All Subjects 
(N = x) 
Event 
n 
% 
At least one AE 
x 
x 
At least one related AE, mild (grade 1) 
x 
x 
At least one related AE, moderate (grade 2)  
x 
x 
At least one related AE, severe (grade 3)  
x 
x 
At least one serious AE, any 
x 
x 
At least one serious AE, related 
x 
x 
At least one AE leading to early termination 
x 
x 
N = Number of subjects in the Safety Population.  Subjects are counted once for each category regardless of the number of 
events. 


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14.3.1.1 
Solicited Adverse Events 
There are no solicited AEs. 
 


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14.3.1.2 
Unsolicited Adverse Events 
Table 12: 
Summary of Unsolicited Adverse Events by MedDRA System Organ Class, Higher Level 
Group Term, and Preferred Term 
MedDRA System 
Organ Class 
MedDRA Higher 
Level Group Term 
MedDRA Preferred 
Term 
Any Time Post Dose 
(N=X) 
n 
% 
95% CI 
Events 
Any SOC 
Any HLGT 
Any PT 
x 
xx 
xx, xx 
X 
[SOC 1] 
HLGT 1 
[PT 1] 
 
 
 
 
 
 
[PT 2] 
 
 
 
 
[SOC 2] 
HLGT 2 
[PT 1] 
 
 
 
 
 
 
[PT 2] 
 
 
 
 
 
 


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Table 13: 
Unsolicited Adverse Events by MedDRA System Organ Class, Higher Level Group Term, Preferred Term, Maximum Severity, 
and Relationship 
MedDRA System Organ Class 
MedDRA Higher Level Group Term 
Preferred Term 
Severity 
All Subjects 
(N = X) 
Related 
Any Relatedness 
n 
% 
n 
% 
Any SOC 
Any HLGT 
Any PT 
Any Severity 
x  
x  
x  
x  
 
 
 
Mild 
x  
x  
x  
x  
 
 
 
Moderate 
x  
x  
x  
x  
 
 
 
Severe 
x  
x  
x  
x  
SOC 1 
Any HLGT 
Any PT 
Any Severity 
x  
x  
x  
x  
 
 
 
Mild 
x  
x  
x  
x  
 
 
 
Moderate 
x  
x  
x  
x  
 
 
 
Severe 
x  
x  
x  
x  
SOC 2 
HLGT 1 
Any PT 
Any Severity 
x  
x  
x  
x  
 
 
 
Mild 
x  
x  
x  
x  
 
 
 
Moderate 
x  
x  
x  
x  
 
 
 
Severe 
x  
x  
x  
x  
SOC 3 
HLGT 1 
PT 1 
Any Severity 
x  
x  
x  
x  
 
 
 
Mild 
x  
x  
x  
x  
 
 
 
Moderate 
x  
x  
x  
x  
 
 
 
Severe 
x  
x  
x  
x  
Note: N = Number of subjects in the Safety Analysis Population. 
[1] For severity, a subject is counted once per preferred term and is summarized according to their highest severity.  Events are summarized separately for related events only and all AEs regardless of 
relatedness. 
 


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14.3.2 Listing of Deaths, Other Serious and Significant Adverse Events 
Table 14: 
Listing of Serious Adverse Events 
AE 
No. of 
Days Post 
Associated 
Dose 
(Duration) 
No. of Days 
Post Dose the 
Event 
Became 
Serious 
Reason 
Reported 
as an SAE 
Severity 
Relationship 
to Study 
Treatment 
If Not 
Related, 
Alternative 
Etiology 
Action 
Taken 
with Study 
Treatment 
Subject 
Discontinued 
Due to AE 
Outcome 
MedDRA 
System 
Organ Class 
MedDRA 
Higher Level 
Group Term 
MedDRA 
Preferred 
Term 
Subject ID:, AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
 
Subject ID:,  AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
 
 


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Table 15: 
Listing of Non-Serious, Unsolicited, Moderate or Severe Adverse Events 
AE 
No. of Days 
Post 
Associated 
Dose 
(Duration) 
No. of Days 
Post Dose the 
Event Became 
Serious 
Reason 
Reported 
as an 
SAE 
Severity 
Relationship 
to Study 
Treatment 
If Not 
Related, 
Alternative 
Etiology 
Action 
Taken 
with Study 
Treatment 
Subject 
Discontinued 
Due to AE 
Outcome 
MedDRA 
System 
Organ 
Class 
MedDRA 
Higher Level 
Group Term 
MedDRA 
Preferred 
Term 
Subject ID:,  AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
 
Subject ID:,  AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
 


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14.3.3 Narratives of Deaths, Other Serious and Significant Adverse Events 
This is a placeholder for the CSR. 
 


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14.3.4 Abnormal Laboratory Value Listings (by Subject) 
Table 16: 
Listing of Abnormal Laboratory Results - Chemistry 
Subject 
ID 
Sex 
Age (years) 
Fasting Status 
Planned Time 
Point 
Actual 
Study Day 
Laboratory 
Parameter 
(Units) 
Result (Severity) 
Relationship to 
Treatment 
If Not Related, 
Alternate 
Etiology 
Clinically 
Significant? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 17: 
Listing of Abnormal Laboratory Results - Hematology 
Subject 
ID 
Sex 
Age (years) 
Planned Time 
Point 
Actual Study 
Day 
Laboratory 
Parameter 
(Units) 
Result (Severity) 
Relationship to 
Treatment 
If Not Related, 
Alternate Etiology 
Clinically 
Significant? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 18: 
Listing of Abnormal Laboratory Results - Urinalysis 
Subject 
ID 
Sex 
Age (years) 
Planned Time 
Point 
Actual Study 
Day 
Laboratory 
Parameter 
(Units) 
Result (Severity) 
Relationship to 
Treatment 
If Not Related, 
Alternate Etiology 
Clinically 
Significant? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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14.3.5 Displays of Laboratory Results 
14.3.5.1 
Chemistry Results 
Table 19:  
Chemistry Laboratory Results by Severity and Time Point – Any Chemistry Parameter 
 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
Time Point 
N 
n 
% 
N 
% 
n 
% 
N 
% 
n 
% 
Baseline 
x 
x 
x 
X 
X 
x 
x 
X 
x 
x 
X 
Day 4 
x 
x 
x 
X 
X 
x 
x 
X 
x 
x 
X 
Max Severity Post Baseline 
x 
x 
x 
X 
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, including unscheduled assessments. N=Number of subjects in the Safety Population. 
 
