A Phase 1, First-In-Human, Randomized, Double-Blind, Placebo-Controlled, Single Dose-Escalation Study to Evaluate the Safety and Pharmacokinetics of Single Oral Doses of VT-1598 in Healthy Adult Subjects
Phase: PHASE1
Conditions: Coccidioidomycosis
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

DMID Protocol 17-0087 
Version 5.0 
Safety and Pharmacokinetics of VT-1598                                                                                        
18 Jun 2021 
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DMID/NIAID/NIH 
 
 
 
 
 
 
 
 
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CONFIDENTIAL 
  
A Phase 1, First-In-Human, Randomized, Double-Blind, Placebo-
Controlled, Single Dose-Escalation Study to Evaluate the Safety and 
Pharmacokinetics of Single Oral Doses of VT-1598 in Healthy Adult 
Subjects 
 
DMID Protocol Number: 17-0087 
DMID Funding Mechanism: HHSN272201500007I 
Pharmaceutical Support: NQP 1598, Ltd. 
IND Sponsor: DMID 
Lead Principal Investigator:  Cassandra Key, MD 
DMID Clinical Project Manager:  Maureen Mehigan 
Draft or Version Number:  5.0 
Day Month Year 
18 Jun 2021 
 
 
 

DMID Protocol 17-0087 
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STATEMENT OF ASSURANCE 
Each Institution will hold a current Federal Wide Assurance (FWA) issued by the Office of 
Human Research Protections (OHRP) for federally-funded human subjects research.  Each FWA 
will designate at least one Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) registered with OHRP, for which the research will be reviewed and approved by the 
IRB/IEC and will be subject to continuing review [45 CFR 46.103(b)]. The IRB/IEC designated 
under an FWA may include an institution’s IRB/IEC, an independent IRB/IEC, or an IRB/IEC of 
another institution after establishing a written agreement with that other institution. 
 

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STATEMENT OF COMPLIANCE 
The study trial will be carried out in accordance with Good Clinical Practice (GCP) and as 
required by the following: 
• 
United States Code of Federal Regulations (CFR) 45 CFR Part 46: Protection of Human 
Subjects; 
• 
Food and Drug Administration (FDA) Regulations, as applicable: 21 CFR Part 50 
(Protection of Human Subjects), 21 CFR Part 54 (Financial Disclosure by Clinical 
Investigators), 21 CFR Part 56 (Institutional Review Boards), 21 CFR Part 11, and 21 
CFR Part 312 (Investigational New Drug Application);  
• 
International Conference on Harmonization: Good Clinical Practice (ICH E6); 62 Federal 
Register 25691 (1997); and future revisions; 
• 
Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects 
of Research, Report of the National Commission for the Protection of Human Subjects of 
Biomedical and Behavioral Research; 
• 
National Institutes of Health (NIH) Office of Extramural Research, Research Involving   
Human Subjects, as applicable;  
• 
National Institute of Allergy and Infectious Diseases (NIAID) Clinical Terms of Award, 
as applicable; 
• 
Applicable Federal, State, and Local Regulations and Guidance. 
 

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SIGNATURE PAGE 
Protocol Title:  A Phase 1, First-In-Human, Randomized, Double-Blind, Placebo-Controlled, 
Single Dose-Escalation Study to Evaluate the Safety and Pharmacokinetics of Single Oral Doses 
of VT-1598 in Healthy Adult Subjects 
Protocol Number: 17-0087 
Protocol Version (Issue Date): 
The signature below provides the necessary assurance that this trial will be conducted according 
to all stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable US federal regulations and 
ICH E6 Good Clinical Practice (GCP) guidelines. 
I agree to conduct the study in compliance with GCP and applicable regulatory requirements. 
I agree to conduct the study in accordance with the current protocol and will not make changes to 
the protocol without obtaining the sponsor’s approval and IRB/IEC approval, except when 
necessary to protect the safety, rights, or welfare of subjects. 
Site Investigator Signature: 
 
Signed: 
 
Date: 
 
 
Cassandra Key, MD 
Site Principal Investigator 
 
 
 
 

DMID Protocol 17-0087 
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Safety and Pharmacokinetics of VT-1598                                                                                        
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TABLE OF CONTENTS 
STATEMENT OF ASSURANCE ...................................................................................................2 
STATEMENT OF COMPLIANCE .................................................................................................3 
SIGNATURE PAGE .......................................................................................................................4 
TABLE OF CONTENTS .................................................................................................................5 
LIST OF TABLES .........................................................................................................................10 
LIST OF FIGURES .......................................................................................................................11 
LIST OF ABBREVIATIONS ........................................................................................................12 
PROTOCOL SUMMARY .............................................................................................................15 
 
KEY ROLES.........................................................................................................................20 
 
BACKGROUND AND SCIENTIFIC RATIONALE ..........................................................21 
 
Background .................................................................................................................21 
 
Scientific Rationale .....................................................................................................25 
 Purpose of Study ............................................................................................25 
 Study Population ............................................................................................26 
 
Potential Risks and Benefits .......................................................................................27 
 Potential Risks ...............................................................................................27 
 Potential Benefits ...........................................................................................29 
 
STUDY DESIGN, OBJECTIVES AND ENDPOINTS OR OUTCOME MEASURES .....30 
 
Study Design Description ...........................................................................................30 
 Overall Study Design .....................................................................................30 
 Dosing Scheme and Duration of Study ..........................................................30 
 Number of Subjects ........................................................................................31 
 Rationale for Starting Dose ............................................................................31 
 Dose Escalations ............................................................................................31 
 
Study Objectives .........................................................................................................32 
 Primary ...........................................................................................................32 
 Secondary .......................................................................................................32 

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 Study Endpoints or Outcome Measures .........................................................33 
 Primary Outcome Measures ...........................................................................33 
 Secondary Outcome Measures .......................................................................33 
 
STUDY INTERVENTION/INVESTIGATIONAL PRODUCT .........................................34 
 
Study Product Description ..........................................................................................34 
 Formulation, Packaging, and Labeling ..........................................................34 
 Product Storage and Stability .........................................................................34 
 
Acquisition/Distribution .............................................................................................34 
 
Dosage/Regimen, Preparation, Dispensing and Administration of Study 
Intervention/Investigational Product.........................................................................35 
 
Accountability Procedures for the Study Intervention/Investigational Product(s) .....35 
 
SELECTION OF SUBJECTS AND STUDY ENROLLMENT AND WITHDRAWAL ....37 
 
Eligibility Criteria .......................................................................................................37 
 Subject Inclusion Criteria...............................................................................37 
 Subject Exclusion Criteria .............................................................................38 
 
Withdrawal from the Study, Discontinuation of Study Product, or Study Termination
 ..................................................................................................................................40 
 Withdrawal from the Study or Discontinuation of the Study Product ...........40 
 Subject Replacement ......................................................................................42 
 Study Termination .........................................................................................42 
 
STUDY PROCEDURES ......................................................................................................43 
 
Screening ....................................................................................................................43 
6.1.1 Day -28 to Day -2 (Screening) .......................................................................43 
 
Enrollment ..................................................................................................................44 
6.2.1 Day -1 (Admission to Clinic; approximately 24 hours prior to dosing) ........44 
 
Treatment Period ........................................................................................................45 
6.3.1 Day 1 – Inpatient CRU ..................................................................................45 
 Day 2 – Inpatient CRU ..................................................................................46 
 Day 3 – Inpatient CRU ..................................................................................47 

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 Day 4 – Discharge from CRU ........................................................................47 
 
Follow-up ....................................................................................................................48 
 Day 7 ± 1 ........................................................................................................48 
6.4.2 Day 14± 1 .......................................................................................................49 
6.5 
Final Study Visit .........................................................................................................50 
6.5.1 Day 21 ± 2 ......................................................................................................50 
 
Early Termination Visit ..............................................................................................51 
 
Unscheduled Study Visits ...........................................................................................51 
 
Protocol Deviations ....................................................................................................52 
 
DESCRIPTION OF CLINICAL AND LABORATORY EVALUATIONS .......................53 
 
Clinical Evaluations ....................................................................................................53 
 Safety Tests and Assessments ........................................................................53 
 Assessment of Concomitant Medications/Treatments other than Study 
Product ...........................................................................................................55 
 Assessment of Subject Compliance with Study Intervention/Investigational 
Product/Investigational Device ......................................................................57 
 
Laboratory Evaluations ...............................................................................................57 
 Clinical Laboratory Evaluations ....................................................................57 
 Research Assays .............................................................................................59 
 
ASSESSMENT OF SAFETY ...............................................................................................62 
 
Assessing and Recording Safety Parameters ..............................................................62 
 Adverse Events (AEs) ....................................................................................62 
 
Serious Adverse Events (SAEs) .................................................................................63 
 
Specification of Safety Parameters .............................................................................64 
 Dose Escalation Criteria ................................................................................64 
 Reporting Serious Adverse Events ................................................................65 
 Regulatory Reporting for Studies Conducted Under DMID-Sponsored IND
 ........................................................................................................................66 
 Reporting of Pregnancy .................................................................................66 
 
Type and Duration of Follow-up of Subjects after Adverse Events ...........................67 

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Procedures to be Followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings......................................................................................67 
 
Halting Rules ..............................................................................................................67 
 Study Halting Criteria ....................................................................................67 
 Dose Escalation Halting Criteria....................................................................68 
 
Safety Oversight .........................................................................................................68 
 Independent Safety Monitor (ISM) ................................................................68 
 Safety Monitoring Committee (SMC) ...........................................................69 
 
HUMAN SUBJECTS PROTECTION .................................................................................71 
 
Institutional Review Board/Independent Ethics Committee ......................................71 
 
Informed Consent Process ..........................................................................................71 
 
Consent for Future Use of Stored Specimens and Data .............................................73 
 
Exclusion of Women, Minorities, and Children (Special Populations) ......................74 
 
Subject Confidentiality ...............................................................................................74 
 
Certificate of Confidentiality ......................................................................................75 
 
Costs, Subject Compensation, and Research Related Injuries ...................................75 
 
STATISTICAL CONSIDERATIONS .................................................................................77 
 Study Hypotheses .......................................................................................................77 
 Sample Size Considerations .......................................................................................77 
 Treatment Assignment Procedures .............................................................................77 
 Randomization Procedures ............................................................................77 
 Masking Procedures .......................................................................................79 
 Planned Interim Analyses ...........................................................................................80 
 Final Analysis Plan .....................................................................................................80 
 Adverse and Serious Adverse Events ............................................................80 
 Clinical Safety Labs, Vital Signs, and Electrocardiograms ...........................80 
 Pharmacokinetic Analysis Plan ..................................................................................81 
 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ..............83 
 Compliance with Standards of Medical Research/ Deviations ...................................83 

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QUALITY CONTROL AND QUALITY ASSURANCE ...................................................84 
 
DATA HANDLING AND RECORD KEEPING ................................................................85 
 Data Management Responsibilities ............................................................................85 
 Data Coordinating Center/Biostatistician Responsibilities ........................................86 
 Data Capture Methods ................................................................................................86 
 Types of Data ..............................................................................................................87 
 Study Records Retention ............................................................................................87 
 
CLINICAL MONITORING .................................................................................................88 
 Site Monitoring Plan ...................................................................................................88 
 
PUBLICATION POLICY ....................................................................................................89 
 
LITERATURE REFERENCES ............................................................................................90 
 
APPENDICES ......................................................................................................................92 
 
VT-1598 SCHEDULE OF STUDY PROCEDURES AND 
EVALUATIONS ......................................................................................................93 
 
VT-1598 TOXICITY GRADING CRITERIA FOR NORMAL 
HUMAN SUBJECTS ...............................................................................................97 
 
 

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LIST OF TABLES 
Table 1: Single Dose* Escalation ..................................................................................................18 
Table 2: Blood PK Sampling Timepoints ......................................................................................59 
Table 3: Urine PK Sampling Timepoints.......................................................................................60 
Table 4: Total Volume of Blood Drawn From Each Subject ........................................................60 
 
 

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LIST OF FIGURES 
Figure 1: 
 Schematic of Study Design ........................................................................................19 
 
 

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LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
ACTH 
Adrenocorticotropic Hormone 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BMI 
Body Mass Index 
CAR 
Clinical Agents Repository 
CDC 
Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CMS 
Clinical Material Services 
CPKt 
Creatinine Phosphokinase 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CROMS 
Clinical Research Operations and Management Support 
CRU 
Clinical Research Unit 
CYP 
Cytochrome P 
DHHS 
Department of Health and Human Services 
DMID 
Division of Microbiology and Infectious Diseases 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EDTA 
Ethylenediaminetetraacetic Acid 
FDA 
Food and Drug Administration 

DMID Protocol 17-0087 
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FSH 
Follicle Stimulating Hormone 
GGT 
Gamma-Glutamyl Transferase  
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HBsAg 
Hepatitis B Surface Antigen 
HCV 
Hepatitis C Virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HLGT 
High-Level Group Term 
ICF 
Informed Consent Form 
ICH 
The International Council for Harmonization  
ICON BAL 
ICON Bioanalytical Laboratory 
ICON GPHS 
ICON Government and Public Health Solutions 
IEC 
Independent or Institutional Ethics Committee 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
IUD 
Intrauterine Device 
LARC 
Long Acting Reversible Contraceptive 
LC-MS/MS 
Liquid Chromatography with Tandem Mass Spectrometry 
LLN 
Lower Limit of Normal 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
N 
Number (typically refers to subjects) 

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NEJM 
New England Journal of Medicine 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
NOAEL 
No-Observed-Adverse-Effect-Level 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
QA 
Quality Assurance 
QC 
Quality Control 
SAD 
Single Ascending Dose 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SAP 
Statistical Analysis Plan 
SDCC 
Statistical and Data Coordinating Center 
SMC 
Safety Monitoring Committee 
SOCS 
Safety Oversight Committee Support 
SOP 
Standard Operating Procedure 
ULN 
Upper Limit of Normal 
US 
United States 
VCT 
Verified Clinical Trials 
WHO 
World Health Organization 
 
 
 

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PROTOCOL SUMMARY 
 
Title: 
A Phase 1, First-In-Human, Randomized, Double-Blind, 
Placebo-Controlled, Single Dose-Escalation Study to Evaluate 
the Safety and Pharmacokinetics of Single Oral Doses of VT-
1598 in Healthy Adult Subjects 
Design of the Study: 
 
This is a Phase 1, first-in-human, randomized, double-blind, 
placebo-controlled, single ascending dose (SAD) study, in six (6) 
cohorts (five fasted cohorts, one fed cohort).  Each cohort 
contains 8 subjects (N = 8), 6 subjects will be given an oral dose 
of VT-1598 and 2 subjects will receive placebo. 
Study Phase: 
1 
Study Population: 
Up to forty-eight (48) healthy male and female subjects, 
ages 18-45 (inclusive). 
Number of Sites: 
1 
Description of Study 
Product or Intervention: 
VT-1598 will be supplied as 40 mg and 80 mg tablets.  
Placebo will be supplied as the same size, weight, and color as 
the VT-1598 tablets. 
Study Objectives: 
 
 
Primary: 
• To determine the safety of single-ascending oral doses of 
VT-1598 in healthy adult subjects in a fasted state.   
• To determine the safety of single oral dose of VT-1598 in 
healthy adult subjects in a fed state.     
 

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Secondary: 
• To determine the pharmacokinetic (PK) profile in plasma 
and urine of VT-1598 and its primary metabolite, VT-
11134, in healthy adult subjects 
• 
To determine the effect of a high-fat, high-calorie meal on 
the PK profile of VT-1598 and VT-11134 when a single 
oral dose of VT-1598 is given. 
 
Study Outcome Measures: 
Primary: 
• Safety will be evaluated for single-ascending fasting oral 
doses of VT-1598. Safety will be assessed by adverse 
events from start of dosing to Day 21, clinical laboratory 
tests at baseline and from Day 4 to Day 21, ECGs at 
baseline and on Day 4 and Day 21, and vital signs at 
baseline and from Day 1 to Day 21;  
• Safety will be evaluated for single oral dose of VT-1598 
administered after being fed a high-fat, high calorie meal. 
Safety will be assessed by adverse effects from start of 
dosing to Day 21, clinical laboratory tests at baseline and 
from Day 4 to Day 21, ECGs at baseline and on Day 4 and 
Day 21, and vital signs at baseline and from Day 1 to Day 
21.  
Secondary: 
• PK profiles of VT-1598 and its primary metabolite, VT-
11134, will be assessed by measurement of VT-1598 and 
VT-11134 levels in both plasma and urine after VT-1598 
administration in each cohort, when fasting.  Plasma for PK 
analysis will be collected at planned time points up to 480 
hours post-dose and urine for PK analysis will be collected 
in planned intervals up to 72 hours post-dose;  

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• PK profiles of VT-1598 and its primary metabolite, VT-
11134, will be assessed by measurement of VT-1598 and 
VT-11134 levels in both plasma and urine after 
administration of VT-1598 following consumption of a 
high-fat, high calorie meal. Plasma for PK analysis will be 
collected at planned time points up to 480 hours post-dose 
and urine for PK analysis will be collected in planned 
intervals up to 72 hours post-dose.   
Duration of Individual 
Subject Participation: 
Individual subject participation will be approximately 50 days to 
include up to 28 days pre-enrollment (screening period) and 21 
days of follow-up post-dosing. Note: Subjects who participate in 
both cohorts 3 and 6, their participation will exceed 50 days.     
Estimated Time to Last 
Subject/Last Study Day: 
Approximately 6 months. 
 
 
 

DMID Protocol 17-0087 
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Table 1: Single Dose* Escalation 
Cohort 1 - 
fasting 
Dose:  40 mg 
6 
subjects** 
Single 40 mg VT-1598 
tablet 
Safety data for Cohort 1 subjects through Day 7 will 
be confirmed by reviewing objective pre-defined 
criteria before continuing to Cohort 2. 
 