 


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Table 20: 
Chemistry Laboratory Results by Severity and Time Point – Sodium 
 
None 
Mild/ 
Grade 1 
(Low) 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(Low) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(Low) 
Severe/ 
Grade 3 
(High) 
Missing 
Time Point 
N 
n 
% 
n 
% 
N 
% 
n 
% 
n 
% 
n 
% 
N 
% 
n 
% 
Baseline 
x 
x 
x 
x 
x 
X 
x 
x 
x 
x 
x 
x 
x 
X 
x 
x 
x 
Day 4 
x 
x 
x 
x 
x 
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Max Severity Post 
Baseline 
x 
x 
x 
x 
x 
X 
x 
x 
x 
x 
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, including unscheduled 
assessments. N=Number of subjects in the Safety Population. 


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Table 21: 
Chemistry Laboratory Results by Severity and Time Point – Potassium 
This table will repeat Table 20 for Potassium. 
 
 
Table 22: 
Chemistry Laboratory Results by Severity and Time Point – Bicarbonate 
This table will repeat Table 20 for Bicarbonate. 
 
 
Table 23: 
Chemistry Laboratory Results by Severity and Time Point – Glucose 
This table will repeat Table 20 for Glucose. 
 
 


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Table 24: 
Chemistry Laboratory Results by Severity and Time Point – Blood Urea Nitrogen 
This table will repeat Table 19 for Blood Urea Nitrogen. 
 
 
Table 25: 
Chemistry Laboratory Results by Severity and Time Point – Creatinine 
This table will repeat Table 19 for Creatinine. 
 
 
Table 26: 
Chemistry Laboratory Results by Severity and Time Point – Protein 
This table will repeat Table 19 for Protein. 
 
 
Table 27: 
Chemistry Laboratory Results by Severity and Time Point – Albumin 
This table will repeat Table 19 for Albumin. 
 
 
Table 28: 
Chemistry Laboratory Results by Severity and Time Point – Aspartate Aminotransferase 
This table will repeat Table 19 for Aspartate Aminotransferase. 
 
 
Table 29: 
Chemistry Laboratory Results by Severity and Time Point – Alanine Aminotransferase 
This table will repeat Table 20 for Alanine Aminotransferase. 
 
 
Table 30: 
Chemistry Laboratory Results by Severity and Time Point – Alkaline Phosphatase 
This table will repeat Table 19 for Alkaline Phosphatase. 
 


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Table 31:  
Chemistry Laboratory Results by Severity and Time Point – Bilirubin 
This table will repeat Table 19 for Bilirubin. 
 
 


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Table 32 
Chemistry Abnormal Laboratory Results Related to Study Treatment by Severity and Time Point – Any Chemistry Parameter 
 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Time Point 
N 
n 
% 
n 
% 
N 
% 
Baseline 
x 
x 
x 
x 
x 
X 
x 
Day 4 
x 
x 
x 
x 
x 
X 
x 
Max Severity Post Baseline 
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, including unscheduled assessments. N=Number of subjects in the Safety Population. 
 
Table 33:  
Chemistry Abnormal Laboratory Results Related to Study Treatment by Severity and Time Point – Sodium 
 
Mild/ 
Grade 1 
(Low) 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(Low) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(Low) 
Severe/ 
Grade 3 
(High) 
Time Point 
N 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Baseline 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Day 4 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Max Severity Post 
Baseline 
x 
x 
x 
x 
x 
x 
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, including 
unscheduled assessments. N=Number of subjects in the Safety Population. 
 


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Table 34:  
Chemistry Abnormal Laboratory Results Related to Study Treatment by Severity and Time Point – Potassium 
This table will repeat Table 33 for Potassium. 
 
 
Table 35: 
 Chemistry Abnormal Laboratory Results Related to Study Treatment by Severity and Time Point – Bicarbonate 
This table will repeat Table 33 for Bicarbonate. 
 
 
Table 36: 
Chemistry Abnormal Laboratory Results Related to Study Treatment by Severity and Time Point – Glucose 
This table will repeat Table 33 for Glucose. 
 
 
Table 37:  
Chemistry Abnormal Laboratory Results Related to Study Treatment by Severity and Time Point – Blood Urea Nitrogen 
This table will repeat Table 32 for Blood Urea Nitrogen. 
 
 
Table 38:  
Chemistry Abnormal Laboratory Results Related to Study Treatment by Severity and Time Point – Creatinine 
This table will repeat Table 32 for Creatinine. 
 


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Table 39: 
Chemistry Abnormal Laboratory Results Related to Study Treatment by Severity and Time Point – Protein 
This table will repeat Table 32 for Protein. 
 
 
Table 40: 
Chemistry Abnormal Laboratory Results Related to Study Treatment by Severity and Time Point – Albumin 
This table will repeat Table 32 for Albumin. 
 
 
Table 41:  
Chemistry Abnormal Laboratory Results Related to Study Treatment by Severity and Time Point – Aspartate Aminotransferase 
This table will repeat Table 32 for Aspartate Aminotransferase. 
 
 
Table 42:  
Chemistry Abnormal Laboratory Results Related to Study Treatment by Severity and Time Point – Alanine Aminotransferase 
This table will repeat Table 32 for Alanine Aminotransferase. 
 
 
Table 43:  
Chemistry Abnormal Laboratory Results Related to Study Treatment by Severity and Time Point – Alkaline Phosphatase 
This table will repeat Table 32 for Alkaline Phosphatase. 
 
 
Table 44:  
Chemistry Abnormal Laboratory Results Related to Study Treatment by Severity and Time Point – Bilirubin 
This table will repeat Table 32 for Bilirubin. 
 
 


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Table 45:  
Chemistry Laboratory Summary Statistics by Time Point – Sodium (mmol/L) 
Time Point 
N 
Mean 
Standard Deviation 
Median 
Min, Max 
Baseline 
x 
x.x 
x.x 
x.x 
x, x 
Day 4 
x 
x.x 
x.x 
x.x 
x, x 
Day 4, Change from Baseline 
x 
x.x 
x.x 
x.x 
x, x 
Note: N=Number of subjects in the Safety Population with the laboratory result assessed at the respective time point. 
 
 
Table 46:  
Chemistry Laboratory Summary Statistics by Time Point – Potassium (mmol/L) 
This table will repeat Table 45 for Potassium. 
 
 
Table 47:  
Chemistry Laboratory Summary Statistics by Time Point – Magnesium (mg/dL) 
This table will repeat Table 45 for Magnesium. 
 
 
Table 48:  
Chemistry Laboratory Summary Statistics by Time Point – Chloride (mmol/L) 
This table will repeat Table 45 for Chloride. 
 
 
Table 49:  
Chemistry Laboratory Summary Statistics by Time Point – Bicarbonate (mmol/L) 
This table will repeat Table 45 for Bicarbonate. 
 
 
Table 50:  
Chemistry Laboratory Summary Statistics by Time Point – Glucose (mg/dL) 
This table will repeat Table 45 for Glucose. 
 
 


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Table 51:  
Chemistry Laboratory Summary Statistics by Time Point – Blood Urea Nitrogen (mg/dL) 
This table will repeat Table 45 for Blood Urea Nitrogen. 
 
 
Table 52:  
Chemistry Laboratory Summary Statistics by Time Point – Creatinine (mg/dL) 
This table will repeat Table 45 for Creatinine. 
 
 
Table 53:  
Chemistry Laboratory Summary Statistics by Time Point – Protein (g/dL) 
This table will repeat Table 45 for Protein. 
 
 
Table 54:  
Chemistry Laboratory Summary Statistics by Time Point – Albumin (g/dL) 
This table will repeat Table 45 for Albumin. 
 
 
Table 55: 
Chemistry Laboratory Summary Statistics by Time Point – Aspartate Aminotransferase (U/L) 
This table will repeat Table 45 for Aspartate Aminotransferase. 
 
 
Table 56: 
Chemistry Laboratory Summary Statistics by Time Point – Alanine Aminotransferase (U/L) 
This table will repeat Table 45 for Alanine Aminotransferase. 
 
 
Table 57: 
Chemistry Laboratory Summary Statistics by Time Point – Alkaline Phosphatase (U/L) 
This table will repeat Table 45 for Alkaline Phosphatase. 
 
 


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Table 58: 
Chemistry Laboratory Summary Statistics by Time Point – Bilirubin (mg/dL) 
This table will repeat Table 45 for Bilirubin. 
 
 
Table 59:  
Chemistry Laboratory Summary Statistics by Time Point – Direct Bilirubin (mg/dL) 
This table will repeat Table 45 for Direct Bilirubin. 
 
 


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Table 60:  
Hematology Laboratory Results by Severity and Time Point – Any Hematology Parameter 
This table will repeat Table 19 for Any Hematology Parameter. 
 
 
Table 61:  
Hematology Laboratory Results by Severity and Time Point – Hemoglobin 
This table will repeat Table 19 for Hemoglobin. 
 
 
Table 62:  
Hematology Laboratory Results by Severity and Time Point – Leukocytes 
This table will repeat Table 19 for Leukocytes. 
 
 
Table 63:  
Hematology Laboratory Results by Severity and Time Point – Neutrophils 
This table will repeat Table 19 for Neutrophils. 
 
 
Table 64:  
Hematology Laboratory Results by Severity and Time Point – Lymphocytes 
This table will repeat Table 19 for Lymphocytes. 
 
 
Table 65:  
Hematology Laboratory Results by Severity and Time Point – Monocytes 
This table will repeat Table 19 for Monocytes. 
 
 
Table 66:  
Hematology Laboratory Results by Severity and Time Point – Eosinophils 
This table will repeat Table 19 for Eosinophils. 
 
 


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Table 67:  
Hematology Laboratory Results by Severity and Time Point – Basophils 
This table will repeat Table 19 for Basophils. 
 
 
Table 68:  
Hematology Laboratory Results by Severity and Time Point – Platelets 
This table will repeat Table 19 for Platelets. 
 


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Table 69:  
Hematology Abnormal Laboratory Results Related to Study Treatment by Severity and Time Point – Any Hematology Parameter 
This table will repeat Table 32 for Any Hematology Parameter. 
 
 
Table 70:  
Hematology Abnormal Laboratory Results Related to Study Treatment by Severity and Time Point – Hemoglobin 
This table will repeat Table 32 for Hemoglobin. 
 
 
Table 71:  
Hematology Abnormal Laboratory Results Related to Study Treatment by Severity and Time Point – Leukocytes 
This table will repeat Table 32 for Leukocytes. 
 
 
Table 72:  
Hematology Abnormal Laboratory Results Related to Study Treatment by Severity and Time Point – Neutrophils 
This table will repeat Table 32 for Neutrophils. 
 
 
Table 73:  
Hematology Abnormal Laboratory Results Related to Study Treatment by Severity and Time Point – Lymphocytes 
This table will repeat Table 32 for Lymphocytes. 
 
 
Table 74:  
Hematology Abnormal Laboratory Results Related to Study Treatment by Severity and Time Point – Monocytes 
This table will repeat Table 32 for Monocytes. 
 
 
Table 75:  
Hematology Abnormal Laboratory Results Related to Study Treatment by Severity and Time Point – Eosinophils 
This table will repeat Table 32 for Eosinophils. 
 
 


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Table 76:  
Hematology Abnormal Laboratory Results Related to Study Treatment by Severity and Time Point – Basophils 
This table will repeat Table 32 for Basophils. 
 
 
Table 77:  
Hematology Abnormal Laboratory Results Related to Study Treatment by Severity and Time Point – Platelets 
This table will repeat Table 32 for Platelets. 
 


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Table 78:  
Hematology Laboratory Summary Statistics by Time Point – Hemoglobin (g/dL) 
This table will repeat Table 45 for Hemoglobin. 
 
 
Table 79:  
Hematology Laboratory Summary Statistics by Time Point – Hematocrit (%) 
This table will repeat Table 45 for Hematocrit. 
 
 
Table 80:  
Hematology Laboratory Summary Statistics by Time Point – Erythrocytes (10^12/L) 
This table will repeat Table 45 for Erythrocytes. 
 
 
Table 81:  
Hematology Laboratory Summary Statistics by Time Point – Leukocytes (10^9/L) 
This table will repeat Table 45 for Leukocytes. 
 
 
Table 82:  
Hematology Laboratory Summary Statistics by Time Point – Neutrophils (10^9/L) 
This table will repeat Table 45 for Neutrophils. 
 
 
Table 83:  
Hematology Laboratory Summary Statistics by Time Point – Lymphocytes (10^9/L) 
This table will repeat Table 45 for Lymphocytes. 
 
 
Table 84:  
Hematology Laboratory Summary Statistics by Time Point – Monocytes (10^9/L) 
This table will repeat Table 45 for Monocytes. 
 