2 
subjects** 
Single 40 mg 
matching Placebo 
Cohort 2 - 
fasting 
Dose:  80 mg 
6 
subjects** 
Two 40 mg VT-1598 
tablets 
Safety data for Cohort 2 subjects through Day 7 will 
be confirmed by reviewing objective pre-defined 
criteria before continuing to Cohort 3. 
2 
subjects** 
Two 40 mg matching 
Placebo tablets 
Cohort 3 - 
fasting 
Dose:  160 mg 
6 
subjects** 
Four 40 mg VT-1598 
tablets 
Safety data for Cohort 3 subjects through Day 7 will 
be confirmed by reviewing objective pre-defined 
criteria before continuing to Cohort 4 and 6. Interim 
analysis of PK data (Cohorts 1-3)***  
2 
subjects** 
Four 40 mg matching 
Placebo tablets 
Cohort 4 – 
fasting  
Dose:  320 mg 
6 
subjects** 
Four 80 mg VT-1598 
tablets 
Cumulative safety data for all subjects in Cohorts 1-4 
through Day 21 will be reviewed by the SMC for 
recommendation/confirmation of dosing before 
continuing to Cohort 5 
2 
subjects** 
Four 80 mg matching 
Placebo tablets 
Cohort 5 – 
fasting 
Dose: 640 mg 
6 
subjects** 
Eight 80 mg VT-1598 
tablets 
 
 
2 
subjects** 
Eight 80 mg matching 
Placebo tablets 
Cohort 6 – fed 
(high-fat, high-
calorie meal) 
Dose:  160 mg 
6 subjects 
Four 40 mg VT-1598 
tablets 
Cohort 6 is comprised of the same subjects as Cohort 
3****. These subjects will receive the same treatment 
in Cohort 6 as Cohort 3. Cohort 6 may start enrolling 
prior to convening the SMC meeting and prior to the 
start of Cohort 5.  
2 subjects 
Four 40 mg matching 
Placebo tablets 
*Dose refers to the free base equivalent of the drug. 
**Within each fasted cohort two sentinel subjects will be admitted initially, and the randomization scheme will be 
designed to ensure that one subject will receive VT-1598 and the other will receive placebo.  All sentinel subject 
safety data through Day 3 is reviewed by PI prior to dosing remainder of cohort. 
***PK data only; enrollment for Cohort 4 will not stop for the PK interim analysis. 
**** The Cohort 6 replacement subjects will receive the same treatment as assigned to the Cohort 3 subject they are 
replacing. 
 
 

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PK blood sampling (all subjects)
pre-dose; post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 14hr
PK urine sampling (all subjects):
pre-dose; post-dose 0-6, 6-12, 12-24 hr
Day 21 (+/- 2 days)
PE, vitals, ECG, clin labs
480hr PK blood samples
Days 7 & 14 outpatient (+/- 1 day)
vitals, clin labs
144 & 312 hour PK blood samples
Day 4
Physical exam, vitals, ECG, Clin labs
72 hr PK blood & 60-72 hr PK urine samples
Discharge from CRU
Days 2 & 3 (confined)
Vitals, Conmeds
 24, 36, 48, 60 hr PK blood samples & 24-36, 36-48, 48-60 hr PK urine samples
Day 1
Study product administration (per cohort dose regimen)
PK blood sampling through 14hr post-dose- PK urine sampling up to 24 hr post-dose (time points below)
Day -1
Enrollment and baseline assessments
Admitted and confined to CRU
Randomization
Up to Day -28
Screening
 
Figure 1: 
 Schematic of Study Design 
 
 

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KEY ROLES 
 
Lead Principal 
Investigator: 
 
                                      
 
 
: 
Cassandra Key, MD 
ICON Early Phase Services, LLC 
8307 Gault Lane 
San Antonio, TX    78209 
Phone: 210-283-4120 
Email: Cassandra.key@iconplc.com  
 
 
DMID Clinical Project 
Manager 
Maureen Mehigan 
5601 Fisher Lane 7E54 
Bethesda, MD  20892 
Phone: 240-627-3317 
Cell: 240-507-9599 
Email: mmehigan@niaid.nih.gov 
Statistical and Data 
Coordinating Center: 
 
Emmes Company, LLC 
401 North Washington Street, Suite 700 
 
Rockville, MD  20850 
Phone: 301-251-1161 
Email: phase1@emmes.com 
Contact information for additional key personnel is located in the Manual of Procedures 
(MOP) for this study. 

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BACKGROUND AND SCIENTIFIC RATIONALE 
 
Background  
CYP51 (lanosterol demethylase) is a metalloenzyme essential for fungal growth and catalyzes an 
early step in the biosynthetic pathway of ergosterol, a sterol required for fungal cell membrane 
formation and integrity.1 Inhibition of CYP51 not only blocks the pathway leading to ergosterol 
but also results in the accumulation of 14-methylated sterols, some of which are toxic to the 
fungus. Fungal CYP51 is the molecular target of the class of drugs referred to as ‘azole 
antifungals’. All currently approved azole drugs contain either an imidazole or triazole ring 
system2 that binds tightly to the catalytic heme-iron of fungal CYP51 as well as to the heme-iron 
of many off-target mammalian cytochrome P450 (CYP) enzymes. This inherent lack of 
selectivity is responsible for many of the side effects associated with the azole antifungals. For 
example, the potent inhibition of one or more human CYP enzymes found in the liver (e.g., 
CYP3A4, CYP2C9, CYP2C19) or in the adrenal and sex organs (e.g., CYP11B, CYP19, 
CYP17) is the basis for azole drug-drug interactions (DDI)3 and endocrine toxicities, including 
reproductive warnings,4 respectively. 
Additional azole class toxicities that are less well understood but may be related to other off-
target human CYP interactions include hepatic toxicity, skin photosensitivity, and vision 
impairment. In the acute care setting, the dose-limiting side effects not only are limitations in and 
of themselves but also prevent attainment of plasma drug levels that might reduce the long-
standing high mortality rates attributed to invasive fungal infections. For example, the mortality 
rate (40%) due to coccidioidal meningitis in a 2008 study has not changed since 1980.5 
VT-1598 is a novel, potent antifungal compound designed to selectively bind to fungal CYP51 
rather than human CYP enzymes so as to minimize the off-target effects associated with 
currently approved azole antifungals agents. In both in vitro and in vivo studies, VT-1598 has 
demonstrated highly-potent antifungal activity against Coccidioides species. 
Approximately 50,000 cases of coccidioidomycosis are estimated to occur annually that are 
sufficiently severe to require medical attention. Among these cases, several thousand patients 
suffer serious pulmonary sequelae, and disseminated infection will result in death in 
approximately 160 individuals.6,7,8,9 The disease can be highly-debilitating and places 
considerable demands on healthcare resources. In a survey of nearly 500 recently diagnosed 
cases of coccidioidomycosis in Arizona, 85% of cases had disease limited to the lungs, the 
median duration of illness was 4 months, and the median time lost from work was 2 weeks. 
Forty-one percent of patients required hospitalization, incurring an average cost of $30,000 per 
patient just for inpatient care.10 From 2000-2011, 25,217 coccidioidomycosis-associated 

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hospitalizations occurred in California, involving 15,747 patients. Among these patients, there 
were 1,220 deaths: 626 due to primary pulmonary coccidioidomycosis, 309 due to other forms of 
progressive disease, and 196 due to coccidioidal meningitis.11 Coccidioidal meningitis is the 
most severe form of disseminated disease, and is associated with a high degree of morbidity and 
mortality. Khan and Brady identified 1251 hospitalizations in 623 patients with coccidioidal 
meningitis in non-federal facilities in Arizona from 2008-2014.12 Readmission was common 
(41%) and 61% of hospitalizations included time in the intensive care unit. 
Treatment regimens (choice of agent and doses) for coccidioidomycosis vary considerably 
depending on the clinical presentation of the disease, and all current regimens have significant 
limitations. Currently, ketoconazole and amphotericin B are the only antifungal agents approved 
for this disease, despite significant toxicity concerns. The Infectious Diseases Society of America 
guidelines recommend that coccidioidomycosis be managed with various antifungal agents 
including off-label use of fluconazole and itraconazole, as well as amphotericin B, depending on 
disease presentation.13 However, with currently available antifungal agents, coccidioidomycosis 
continues to be associated with substantial, preventable morbidity and mortality, and relapse is a 
common occurrence. Treatment outcomes are particularly poor for disseminated disease (~40% 
mortality) and a comparison of matched cohorts from 1980 and 2008 suggests that outcomes did 
not improve over that time span.5 In addition, existing oral agents are generally administered at 
high doses for extended durations and are associated with significant toxicity, including a risk of 
serious hepatotoxicity that increases with dose and duration of treatment. High-dose and 
prolonged use of the commonly-prescribed fluconazole is also associated with congenital 
anomalies in infants exposed in utero. Finally, all prescribed azole antifungals have significant 
DDIs due to poor selectivity for fungal versus human CYP enzymes, complicating both 
treatment decisions and drug monitoring. Therefore, there is an urgent need for new therapeutic 
options that can address gaps in efficacy and provide a better safety profile.  
Nonclinical Studies 
Nonclinical Pharmacology 
Binding and Inhibition 
In vitro pharmacology studies have demonstrated that VT-1598 is a potent inhibitor of fungal 
CYP51 and that the activity of VT-1598 is highly selective for fungal CYP51 versus human 
CYPs. 
 
 

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Microbiology 
VT-1598 was tested under Clinical Laboratory Standards Institute guidelines against a broad 
panel of fungal samples (N = 10-50/species) including clinical yeast, mold and endemic fungal 
isolates, and showed potent intrinsic antifungal activity (geometric mean minimum inhibitory 
concentrations ranging from 0.004 to 3.5 µg/mL for the 15-different species tested). 
Activity in Animal Models of Infection 
In murine models of invasive infections with Coccidioides posadasii, Cryptococcus neoformans, 
Candida albicans, and Aspergillus fumigatus, and of a mucosal infection with C. albicans, VT-
1598 free base or tosylate salt at oral once daily doses ranging from 3 to 50 mg/kg (doses 
expressed as the free base equivalent) were highly effective in reducing fungal burden and 
demonstrated a survival benefit of up to 100% protection across multiple studies. In two models, 
VT-1598 reduced fungal burden to below pre-treatment levels. In murine central nervous system 
models of coccidioidomycosis and cryptococcosis, VT-1598 not only achieved highly significant 
survival benefit, it also reduced brain fungal burden up to 5-6.5 orders of magnitude, with 
undetectable viable fungus in several of the tissue samples assessed. 
Nonclinical Drug Metabolism and Pharmacokinetics 
Pharmacokinetics 
Single-dose PK studies were conducted in Swiss albino mice, Sprague-Dawley rats, Beagle dogs, 
and cynomolgus monkeys, with the primary goal to identify the version/form and formulation 
that would give optimized exposures for preclinical safety assessment. Repeat-dose PK and 
toxicokinetics studies showed that orally administered VT-1598 was well absorbed and reached a 
maximum measured plasma concentration (Cmax) of 30-40 µg/mL in rats and 50-60 µg/mL in 
monkeys after repeated doses up to 28 days in duration. VT-1598 exposures increased as doses 
increased in all animal species, but exposure increases were less than dose-proportional. 
Terminal elimination half-lives were relatively long (25-33 hours in rats and 64-72 hours in 
monkeys), leading to accumulation in repeat-dose studies (2- to 4-fold increases in rats and 10- 
to 15-fold increases in monkeys). In the large majority of studies, no differences were observed 
between males and females (although there were higher exposures in females at the end of the 
28-day Good Laboratory Practice [GLP] rat toxicity study). VT-1598 has very high plasma 
protein binding (≥99.9%). 
Metabolism 
VT-1598 was metabolized to varying extents when incubated with mouse, rat, dog, monkey, or 
human liver microsomes and with rat, dog, and human hepatocytes. A single metabolite was 

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observed following incubations with human hepatocytes; its structure is consistent with O-
dealkylation at the internal ether linkage of VT-1598. 
CYP Interactions 
When tested in biochemical assays using 1 mg/mL microsomal protein, VT-1598 weakly 
inhibited human CYP enzymes (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, 
CYP2D6, CYP2E1, CYP3A4, CYP11B1/2, CYP17, and CYP19). The range of half maximal 
inhibitory concentration (IC50) values was 6.8 to >200 µM. When tested in assays using 0.01-0.1 
µg/mL, IC50 values were lower: CYP1A2 (IC50 = >4.5 µM), CYP2D6 (IC50 = >4.5 µM), 
CYP2C9 (IC50 =>4.5 µM), CYP2B6 (IC50 = 3.8 µM), CYP3A4/5 (IC50 = 2.8 µM with 
testosterone as substrate), CYP2C8 (IC50 = 0.96 µM), CYP2C19 (IC50 = 0.91 µM), and 
CYP3A4/5 (IC50 = 0.59 µM) with midazolam as substrate. 
Nonclinical Safety Assessments 
Safety Pharmacology 
The effects of orally-administered VT-1598 on the neurological and pulmonary systems were 
evaluated in Sprague-Dawley rats. No observable adverse effects were found at the top dose of 
150 mg/kg VT-1598 in either study. Evaluation of cardiovascular function in telemetered 
monkeys revealed no adverse changes in heart rate, blood pressure, cardiac rhythm or 
morphology, including the QT/QTc interval, at oral doses up to 300 mg/kg administered twice-
daily for 7 days. VT-1598 did not inhibit the human ether-à-go-go related gene (commonly 
known as hERG) potassium current up to the highest soluble concentration tested (with the 
estimated IC50 of >2.9 µM). 
Toxicology 
Oral VT-1598 has been evaluated in general toxicity studies in rats and monkeys of up to 28 
days in duration. Based on the pivotal 28-day GLP toxicology studies, rats were more sensitive 
to the toxicological effects of oral administration of VT-1598 than monkeys. 
In the 28-day GLP rat toxicity study, once daily oral doses of VT-1598 resulted in test article- 
related mortality at 300 mg/kg/day. VT-1598-related changes in body weight, food consumption, 
clinical pathology parameters, organ weights and/or histopathology were observed ≥10 
mg/kg/day but were considered to be non-adverse. Exposure to VT-1598 and its primary 
metabolite (VT-11134) increased less than proportionally to the increase in dose and 
accumulated with repeated dosing as predicted by the long half-life of the molecule (terminal 
elimination half-life was calculated to be 25-33 hours). The no-observed-adverse-effect-level 
(NOAEL) for VT-1598 established in this study was 100 mg/kg/day; Day 28 Cmax and an area 
under the plasma concentration versus time curve from time zero to 24 hours post-dose (AUC0-

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24) in males were 12.6 μg/mL and 201 µghr/mL, respectively, and Cmax and AUC24 values in 
females were 32.0 μg/mL and 475 µg·hr/mL, respectively. 
In the 28-day GLP oral toxicity study in cynomolgus monkeys following twice daily dosing with 
VT-1598, findings were generally limited to the highest dose tested (100 mg/kg/dose) and 
included clinical observations, mild increase in QTc interval, and increased organ weights with 
correlative histopathological changes. Increased adrenal gland and liver weights were associated 
with cortical hypertrophy and hepatocellular hypertrophy, respectively, which were observed 
across dose-groups, although not necessarily dose-dependent. No test article-related changes 
were present in recovery animals. Exposure to VT-1598 and VT-11134 generally increased in a 
dose- related manner; however, the increase in exposure was less than proportional to the 
increase in dose. VT-1598 and VT-11134 accumulated with repeated dosing as predicted by the 
long half- life of the molecule (terminal elimination half-life was calculated to be 64-72 hours). 
The NOAEL for VT-1598 for this study was the high dose level of 100 mg/kg/dose (200 
mg/kg/day), associated with a Day 28 Cmax of 65.2 µg/mL, and AUC24 of 1,330 µgh·r/mL. 
Genotoxicity 
VT-1598 was found to be negative for genotoxicity in the in vitro bacterial reverse mutation 
assay, the in vitro chromosome aberrations assay in human peripheral lymphocytes, and the in 
vivo bone marrow micronucleus assay in rats. 
Clinical Studies 
To date, no clinical studies have been conducted with VT-1598.  
 
Scientific Rationale 
 
Purpose of Study 
Coccidioidomycosis, also called Valley Fever, is an infectious disease caused by dimorphic fungi 
of the genus Coccidioides. Coccidioides species (C. immitis and C. posadasii) are endemic to the 
lower Sonoran life zone of the western hemisphere, including southern Arizona, the southern and 
central valleys of California, southwestern New Mexico, and west Texas in the US.6 Recent 
reports have documented the presence of C. immitis as far north as south-central Washington 
state.14 
In endemic states in which coccidioidomycosis is reportable to the US Centers for Disease 
Control and Prevention (CDC); (Arizona, California, Nevada, New Mexico, and Utah), the 
incidence of coccidioidomycosis increased from 5.3 cases per 100,000 population in 1998 to 
42.6 cases per 100,000 population in 2011.15 During that time period, 111,717 cases of 
coccidioidomycosis were reported to the CDC.15 Arizona and California account for 66 and 31 

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percent, respectively, of all nationally reported infections.15 Reportable-disease data rely on 
positive diagnostic test results and given the low rate of testing even in highly endemic areas, it 
is clear that the actual number of coccidioidomycosis cases far exceeds the reported numbers.16 
With population and industrial expansion into the southwestern deserts, the numbers of 
infections are expected to continue to climb. Additionally, the National Institute of Allergy and 
Infectious Diseases (NIAID) has designated Coccidioides species as a Category C pathogen due 
to its potential to be engineered as a bioterrorism weapon.17 
VT-1598 has been shown in preclinical studies to be a potent and selective, orally-available 
inhibitor of fungal CYP51. Fungal CYP51 is the target of the azole class of antifungal drugs. 
Azoles rely heavily on the potent interaction between either an imidazole or triazole moiety and 
the active site heme iron of this CYP, which also leads to potent inhibition of human CYPs. VT-
1598 blocks the production of ergosterol, an essential component of the fungal cell membrane. 
Due to VT-1598’s high fungal CYP selectivity, low cross reactivity with human CYP, and 
highly-potent antifungal activity, VT-1598 should have a greater clinical safety margin than 
currently available azole antifungal treatments. As a result of VT-1598’s substantial potency 
against Coccidioides species, VT-1598 was selected for further preclinical development targeting 
the treatment of coccidioidomycosis. 
 
Study Population 
Up to 48 subjects aged 18-45 (inclusive) who are in good health and meet all eligibility criteria 
will be enrolled in the study. The demographics in the local population should ensure that male, 
female and minorities (African American and Hispanics) will be represented in the enrolled 
population. Subjects will be recruited using IRB-approved advertising/web site listing of the 
essential inclusion and exclusion criteria. Subjects will self-schedule online for a screening 
appointment based on their desire to participate and their evaluation of their suitability based on 
inclusion/exclusion criteria. Children, pregnant or breast-feeding women, prisoners, and other 
vulnerable populations will not be enrolled. See Section 9.4 Exclusion of Women, Minorities and 
Children (Special Populations). 
Neither women nor minorities will be excluded from participation in this study. Women of child 
bearing potential may be included as per the inclusion criteria (Section 5.1 Eligibility Criteria). 
Subjects will be recruited without regard to gender or race. It is expected that race will reflect 
that within the community.  