 


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Table 85:  
Hematology Laboratory Summary Statistics by Time Point – Eosinophils (10^9/L) 
This table will repeat Table 45 for Eosinophils. 
 
 
Table 86:  
Hematology Laboratory Summary Statistics by Time Point – Basophils (10^9/L) 
This table will repeat Table 45 for Basophils. 
 
 
Table 87:  
Hematology Laboratory Summary Statistics by Time Point – Platelets (10^9/L) 
This table will repeat Table 45 for Platelets. 
 
 


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Table 88:  
Urinalysis Laboratory Results by Severity and Time Point – Any Urinalysis Parameter 
This table will repeat Table 19 for Any Urinalysis Parameter. 
 
 
Table 89:  
Urinalysis Laboratory Results by Severity and Time Point – Protein 
This table will repeat Table 19 for Protein. 
 
 
Table 90:  
Urinalysis Laboratory Results by Severity and Time Point – Glucose 
This table will repeat Table 19 for Glucose. 
 
 
Table 91:  
Urinalysis Laboratory Results by Severity and Time Point – Hemoglobin 
This table will repeat Table 19 for Hemoglobin. 
 
 


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Table 92:  
Urinalysis Abnormal Laboratory Results Related to Study Treatment by Severity and Time Point – Any Urinalysis Parameter 
This table will repeat Table 32 for Any Urinalysis Parameter. 
 
 
Table 93:  
Urinalysis Abnormal Laboratory Results Related to Study Treatment by Severity and Time Point – Protein 
This table will repeat Table 32 for Protein. 
 
 
Table 94:  
Urinalysis Abnormal Laboratory Results Related to Study Treatment by Severity and Time Point – Glucose 
This table will repeat Table 32 for Glucose. 
 
 
Table 95:  
Urinalysis Abnormal Laboratory Results Related to Study Treatment by Severity and Time Point – Hemoglobin 
This table will repeat Table 32 for Hemoglobin. 
 


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14.3.6 Displays of Vital Signs 
Table 96: 
Vital Signs by Assessment, Maximum Severity, and Time Point – Any Assessment 
This table will repeat Table 19 for Vital Signs – Any Assessment. 
 
 
Table 97: 
Vital Signs by Assessment, Maximum Severity, and Time Point – Systolic Blood Pressure 
This table will repeat Table 20 for Vital Signs – Systolic Blood Pressure. 
 
 
Table 98: 
Vital Signs by Assessment, Maximum Severity, and Time Point – Diastolic Blood Pressure 
This table will repeat Table 19 for Vital Signs – Diastolic Blood Pressure. 
 
 
Table 99: 
Vital Signs by Assessment, Maximum Severity, and Time Point – Pulse Rate 
This table will repeat Table 20 for Vital Signs – Pulse Rate. 
 
 
Table 100: 
Vital Signs by Assessment, Maximum Severity, and Time Point – Respiratory Rate 
This table will repeat Table 19 for Vital Signs – Respiratory Rate. 
 
 
Table 101: 
Vital Signs by Assessment, Maximum Severity, and Time Point –Temperature 
This table will repeat Table 19 for Vital Signs – Temperature. 
 


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Table 102: 
Vital Signs Summary Statistics by Assessment and Time Point – Systolic Blood Pressure (mmHg) 
Time Point 
N 
Mean 
Standard Deviation 
Median 
Min, Max 
Baseline 
 
 
 
 
 
1 h (± 10 min) after dosing 
 
 
 
 
 
1 h, Change from Baseline 
 
 
 
 
 
2 h (± 10 min) after dosing 
 
 
 
 
 
2 h, Change from Baseline 
 
 
 
 
 
4 h (± 10 min) after dosing 
 
 
 
 
 
4 h, Change from Baseline 
 
 
 
 
 
Day 2 
 
 
 
 
 
Day 2, Change from Baseline 
 
 
 
 
 
Day 3 
 
 
 
 
 
Day 3, Change from Baseline 
 
 
 
 
 
Day 4 
 
 
 
 
 
Day 4, Change from Baseline 
 
 
 
 
 
Day 8 
 
 
 
 
 
Day 8, Change from Baseline 
 
 
 
 
 
N = number of subjects in the Safety Population with the vital sign assessed for the respective time point 
 


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Table 103: 
Vital Signs Summary Statistics by Assessment and Time Point – Diastolic Blood Pressure (mmHg) 
This table will repeat Table 102 for Diastolic Blood Pressure. 
 
 
Table 104: 
Vital Signs Summary Statistics by Assessment and Time Point – Pulse Rate (beats/min) 
This table will repeat Table 102 for Pulse Rate. 
 
 
Table 105: 
Vital Signs Summary Statistics by Assessment and Time Point – Respiratory Rate (breaths/min) 
This table will repeat Table 102 for Respiratory Rate. 
 
 
Table 106: 
Vital Signs Summary Statistics by Assessment and Time Point –Temperature (C) 
This table will repeat Table 102 for Temperature. 
 


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14.3.7 
Displays of ECG Measurements 
Table 107: 
ECG Overall Interpretations, Post Dose Compared to Baseline 
ECG Interpretation 
n (%) 
1 Hours (± 10 min) After Dosing   (N=X) 
Normal at Both Times 
x (x) 
Normal to Abnormal, NCS 
x (x) 
Normal to Abnormal, CS 
x (x) 
Abnormal, NCS at Both Times 
x (x) 
Abnormal, NCS to Abnormal, CS 
x (x) 
Abnormal, NCS to Normal 
x (x) 
2 Hours (± 10 min) After Dosing   (N=X) 
Normal at Both Times 
x (x) 
Normal to Abnormal, NCS 
x (x) 
Normal to Abnormal, CS 
x (x) 
Abnormal, NCS at Both Times 
x (x) 
Abnormal, NCS to Abnormal, CS 
x (x) 
Abnormal, NCS to Normal 
x (x) 
4 Hours (± 10 min) After Dosing   (N=X) 
Normal at Both Times 
x (x) 
Normal to Abnormal, NCS 
x (x) 
Normal to Abnormal, CS 
x (x) 
Abnormal, NCS at Both Times 
x (x) 
Abnormal, NCS to Abnormal, CS 
x (x) 
Abnormal, NCS to Normal 
x (x) 
72 Hours (± 2 hours) After Dosing   (N=X) 
Normal at Both Times 
x (x) 
Normal to Abnormal, NCS 
x (x) 
Normal to Abnormal, CS 
x (x) 
Abnormal, NCS at Both Times 
x (x) 
Abnormal, NCS to Abnormal, CS 
x (x) 
Abnormal, NCS to Normal 
x (x) 
Note: N = number of subjects in safety population with the ECG measurement at the visit indicated above the table. CS = clinically significant; 
NCS = not clinically significant. 
 