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Potential Risks and Benefits 
 
Potential Risks 
As VT-1598 has not yet been studied in humans, no information is currently available regarding 
AEs associated with its use. 
When oral VT-1598 was evaluated in general toxicity studies in rats and monkeys, the following 
side effects were noted:   
- slight decreases in body temperature and heart rate 
- minimal to mild increases in serum cholesterol 
- decreases in mean body weight and food consumption 
- decreases in lymphocyte and eosinophil counts and/or increases in monocyte counts 
- moderate to marked prolongations of APTT and prothrombin times 
- minimal to mild decreases in alkaline phosphatase 
- mild to moderate decreases in serum albumin 
- mild decrease in serum creatinine 
- mild to moderate, dose-dependent increases in gamma-glutamyl transferase (GGT) 
- mild to moderate decreases in urine pH and specific gravity 
- mild increase in urine volume. 
 
Among the currently-available azole antifungal agents, numerous clinically-significant drug 
interactions have been identified.18  Most of these interactions are a result of competitive 
inhibition of liver oxidative metabolism via reversible binding to CYP enzymes. Azoles interfere 
mainly with CYP3A4, CYP2C9, and CYP2C19 characterized by individual affinity and they 
therefore exhibit slightly different drug interaction profiles. In addition, itraconazole, 
posaconazole and isavuconazole are inhibitors of gastric P-glycoprotein, which limits systemic 
exposure to many drugs by inhibiting gastrointestinal absorption. 
Adverse effects of the currently-available azole antifungals vary across the individual agents and 
are described in the following paragraphs: 
Fluconazole: Fluconazole is generally well tolerated and serious adverse events (SAEs), mainly 
hepatotoxicity, are rare. Gastrointestinal disturbances are the most common complaints. High 
doses (400-800 mg/day) of fluconazole may be associated with a rare and distinct set of birth 
defects in infants whose mothers were treated with the drug during the first trimester of 
pregnancy. The US Food and Drug Administration (FDA) is evaluating the results of a Danish 
study that concluded there is a possible increased risk of miscarriage with the use of oral 
fluconazole for yeast infections. 

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Ketoconazole: Nausea and vomiting may occur when using ketoconazole. Serious and 
sometimes fatal liver problems, including the need for liver transplant, have occurred with the 
use of ketoconazole. Ketoconazole can cause elevated plasma concentrations of certain drugs 
and may prolong QT intervals, sometimes resulting in life-threatening ventricular dysrhythmias 
such as torsades de pointes. Ketoconazole, when used in high doses, may cause adrenal 
insufficiency. 
Itraconazole: Itraconazole causes frequent gastrointestinal symptoms, mainly nausea and 
vomiting; other common adverse effects include elevated hepatic transaminases, hypokalemia 
(sometimes severe), and rashes. Serious hepatotoxicity leading to liver failure has been reported 
with itraconazole but is rare. Heart failure due to itraconazole is caused by a direct negative 
inotropic effect and has resulted in a “black box” warning in the label. 
Voriconazole: The most common AEs after treatment with voriconazole include visual 
disturbances in up to 20-40% of recipients. Most reports are of blurring, photopsia, photophobia, 
and color changes soon after dosing; these are reversible and tend to dissipate with continued 
dosing. Like the other triazoles, voriconazole has been associated with hepatotoxicity which can 
rarely be serious or fatal and is dose-related. Other side effects include visual and auditory 
hallucinations, confusion, skin rashes (mostly photosensitivity), QTc prolongation, and 
peripheral neuropathy. 
Posaconazole: The safety profile of posaconazole is improved compared to voriconazole. 
Common AEs include headaches and gastrointestinal disturbances. Hepatotoxicity is uncommon 
and reported in 2-3% of recipients. Hypokalemia and rashes occur but less commonly than with 
itraconazole and voriconazole. 
Isavuconazole: The most frequent adverse effects of isavuconazole are nausea, vomiting, 
diarrhea, headache, elevated liver chemistry tests, hypokalemia, constipation, dyspnea, cough, 
peripheral edema and back pain. Isavuconazole is contraindicated for use in patients with 
familial short QT syndrome and rare but serious hepatic reactions have also been reported with 
its use. 
As noted above, the differentiating properties of VT-1598 should translate to greater efficacy 
with an improved safety and tolerability profile compared to the existing azole agents. In 
addition, the animal toxicology studies completed to date do not suggest any unusual or 
unexpected toxicities related to VT-1598 exposure. The present study provides for careful 
monitoring for the AEs that have been observed with existing azole agents. In addition, all 
subjects that have pre-existing abnormalities in body systems associated with the more severe 
AEs reported for existing azoles (e.g., visual disturbances, hepatic disease, and cardiac 
conduction abnormalities) will be excluded from participation. 

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As with taking any product/drug, there is a risk of allergic reaction. There may be risk of death if 
there is a very serious allergic reaction. Other risks include temporary physical discomfort and 
potential emotional stress due to the nature of the exams and specimen collection procedures. 
The risks associated with insertion of the indwelling intravenous catheter and frequent blood 
draws are fainting, pain, bruising, and scarring. The catheter may be at risk for clotting and 
infection.  These risks are discussed with the subject during the consent process. 
  
In addition to the above risks, the risk of volunteering for this study includes a potential failure to 
protect the subject’s private health and other information through an accidental breach of 
confidentiality.  This risk of breach of confidentiality and the associated safeguards to protect 
confidentiality will be defined in each informed consent document. 
 
 
Potential Benefits 
There are no known benefits to subjects participating in this study. The knowledge gained in this 
trial may help society, especially those exposed to Coccidioides species. 

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STUDY DESIGN, OBJECTIVES AND ENDPOINTS OR 
OUTCOME MEASURES 
 
Study Design Description 
 Overall Study Design 
This is a Phase 1, randomized, double-blind, placebo-controlled, SAD study in healthy adult 
subjects. It is designed to evaluate the safety and PK of single oral doses of VT-1598. Subjects 
who provide informed consent and meet all study eligibility criteria will be enrolled in the study 
and randomized to receive either VT-1598 or placebo in 6 dosage cohorts (five fasted cohorts 
and one fed cohort).  For all cohorts, Screening, Enrollment, Treatment Period, and Follow-Up 
procedures/activities (Day -28 to Day 21) will follow the same process, with the exception of the 
fed Cohort (Cohort 6) who receives the study product after a high-calorie, high-fat meal vs. when 
fasted (Cohorts 1-5).  Cohort 6 may be started prior to the SMC meeting or prior to the start of 
Cohort 5 (but no less than 60 days following their first dose after completion of Cohort 3). 
  Dosing Scheme and Duration of Study 
For each dosage cohort, 6 subjects will receive VT-1598 and 2 subjects will receive placebo. 
Within each of the fasted cohorts (Cohorts 1-5), two sentinel subjects will be admitted initially, 
and the randomization scheme will be designed to ensure that one subject will receive VT-1598 
and the other will receive placebo.  The dosing of the next 6 subjects for each subsequent fasting 
dose escalation group (Cohorts 2-5) will not be initiated until at least 3 days have passed and 
none of the predefined objective halting criteria for sentinels have been met. The remaining 6 
subjects in the cohort will then be admitted and dosed.  
Pending subject availability, the fed group (Cohort 6) will be comprised of the same subjects as 
Cohort 3, however they will not be randomized; the same 6 subjects who received VT-1598 and 
the 2 subjects who received placebo in Cohort 3 will receive the same treatment in Cohort 6. 
Cohort 6 subjects are dosed at the same level as Cohort 3 (160 mg) following a high-fat, high-
calorie meal.  Cohort 6 will not include sentinel subjects. Providing no halting criteria is met, 
Cohort 3 subjects may proceed to Cohort 6 and be dosed prior to the Safety Monitoring 
Committee meeting but no less than 60 days following their first dose (wash-out period). 
Subjects who complete Cohort 3 but are not eligible or withdraw prior to dosing for Cohort 6 
will be replaced.  The Cohort 6 replacement subjects will receive the same treatment as assigned 
to the Cohort 3 subject they are replacing.  

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Safety data through Day 7 for every subject in the current cohort will be available prior to 
making dose escalation decisions. Dose escalation may occur if none of the predefined objective 
halting criteria for dose escalation have been met. The duration of individual subject 
participation, from start of screening until final follow-up, will be up to 50 days (Note: Subjects 
who participate in cohort 3/6, their participation will exceed 50 days). Screening for eligibility 
will occur from Day -28 to Day -2. Subjects will be admitted to the CRU on the day before 
dosing (Day -1). Subjects will be administered VT-1598 or placebo on Day 1 and will remain in 
the CRU for at least 72 hours post-dose (Day 4) for safety monitoring and PK assessments. 
Subjects will return to the CRU on Days 7, 14, and 21 for safety monitoring and PK assessments. 
The study duration from the start of screening until last follow-up of the last dose cohort will be 
approximately 6 months. 
 Number of Subjects 
A sufficient number of subjects will be screened to enroll up to 48 subjects into the study in 6 
cohorts, and each cohort contains 8 subjects (6 for active drug VT-1598 and 2 for placebo). 
Cohort 6 (fed Cohort).Subjects will be enrolled from 1 site in the US. 
 Rationale for Starting Dose 
The proposed clinical start dose is based on the FDA guidance document “Estimating the 
Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Healthy Volunteers”, 
July 2005. The rat was determined to be the most sensitive species in 28-day toxicity studies. 
The NOAEL for this study was 100 mg/kg/day (dose expressed as the free base equivalent 
throughout the document). Using 100 mg/kg/day as the NOAEL in rat, the human equivalent 
dose calculation of 40 mg for a starting dose incorporates a 28-fold safety margin.   
 Dose Escalations 
The initial cohort of 8 subjects will be administered 40 mg of VT-1598 (6 subjects) or placebo (2 
subjects) as a single oral dose. Two sentinel subjects will be included in cohorts 1-5 as described 
in Section 3.1.2 Dosing Scheme and Duration of Study.  
Dose escalation to each successive cohort will occur if none of the predefined dose escalation 
halting criterion is met (for all subjects through Day 7). This will be communicated through the 
following process: 
1. A halting criteria report will be provided by the SDCC to the study  
2. If based on the data entered in EDC, none of the halting criteria are met, then the email 
from the SDCC will be provided and the Sponsor will notify the study team that the next 
cohort can be opened for enrollment.    

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3. If any of the halting criteria are met, the SDCC will provide the dose escalation report 
and an ad-hoc SMC meeting will be convened to seek recommendation from the SMC. 
 
There will be a scheduled SMC data review meeting prior to start of Cohort 5.  
The nominal dose-escalation scheme will be 40, 80, 160, 320 and 640 mg or matching placebo 
administered in a fasting state. The effect of a high-fat, high-calorie meal on the PK of VT-1598 
is planned in an additional cohort that will be dosed at 160 mg.  The fed cohort will be dosed at 
160 mg, after the 320 mg fasted cohort has been dosed. This provides additional safety data to 
cover the possibility that the bioavailability of VT-1598 is increased in the presence of food. The 
highest proposed dose in this study is 640 mg, which is 53% of the body surface area equivalent 
of the NOAEL in the most sensitive species.   
In order to efficiently identify the optimal therapeutic doses for use in future clinical trials, a 
flexible scheme of dose escalation, (based on ongoing study data) will be used that allows 
intermediate doses higher or lower than the planned doses (40, 80, 160, 320 and 640 mg), upon 
protocol amendment and with IRB approval.   However, no cohort will be dosed higher than the 
640 mg free base equivalent. 
See Figure 1 Schematic of Study Design. 
 
Study Objectives 
 Primary  
• 
To determine the safety of single-ascending oral doses of VT-1598 in healthy adult subjects 
in a fasted state;   
• 
To determine the safety of single oral dose of VT-1598 in healthy adult subjects in a fed 
state.     
 Secondary 
• 
To determine the pharmacokinetic (PK) profile in plasma and urine of VT-1598 and its 
primary metabolite, VT-11134, in healthy adult subjects; 
• 
To determine the effect of a high-fat, high-calorie meal on the PK profile of VT-1598 and 
VT-11134 when a single oral dose of VT-1598 is given. 

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 Study Endpoints or Outcome Measures 
 Primary Outcome Measures 
• 
Safety will be evaluated for single-ascending fasting oral doses of VT-1598. Safety will be 
assessed by adverse events from start of dosing to Day 21, clinical laboratory tests at 
baseline and from Day 4 to Day 21, ECGs at baseline and on Day 4 and Day 21, and vital 
signs at baseline and from Day 1 to Day 21;  
• 
Safety will be evaluated for single oral dose of VT-1598 administered after being fed a 
high-fat, high calorie meal. Safety will be assessed by adverse effects from start of dosing to 
Day 21, clinical laboratory tests at baseline and from Day 4 to Day 21, ECGs at baseline and 
vital signs at baseline and from Day 1 to Day 21.  
 Secondary Outcome Measures 
• 
PK profiles of VT-1598 and its primary metabolite, VT-11134, will be assessed by 
measurement of VT-1598 and VT-11134 levels in both plasma and urine after VT-1598 
administration in each cohort, when fasting.  Plasma for PK analysis will be collected at 
planned time points up to 480 hours post-dose and urine for PK analysis will be collected in 
planned intervals up to 72 hours post-dose;  
• 
PK profiles of VT-1598 and its primary metabolite, VT-11134, will be assessed by 
measurement of VT-1598 and VT-11134 levels in both plasma and urine after 
administration of VT-1598 following consumption of a high-fat, high calorie meal. Plasma 
for PK analysis will be collected at planned time points up to 480 hours post-dose and urine 
for PK analysis will be collected in planned intervals up to 72 hours post-dose.   
 
 
 

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STUDY INTERVENTION/INVESTIGATIONAL PRODUCT 
 
Study Product Description 
VT-1598 is a novel oral agent for the treatment of fungal infections. VT-1598 in its physical 
form is a lightly colored solid with a molecular formula of C31H20F4N6O2 and a molecular weight 
of 584.5 g/mol. 
 Formulation, Packaging, and Labeling 
VT-1598 will be supplied as 40 mg and 80 mg tablets. Each tablet is formulated as a spray-dried 
dispersion with standard excipients including Eudragit® L100, microcrystalline cellulose, 
mannitol, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, and FD&C 
Yellow #5 aluminum lake (United States Pharmacopeia).  
Placebo will be supplied as matching tablets (to 40 mg and 80 mg VT-1598 tablets) containing 
the inactive components of VT-1598.  In order to maintain the blind, the placebo tablets, are the 
same size, weight, and color as the VT-1598 tablets.  
VT-1598 and placebo tablets will be packaged in identical white opaque, high density 
polyethylene (HDPE) bottles containing 30 tablets. Each container will also be labeled in 
compliance with applicable regulatory requirement, including the FDA-required cautionary 
statement “Caution: New Drug-Limited by Federal (or United States) Law to Investigational 
Use”. 
 Product Storage and Stability 
VT-1598 must be stored in a secure location at a controlled room temperature of 15°C to 25°C 
(59°F to 77°F) and protected from light and moisture.  
Matching placebo tablets must be stored in a secure location at a controlled room temperature of 
15°C to 25°C (59°F to 77°F) and protected from light and moisture.  
 
Acquisition/Distribution 
VT-1598 will be provided by NQP 1598, Ltd. or its designee.  
Matching placebo will be provided by NQP 1598, Ltd, or its designee. 
Study products (VT-1598 and placebo) will be distributed through the DMID Clinical Material 
Services (CMS, Fisher BioServices) and shipped from the DMID CMS to the ICON CRU site 
upon request and approval by DMID.  

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Dosage/Regimen, Preparation, Dispensing and Administration of Study 
Intervention/Investigational Product 
Only subjects enrolled in the study may receive study products, and only authorized site staff 
may supply or administer study products. The unblinded pharmacist or designee will prepare the 
study product.  
Subjects will take the study product on Day 1 as follows: 
Designated tablets of VT-1598 or placebo are taken in the morning by mouth after an overnight 
fast of at least 8 hours. The dose given will be the dose designated for that dosage cohort (see 
Table 1). In the nominal dose escalation, subjects will be administered the study product and 
remain in a fasting state for 4 hours post-dose. In the planned additional cohort to evaluate the 
impact of a meal on PK at a previously evaluated dose level, the subjects will fast overnight for 
at least 8 hours prior to the start of a high-fat, high-calorie meal which will be entirely consumed 
in less than 30 minutes. The dose of study product will be administered 30 minutes after the start 
of the meal. The dates and times of study product administration and meal start, and end times 
will be recorded in the subjects’ electronic Case Report Form (eCRF). Any subject who does not 
finish the meal within 30 minutes will not be dosed and will be replaced. 
Water consumption for all cohorts will be restricted from one hour prior to dosing to one hour 
after dosing.  Subjects will consume approximately 240 mL of ambient temperature water with 
the dose of study product.  An additional 120 mL of water, if needed by the subject to swallow 
multiple tablets, will be documented in the eCRF. Each subject dose is to occur with 5 minutes. 
Any deviations from the dosage schedule will be recorded. 
The planned final doses of VT-1598 or placebo for subjects in each cohort are described in Table 
1. Details regarding planned dosing are included in Section 3.1.2 Dosing Scheme and Duration 
of Study and in the MOP. 
 
Accountability Procedures for the Study Intervention/Investigational 
Product(s) 
The United States Food and Drug Administration (FDA) requires accounting for the disposition 
of all investigational products. The Site Principal Investigator (PI) is responsible for ensuring 
that a current record of product disposition is maintained, and product is dispensed only at an 
official study site by authorized personnel as required by applicable regulations and guidelines. 
The Site PI will delegate to the Research Pharmacist responsibility for study product 
accountability. 