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Table 108: 
ECG by Parameter, Maximum Severity, and Time Point – PR Interval, Aggregate 
 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
Time Point 
N 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Baseline 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
1 hr Post-Dose 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
2 hr Post-Dose 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
4 hr Post-Dose 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
72 hr Post-Dose 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Max Severity Post Baseline 
x 
x 
x 
x 
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, including unscheduled assessments. N=Number of subjects in the Safety Population. 
 
 
Table 109: 
ECG by Parameter, Maximum Severity, and Time Point – QTcF Interval, Aggregate 
This table will repeat Table 108 for QTcF Interval, Aggregate. 
 
 


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Table 110: 
ECG Summary Statistics by Parameter and Time Point – PR Interval, Aggregate (msec) 
Time Point 
N 
Mean 
Standard Deviation 
Median 
Min, Max 
Baseline 
 
 
 
 
 
1 h (± 10 min) after dosing 
 
 
 
 
 
1 h, Change from Baseline 
 
 
 
 
 
2 h (± 10 min) after dosing 
 
 
 
 
 
2 h, Change from Baseline 
 
 
 
 
 
4 h (± 10 min) after dosing 
 
 
 
 
 
4 h, Change from Baseline 
 
 
 
 
 
72 h (± 2 h) after dosing 
 
 
 
 
 
72 h, Change from Baseline 
 
 
 
 
 
N = number of subjects in the Safety Population with the ECG parameter assessed for the respective time point 
 
 
Table 111: 
ECG Summary Statistics by Parameter and Time Point – QRS Duration, Aggregate (msec) 
This table will repeat Table 110 for QRS Duration, Aggregate. 
 
 
Table 112: 
ECG Summary Statistics by Parameter and Time Point – QT Interval, Aggregate (msec) 
This table will repeat Table 110 for QT Interval, Aggregate. 
 
 
Table 113: 
ECG Summary Statistics by Parameter and Time Point – QTcF Interval, Aggregate (msec) 
This table will repeat Table 110 for QTcF Interval, Aggregate. 
 
 


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Table 114: 
ECG Summary Statistics by Parameter and Time Point – RR Interval, Aggregate (msec) 
This table will repeat Table 110 for RR Interval, Aggregate. 
Table 115: 
ECG Summary Statistics by Parameter and Time Point – ECG Mean Ventricular Rate (msec) 
This table will repeat Table 110 for ECG Mean Ventricular Rate. 
 


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Table 116: 
ECG Measurements, Frequency of QTcF Prolongation 
Time Point 
Prolongation Between 30 and <60 msec 
Prolongation ≥60 msec 
N 
n (%) 
N 
n (%) 
1 h Post Dose 
 
 
 
 
2 h Post Dose 
 
 
 
 
4 h Post Dose 
 
 
 
 
72 h Post Dose 
 
 
 
 
 


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14.4 
Summary of Prior and Concomitant Medications 
Table 117: 
Number and Percentage of Subjects with Prior Medications by WHO Drug Classification  
WHO Drug Code 
Level 1, Anatomic Group 
WHO Drug Code 
Level 2, Therapeutic Subgroup 
All Subjects 
(N=X) 
n 
% 
Any Level 1 Codes 
Any Level 2 Codes 
x 
xx 
[ATC Level 1 - 1] 
Any [ATC 1 – 1] 
 
 
 
[ATC 2 - 1] 
 
 
 
[ATC 2 - 2] 
 
 
 
[ATC 2 - 3] 
 
 
[ATC Level 1 – 2] 
[ATC 2 - 1] 
 
 
 
[ATC 2 - 2] 
 
 
 
[ATC 2 - 3] 
 
 
N = number of subjects in safety population. n = Number of subjects reporting taking at least one medication in the specific WHO Drug Class. 
 


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Table 118: 
Number and Percentage of Subjects with Concomitant Medications by WHO Drug Classification  
WHO Drug Code 
Level 1, Anatomic Group 
WHO Drug Code 
Level 2, Therapeutic Subgroup 
All Subjects 
(N=X) 
n 
% 
Any Level 1 Codes 
Any Level 2 Codes 
x 
xx 
[ATC Level 1 - 1] 
Any [ATC 1 – 1] 
 
 
 
[ATC 2 - 1] 
 
 
 
[ATC 2 - 2] 
 
 
 
[ATC 2 - 3] 
 
 
[ATC Level 1 – 2] 
[ATC 2 - 1] 
 
 
 
[ATC 2 - 2] 
 
 
 
[ATC 2 - 3] 
 
 
N = number of subjects in safety population. n = Number of subjects reporting taking at least one medication in the specific WHO Drug Class. 
 


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APPENDIX 2.  FIGURE MOCK-UPS 
LIST OF FIGURES 
Figure 1: 
Incidence of Related Adverse Events by MedDRA System Organ Class and 
Severity .......................................................................................................................92 
Figure 2: 
Frequency of Related Adverse Events by MedDRA System Organ Class and 
Maximum Severity .....................................................................................................93 
Figure 3: 
Individual Laboratory Results by Scheduled Visits: Changes from Baseline – 
Sodium ........................................................................................................................94 
Figure 4: 
Individual Laboratory Results by Scheduled Visits: Changes from Baseline – 
Potassium ....................................................................................................................95 
Figure 5: 
Individual Laboratory Results by Scheduled Visits: Changes from Baseline – 
Magnesium .................................................................................................................95 
Figure 6: 
Individual Laboratory Results by Scheduled Visits: Changes from Baseline – 
Chloride ......................................................................................................................95 
Figure 7: 
Individual Laboratory Results by Scheduled Visits: Changes from Baseline – 
Bicarbonate .................................................................................................................95 
Figure 8: 
Individual Laboratory Results by Scheduled Visits: Changes from Baseline – 
Glucose .......................................................................................................................95 
Figure 9: 
Individual Laboratory Results by Scheduled Visits: Changes from Baseline – 
Blood Urea Nitrogen ...................................................................................................95 
Figure 10: Individual Laboratory Results by Scheduled Visits: Changes from Baseline – 
Creatinine ....................................................................................................................95 
Figure 11: Individual Laboratory Results by Scheduled Visits: Changes from Baseline – 
Protein .........................................................................................................................95 
Figure 12: Individual Laboratory Results by Scheduled Visits: Changes from Baseline – 
Albumin ......................................................................................................................95 
Figure 13: Individual Laboratory Results by Scheduled Visits: Changes from Baseline – 
Aspartate Aminotransferase ........................................................................................95 
Figure 14: Individual Laboratory Results by Scheduled Visits: Changes from Baseline – 
Alanine Aminotransferase ..........................................................................................96 
Figure 15: Individual Laboratory Results by Scheduled Visits: Changes from Baseline – 
Alkaline Phosphatase ..................................................................................................96 
Figure 16: Individual Laboratory Results by Scheduled Visits: Changes from Baseline – 
Bilirubin ......................................................................................................................96 
Figure 17: Individual Laboratory Results by Scheduled Visits: Changes from Baseline – 
Direct Bilirubin ...........................................................................................................96 


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Figure 18: Individual Laboratory Results by Scheduled Visits: Changes from Baseline – 
Hemoglobin ................................................................................................................96 
Figure 19: Individual Laboratory Results by Scheduled Visits: Changes from Baseline – 
Hematocrit ..................................................................................................................96 
Figure 20: Individual Laboratory Results by Scheduled Visits: Changes from Baseline – 
Erythrocytes ................................................................................................................96 
Figure 21: Individual Laboratory Results by Scheduled Visits: Changes from Baseline – 
Leukocytes ..................................................................................................................96 
Figure 22: Individual Laboratory Results by Scheduled Visits: Changes from Baseline – 
Neutrophils .................................................................................................................96 
Figure 23: Individual Laboratory Results by Scheduled Visits: Changes from Baseline – 
Lymphocytes ...............................................................................................................96 
Figure 24: Individual Laboratory Results by Scheduled Visits: Changes from Baseline – 
Monocytes ...................................................................................................................96 
Figure 25: Individual Laboratory Results by Scheduled Visits: Changes from Baseline – 
Eosinophils .................................................................................................................97 
Figure 26: Individual Laboratory Results by Scheduled Visits: Changes from Baseline – 
Basophils.....................................................................................................................97 
Figure 27: Individual Laboratory Results by Scheduled Visits: Changes from Baseline – 
Platelets .......................................................................................................................97 
Figure 28: Individual Vital Signs by Scheduled Visits: Systolic Blood Pressure ........................98 
Figure 29: Individual Vital Signs by Scheduled Visits: Diastolic Blood Pressure ......................99 
Figure 30: Individual Vital Signs by Scheduled Visits: Pulse Rate .............................................99 
Figure 31: Individual Vital Signs by Scheduled Visits: Respiratory Rate ...................................99 
Figure 32: Individual Vital Signs by Scheduled Visits: Temperature .........................................99 
Figure 33: Individual ECG by Scheduled Visits: PR Interval, Aggregate .................................100 
Figure 34: Individual ECG by Scheduled Visits: QRS Duration, Aggregate ............................101 
Figure 35: Individual ECG by Scheduled Visits: QT Interval, Aggregate ................................101 
Figure 36: Individual ECG by Scheduled Visits: QTcF Interval, Aggregate ............................101 
Figure 37: Individual ECG by Scheduled Visits: QTcF Interval, Aggregate, Change 
from Baseline ............................................................................................................101 
Figure 38: Individual ECG by Scheduled Visits: RR Interval, Aggregate ................................101 
Figure 39: Individual ECG by Scheduled Visits: ECG Mean Ventricular Rate ........................101 


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14.3.1.2 
Unsolicited Adverse Events 
Figure 1: 
Incidence of Related Adverse Events by MedDRA System Organ Class and Severity 
 
 


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Figure 2: 
Frequency of Related Adverse Events by MedDRA System Organ Class and Maximum 
Severity  
 
 
 


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14.3.5 
Displays of Laboratory Results 
Figure 3: 
Individual Laboratory Results by Scheduled Visits: Changes from Baseline – Sodium 
 
 


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Figure 4: 
Individual Laboratory Results by Scheduled Visits: Changes from Baseline – Potassium 
This figure will repeat Figure 3 for Potassium. 
 
 
Figure 5: 
Individual Laboratory Results by Scheduled Visits: Changes from Baseline – Magnesium 
This figure will repeat Figure 3 for Magnesium. 
 
 
Figure 6: 
Individual Laboratory Results by Scheduled Visits: Changes from Baseline – Chloride 
This figure will repeat Figure 3 for Chloride. 
 
 
Figure 7: 
Individual Laboratory Results by Scheduled Visits: Changes from Baseline – 
Bicarbonate 
This figure will repeat Figure 3 for Bicarbonate. 
 
 
Figure 8: 
Individual Laboratory Results by Scheduled Visits: Changes from Baseline – Glucose 
This figure will repeat Figure 3 for Glucose. 
 
 
Figure 9: 
Individual Laboratory Results by Scheduled Visits: Changes from Baseline – Blood Urea 
Nitrogen 
This figure will repeat Figure 3 for Blood Urea Nitrogen. 
 
 
Figure 10: 
Individual Laboratory Results by Scheduled Visits: Changes from Baseline – Creatinine  
This figure will repeat Figure 3 for Creatinine. 
 
 
Figure 11: 
Individual Laboratory Results by Scheduled Visits: Changes from Baseline – Protein  
This figure will repeat Figure 3 for Protein. 
 
 
Figure 12: 
Individual Laboratory Results by Scheduled Visits: Changes from Baseline – Albumin 
This figure will repeat Figure 3 for Albumin. 
 
 
Figure 13: 
Individual Laboratory Results by Scheduled Visits: Changes from Baseline – Aspartate 
Aminotransferase 
This figure will repeat Figure 3 for Aminotransferase. 


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Figure 14: 
Individual Laboratory Results by Scheduled Visits: Changes from Baseline – Alanine 
Aminotransferase 
This figure will repeat Figure 3 for Alanine Aminotransferase. 
 
 
Figure 15: 
Individual Laboratory Results by Scheduled Visits: Changes from Baseline – Alkaline 
Phosphatase 
This figure will repeat Figure 3 for Alkaline Phosphatase. 
 
 
Figure 16: 
Individual Laboratory Results by Scheduled Visits: Changes from Baseline – Bilirubin 
This figure will repeat Figure 3 for Bilirubin. 
 