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The Research Pharmacist (or designee) will keep a record of the dates and amounts of study 
product received (including packing slips), the amount dispensed to study subjects, any amount 
destroyed, the amount unused, and temperature and storage conditions. Product accountability 
will be recorded by the Research Pharmacist on a Product Disposition Record or equivalent 
document with a separate accountability record for study product and placebo. The pharmacy 
records must be available for inspection by the DMID monitoring contractors and is subject to 
inspection by a regulatory agency (e.g., FDA) at any time. An assigned Study Monitor will 
review the pharmacy records. 
Unused investigational product will be stored in the Investigational Pharmacy until clinical trial 
accountability is completed. At study termination, all unused investigational product will be 
handled in accordance with the MOP following complete drug accountability and monitoring. 
Unused placebo will be handled in accordance with the MOP. 
 

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SELECTION OF SUBJECTS AND STUDY ENROLLMENT 
AND WITHDRAWAL 
Upon arrival to the clinic, subjects are checked for eligibility through the Verified Clinical Trials 
(VCT) process (after signing the IRB - approved VCT consent) and are then given the IRB 
approved consent and HIPPA forms.  After a presentation of the consent and when subjects 
indicate their desire to proceed, the subject is brought to a private room and given an opportunity 
to ask questions of the licensed nurse or MD delegated to perform consenting.  After signing 
consent, protocol procedures are executed. 
Study retention strategies will include education and explanation of the study schedule and 
procedures during Screening and Enrollment visits. In addition, reimbursements will be 
disbursed at specific time points during the study with the amount contingent on completing 
study procedures. Participating subjects will be reminded of visits ahead of time, and study staff 
will contact subjects who miss appointments to encourage them to return for completion of 
safety evaluations. 
 
Eligibility Criteria 
 Subject Inclusion Criteria 
Subjects may be entered in the study only if all the following criteria are met: 
1. Willing and able to provide written informed consent and authorization for use of protected 
health information; 
2. Willing and able to comply with protocol requirements, instructions, and protocol-stated 
restrictions (including confinement to the CRU) and is likely to complete the study as 
planned; 
3. Male or female subjects, 18-45 years of age (inclusive); 
4. Subject is in good health to be safely enrolled in this protocol as determined by medical 
history and physical exam. 
5. BMI of 18-35 kg/m
2, inclusive, and minimum weight of 50 kg; 
6. If a female participant is of childbearing potential*, she must use a highly effective 
contraceptive method† from 30 days before enrollment through the 3 months after dosing. 

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*A woman is considered of childbearing potential unless post-menopausal (subject is at least 50 years old and 
has history of ≥2 years without menses without other known or suspected cause and has a FSH level >40 IU/L), 
or permanently surgically sterilized. 
 
†A highly effective contraceptive method includes surgical sterilization methods such as tubal ligation, bilateral 
oophorectomy, salpingectomy, hysterectomy, or successful tubal obliteration (e.g., Essure®) with documented 
radiological confirmation test at least 90 days after the procedure, or long-acting reversible contraception 
(progestin-releasing subdermal implants, copper intrauterine devices (IUDs), levonorgesterel-releasing IUDs. 
 
7. Males* having sexual intercourse with women of childbearing potential must agree to 
consistent use of condoms from study product administration through 3 months after 
dosing**; 
* including vasectomized men 
** and must also agree to not donate sperm during this same time period 
8. Subject has adequate venous access for blood collection. 
 Subject Exclusion Criteria 
1. has a chronic condition that may increase risk to subject or interfere with endpoint 
assessment (e.g., liver disease, kidney disease, immunodeficiency). 
2. Chronic condition diagnosed within 90 days of the screening visit 
3. Unstable chronic disease* within 6 months of the screening visit 
*as defined by need for medical intervention that lead to a change in medications and/or required 
hospitalization, surgery/procedure, or ED/urgent care visit 
4. History of psychiatric condition that has required hospitalization in the last 5 years or patient 
is considered unstable by study investigator 
5. Any condition that in the opinion of the Investigator could significantly impact drug 
absorption, distribution, or elimination; 
6. Any out of normal range laboratory value* at screening or enrollment (Section 8.1 and 
Appendix B).  
*A laboratory value that is Grade 1 (with the exception of ALT, AST, Total bilirubin, hemoglobin or serum 
creatinine) will be allowed if not considered to be clinically significant by the investigator. 
7. Abnormal ECGs. See Section 7.1 Clinical Evaluations for exceptions; 
8. Electrocardiographic QTcF interval >430 msec for males and >450 msec for females at 
Screening; 
9. Positive test for antibodies to HIV-1, HIV-2, HBsAg, or HCV; 
10. Positive urine drug test.  The drugs that will be screened for includes amphetamines, 
barbiturates , cocaine, opiates, cannabinoids, phencyclidine, and benzodiazepines. 

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11. Female subject of childbearing potential who is pregnant*, lactating, or planning to become 
pregnant during the study period or 3 months after the final dose of study product; 
*Having a positive serum pregnancy test at the Screening Visit or any other specified time point prior to the 
dose of study product. 
12. Received any study product in a clinical trial within 30 days prior to Screening; 
13. Admitted or documented illicit drug use or alcohol abuse within 6 months prior to Screening 
or during their participation in the trial; 
14. Consumed alcohol within 72 hours of Day -1, until after the visit to the CRU on Day 14 or 
have a positive alcohol test at Screening or on admission to the CRU; 
15. Tobacco* use within 90 days prior to the Screening Visit or while a subject is enrolled in the 
study OR A positive urine drug test for cotinine;  
*Tobacco use includes vaping, smoking tobacco, the use of snuff and chewing tobacco, and other nicotine or 
nicotine- containing products. 
16. Use of prescription drugs within 14 days prior to the dose of study product with the exception 
of hormonal contraceptives, which are permitted throughout the study; 
17. Received any non-prescription medications, vitamins, or dietary supplements* within 7 days of 
dosing, unless prior approval is granted by both the Investigator and the Sponsor; 
*Excluded from this list is intermittent use of acetaminophen at doses of ≤2 g/day or ibuprofen ≤1200 mg/day. 
Herbal supplements must be discontinued 7 days prior to the dose of the study product. 
18. History of intolerance or hypersensitivity to azole antifungals; 
19. Blood donation or other significant blood loss within 60 days of screening and for the 
duration of the study; 
20. Inability or difficulty swallowing whole capsules/tablets and/or multiple capsules/tablets; 
21. Consumption of beverages and foods containing caffeine for 24 hours prior to Day -1 until 
discharge from the CRU on Day 4; 
22. Consumption of grapefruit, or juices containing grapefruit or Seville oranges within 7 days 
prior to the scheduled dose of the study product until after the visit to the CRU on Day 14;  
23. Subject has plans to enroll or is already enrolled in another clinical trial that could interfere 
with safety assessment of the investigational product at any time during the study period*;  
 
*Includes trials that have a study intervention such as a drug, biologic, or device 

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24. Having dietary restrictions that would preclude the subject from participating in either fed or 
fasting cohorts; 
25. Having sensitivity or allergy to aspirin. 
 Withdrawal from the Study, Discontinuation of Study Product, or Study 
Termination  
 Withdrawal from the Study or Discontinuation of the Study Product  
Subjects may voluntarily withdraw their consent for study participation at any time without 
penalty or loss of benefits to which they are otherwise entitled.   
An investigator may also withdraw a subject from receiving the study product for any reason. 
Follow-up safety evaluations will be conducted, if the subject agrees.  If a subject withdraws or 
is withdrawn prior to completion of the study, the reason for this decision must be recorded in 
the case report forms (CRFs). If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the Investigator must document this in the site study 
records and communicate this request to the Sponsor. However, the investigator will inform the 
subject that already collected data will be retained and analyzed even if the subject withdraws 
from this study.  
The reasons for withdrawal might include, but are not limited to the following: 
• 
Subject withdraws consent; 
• 
subject becomes noncompliant; 
• 
medical disease or condition, or new clinical finding(s) for which continued participation, in 
the opinion of the investigator might compromise the safety of the subject, interfere with the 
subject's successful completion of this study, or interfere with the evaluation of responses; 
• 
subject lost to follow-up; 
• 
request of primary care provider; 
• 
at the request of the IRB/IEC, FDA, or NIAID; 
• 
the subject’s well-being, based on the opinion of the investigator. 

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The investigator will inform the subject that already collected data will be retained and analyzed 
even if the subject withdraws from this study. Subjects will be informed that they have the right 
to withdraw from the study at any time for any reason without prejudice to their medical care. If 
the subject has received the study drug, data collected for withdrawn subjects will be evaluated 
for safety and PK. 
In all cases of withdrawal, the reason for withdrawal will be recorded. Subjects who receive any 
amount of study product and who are discontinued from the study will be asked to complete all 
Day 21 safety assessments including follow-up of any AEs prior to termination from the study.   
Lost to Follow Up 
The following actions must be taken in relation to a subject who fails to attend the clinic for a 
required study visit: 
• 
The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible; 
• 
The site must counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether the subject wishes to and/or should continue in the study; 
• 
In cases where the subject is deemed ‘lost to follow-up’, the Investigator or designee must 
make every effort to regain contact with the subject (e.g., multiple telephone calls on 
various dates/time, a certified letter to the subject’s last known mailing address, or 
equivalent methods). These contact attempts should be documented in the subject’s medical 
record. 
• 
should the subject continue to be unreachable, only then will they be considered to have 
withdrawn from the study with a primary reason of “Lost to Follow-up”. 
 Early Withdrawal 
In the event that a subject is prematurely discontinued from the study after receiving any amount 
of the study product but prior to discharge from the CRU, the Unscheduled Visit (Section 6.7 
Unscheduled Study Visits) procedures should be performed prior to discharging the subject from 
the CRU. If a subject receives any amount of study product and is prematurely discontinued from 
the study after discharge from the CRU, but prior to the Day 21/End-of-Study visit, an attempt 
should be made to have the subject return to the CRU to perform the Unscheduled Visit (Section 
6.7 Unscheduled Study Visits) 

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 Subject Replacement 
Subjects who have not received any amount of study product and discontinue from participation 
may be replaced, as well as subjects who experience emesis within the first 12 hours following 
dosing.  
Subjects who complete Cohort 3 but are not eligible or withdraw prior to dosing for Cohort 6 
will be replaced.  The Cohort 6 replacement subjects will receive the same treatment as assigned 
to the Cohort 3 subject they are replacing. 
Additionally, the first subject in each cohort to discontinue from participation due to loss to 
follow up, after receiving any amount of study product, is not replaced; if more than one subject 
in any cohort discontinues participation, these subjects will be replaced. Replacement of any 
subject is at the discretion of the Investigator in consultation with the Sponsor.  Replacement 
subjects should be allocated to the same treatment as the subject they replaced.  
 Study Termination  
As DMID, FDA and NQP 1598, Ltd. may terminate the study in the interest of subject safety and 
welfare. In addition, DMID reserves the right to terminate the study at any time for any other 
reason. If DMID terminates the study, the PI, IRB, SMC, ISM, designated contractors of DMID, 
,NQP 1598, Ltd., and the FDA will be informed, activities will be closed, and a study report will 
be prepared.  
If the study is prematurely terminated by the sponsor, any regulatory authority, or the 
investigator for any reason, the investigator will promptly inform the study subjects and assure 
appropriate follow-up for the subjects. The investigator will provide a detailed written 
explanation of the termination to the IRB. 

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STUDY PROCEDURES 
 
Screening  
6.1.1 Day -28 to Day -2 (Screening) 
Subjects will be screened within 28 days prior to study product administration. A sufficient 
number of subjects will be screened to enroll 48 subjects in the study. After the subject has 
signed the IRB-approved ICF, the following evaluations will be performed as indicated in the 
Schedule of Study Procedures and Evaluations (Appendix A VT-1598 Schedule of Study 
Procedures and Evaluations) and as detailed in Section 7 Description of Clinical and Laboratory 
Evaluations: 
• 
Demographics (date of birth, sex, and ethnic origin); 
• 
complete medical/medication history to include all past illnesses, alcohol and 
tobacco/vaping, illicit drug use history (previous 6 months), and all other drugs/medications 
taken, including non- prescription and herbal products,(previous 30 days) prior to screening 
procedures; complete physical examination including vital signs (heart rate, blood pressure, 
oral temperature and respiration rate, taken after being at rest for at least 5 minutes), height, 
and weight (for BMI calculation). If abnormal, these measurements may be repeated once; 
within 15 minutes of the original assessment; 
• 
obtain 12-lead ECGs after at least 5 minutes in the supine position (triplicate readings, at 
least 1 minute apart within a 15-minute period) to assess heart rate, rhythm, and interval 
information such as RR, PR, QRS, QT, QTc and QTcF; 
• 
obtain blood samples for fasting (at least 8 hours) clinical chemistry, hematology, 
coagulation tests, serum pregnancy test [if female of childbearing potential], FSH [if female 
and post-menopausal], and immunology screen (serum HIV, HBsAg, and HCV antibodies); 
• 
obtain urine sample for urinalysis, drugs of abuse and cotinine;  
• 
obtain urine test for alcohol; 
• 
review of Inclusion/Exclusion criteria to determine eligibility for entry into the study; 
• 
consult about birth control methods, permitted/non-permitted medications, non-medications, 
dietary and activity restrictions. 

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Enrollment 
6.2.1 Day -1 (Admission to Clinic; approximately 24 hours prior to dosing) 
Eligible subjects will return to the CRU on Day -1, the day prior to dosing, will undergo baseline 
evaluations as indicated in the Schedule of Study Procedures and Evaluations (Appendix A 
VT-1598 Schedule of Study Procedures and Evaluations ) and as detailed in Section 7, 
Description of Clinical and Laboratory Evaluations,  Study Procedures/Evaluations: 
• 
Review inclusion/exclusion criteria; 
• 
confirm that subject adhered to dietary restrictions (no food/beverages containing alcohol 
for previous 72 hours or caffeine for the previous 24 hours; no grapefruit, grapefruit juice, 
or juices containing grapefruit, or Seville oranges for previous 7 days); see Section 5.2.1); 
• 
review and record prior concomitant medications and non-pharmacologic 
treatments/procedures history since Screening; 
• 
review any change in medical history since Screening; 
• 
complete a targeted physical examination (general appearance, heart, lungs, skin, and 
abdomen); 
• 
obtain resting vital signs (heart rate, blood pressure, oral temperature and respiration rate, 
taken after being at rest for at least 5 minutes), and weight, BMI. If abnormal, these 
measurements may be repeated once, within 15 minutes of the original assessment; 
• 
obtain blood samples for baseline fasting (at least 8 hours) clinical chemistry, hematology, 
coagulation tests, serum pregnancy test [if female of childbearing potential]);  
• 
obtain urine sample for urinalysis, drugs of abuse (amphetamines, barbiturates, cocaine, 
opiates, cannabinoids, phencyclidine, and benzodiazepines) and cotinine;  
• 
obtain urine test for alcohol; 
• 
if screening criteria are satisfied, admit subject to CRU.  If screening criteria are not 
satisfied, the subject is then entered as a screening failure into the AdvantageEDCSM 
(Electronic Data Capture System, Emmes). 

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 Treatment Period 
6.3.1 Day 1 – Inpatient CRU 
Study product will be administered on the morning of Day 1.  Subjects are inpatients in the CRU 
and will undergo procedures as indicated in the Schedule of Study Procedures and Evaluations 
(Appendix A VT-1598 Schedule of Study Procedures and Evaluations) and as detailed in, 
Section 7 Description of Clinical and Laboratory Evaluations, listed below: 
• 
Review and record any concomitant medications and non-pharmacologic 
treatments/procedures since admission to the CRU; 
• 
confirm that subject adhered to fasting requirements of at least 8 hours before the dosing 
(for fasted cohorts; fed cohort will receive dose 30 minutes after starting a high-fat, high 
calorie meal); 
• 
obtain baseline urine sample for PK analysis (t=0), to be taken any time within 6 hours prior 
to dose; 
• 
obtain baseline blood sample for PK analysis (t=0), to be taken a time within 60 minutes 
prior to the dose (for fasted cohorts; within 30 minutes prior to the start of the pre-dose meal 
for the fed cohort); 
• 
targeted physical examination (general appearance, heart, lungs, skin and abdomen) 
including pre-dose resting vital signs (heart rate, blood pressure, oral temperature and 
respiration rate, taken after being at rest for at least 5 minutes and anytime within 60 
minutes prior to dosing) (for fasted cohorts; within 30 minutes prior to the start of the 
pre-dose meal for the fed cohort);. If abnormal, these measurements may be repeated once 
within 15 minutes of the original assessment; 
• 
obtain 12-lead ECGs after at least 5 minutes in the supine position (taken pre-dose any time 
within 60 minutes prior to dosing for fasting cohorts and any time within 60 minutes prior to 
dosing for the fed cohort); triplicate readings, at least 1 minute apart within a 15-minute 
period); 
• 
administer study product.   For the nominal dose escalations (Cohorts 1-5), study drug will 
be administered in a fasting state and subjects will remain fasted for at least 4 hours post-
dose. In Cohort 6, the planned additional cohort to evaluate the effect of a meal on PK, the 
subjects will be fed a high-fat, high-calorie meal which will be entirely consumed in less 

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than 30 minutes. The dose of the study product will be administered 30 minutes after the 
start of the meal. 
Following the administration of study product, the following procedures will be performed. PK 
samples (blood and urine) will be obtained (after the ECGs and vital signs whenever possible if 
the times coincide with one another): 
• 
Obtain blood samples for PK analysis at 0.5 h (±5 min), 1 h (±10 min), 1.5 h (±10 min), 2 h 
(±10 min), 3 h (±10 min), 4 h (±10 min), 6 h (±10 min), 8 h (±10 min), 10 h (±10 min), 12 h 
(±10 min), and 14 h (±10 min) hours post-dose; 
• 
collect urine samples for PK analysis in the following intervals following study product 
administration on Day 1:  0-6, 6-12, 12-24, hours post-dose;    
• 
obtain post-dose (6 h [±10 min]) blood sample for possible use in future research studies, if 
applicable. See Section 9.3 Consent for Future Use of Stored Specimens and Data. Consent 
for Future Use of Stored Specimens and Data and Schedule of Procedures (Appendix A VT-
1598 Schedule of Study Procedures and Evaluations); 
• 
12-lead ECGs obtained after at least 5 minutes in the supine position; taken post-dose [4 
hours (+/-10 minutes)]; triplicate readings, at least 1 minute apart within a 15-minute 
period); 
• 
obtain resting vital signs (heart rate, blood pressure, oral temperature and respiration rate, 
taken after being at rest for at least 5 minutes) at 1 h (±10 min), 2 h (±10 min), 4 h (±10 
min), and 8 h (±10 min), post-dose.  If abnormal, these measurements may be repeated once, 
within 15 minutes of the original assessment; 
• 
collect and record adverse events (AEs) and concomitant medications. 
 