 
Figure 17: 
Individual Laboratory Results by Scheduled Visits: Changes from Baseline – Direct 
Bilirubin 
This figure will repeat Figure 3 for Direct Bilirubin. 
 
 
Figure 18: 
Individual Laboratory Results by Scheduled Visits: Changes from Baseline – 
Hemoglobin 
This figure will repeat Figure 3 for Hemoglobin. 
 
 
Figure 19: 
Individual Laboratory Results by Scheduled Visits: Changes from Baseline – Hematocrit 
This figure will repeat Figure 3 for Hematocrit. 
 
 
Figure 20: 
Individual Laboratory Results by Scheduled Visits: Changes from Baseline – 
Erythrocytes 
This figure will repeat Figure 3 for Erythrocytes. 
 
 
Figure 21: 
Individual Laboratory Results by Scheduled Visits: Changes from Baseline – Leukocytes  
This figure will repeat Figure 3 for Leukocytes. 
 
 
Figure 22: 
Individual Laboratory Results by Scheduled Visits: Changes from Baseline – Neutrophils 
This figure will repeat Figure 3 for Neutrophils. 
 
 
Figure 23: 
Individual Laboratory Results by Scheduled Visits: Changes from Baseline – 
Lymphocytes 
This figure will repeat Figure 3 for Lymphocytes. 
 
 
Figure 24: 
Individual Laboratory Results by Scheduled Visits: Changes from Baseline – Monocytes 
This figure will repeat Figure 3 for Monocytes. 
 
 


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Figure 25: 
Individual Laboratory Results by Scheduled Visits: Changes from Baseline – Eosinophils 
This figure will repeat Figure 3 for Eosinophils. 
 
 
Figure 26: 
Individual Laboratory Results by Scheduled Visits: Changes from Baseline – Basophils 
This figure will repeat Figure 3 for Basophils. 
 
 
Figure 27: 
Individual Laboratory Results by Scheduled Visits: Changes from Baseline – Platelets 
This figure will repeat Figure 3 for Platelets. 


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Section 14.3.6  
Displays of Vital Signs 
Figure 28: 
Individual Vital Signs by Scheduled Visits: Systolic Blood Pressure 
 
 


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Figure 29: 
Individual Vital Signs by Scheduled Visits: Diastolic Blood Pressure 
This figure will repeat Figure 28 for Diastolic Blood Pressure. 
 
 
Figure 30: 
Individual Vital Signs by Scheduled Visits: Pulse Rate 
This figure will repeat Figure 28 for Pulse Rate. 
 
 
Figure 31: 
Individual Vital Signs by Scheduled Visits: Respiratory Rate 
This figure will repeat Figure 28 for Respiratory Rate. 
 
 
Figure 32: 
Individual Vital Signs by Scheduled Visits: Temperature 
This figure will repeat Figure 28 for Temperature. 
 


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Figure 33: 
Individual ECG by Scheduled Visits: PR Interval, Aggregate 
 


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Figure 34: 
Individual ECG by Scheduled Visits: QRS Duration, Aggregate 
This figure will repeat Figure 33 for Diastolic Blood Pressure. 
 
 
Figure 35: 
Individual ECG by Scheduled Visits: QT Interval, Aggregate 
This figure will repeat Figure 33 for Pulse Rate. 
 
 
Figure 36: 
Individual ECG by Scheduled Visits: QTcF Interval, Aggregate 
This figure will repeat Figure 33 for QTcF Interval, Aggregate. 
 
 
Figure 37: 
Individual ECG by Scheduled Visits: QTcF Interval, Aggregate, Change from Baseline 
This figure will repeat Figure 33 for QTcF Interval, Aggregate, Change from Baseline. 
 
 
Figure 38: 
Individual ECG by Scheduled Visits: RR Interval, Aggregate 
This figure will repeat Figure 33 for RR Interval, Aggregate. 
 
 
Figure 39: 
Individual ECG by Scheduled Visits: ECG Mean Ventricular Rate 
This figure will repeat Figure 33 for ECG Mean Ventricular Rate. 
  


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APPENDIX 3. LISTINGS MOCK-UPS 
LISTINGS 
Listing 1: 16.2.1 Early Terminations or Discontinued Subjects ...............................................104 
Listing 2: 16.2.2.1: Subject-Specific Protocol Deviations ........................................................105 
Listing 3: 16.2.2.2: Non-Subject-Specific Protocol Deviations ................................................106 
Listing 4: 16.2.3: Subjects Excluded from Analysis Populations .............................................107 
Listing 5: 16.2.4.1: Demographic Data .....................................................................................108 
Listing 6: 16.2.4.2: Pre-Existing and Concurrent Medical Conditions .....................................109 
Listing 7: 16.2.5: Compliance and/or Drug Concentration Data ..............................................110 
Listing 8: Unsolicited Adverse Events ......................................................................................111 
Listing 9: 16.2.8.1: Clinical Laboratory Results – Chemistry ..................................................112 
Listing 10: 16.2.8.2: Clinical Laboratory Results – Hematology ...............................................113 
Listing 11: 16.2.8.3: Clinical Laboratory Results – Urinalysis...................................................114 
Listing 12: 16.2.8.4: Clinical Laboratory Results – Other Laboratory Results (Viral 
Serology, Pregnancy Test, Confirmation of Menopause) ........................................115 
Listing 13: 16.2.8.5: Clinical Laboratory Results – Toxicology.................................................116 
Listing 14: 16.2.8.6: Clinical Laboratory Results – Breathalyzer...............................................117 
Listing 15: 16.2.9.1: Vital Signs .................................................................................................118 
Listing 16: 16.2.9.2: Physical Exam Findings ............................................................................119 
Listing 17: 16.2.10: Listing of ECG Measurements ...................................................................120 
Listing 18: Prior Medications ......................................................................................................121 
Listing 19: Concomitant Medications .........................................................................................122 
Listing 20: Birth Control Listing.................................................................................................123 
Listing 21: 16.2.13.1: Pregnancy Reports – Maternal Information ............................................124 
Listing 22: 16.2.13.2: Pregnancy Reports – Gravida and Para ...................................................125 
Listing 23: 16.2.13.3: Pregnancy Reports – Live Birth Outcomes .............................................126 
Listing 24: 16.2.13.4: Pregnancy Reports – Still Birth Outcomes ..............................................126 
Listing25: 16.2.13.5: Pregnancy Reports – Spontaneous, Elective, or Therapeutic 
Abortion Outcomes ...................................................................................................126 
 


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16.1.6 Listing of Subjects Receiving Investigational Product 
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 
Subject ID 
Category 
Reason for Early Termination or Treatment Discontinuation 
Study Day 
 
 
 
 
 
 
 
 


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16.2.2 Protocol Deviations 
Listing 2: 
16.2.2.1: Subject-Specific Protocol Deviations 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 3: 
16.2.2.2: Non-Subject-Specific Protocol Deviations 
Deviation 
Deviation 
Category 
Start Date 
End Date 
Reason for 
Deviation 
Deviation 
Resulted in 
Subject 
Termination? 
Deviation 
Affected 
Product 
Stability? 
Deviation 
Resolution 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.3 Subjects Excluded from the Efficacy Analysis 
Listing 4: 
16.2.3: Subjects Excluded from Analysis Populations 
Subject ID 
Analyses in which 
Subject is Included 
Analyses from which  
Subject is Excluded 
Results Available? 
Reason Subject Excluded 
 
[e.g., Safety, PK] 
[e.g., Safety, PK] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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. 
 
 


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16.2.4 Demographic Data 
Listing 5: 
16.2.4.1: Demographic Data 
Subject ID 
Sex 
Age at Enrollment (years) 
Height (kg) 
Weight (m) 
BMI (kg/m2) 
Ethnicity 
Race 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 6: 
16.2.4.2: Pre-Existing and Concurrent Medical Conditions 
Subject ID 
MH Number 
Medical History Term 
Condition Start Day  
Condition End Day 
MedDRA System Organ Class 
MedDRA® Preferred Term 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.5 Compliance and/or Drug Concentration Data (if available) 
Listing 7: 
16.2.5: Compliance and/or Drug Concentration Data 
Subject ID  
Date of Administration 
Start Time of Administration 
End Time of Administration 
Volume of Product 
Administered (mL) 
Amount of Product 
Administered 
(g) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.7 Adverse Events 
16.2.7.3 
Unsolicited Adverse Events 
Listing 8: 
Unsolicited Adverse Events 
AE 
No. of Days 
Post 
Associated 
Dose 
(Duration) 
Severity 
SAE? 
Relationship 
to Study 
Treatment 
In Not 
Related, 
Alternative 
Etiology 
Action 
Taken with 
Study 
Treatment 
Subject 
Discontinued 
Due to AE 
Outcome 
MedDRA 
System Organ 
Class 
MedDRA 
Higher 
Level 
Group 
Term 
MedDRA 
Preferred 
Term 
Subject ID: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
Subject ID: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
Note: For additional details about SAEs, see Tables 11-16. 
 
 


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16.2.8 Individual Laboratory Measurements 
Listing 9: 
16.2.8.1: Clinical Laboratory Results – Chemistry 
Subject ID 
Planned 
Time Point 
Actual 
Study Day 
Sex 
Laboratory 
Parameter 
(Units) 
Result 
(Severity 
Grade) 
Change from 
Baseline 
Reference 
Range Low 
Reference 
Range High 
Relatedness 
Alternate 
Etiology 
Clinical 
Significance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 10: 
16.2.8.2: Clinical Laboratory Results – Hematology  
Subject ID 
Planned 
Time Point 
Actual 
Study Day 
Sex 
Laboratory 
Parameter 
(Units) 
Result 
(Severity 
Grade) 
Change from 
Baseline 
Reference 
Range Low 
Reference 
Range High 
Relatedness 
Alternate 
Etiology 
Clinical 
Significance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 11: 
16.2.8.3: Clinical Laboratory Results – Urinalysis  
Subject ID 
Planned 
Time Point 
Actual 
Study Day 
Sex 
Laboratory 
Parameter 
(Units) 
Result 
(Severity 
Grade) 
Change from 
Baseline 
Reference 
Range Low 
Reference 
Range High 
Relatedness 
Alternate 
Etiology 
Clinical 
Significance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 12: 
16.2.8.4: Clinical Laboratory Results – Other Laboratory Results (Viral Serology, Pregnancy Test, Confirmation of Menopause) 
Subject ID 
Sex 
Planned Time Point 
Actual Study Day 
 
Category 
Parameter 
Result 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 13: 
16.2.8.5: Clinical Laboratory Results – Toxicology 
Subject ID 
Sex 
Planned Time Point 
Actual Study Day 
Drug 
Result 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 14: 
16.2.8.6: Clinical Laboratory Results – Breathalyzer 
Subject ID 
Sex 
Planned Time Point 
Actual Study Day 
Result 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.9 Vital Signs and Physical Exam Findings 
Listing 15: 
16.2.9.1: Vital Signs 
Subject ID 
Visit 
Parameter (units) 
Date of Assessment 
Time of Assessment 
(hh:mm) 
Result 
(Severity) 
Change 
from 
Baseline 
 
1 hour post dose 
Temperature (°C) 
ddMMMyyyy 
 
38.4 
(Moderate) 
0.7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 16: 
16.2.9.2: Physical Exam Findings 
Subject ID 
Planned Time 
Point 
Actual Study 
Day 
Body System 
Abnormal Finding 
Reported as an AE? 
(AE Description; Number) 
Clinical Significance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 17: 
16.2.10: Listing of ECG Measurements 
Subject ID 
Visit 
Parameter (units) 
Date of Assessment 
Time of Assessment 
(hh:mm) 
Result 
(Severity) 
Change 
from 
Baseline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.11 Prior and Concomitant Medications 
Listing 18: 
Prior Medications 
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 
ATC Level 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 19: 
Concomitant Medications 
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 ATC Level 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.12 Birth Control Reports 
Listing 20: 
Birth Control Listing 
Subject ID 
Sex 
Child Bearing 
Potential 
Birth Control 
Method 
Start Date 
Start Date 
Certainty 
End Date 
End Date 
Certainty 
Ongoing? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.13 Pregnancy Reports 
Listing 21: 
16.2.13.1: Pregnancy Reports – Maternal Information 
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 AE listing. Medications taken during pregnancy are included in the Concomitant Medications Listing. 


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Listing 22: 
16.2.13.2: 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 
 
 


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Listing 23: 
16.2.13.3: 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 AE listing. 
Listing 24: 
16.2.13.4: 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? 
 
 
 
 
 
 
 
 
 
 
 
 
Listing25: 
16.2.13.5: 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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APPENDIX 4. NONCOMPARTMENTAL ANALYSIS TEMPLATE 
Details of the PK analysis can be found in the PK SAP.