Day 2 – Inpatient CRU 
Subjects are inpatients in the CRU and will undergo procedures as indicated in the Schedule of 
Study Procedures and Evaluations (Appendix A VT-1598 Schedule of Study Procedures and 
Evaluations) and as detailed in Section 7 Description of Clinical and Laboratory Evaluations,  
Study Procedures/Evaluations: listed below: 
• 
Review and record any concomitant medications and non-pharmacologic 
treatments/procedures since Day 1;  
• 
obtain blood samples for PK analysis at 24 h (±30 min), and 36 h (±30 min) post-dose; 

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• 
collect urine samples for PK analysis in the following intervals following study product 
administration on Day 1:  24-36, 36-48 hours post-dose;    
• 
obtain resting vital signs (heart rate, blood pressure, oral temperature and respiration rate, 
taken after being at rest for at least 5 minutes) at 24 h (±30 min), post-dose.  If abnormal, 
these measurements may be repeated once, within 15 minutes of the original assessment; 
• 
collect and record adverse events (AEs). 
 Day 3 – Inpatient CRU 
Subjects are inpatients in the CRU and will undergo procedures as indicated in the Schedule of 
Study Procedures and Evaluations (Appendix A VT-1598 Schedule of Study Procedures and 
Evaluations) and as detailed in Section 7 Description of Clinical and Laboratory Evaluations. 
Study Procedures/Evaluations: listed below: 
• 
Review and record any concomitant medications and non-pharmacologic 
treatments/procedures since Day 2; 
• 
obtain blood sample for PK analysis at 48 h (±30 min) and 60 h (± 30 min) post-dose;  
• 
collect urine sample for PK analysis in the following interval following study product 
administration on Day 1:  48-60 hours post-dose;    
• 
obtain resting vital signs (heart rate, blood pressure, oral temperature and respiration rate, 
taken after being at rest for at least 5 minutes) at 48 h (±30 min), post-dose.  If abnormal, 
these measurements may be repeated once, within 15 minutes of the original assessment; 
• 
collect and record adverse events (AEs).  
 Day 4 – Discharge from CRU 
Subjects are inpatients in the CRU and will undergo procedures as indicated in the Schedule of 
Study Procedures and Evaluations (Appendix A VT-1598 Schedule of Study Procedures and 
Evaluations) and as detailed in  Section 7 Description of Clinical and Laboratory Evaluations.  
Study Procedures/Evaluations: listed below, prior to discharge from CRU: 
• 
Review and record any concomitant medications and non-pharmacologic 
treatments/procedures since Day 3; 
• 
obtain blood sample for PK analysis at 72 h (±30 min) post-dose;  

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• 
collect urine sample for PK analysis in the following interval following study product 
administration on Day 1:  60-72 hours post-dose;  
• 
obtain blood samples for fasting (at least 8 hours and prior to 10 AM ) clinical chemistry, 
hematology, and coagulation tests;  
• 
obtain urine sample for urinalysis;  
• 
targeted physical examination (general appearance, heart, lungs, skin and abdomen) 
including resting vital signs (heart rate, blood pressure, oral temperature and respiration rate, 
taken at 72 hours (±30 min) post-dose and after being at rest for at least 5 minutes). If 
abnormal, these measurements may be repeated once, within 15 minutes of the original 
assessment; 
• 
12-lead ECGs obtained after at least 5 minutes in the supine position; taken at 72 hours (±30 
min) post-dose; triplicate readings, at least 1 minute apart within a 15-minute period; 
• 
collect and record adverse events (AEs); 
• 
review post-discharge instructions (including birth control methods, permitted/non-
permitted medications, non-medications, dietary and activity restrictions), and schedule 
follow-up visits; 
• 
discharge from CRU. 
 
Follow-up  
Subjects will return to the CRU within the window indicated for each follow-up timepoint and 
will undergo procedures as indicated in the Schedule of Study Procedures and Evaluations 
(Appendix A VT-1598 Schedule of Study Procedures and Evaluations) and as detailed in Section 
7 Description of Clinical and Laboratory Evaluations. Study Procedures/Evaluations: listed 
below: 
 
Day 7 ± 1   
• 
Review and record any concomitant medications and non-pharmacologic 
treatments/procedures since Day 4; 
• 
review any change in medical history since Day 4; 

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• 
obtain resting vital signs (heart rate, blood pressure, oral temperature and respiration rate, 
taken after being at rest for at least 5 minutes). If abnormal, these measurements may be 
repeated once, within 15 minutes of the original assessment; 
• 
obtain blood sample for PK analysis at 144 (±24) hours post-dose;  
• 
obtain blood samples for fasting (at least 8 hours) clinical chemistry, hematology, and 
coagulation tests;  
• 
obtain urine sample for urinalysis;  
• 
collect and record adverse events (AEs); 
• 
review post-discharge instructions (including birth control methods, permitted/non-
permitted medications, non-medications, dietary and activity restrictions); 
• 
subjects are released from the CRU after all assessments and procedures are completed and 
instructed to return for further follow-up evaluation on Day 14. 
6.4.2 
Day 14± 1   
• 
Review and record any concomitant medications and non-pharmacologic 
treatments/procedures since Day 7; 
• 
review any change in medical history since Day 7; 
• 
obtain resting vital signs (heart rate, blood pressure, oral temperature and respiration rate, 
taken after being at rest for at least 5 minutes). If abnormal, these measurements may be 
repeated once, within 15 minutes of the original assessment; 
• 
obtain blood sample for PK analysis at 312 (±24) hours post-dose;  
• 
obtain blood samples for fasting (at least 8 hours) clinical chemistry, hematology, and 
coagulation tests; 
• 
obtain urine sample for urinalysis;  
• 
collect and record adverse events (AEs); 

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• 
review post-discharge instructions (including birth control methods, permitted/non-
permitted medications, non-medications, dietary and activity restrictions); 
• 
subjects are released from the CRU after all assessments and procedures are completed and 
instructed to return for final study visit on Day 21. 
6.5 
Final Study Visit 
6.5.1 Day 21 ± 2  
• 
Review and record any concomitant medications and non-pharmacologic 
treatments/procedures since Day 14; 
• 
review any change in medical history since Day 14; 
• 
obtain 12-lead ECGs after at least 5 minutes in the supine position (triplicate readings, at 
least 1 minute apart within a 15-minute period) to assess heart rate, rhythm, and interval 
information such as RR, PR, QRS, QT, QTc and QTcF; 
• 
obtain blood sample for PK analysis at 480 (±48) hours post-dose; 
• 
obtain blood samples for fasting (at least 8 hours) clinical chemistry, hematology, 
coagulation and serum pregnancy test [if female of childbearing potential] tests;  
• 
obtain urine sample for urinalysis;  
• 
targeted physical examination (general appearance, heart, lungs, skin and abdomen) 
including resting vital signs (heart rate, blood pressure, oral temperature and respiration rate, 
taken after being at rest for at least 5 minutes).  If abnormal, these measurements may be 
repeated once, within 15 minutes of the original assessment; 
• 
collect and record adverse events (AEs); 
• 
review post-study period instructions (including use of contraceptives and instructions to 
report pregnancy, should it occur, up to 3 months following dose of study drug). 

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 Early Termination Visit  
The clinic will make every effort to perform all assessments outlined for the Final Study Visit 
(Day 21±2) if a subject is terminated prematurely from the study. All information collected will 
be documented in the study records including eCRF. 
 Unscheduled Study Visits  
Subjects will return to the CRU at the direction of the site investigator for follow-up and data 
from unscheduled visits or procedures (if any) will be captured in the EDC system. Safety 
assessments including the following onsite evaluations: AE, PE, and any other study procedures 
deemed necessary by the PI will be obtained. 
Subjects returning to the CRU for Unscheduled visit(s) may undergo procedures as indicated in 
the Schedule of Study Procedures and Evaluations (Appendix A VT-1598 Schedule of Study 
Procedures and Evaluations) and as detailed in Section 7 Description of Clinical and Laboratory 
Evaluations Study, Procedures/Evaluations: listed below: 
• 
Review and record any concomitant medications and non-pharmacologic 
treatments/procedures since last visit; 
• 
standard 12-lead ECG (recording in triplicates) to assess heart rate, rhythm, and interval 
information such as PR, QRS, QT, QTc and QTcF, obtained after at least 5 minutes in the 
supine position;  
• 
obtain blood samples for clinical chemistry, hematology, and coagulation tests; 
• 
obtain blood sample for PK analysis; 
• 
obtain urine sample for urinalysis.  
• 
targeted physical examination (general appearance, heart, lungs, skin and abdomen; 
additional evaluation will be targeted to the suspected organ system described in any AE.)    
including resting vital signs (heart rate, blood pressure, oral temperature and respiration rate, 
taken after being at rest for at least 5 minutes.  If abnormal, these measurements may be 
repeated once, within 15 minutes of the original assessment; 
• 
collect and record adverse events (AEs). 

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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 site 
principal investigator, or the site personnel.  As a result of deviations, corrective actions 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 principal investigator and personnel to use continuous vigilance 
to identify and report deviations within five working days of identification of the protocol 
deviation, or within five working days of the scheduled protocol-required activity.  All 
deviations must be promptly reported to DMID per the SDCC protocol deviation reporting 
procedures. 
All protocol deviations, as defined above, must be addressed in study subject data collection 
forms.  A completed copy of the DMID Protocol Deviation Form must be maintained in the 
Regulatory File, as well as in the subject's chart.  Protocol deviations must be sent to the local 
IRB per their guidelines.  The site principal investigator and personnel are responsible for 
knowing and adhering to their IRB requirements. 

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DESCRIPTION OF CLINICAL AND LABORATORY 
EVALUATIONS 
 
Clinical Evaluations 
 Safety Tests and Assessments 
Safety assessments will include attention to relevant changes in the following parameters, which 
are identified as occurring after the start of study product, regardless of whether the change is in 
an examination finding, test result, or symptom(s) reported by a subject, and regardless of 
presumed relationship to VT-1598.  
Height, Weight, BMI 
Height and/or body weight will be collected at times specified in the Schedule of Assessments 
and Procedures Appendix A VT-1598 Schedule of Study Procedures and Evaluations. BMI is 
calculated from height at Screening and weight at time of assessment. 
Vital Signs 
Vital signs (resting) to include body temperature, heart rate (pulse), breathing rate, and blood 
pressure will be obtained at times specified in the Schedule of Assessments and Procedures 
Appendix A VT-1598 Schedule of Study Procedures and Evaluations. Vital signs should be 
taken after at least 5 minutes at rest. If abnormal, these measurements may be repeated once, 
within 15 minutes of the original assessment. 
The pre-dose Day 1 vital signs measurements should be taken any time within 60 minutes prior 
to dosing (within 30 minutes prior to the start of the pre-dose meal for the fed cohort). Day 1 
post-dose vital signs measurements should be taken within ± 10 minutes of the nominal 
timepoint. All other vital signs measurements during the inpatient stay should be taken within ± 
30 minutes of the nominal time point. For outpatient visits, vital signs measurements should be 
taken within the visit window. 
 
Physical Exam 
A complete physical examination will include review of resting vital signs (taken after being at 
rest for at least 5 minutes); general appearance; head, eyes, ears, nose, and throat; neck; chest and 
lungs; cardiovascular system, abdomen, musculoskeletal system, lymph nodes, extremities/skin, 
and neurological system will be performed at Screening.   
A targeted physical examination (general appearance, heart, lungs, skin and abdomen) will 
include review of the resting vital signs which will be taken at 72 hours (±30 min) post-dose and 

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after being at rest for at least 5 minutes.  Additional evaluation will be targeted to the suspected 
organ system described in any AE. Targeted physical examinations will be performed at times 
specified in the Schedule Assessments and Procedures  Appendix A VT-1598 Schedule of Study 
Procedures and Evaluations . 
Electrocardiograms 
Standard 12-lead ECGs to assess heart rate, rhythm, and interval information such as PR, QRS, 
QT, and QTc will be obtained at times specified in the Schedule of Assessments and Procedures 
Appendix A VT-1598 Schedule of Study Procedures and Evaluations. The QT interval will be 
corrected using the Fridericia formula (QTcF).  
Electrocardiograms should be taken after at least 5 minutes in the supine position. The pre-dose 
Day 1 ECGs should be taken within 60 minutes prior to dosing (within 60 minutes prior to 
dosing for the fed cohort); the post-dose ECG on Day 1 should be taken at 4 hours post-dose ( ± 
30 minutes).  The Day 4 ECG should be taken at 72 hours (± 30 minutes) post-dose.  For the Day 
21 outpatient visit, the ECG should be taken within the visit window. 
Subjects will be placed in a supine position for at least 5 minutes prior to recording an ECG. 
Triplicate 12- lead ECG readings will be collected at scheduled times as shown in Appendix A 
VT-1598 Schedule of Study Procedures and Evaluations . The screening ECG will be used by 
the PI to determine subject’s eligibility for enrollment. The Day 1 pre-dose ECG will be 
reviewed to determine if subjects are safe and appropriate to dose and will be used to determine 
baseline for waveform and QTc. 
All ECGs will be reviewed by the PI or designee. ECGs with the following readings will be 
considered acceptable for study and will not be considered abnormal for study purposes unless 
the PI or physician designee believes they represent a new medical condition when compared to 
baseline ECGs. In such cases an AE will be documented, and the subject will be followed for 
safety evaluations as appropriate. The following pre-existing conditions identified at enrollment 
will not be considered adverse events and will be documented on the Medical History eCRF: 
• 
Sinus bradycardia; 
• 
Sinus arrhythmia. 
Subjects without a history of prolonged QTc and an abnormal baseline QTcF interval (not 
meeting exclusion criteria) should undergo repeat ECG assessment within screening period prior 
to randomization to confirm prolongation. If the repeat ECG QTcF is within normal limits the 
subject may be considered for enrollment 

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The Sponsor may review all or individual screening or Day 1 ECGs or may delegate to PI 
determine if meets intention of entry criteria goal of enrolling healthy normal study subjects. 
The mean of triplicate QTcF measurements post-dose will be used to assess QTcF prolongation 
(including assessment of halting rules described in Section 8.6), and will be compared to the 
mean of the baseline measurements to calculate change from baseline. 
In the event of a prolongation of QTc post dosing, the site will start telemetry monitoring of the 
subject and capture triplicate 12 lead ECG (3 tracings within a 5-minute period) every 30 
minutes (±10 minutes) until the average for the triplicates has returned within 60ms of the 
baseline value at which time telemetry maybe discontinued. Persistent (1 hour or more) elevation 
in QTcF (>500ms) should prompt immediate consideration of transfer to appropriate emergency 
department for further evaluation, monitoring, and/or treatment. 
In the event of a change in ECG wave forms consistent with a change in cardiac function or 
conduction when compared to baseline tracings, or in the event of a subject with possible cardiac 
related symptoms, repeat ECG should be obtained every 30 minutes (±10 minutes) until wave 
form change reverts to baseline appearance, or symptoms resolve, or are determined not to be 
cardiac in origin. Subjects with cardiac related symptoms associated with ECG changes will be 
transferred to appropriate emergency department for further evaluation and treatment. 
 
Assessment of Concomitant Medications/Treatments other than Study Product 
Prohibited Medications/Non-Medications 
Subjects are required to abide by the following rules regarding intake of medications and other 
substances before and during the study: 
• 
Refrain from the use of all prescription medications (with the exception of hormonal 
contraceptives), including any type of prescription antibiotic drug (topical or systemic) for 
at least 14 days prior to administration of the dose of study product on Day 1 until after the 
final study visit to the CRU; 
• 
refrain from the use of all non-prescription medications, vitamins, or dietary supplements, 
within 7 days prior to administration of the dose of study product on Day 1 until after the 
visit to the CRU on Day 14; 
• 
herbal supplements must be discontinued 7 days prior to the dose of study product on Day 1 
until after the visit to the CRU on Day 14; 

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• 
the consumption of beverages and foods containing alcohol is prohibited for 72 hours prior 
to Day -1 until after the visit to the CRU on Day 14. A urine alcohol test will be performed 
at Screening and upon admission to the CRU; 
• 
the consumption of beverages and foods containing caffeine is prohibited for 24 hours prior 
to Day -1 until discharge from the CRU on Day 4; 
• 
consumption of grapefruit, grapefruit juice, or juices containing grapefruit, or Seville 
oranges is prohibited within 7 days prior to the dose of study product until after the visit to 
the CRU on Day 14; 
• 
the use of tobacco product, including smoking and the use of snuff and chewing tobacco, 
and other nicotine or nicotine-containing products, is not permitted by a subject within 90 
days of Screening for the study or while a subject is enrolled in the study. A urine test for 
cotinine will be performed at Screening and upon admission to the CRU; 
• 
the use of illegal drugs is not permitted while a subject is enrolled in this study. A urine drug 
test, including amphetamines, barbiturates, cocaine, opiates, phencyclidine, cannabinoids 
and benzodiazepines, will be performed at Screening and upon admission to the CRU. 
If a subject is unable to comply with the restrictions described above, the subject’s continued 
participation in the study will be re-evaluated by the Investigator, in consultation with the 
Medical Monitor. 
Permitted Medications/Non-Medications 
Medications to treat any AEs the subject experiences during the study are permitted at the 
Investigator’s discretion and/or in consultation with the Medical Monitor. Intermittent use of 
acetaminophen at doses of ≤ 2 g/day or ibuprofen ≤1200 mg/day is allowed throughout the study. 
Hormonal contraceptives are permitted throughout the study. 
Meals and Dietary Restrictions/Dosing Under Fasting Conditions 
Subjects will fast overnight for at least 8 hours prior to dosing on Day 1. Subjects will remain 
fasted until at minimum 4 hours after dosing, at which time lunch may be consumed. Other 
meals will be supplied at appropriate times thereafter while subjects are resident in the unit. 
Food Impact Evaluation Under Fed Conditions 
Subjects will fast overnight for at least 8 hours prior to the start of a high-fat, high-calorie meal 
which will be entirely consumed in less than 30 minutes. The dose of VT-1598 will be 
administered 30 minutes after the start of the meal (defined as the time when the first bite of the 

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meal is taken) with 8 ounces (240 mL) of water. The high-fat, high-calorie test meal will be 
comprised of a breakfast of approximately 900-1000 calories, with approximately 150 calories 
from protein, 250 calories from carbohydrates, and 500-600 calories from fat (an example of a 
high-fat, high-calorie breakfast is: 2 eggs fried in butter, 2 strips of bacon, 2 slices of toast with 
butter, 4 ounces of hash brown potatoes fried with butter and 8 ounces or 240 mL of whole 
milk). No other food will be ingested until after a minimum of 4 hours after dosing, at which 
time lunch may be consumed. Water can be allowed as desired except for one hour before and 
after drug administration. Other meals will be supplied at appropriate times thereafter while 
subjects are resident in the unit. 
Exercise 
Subjects will be prohibited from engaging in strenuous activity within 48 hours prior to dosing 
and should be discouraged from engaging in strenuous activity within 48 hours prior to returning 
to the CRU on Days 7, 14, and 21 Subjects will not engage in strenuous activity at any time 
during the confinement period. Walking at a normal pace will be permitted. 
 Assessment of Subject Compliance with Study Intervention/Investigational 
Product/Investigational Device  
Subjects will be directly observed at the time of dosing by a member of the clinical research 
team who is licensed to administer the study product. Study personnel will examine the oral 
cavity of each subject following each dose to assure that all study product was swallowed. 
Administration will be documented and entered into the eCRF. 
 
Laboratory Evaluations 
 Clinical Laboratory Evaluations 
All laboratory assessments will be done by the clinical site’s certified laboratory. Laboratory 
toxicity grading will be determined by use of the FDA Guidance for Industry: Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical 
Trials September 2007 and the Division of Microbiology and Infectious Diseases (DMID) Adult 
Toxicity Table November 2007, as modified for this study and appropriate for the administration 
of VT-1598 (Appendix B VT-1598 Toxicity Grading Criteria for Normal Human Subjects). 
At Screening and at baseline, laboratory test values that fall outside the reference range on the 
laboratory reports and deemed not clinically significant by the Investigator may be repeated at 
the discretion of the Investigator (to assess for transitional conditions). A laboratory value that is 
Grade 1 (with the exception of ALT, AST, Total bilirubin, hemoglobin or serum creatinine) will 
be allowed if not considered to be clinically significant by the investigator 

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If a single repeat Screening evaluation or baseline is within the reference range, the subject may 
be further considered for study eligibility Note: Hematuria during active menses causing 
urinalysis results outside the reference range will not be considered clinically significant (not an 
AE). Post-dose serum cortisol levels Grade 2 or greater must be repeated and if confirmed, then 
an ACTH stimulation test should be performed. 
*See Appendix B VT-1598 Toxicity Grading Criteria for Normal Human Subjects. 
Pregnancy Testing 
All women of childbearing potential must undergo serum pregnancy testing at Screening and 
Baseline to assess protocol eligibility. Serum pregnancy tests will be performed thereafter as 
specified in the Schedule of Assessments and Procedures. Appendix A VT-1598 Schedule of 
Study Procedures and Evaluations 
Female subjects reporting as post-menopausal must undergo testing for serum FSH levels to 
assess childbearing potential at Screening. 
Immunology 
All subjects must undergo testing for the detection of antibodies to HIV-1 and HIV-2, HBsAg, 
and antibodies to HCV at Screening to assess protocol eligibility. 
Clinical Chemistry Panel 
All subjects must undergo clinical chemistry testing (albumin, glucose, blood urea nitrogen or 
urea, potassium, calcium, sodium, chloride, total protein, creatinine, triglycerides, total 
cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, total carbon 
dioxide, creatine phosphokinase, phosphorus, magnesium, gamma-glutamyl transferase (GGT), 
alkaline phosphatase, AST, ALT, total bilirubin, direct bilirubin and serum cortisol) at Screening 
and Baseline to assess protocol eligibility. Clinical chemistry tests will be performed thereafter 
as specified in the Appendix A Schedule of Assessments and Procedures. Subjects must fast a 
minimum of 8 hours before blood collection for a clinical chemistry panel. Serum cortisol levels 
must be drawn prior to 10 a.m. 
Hematology and Coagulation 
All subjects must undergo hematology (red blood cell count, total and differential white blood 
cell counts, hemoglobin, hematocrit, and platelet count) and coagulation (activated partial 
thromboplastin time, prothrombin time, and international normalized ratio) testing at Screening 
and Baseline to assess protocol eligibility. Hematology and coagulation tests will be performed 
thereafter as specified in the Appendix A Schedule of Assessments and Procedures.    

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Urinalysis 
All subjects must undergo urinalysis testing (leukocyte esterase, blood, pH, and specific gravity 
[microscopic tests to be completed if dipstick urinalysis is abnormal]) at Screening and Baseline 
to assess protocol eligibility. Urinalysis testing will be performed thereafter as specified in the 
Appendix A Schedule of Assessments and Procedures. 
 Research Assays  
Plasma and urine samples will be analyzed to determine concentrations of VT-1598 and VT-
11134 using validated liquid chromatography/tandem mass spectrometry methods by the 
bioanalytical contractor, ICON BAL.  
Analytical Sample Collection and Handling 
Blood samples for the determination of VT-1598 and VT-11134 plasma concentrations will be 
collected as shown in Table 2:  
Table 2: Blood PK Sampling Timepoints 
Blood Sampling Timepoints for VT-1598 and VT-11134 Pharmacokinetic Analyses 
Day 1 (pre-dose) 
Cohorts 1-5 (fasting):  Taken within 60 minutes prior to dosing 
Cohort 6 (fed):  Taken within 30 minutes prior to start of pre-dose 
meal. 
Day 1 (hours post 
dose*) 
0.5  
1 
1.5 
2 
3 
4 
6 
8  
10 
12 
14 
Day 2 (hours post 
dose**) 
24 
36 
 
Day 3 (hours post 
dose**) 
48 
60 
 
Day 4 (hours post 
dose**) 
72 
 
Day 7 (hours post 
dose)*** 
144 
 
Day 14 (hours post 
dose)*** 
312 
 
Day 21 (hours post 
dose)*** 
480 
 
*The 0.5-hour post dose blood sample should be taken within ± 5 minutes of the nominal 
timepoint.  The remaining post dose blood samples on Day 1 should be taken within ± 10 
minutes of the nominal time points.  

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**The post dose blood samples during the inpatient stay should be taken within ± 30 minutes of 
the nominal time point on Days 2, 3 and 4. 
***For outpatient visits, blood samples should be taken within the visit window. 
The exact dates and times of blood collection must be recorded in the eCRF and source 
documents. The blood samples will be obtained via direct venipuncture or via indwelling 
intravenous catheter using saline flushes to maintain catheter patency. Specific details for blood 
sample collection, process blood to plasma, and sample handling are included in the MOP for 
this study. 
Urine samples for the determination of VT-1598 and VT-11134 amounts will be collected in the 
intervals shown in Table 3: 
Table 3: Urine PK Sampling Timepoints 
Urine Sampling Timepoints for VT-1598 and VT-11134 Pharmacokinetic Analyses 
Day 1 (pre-dose) 
Collected from -6 hours until 0 hours pre-dose (For fasted 
cohorts) 
Day 1 (hours post dose) 
0-6 
>6-12 
>12-24 
Day 2 (hours post dose) 
24-36 
36-48 
 
Day 3 (hours post dose) 
48-60 
60-72 
 
The exact dates, start and stop time for each intervals and volumes of urine collection must be 
recorded in the eCRF and source documents.  For each interval, volume will be measured, and an 
aliquot will be retained and analyzed for the determination of VT-1598 urine concentrations. 
Specific details for urine specimen collection and handling are included in the MOP for this 
study. 
Laboratory Specimen Preparation, Handling, and Storage 
Detailed instructions for plasma and urine specimen preparation, handling and storage are 
outlined in the MOP for this study. 
Total Blood Volume Drawn   
The total volume of blood that will be drawn from each subject is described in Table 4. 
Table 4: Total Volume of Blood Drawn From Each Subject 
Type 
Laboratory Test 
Sample Volume 
(mL) 
Number of 
Samples 
Total Volume 
(mL) 

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Safety: 
Clinical chemistry 
3.5 
7 
24.5 
Cortisol 
3.5 
7 
24.5 
Hematology 
2 
7 
14 
Coagulation 
2.7 
7 
18.9 
Serology 
4 
1 
4 
future assays[a] 
6 
1 
6 
Pharmacokinetic: 
3 
20 
60 
When using an indwelling catheter 1.0 mL of blood will be removed prior to sample collection 
Total 
24.7 
50 
151.9 
[a] EDTA Blood sample will be collected 6 hours post-dose; plasma will be processed and stored 
to allow for the option to test for additional parameters. See Section 9.3 Consent for Future Use 
and Storage of Specimens.  
 
Laboratory Specimen Shipping 
All PK and future use specimens will be shipped to the Fisher Biorepository for storage and/or 
transfer to the ICON BAL.  Detailed instructions for shipping plasma and urine samples are 
outlined in the MOP for this study.   

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ASSESSMENT OF SAFETY 
 
Assessing and Recording Safety Parameters 
Safety will be assessed by collection of AEs, physical examinations, clinical laboratory results, 
vital signs, and ECG from time of dosing until final visit. 
 Adverse Events (AEs) 
ICH E6 defines an AE as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product regardless of its causal relationship to the study 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product. The occurrence of an AE may come to the attention of study personnel 
during study visits and interviews of a study recipient presenting for medical care, or upon 
review by a study monitor. 
All adverse events should be captured on the appropriate eCRF. Information to be collected 
includes event description, date of onset, clinician’s assessment of severity, relationship to study 
product (assessed only by those with the training and authority to make a diagnosis and listed on 
the Form FDA 1572 as an investigator) date of resolution/stabilization of the event, outcome and 
severity. All AEs occurring while in study must be documented appropriately regardless of 
relationship. All AEs will be followed to resolution/stabilization. 
Any medical or laboratory condition that is present at the time that the subject is screened up 
through ingestion of the dose should be considered as baseline/pre-existing condition and not 
reported as an AE. However, if it deteriorates at any time during the study after ingestion of the 
dose, it should be recorded as an AE. 
Adverse Events Grading 
AEs will be assessed by a licensed study physician listed on the Form FDA 1572 as the site 
principal investigator or appropriate sub-investigator using a protocol-defined grading system. 
For events not included in the protocol-defined grading system (Section 8 Assessment of 
Safety/Appendix B VT-1598 Toxicity Grading Criteria for Normal Human Subjects), the 
following guidelines will be used to quantify severity:  
• 
• Mild (Grade 1): Events require minimal or no treatment and do not interfere with the 
subject’s daily activities;  

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• 
• Moderate (Grade 2): Events result in a low level of inconvenience or concern with 
therapeutic measures. Moderate events may cause some interference with functioning and 
daily activities and use of over the counter medication;  
• 
• Severe (Grade 3): Events interrupt the subject’s usual daily activities and may require 
systemic drug therapy or other treatment. Severe events are usually incapacitating. 
Relationship to Study Products: The assessment of the relationship of an AE to the 
administration of study product is made only by those with the training and authority to make a 
diagnosis and listed on the Form FDA 1572 as an investigator based on all available information 
at the time of the completion of the eCRF.  Whether the AE is related or not, is not a factor in 
determining what is or is not reported in this trial.  If there is any doubt as to whether a clinical 
observation is an AE, the event should be reported.   
In a clinical trial, the study product must always be suspect.  To help assess, the following 
guidelines are used. 
• 
Related – There is a reasonable possibility that the study product caused the adverse event. 
Reasonable possibility means that there is evidence to suggest a causal relationship between 
the study product and the adverse event; 
• 
Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event. 
 Serious Adverse Events (SAEs) 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or sponsor, it results in any of the following outcomes:  
• 
Death; 
• 
a life-threatening adverse event1; 
• 
inpatient hospitalization or prolongation of existing hospitalization; 
• 
a persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions, or;  
• 
a congenital anomaly/birth defect;   
• 
important medical events that may not result in death, be life-threatening, or require 
hospitalizations may be considered serious when, based upon appropriate medical judgment 
they may jeopardize the patient or subject and may require medical or surgical intervention to 

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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. 
1 Life-threatening adverse event. An adverse event is considered “life-threatening” if, in the view 
of either the site principal investigator or sponsor, its occurrence places the patient or subject at 
immediate risk of death.  It does not include an adverse event, 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 (if not related 
to study drug); 
• 
recorded on the appropriate SAE data collection form and eCRF; 
• 
followed through resolution; 
• 
reviewed and evaluated by an Independent Safety Monitor (ISM) (as deemed necessary), the 
SMC (periodic review unless related), DMID, and the IRB; 
SAEs will be followed until resolution even if this extends beyond the study-reporting period.  
Resolution of an AE/SAE is defined as the return to pretreatment status or stabilization of the 
condition with the expectation that it will remain chronic.  
 
Specification of Safety Parameters 
 Dose Escalation Criteria 
The initial cohort of 8 subjects will be administered 40 mg of VT-1598 (6 subjects) or placebo (2 
subjects) as a single oral dose. Two sentinel subjects will be included in Cohorts 1-5 as described 
in Section 4.2 Acquisition/Distribution. 
Dose escalation to each successive cohort of subjects will occur if none of the predefined dose 
escalation halting criteria are met (for all subjects through Day 7). Emmes will provide 
notification to the PI upon analysis of data for the cohort (for all subjects through Day 7) for 
halting criteria as described in Section 3 Study Design, Objectives and Endpoints or Outcome 
Measures, Dose Escalation. If any of the criteria for dose escalation are met, or, at the discretion 
of the PI or DMID Medical Monitor, the study enrollment and dosing will be stopped until the 

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SMC reviews the data and provides its recommendations. There will be a scheduled SMC data 
review meeting prior to start of Cohort 5.  
The nominal dose- escalation scheme will be 40, 80, 160, 320 and 640 mg) or matching placebo 
administered in a fasting state. The effect of a high-fat, high-calorie meal on the PK of VT-1598 
is planned in an additional cohort that will be dosed at 160 mg.  The fed cohort will be dosed at 
160 mg, after the 320 mg fasted cohort has been dosed. This provides additional safety data to 
cover the possibility that the bioavailability of VT-1598 is increased in the presence of food 
under the fed state. The highest proposed dose in this study is 640 mg, which is 53% of the body 
surface area equivalent of the NOAEL in the most sensitive species.   
 Reporting Serious Adverse Events 
Any AE that meets a protocol-defined serious criterion must be submitted immediately (within 
24 hours of site awareness) on an SAE form to the DMID Pharmacovigilance Group, at the 
following address:  
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS) 
6500 Rock Spring Dr. 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 form, select SAE data fields must also be entered into Advantage EDC. 
Please see the protocol-specific MOP for details regarding this procedure.  
Other supporting documentation of the event may be requested by the DMID Pharmacovigilance 
Group and should be provided as soon as possible.  
The site will send a copy of the SAE report(s) to the ISM (as deemed necessary) when they are 
provided to the DMID Pharmacovigilance Group.  The DMID Medical Monitor and DMID 
Clinical Project Manager will be notified of the SAE by the DMID Pharmacovigilance Group.  
The DMID Medical Monitor 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 principal investigator or appropriate sub-
investigator becomes aware of an SAE that is suspected to be related to study product, the site 

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principal investigator or appropriate sub-investigator will report the event to the DMID 
Pharmacovigilance Group.  
 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 adverse reaction that is both serious and unexpected.  DMID 
will report an adverse event as a suspected adverse reaction only if there is evidence to suggest a 
causal relationship between the drug and the adverse event.  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 principal investigator’s IND(s) and NQP 1598, Ltd. 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 adverse reaction 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 request. 
All serious events designated as “not related” to study product(s), will be reported to the FDA at 
least annually in a summary format. 
 Reporting of Pregnancy 
A Notification of Pregnancy form will be completed for any female study subject or for any 
female partner of a male study subject who becomes pregnant following their exposure to study 
product (Day 1) through 3 months after the dose of study product. The site will discuss 
pregnancy reporting with subjects at the Final Study visit with instructions and provide contact 
information in case pregnancy occurs.  The pregnant subject will be followed by monthly 
telephone calls until 2 months after the birth of the baby or until the end of the pregnancy (in 
case pregnancy is terminated) at which time the Pregnancy Outcome form will be completed. 
Infants born to these study subjects will also be monitored for SAEs for up to 2 months after 
birth (information regarding SAEs will be captured on the Pregnancy Outcome form and the 
SAE form). If an SAE occurs during the pregnancy, the SAE will be reported on the appropriate 
SAE form and provided to DMID pharmacovigilance. Pregnancy Outcome forms will be used to 
collect, but not be limited to, data on the following information, should it be identified during the 
monthly telephone calls, at the end of the pregnancy, or at the follow-up telephone call at 2 
months after birth of the baby: 

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1. 
Prior maternal history including congenital abnormalities or pregnancy 
complications; 
2. 
estimated date of conception; 
3. 
estimated and actual date of delivery or pregnancy termination; 
4. 
mode of delivery; 
5. 
maternal complications; 
6. 
neonatal complications (i.e. lethal or nonlethal congenital abnormality). 
 
Type and Duration of Follow-up of Subjects after Adverse Events 
All AEs will be followed until resolution even if this extends beyond the study-reporting period.  
Resolution of an AE/SAE is defined as the return to pretreatment status or stabilization of the 
condition with the expectation that it will remain chronic.  
 
Procedures to be Followed in the Event of Abnormal Laboratory Test 
Values or Abnormal Clinical Findings 
Abnormal laboratory values, performed as part of hematology, chemistry panel, or urinalysis but 
not listed in Appendix B, VT-1598 Toxicity Grading Criteria for Normal Human Subjects,  will 
be evaluated by the study clinicians, recorded in the source document and, if clinically 
significant, considered AEs and graded according to the criteria details described in Section 8.1 
Assessing and Recording Safety Parameters.  
The site principal investigator or appropriate sub-investigator is responsible for recording all AE 
and SAEs that are observed or reported during this study, regardless of the relationship to study 
product.  AE and SAEs or abnormal clinical findings will be collected, assessed, documented, 
reported, and followed appropriately. 
 
Halting Rules 
 Study Halting Criteria 
If any of the criterion below are met, the study will be suspended (enrollment and dosing), and 
the SMC ad hoc meeting will convene:  
• 
Any SAE, regardless of the relationship to the study drug, throughout duration of study, 
unless confirmed to be of reasonable alternative etiology. 

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• 
5 or more subjects in study (cumulative among all cohorts) experience a same grade 2 (or 
higher) related AE (laboratory or systemic) which is coded in the same high-level group 
term (HLGT) per MedDRA coding, throughout duration of study. 
 Dose Escalation Halting Criteria 
Sentinel Subject Halting Rules  
If any of the criterion below are met, the cohort will be suspended (enrollment and dosing), and 
the SMC ad hoc meeting will convene:  
• 
Any SAE (regardless of the relationship to the study drug) through Day 3 of the study; 
• 
any Grade 2 (or higher) adverse event (laboratory or systemic) if not resolved within 1 day, 
through Day 3 of the study. 
Cohort Dose Escalation Halting Rules  
If any of the criterion below are met, the escalation to the next cohort will be suspended 
(enrollment and dosing), and the SMC ad hoc meeting will convene.  
• 
2 or more subjects in a cohort experience the same grade 2 (or higher) related AE 
(laboratory or systemic) which is coded in the same HLGT per MedDRA coding, through 
Day 7 of the study; 
• 
2 or more subjects within a cohort with post-dose QTcF > 500 ms or change from baseline 
>60 ms through Day 7 of the study. 
 
Safety Oversight 
 Independent Safety Monitor (ISM) 
An ISM is a physician with relevant expertise whose primary responsibility is to provide to 
DMID an independent safety assessment in a timely fashion. This ISM is identified by the 
investigator site and approved by DMID. Participation is for the duration of the DMID study and 
is a voluntary position that does not receive payment. The ISM must meet the requirements of 
the NIAID conflict of interest policy.   
The ISM: 
• 
Is in close proximity to the study site and has the authority and ability to readily access 
study participant records in real time; 

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• 
may be a member of the participating institution’s staff but preferably be from a different 
organizational group within the institution; 
• 
should not be in a direct supervisory relationship with the investigator; 
• 
should have no direct involvement in the conduct of the study. 
The ISM will: 
• 
Sign a Conflict of Interest (COI) certification at the time they are asked to participate and 
provide updates to this information as needed; 
• 
receive reports of Serious Adverse Events (SAEs) from the site investigator;  
• 
evaluate the SAE and report their clinical assessment to DMID, through DMID-CROMS 
SOCS in a timely manner using the AE form and email the report to DMID-CROMS SOCS;  
• 
communicate with the investigator at the participating site as needed; 
• 
review additional safety related events at the request of DMID; 
• 
provide additional information to DMID and/or the DSMB by teleconference as requested. 
 Safety Monitoring Committee (SMC) 
The SMC is an independent group of experts (at least 3 members) that monitors subject safety 
and advises DMID. SMC members will be separate and independent of study personnel 
participating in this study and should not have scientific, financial, or other conflicts of interest 
related to the study. The SMC will consist of members with appropriate expertise to contribute to 
the interpretation of the data from this trial. A quorum will consist of a simple majority.  
The SMC will review the safety data at the following timepoints: 
• 
Organizational meeting (prior to start of the study); 
• 
data review meeting; 
• 
between Cohorts 4 and 5;  
• 
scheduled meeting upon completion of dosing and final visit for all cohorts; 
• 
ad hoc meeting(s)  

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o When a halting criterion is met for sentinels, dose escalation or the overall study;  
o at the request of DMID to review a potential safety concern identified by the 
either the PI, DMID medical monitor, participating investigator, or the ISM. 
Procedures for SMC reviews/meetings will be defined in the SMC charter. The SMC will review 
applicable data to include, but not limited to, enrollment, demographic, dosing, laboratory, and 
safety data at scheduled time points during the study as defined in the charter. The SMC will 
receive data in aggregate. The SMC may request to receive data by study product vs placebo in a 
closed session. The SMC may also request that the blind be broken for individual subjects, as 
needed, to assess safety issues. As an outcome of each review/meeting, the SMC will make a 
recommendation in writing to continue, modify, or terminate the study. 
 

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HUMAN SUBJECTS PROTECTION 
 
Institutional Review Board/Independent Ethics Committee 
The site principal investigator will obtain IRB approval for this protocol to be conducted at his 
research site and send supporting documentation to the DMID before initiating recruitment of 
subjects.  The investigator will submit applicable information to the IRB on which it relies for 
the review, to conduct the review in accordance with 45 CFR 46, ICH E6 GCP, and as 
applicable, 21 CFR 56 (Institutional Review Boards) and 21 CFR 50 (Protection of Human 
Subjects), other federal, state, and local regulations. DMID must receive the documentation that 
verifies IRB-approval for this protocol, associated informed consent documents, and upon 
request any recruitment material and handouts or surveys intended for the subjects, prior to the 
recruitment and enrollment of subjects.     
Any amendments to the protocol or consent materials will be approved by the IRB before they 
are implemented.  IRB review and approval will occur at least annually throughout the 
enrollment and follow-up of subjects and may cease if annual review is no longer required by 
applicable regulations.  The investigator will notify the IRB of deviations from the protocol and 
reportable SAEs, as applicable to the IRB policy. 
 
Informed Consent Process 
Informed consent is a process that is initiated prior to an individual agreeing to participate in a 
trial and continuing throughout the individual’s trial participation.  Before any study procedures 
are performed, informed consent will be obtained and documented.  Subjects will receive a 
concise and focused presentation of key information about the clinical trial, verbally and with a 
written consent form. The explanation will be organized and presented in lay terminology and 
language that facilitates understanding why one might or might not want to participate. 
The site principal investigator or designee will describe the protocol to potential subjects face-to-
face. The key information about the purpose of the study, risks and discomforts, and any 
potential benefits to society will be presented first to the subject.   
Subjects will also receive an explanation that the trial involves research, and a detailed summary 
of the proposed study procedures and study interventions/products.  This will include the 
probability for random assignment to treatment groups, 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), and the 
expected duration of the subject’s participation in the trial. 

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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. Subjects 
will receive an explanation as to whether any compensation and any medical treatments are 
available if injury occurs, and, if so, what they consist of, or where further information may be 
obtained. Subjects will be informed of the anticipated financial expenses, if any, to the subject 
for participating in the trial, as well as any anticipated prorated payments, if any, to the subject 
for participating in the trial. They will be informed of whom to contact (e.g., the investigator) for 
answers to any questions relating to the research project.  
Information will also include the foreseeable circumstances and/or reasons under which the 
subject’s participation in the trial may be terminated. The subjects will be informed that 
participation is voluntary and that they are free to withdraw from the study for any reason at any 
time without penalty or loss of benefits to which the subject is otherwise entitled.   
The extent of the confidentiality of the subjects’ records will be defined, and subjects will be 
informed that applicable data protection legislation will be followed. Subjects will be informed 
that the monitor(s), auditors(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 informed consent form, the subject is 
authorizing such access.  
Subjects will be informed that records identifying the subject will be kept confidential, and, to 
the extent permitted by the applicable laws and/or regulations, will not be made publicly 
available and, if the results of the trial are published, the subject’s identity will remain 
confidential. Subjects will be informed whether private information collected from this research 
and/or specimens may be used for additional research, even if identifiers are removed.   
Subjects will be allowed sufficient time to consider participation in this research trial and have 
the opportunity to discuss this trial with their family, friends or legally authorized representative, 
or think about it prior to agreeing to participate. 
Informed consent forms will be IRB approved and subjects will be asked to read and review the 
consent form. Subjects must sign the informed consent form prior to starting any study 
procedures being done specifically for this trial. 
Once signed, a copy of the informed consent form will be given to the subject(s) for their 
records.  The subject(s) may withdraw consent at any time throughout the course of the trial.  
The rights and welfare of the subject(s) will be protected by emphasizing to them that the quality 
of their medical care will not be adversely affected if they decline to participate in this study. 

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New information will be communicated by the site principal investigator to subjects who consent 
to participate in this trial in accordance with IRB requirements.  The informed consent document 
will be updated, and subjects will be re-consented per IRB requirements, if necessary.  Subjects 
will be given a copy of all informed consent forms that they sign. 
 
Consent for Future Use of Stored Specimens and Data 
At enrollment, subjects will be asked for consent to collect a venous blood sample (6 mL) for 
plasma at the presumed Cmax (6 hours post dose) in addition to PK blood samples to be retained 
for possible use in future research studies.  Permission to collect and store these samples will be 
completely voluntary; subjects who are otherwise eligible to participate in the study but do not 
consent to collection of future use specimens will not be excluded from the study. These clinical 
samples will be shipped to and stored up to two (2) years from the end of the study at the Fisher 
Biorepository (DMID CMS) and may be shared with investigators at the participating site and 
with other investigators at other institutions.  
Residual clinical samples with consent for future use will be available upon the completion of 
the study; however, future use clinical samples may be requested from DMID and shipped from 
the DMID CMS at any time. Residual clinical samples without consent for future use should be 
destroyed upon the completion of the study. 
The samples will not be sold or used directly for production of any commercial product.  No 
human genetic tests will be performed on the samples.  Each sample will be encoded (labeled) 
only with a barcode and a unique tracking number to protect subject confidentiality. The 
recipients of specimens will be informed that these specimens have a NIH certificate of 
confidentiality. 
There are no benefits to subjects in the collection, storage and subsequent use of their specimens 
for future research.  Reports about future research done with subjects’ samples will NOT be kept 
in their health records. 
Subjects may be given the option to decide if they want their samples to be used for future 
research or have their samples destroyed at the end of this trial.  The subject’s decision can be 
changed at any time by notifying the study doctors or nurses in writing.  However, if the subject 
originally consents to future use and subsequently changes his/her decision, any data from a 
previously collected sample may still be used for this research. 
Subjects may be given the option to decide if they want their residual specimens to be used for 
future research or have these specimens destroyed at the end of this trial. The subject’s decision 
can be changed at any time by notifying the study doctors or nurses in writing. However, if the 

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subject originally consents to the future use of residual specimens and subsequently changes 
his/her decision, any data from a previously collected specimen may still be used for future 
research. 
 
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 1 trial in healthy individuals, 
there is no known benefit. For these same reasons, this trial will not include other special classes 
of subjects, such as fetuses, neonates, prisoners, institutionalized individuals, or others who may 
be considered vulnerable populations. 
Neither women nor minorities will be excluded from participation in this study. Women of child 
bearing potential may be included as per the inclusion criteria (Section 5.1). Subjects will be 
recruited without regard to gender or race. It is expected that race will reflect that within the 
community.  
 
Subject Confidentiality 
Subject confidentiality is strictly held in trust by the participating investigators, their staff, and 
the Sponsor and their agents. This confidentiality includes documentation, investigation data, 
subject’s clinical information, and all other information generated during participation in the 
study. No information concerning the study, or the data generated from the study will be released 
to any unauthorized third party without prior written approval of the DMID and the subject. 
Subject confidentiality will be maintained when study results are published or discussed in 
conferences.  The study monitors or other authorized representatives of the sponsor or 
governmental regulatory agencies 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 this study. The clinical study site will permit 
access to such records. 
All records will be kept locked and all computer entry and networking programs will be carried 
out with coded numbers only and with password protected systems. All non-clinical specimens, 
evaluation forms, reports, and other records that leave the site will be identified only by a coded 
number. 
To protect privacy, we have received a Certificate of Confidentiality.  With this Certificate, the 
researchers cannot be forced to release information that may identify the research subject, even 
by a court subpoena, in any federal, state, or local civil, criminal, administrative, legislative, or 

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other proceedings.  The researchers will use the Certificate to resist any demands for information 
that would identify the subject, except as explained below. 
 
Certificate of Confidentiality 
To protect privacy, we have received a Certificate of Confidentiality.  With this Certificate, the 
researchers cannot be forced to release information that may identify the research subject, even 
by a court subpoena, in any federal, state, or local civil, criminal, administrative, legislative, or 
other proceedings.  The researchers will use the Certificate to resist any demands for information 
that would identify the subject, except as explained below. 
The Certificate cannot be used to resist a demand for information from personnel of the United 
States Government that is used for auditing or evaluation of federally funded projects, like this 
study, or for information that must be released in order to meet the requirements of the FDA). 
A Certificate of Confidentiality does not prevent the subject from voluntarily releasing 
information about themselves or their involvement in this research.  If any person or agency 
obtains a written consent to receive research information, then the researchers may not use the 
Certificate to withhold that information.   
The Certificate of Confidentiality does not prevent the researchers from reporting without the 
subject’s consent, information that would identify the subject as a participant in the research 
project regarding matters that must be legally reported including: child and elder abuse, sexual 
abuse, or wanting to harm themselves or others.   
The release of individual private information or specimens for other research will only occur if 
consent was obtained from the individual to whom the information, document, or biospecimen 
pertains, or for the purposes of other research that is in compliance with applicable Federal 
regulations governing the protection of human subjects in research.  
 
Costs, Subject Compensation, and Research Related Injuries 
There is no cost to subjects for the research tests, procedures, and study product while taking part 
in this trial.  Procedures and treatment for clinical care may be billed to the subject, subject’s 
insurance or third party.   
Subjects are compensated for their participation in this trial.  Compensation will be in 
accordance with the local IRB’s policies and procedures, and subject to IRB approval. 
If it is determined by the site principal investigator that an injury occurred to a subject as a direct 
result of the tests or treatments that are done for this trial, then referrals to appropriate health care 

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facilities will be provided to the subject.  Study personnel will try to reduce, control, and treat 
any complications from this trial.  Immediate medical treatment may be provided by the 
participating site.  No financial compensation will be provided to the subject by the NIAID, NIH 
or by the participating site to the subject for any injury suffered due to participation in this trial. 
 

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STATISTICAL CONSIDERATIONS 
A formal Statistical Analysis Plan (SAP) will be created prior to final data lock. This document 
will provide a more technical and detailed description of the proposed data analysis methods and 
procedures. Any deviation from the analyses outlined in the protocol will be described in the SAP. 
For continuous variables, data will be summarized using descriptive statistics (such as sample 
size, mean, median, standard deviation, minimum, and maximum). For discrete variables, data 
will be summarized using frequencies and percentages.  
 Study Hypotheses 
The objectives of the study are to obtain safety and pharmacokinetic data for VT-1598. There are 
no formal hypotheses being tested in this Phase 1 trial study. 
 Sample Size Considerations 
As this study is the first assessment of VT-1598 in humans and is primarily aimed at safety and 
PK evaluation, power calculations have not been performed. The sample size of 8 subjects (6 
subjects receiving VT-1598 and 2 subjects receiving placebo) per cohort is based on clinical 
experience and judgment and should provide adequate clinical information to meet the objectives 
of the study.  The comparisons of fed to fasted PK are exploratory rather than formal analyses of 
fed bioequivalence and fed and fasted profiles from 6 subjects are sufficient for the intended 
purpose. 
 Treatment Assignment Procedures 
 Randomization Procedures 
Each subject who completes the study Screening assessments, meets all eligibility criteria, and is 
accepted for the study will be assigned a unique sequential identification number and, with the 
exception of replacement subjects, will receive the corresponding treatment according to the 
randomization schedule. Replacement subjects will receive the same treatment assignment as the 
subject being replaced. Subjects who are not randomized within 28 days of their Screening visit 
will be considered out-of-window and not eligible for randomization. These subjects will be 
eligible to re-screen provided they previously met all other eligibility criteria. 
The randomization schedule will be generated centrally through the AdvantageEDCSM 
(Electronic Data Capture System, Emmes) by the unblinded study biostatistician, and a list will 

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be transferred to the unblinded study pharmacist prior to start of the study for the purpose of an 
emergency back-up. For Cohort 1 through Cohort 5, within each cohort 8 subjects will be 
randomized in a 3:1 ratio to active treatment and placebo.  Cohort 6 will not use randomization. 
For Cohort 1 through Cohort 5, the first two subjects will be randomized in a 1:1 fashion to 
active drug and placebo to ensure that one of the first two subjects receives active treatment and 
the other receives placebo for sentinel dosing placebo.  The product assignment of the remaining 
six subjects in each cohort will be randomly assigned 5:1 active drug to placebo to ensure the 3:1 
ratio for the entire dosing cohort.  Enrollment will occur at one site. An appropriate amount of 
back-up subjects will be brought in per cohort in the event of subject withdrawal prior to dosing. 
After completing the final study visit (Day 21) and at least 60 days after dosing, Cohort 3 
subjects will have enrollment “rollover” to Cohort 6.  Cohort 3 subjects continuing as Cohort 6 
subjects will not be randomized but will receive placebo if he or she received placebo as part of 
Cohort 3 and will otherwise receive drug.  Cohort 3 subjects that do not continue to Cohort 6 will 
be replaced, and the replacement subjects will receive the same type of treatment (placebo vs. 
drug) that the subject being replaced received as part of Cohort 3. Cohort 3 subjects that are no 
longer eligible for the trial after the washout period will not be continued to Cohort 6 but will be 
replaced.  Cohort 6 “rollover” or replacement enrollment may occur before or after planned SMC 
meeting to be held once Cohort 4 has completed follow-up. 
Following review of all eligibility criteria, subjects will be registered and randomized using 
AdvantageEDCSM.  Randomization will occur following admittance to the unit and confirmation 
of eligibility is confirmed.  
Per ICH guideline E6: Good Clinical Practice (GCP), screening records will be kept at the 
participating site to document the reason why an individual was screened, but failed trial entry 
criteria.  The reasons why individuals failed screening will be recorded in the SDCC 
AdvantageEDCSM. 
Enrollment of subjects will be done online using the enrollment module of AdvantageEDCSM.  
The randomization code will be prepared by statisticians at the SDCC and included in the 
enrollment module for this trial.  AdvantageEDCSM will assign each subject to a treatment arm 
after the demographic and eligibility data have been entered into the system.  A designated 
individual at the participating site will be provided with a code list for emergency unblinding 
purposes by the unblinded study biostatistician, which will be kept in a secure place. 
Instructions for use of the enrollment module are included in the AdvantageEDCSM User’s 
Guide.  Manual back-up procedures and instructions are provided for use in the event that a 
participating site temporarily loses access to the Internet or the online enrollment system is 
unavailable. 

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 Masking Procedures 
Blinding 
The Study Pharmacist at the site will be unblinded as to treatment assignment. Study subjects, 
the PI and study site personnel other than the Study Pharmacist and verifier, the bioanalytical 
laboratory staff, and Fisher repository personnel will remain blinded to all randomization 
assignments throughout the study. The DMID medical monitor and NIAID personnel, NQP 1598 
Ltd., and ICON GPHS (CRO) personnel will remain blinded to all subject randomization 
assignments. 
All laboratory personnel performing experimental assays as part of this study will be masked to 
treatment group, subject ID, and study visit for all study specimens. The SDCC will generate 
sample picklists for each laboratory to determine which specimens will be tested. At the 
discretion of DMID, unmasking of laboratories may occur after all data have been locked, 
analyzed and interpreted and the final CSR has been completed.  
The randomization schedule will be provided to the unblinded study personnel (the Study 
Pharmacist and a verifier) at the site. The Pharmacist will perform dose preparation; the 
unblinded verifier is a member of the pharmacy team who will not participate in dose 
preparation. Unblinded personnel at the site will not be involved in study-related assessments or 
have subject contact for data collection following study drug administration. 
Selected individuals not involved in the conduct of the study, including members of the SMC, 
may have access to unblinded data as needed for safety review or other data review. The site 
pharmacist will remain unblinded during the course of the study. 
Emergency Unblinding 
Emergency unblinding of treatment assignment for a subject may be necessary due to a medical 
emergency, or any other significant medical event, should knowledge of the subject’s treatment 
assignment impact the subject’s care. Should an SAE or other circumstance require the blind to 
be broken to ensure a subject’s safety, the PI should immediately notify the DMID Medical 
Monitor if possible (within 24 hours) to discuss the case and reason for unblinding (a written 
narrative must follow within 48 hours of the event). 
Procedures for emergency unblinding are detailed in the MOP for this study.   

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 Planned Interim Analyses 
Safety data will be reviewed by the SMC by treatment received in a closed session in the planned 
safety data review meeting between Cohort 4 and Cohort 5 and may also be reviewed by SMC in 
the closed session of ad hoc meetings.   
There will be an interim analysis of PK data after completion of Cohort 3 which will be made 
available to all investigators, SDCC staff, NQP 1598 Ltd., and DMID staff involved in the study.  
The interim PK report will show PK data in aggregate only and will not include any information 
that could be potentially unblinding.  Enrollment will not stop for the PK interim analysis.  If PK 
is substantially different than expected, the protocol may be amended to change the timing of PK 
samples. 
 Final Analysis Plan 
The safety analysis population will include all subjects that received any amount of study 
product and will be analyzed by treatment received.  Placebo subjects may be pooled across 
multiple cohorts for analysis. The PK analysis population will include all subjects with at least 
one measurable PK concentration. 
    Adverse and Serious Adverse Events 
AEs will be coded with MedDRA (Version 22.1 or later) and summarized descriptively for each 
regimen by system organ class, HLGT, and preferred term. The AE profile will be characterized 
by severity and relationship to the study drug. SAEs will be identified.  
    Clinical Safety Labs, Vital Signs, and Electrocardiograms 
Baseline for clinical safety labs, vital signs, and ECGs will be defined as the last result obtained 
before the dose of study product.  Clinical safety labs, vital signs, and ECGs results and changes 
from baseline will be summarized by treatment arm and visit.  Clinical safety labs and vital signs 
will be graded (Appendix B) and summarized by severity, treatment arm, and visit. If triplicate 
ECG measurements were performed at the same visit, then baseline is the mean value of the 
measurements for the visit closest to, but before, administration of study drug. Similarly, for 
analyses of change from baseline, mean values will be used in the case of replicate 
measurements at a single visit post-baseline. 
Treatment-emergent abnormal laboratory test results will be identified. Treatment-emergent 
abnormal laboratory tests are tests for which the result was not graded as mild or worse at 
baseline but graded as mild or worse after dosing.  Laboratory tests graded as mild at baseline, 

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but moderate or worse any time after dosing will also be regarded as treatment-emergent 
abnormal laboratory test results. 
ECG measurements will include heart rate, RR interval, QT interval, QTcF interval, PR interval, 
and QRS duration. Baseline for ECG measurements is defined per protocol as the value pre-
dosing on Day 1. Change from baseline will be summarized descriptively by regimen at each 
scheduled evaluation. QTc results will be summarized categorically according to the ICH 
Guideline E14 “Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic 
Potential for Non-Antiarrhythmic Drugs” (October 2005). 
• 
QTcF >450 ms; 
• 
QTcF >450 ms, males only; 
• 
QTcF >470 ms, females only; 
• 
QTcF >480 ms;  
• 
QTcF >500 ms; 
• 
QTcF increases from baseline by at least 30 ms but less than 60 ms; 
• 
QTcF increases from baseline by at least 60 ms. 
 Pharmacokinetic Analysis Plan 
Plasma and urine samples from all subjects who received at least one dose of VT-1598 will be 
analyzed for the concentration of VT-1598 and VT-11134 by validated LC-MS/MS methods. 
Plasma concentration-time profiles and plots of amount excreted (Ae(t1-t2)) per urine collection 
period will be constructed for each subject and each dosing cohort.  
The following PK parameters will be estimated, by noncompartmental analysis methods using 
version 7.0 or higher of Phoenix WinNonlin®, for VT-1598 and VT-11134 plasma and urine 
concentration, as appropriate. 
Cmax 
maximum measured plasma concentration 
Tmax 
time to reach maximum measured plasma concentration 
AUClast 
area under the plasma concentration versus time curve from time 0 to 
the time of the last quantifiable concentration 

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AUCinf 
area under the plasma concentration versus time curve from time 0 and 
extrapolated to infinity 
%AUCex 
percentage of AUCinf obtained by extrapolation 
t1/2 
terminal phase half-life 
λz 
apparent first-order terminal elimination rate constant 
Vd/F 
apparent volume of distribution 
CL/F 
apparent oral clearance 
Aelast 
cumulative amount excreted into the urine from time 0 to the time of the 
last quantifiable concentration 
Ae%Dose 
cumulative amount excreted into the urine 
CLR 
renal clearance of drug 
Additional PK parameters may be estimated as appropriate. Dose proportionality for each PK 
exposure parameter (Cmax, AUClast, AUCinf) will be assessed statistically and graphically.  
The more detailed PK analysis will be available in the SAP for this study.   

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SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
The participating site will maintain appropriate medical and research records in compliance with 
ICH E6, Section 4.9 and regulatory and institutional requirements for the protection of 
confidentiality of subjects. The site will permit authorized representatives of the DMID, its 
designees, and appropriate regulatory agencies to examine (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. These representatives will be permitted access to all source data 
and source documents, which include, but are not limited to, hospital records, clinical and office 
charts, laboratory notes, memoranda, subjects’ memory aid or evaluation checklists, 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, and subject files and records kept at the pharmacy, at the laboratories, 
and medico-technical departments involved in the clinical trial.  
 Compliance with Standards of Medical Research/ Deviations 
This protocol will be conducted in accordance with the applicable ICH guidelines and GCP. Any 
instance of noncompliance with the protocol will result in a documented deviation. If a change is 
deemed necessary in order to protect the safety, rights or welfare of a subject, the Sponsor and 
IRB should be notified as soon as possible and preferably prior to introducing the deviation.  
 
 

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QUALITY CONTROL AND QUALITY ASSURANCE 
Following a written DMID-accepted Program Quality Management Plan (cQMP), the 
participating site and its subcontractors are responsible for conducting routine quality assurance 
(QA) and quality control (QC) activities to internally monitor study progress and protocol 
compliance.  The site principal investigator will provide direct access to all study-related sites, 
source data/data collection forms, and reports for the purpose of monitoring and auditing by the 
sponsor, and inspection by local and regulatory authorities.  The site principal investigator will 
ensure all study personnel are appropriately trained and applicable documentations are 
maintained on site. 
The SDCC 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 participating site(s) for clarification and resolution. 
DMID-designated clinical monitors will verify that the clinical trial is conducted, and data are 
generated, documented (recorded), and reported in compliance with the protocol, ICH/GCP 
guidelines, and the applicable regulatory requirements. Clinical monitoring reports will be 
submitted to DMID. 
To ensure compliance with GCP and all applicable regulatory requirements, the Sponsor may 
conduct a quality assurance assessment and/or audit of the site records, and the regulatory agencies 
may conduct a regulatory inspection at any time during or after the completion of the study. In 
the event of an assessment, audit or inspection, the Investigator (and institution) must agree to 
grant the advisor(s), auditor(s), and inspector(s) direct access to all relevant documents and to 
allocate their time and the time of their staff to discuss the conduct of the study, any 
findings/relevant issues, and to implement any corrective and/or preventative actions to address 
any findings/issues identified. 
 

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DATA HANDLING AND RECORD KEEPING 
 Data Management Responsibilities 
The investigator is responsible to ensure the accuracy, completeness, legibility, and timeliness of 
the data reported.  All source documents should be completed in a neat, legible manner to ensure 
accurate interpretation of data.  Black or blue permanent 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 reported in the eCRF derived from source data collection forms should be consistent or the 
discrepancies should be explained. 
The sponsor and/or its designee will provide guidance to the site principal investigators and other 
study personnel on making corrections to the data collection forms and eCRF. 
Training will be provided for the Electronic Data Capture (EDC) system. All personnel using the 
EDC system must have the appropriate education, training, and experience, or any combination 
thereof. The Investigator will be provided with standard operating procedures (SOPs) (contained 
in the MOP or a vendor-specific SOP) on the use of the EDC system. Documentation for employee 
education, training, and previous experience that pertains to the EDC system must be present in 
the Investigator files. 
If electronic data systems other than those provided and maintained by the Sponsor are used for 
documentation and data capture, the Investigator must ensure that the systems are validated and 
ensure regular data back-up. 
The eCRF will be signed by the Investigator or a Sub-Investigator listed on the FDA 1572 form. 
It is the responsibility of the Investigator to ensure the eCRFs are completed and submitted to the 
Sponsor (or designee) in an accurate and timely manner. The processing of eCRFs will include an 
audit trail (to include changes made, reason for change, date of change, and person making 
change). At the completion of the study, the Sponsor will be provided with a final copy of each 
eCRF. 
Management of clinical data will be performed in accordance with applicable Sponsor standards 
and data cleaning procedures to ensure the integrity of the data (e.g., removing errors and 
inconsistencies in the data). Adverse events and concomitant medications will be coded using the 
MedDRA® and World Health Organization Drug Dictionaries (WHO DD) respectively.  Medical 
eCRFs will be retained by the Sponsor and copies will be sent to the Investigator to maintain as 
the Investigator copy. 

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 Data Coordinating Center/Biostatistician Responsibilities 
Any source documents and laboratory reports must be reviewed by the clinical team and data 
management staff, who will ensure their accuracy and completeness. AEs must be recorded on 
the appropriate data collection form, assessed for severity and relationship, and reviewed by the 
site principal investigator or appropriate sub-investigator.  AEs must be graded based on the 
FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials September 2007, as modified for this 
study and as appropriate for the administration of VT-1598 Appendix B VT-1598 Toxicity 
Grading Criteria for Normal Human Subjects. 
Electronic data capture is the responsibility of the clinical trial staff at the site under the 
supervision of the site PI. During the study, the PI must maintain complete and accurate 
documentation for the study. 
Data collection is the responsibility of the study personnel at the participating clinical study site 
under the supervision of the site principal investigator.  During the study, the site principal 
investigator must maintain complete and accurate documentation for the study. 
The data coordinating center for this study, Emmes, will be responsible for data management, 
quality review, analysis, and reporting of the study data. 
 Data Capture Methods 
Clinical data (including but not limited to AEs, physical assessments, clinical laboratory values 
and concomitant medications) will be entered into Advantage EDCSM, a 21 CFR Part 11-
compliant electronic data capture (EDC) system managed by Emmes. The EDC system access is 
password protected. Access is granted to specific individuals based on the roles identified for the 
study. The clinical study site enters the data into EDC from the data collection forms completed 
by the study personnel. Data are validated through a query resolution process, comprising both 
automated and manual queries. 
AE/SAEs, concomitant medications, medical history, physical assessments, and clinical 
laboratory values) and reactogenicity will be collected on data collection forms by study 
personnel then entered into eCRFs via a 21 CFR Part 11-compliant internet data entry system 
provided by the study data coordinating center.    

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 Types of Data 
Data for this study will include all data for safety and PK deemed necessary for the analysis per 
the protocol, demographic data, clinical laboratory values, concomitant medication, AE and 
medical history. 
Externally collected data are received and processed to present a complete dataset reconciled 
with data collected in the EDC. 
 
Study Records Retention 
Study documents will be retained for a minimum of 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 investigational product. These documents will be retained for a 
longer period, however, if required by local regulations. No records will be destroyed without the 
written consent of the sponsor. It is the responsibility of the sponsor to inform the investigator 
when these documents no longer need to be retained. 

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CLINICAL MONITORING 
 Site Monitoring Plan 
Site monitoring is conducted to ensure that the human subjects’ protections, study and laboratory 
procedures, study intervention administration, and data collection processes are of high quality 
and meet sponsor, ICH/GCP guidelines and applicable regulations, and that this trial is 
conducted in accordance with the protocol, protocol-specific MOP and applicable sponsor 
standard operating procedures.  DMID, the sponsoring agency, or its designee will conduct site-
monitoring visits as detailed in the clinical monitoring plan. 
Site visits will be made at standard intervals as defined by DMID and may be made more 
frequently as directed by DMID.  Monitoring visits will include, but are not limited to, review of 
regulatory files, accountability records, eCRFs, informed consent forms, medical 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 site principal investigators to discuss any 
problems and actions to be taken and will document site visit findings and discussions. 

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

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LITERATURE REFERENCES 
1. Yoshida Y. Cytochrome P450 of fungi: primary target for azole antifungal agents. Curr 
Top Med Mycol. 1988; 2: 388-418. 
2. Hitchcock CA. Cytochrome P-450-dependent 14 α-sterol demethylase of Candida 
albicans and its interaction with azole antifungals. Biochem Soc Trans. 1991; 19: 782- 
787. 
3. Bates DW and Yu DT. Clinical impact of drug-drug interactions with systemic azole 
antifungals. Drugs Today. 2003; 39: 801-813. 
4. Zarn JA, Bruschweiler BJ, Schlatter JR. Azole fungicides affect mammalian 
steroidogenesis by inhibiting sterol 14α-demethylase and aromatase. Env Health Pers. 
2003; 111: 255-261. 
5. Mathisen G, Shelub A, Truong J, and Wigen C. Coccidioidal meningitis: clinical 
presentation and management in the fluconazole era. Medicine. 2010; 89: 251-284. 
6. Brown J, Benedict K, Park BJ, and Thompson GR. Coccidioidomycosis: epidemiology. 
Clin Epidemiol. 2013; 5: 185-197. 
7. Welsh O, Vera-Cabrera L, Rendon A, Gonzalez G, Bonifaz A. Coccidioidomycosis. 
Clinics in Dermatology. 2012; 30: 573-591. 
8. Galgiani JN, Ampel NM, Blair JE, Catanzaro A, Johnson RH, Stevens DA, and 
Williams PL. Coccidioidomycosis. Clin Infect Dis. 2005; 41: 1217-23. 
9. Huang JY, Bristow B, Shafir S, and Sorvillo F. Coccidioidomycosis-associated deaths, 
United States, 1990-2008. Emerg Infect Dis. 2012; 18: 1723-8. 
10. Tsang CA, Anderson SM, Imholte SB, et al. Enhanced surveillance of 
coccidioidomycosis, Arizona, USA, 2007-2008. Emerg Infect Dis. 2010; 16: 1738-44. 
11. Sondermeyer G, Lee L, Gilliss D, Tabnak F, and Vugia D. Coccidioidomycosis 
associated hospitalizations, California, USA, 2000-2011. Emerg Infect Dis. 2013; 19: 
1590-7. 
12. Khan M and Brady S. Hospitalizations associated with coccidioidal meningitis in 
Arizona, 2008-2014. ID Week 2016, abstract 1607, New Orleans, LA. 

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13. Galgiani JN, Ampel NM, Blair JE, et al. 2016 Infectious Diseases Society of America 
(IDSA) Clinical Practice Guideline for the Treatment of Coccidioidomycosis. Clin 
Infect Dis. 2016; 63(6): 112-46. 
14. Litvintseva AP, Marsden-Haug N, Hurst S, et al. Valley Fever: Finding new places for 
an old disease: Coccidioides immitis found in Washington state soil associated with 
recent human infection. Clinical Infectious Diseases: An Official Publication of the 
Infectious Diseases Society of America. 2015; 60(1): e1-e3. 
15. Centers for Disease Control and Prevention. Increase in Reported Coccidioidomycosis – 
US, 1998-2011. MMWR. 2013; 62: 217-21. 
16. Chang DC, Anderson S, Wannemuehler K, et al. Testing for coccidioidomycosis among 
patients with community-acquired pneumonia. Emerg Infect Dis. 2008; 14: 1053-9 
17. NIAID Emerging Infectious Diseases/Pathogens. National Institutes of Health, National 
Institute of Allergy & Infectious Diseases website. 
https://www.niaid.nih.gov/research/emerging-infectious-diseases-pathogens. Updated 
October 26, 2016. Accessed November 3, 2016. 
18. Zonios DI and Bennett JE. Update on azole antifungals. Semin Respir Crit Care Med 
2008; 29:198-210. 

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APPENDICES 
 
 
 
 
 
 
 
 
 
 
 
 

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  VT-1598 SCHEDULE OF STUDY PROCEDURES AND 
EVALUATIONS   
Schedule of Study Procedures and Evaluations – Cohort 1 through Cohort 6* 
(X) – As indicated/appropriate  
 
 
 
Activity/ 
Day 
Screening Baseline 
Inpatient (Treatment) 
Period 
Follow-up Period 
Unscheduled 
Visit 1 
Visit 2 
Visit 3 
Visit 4 Visit 5 
Visit 6 
Day -28 
to-2 
Day -1 
Day 1 
Days 2 
& 3 
Day 4 
Day 7 
(±1 day) 
Day 14 
(±1 day) 
Day 21/ 
End-of- 
Studys 
 (±2 days) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
 
 
 
Height, Weight, BMI 
X 
Xa 
 
 
 
 
 
 
 
Medical Historyb 
X 
X
c 
 
 
 
X
c 
X
c 
X
c 
 
Physical Examination 
Xd 
Xe 
Xe 
 
Xe 
 
 
Xe 
Xe 
Vital Signsf 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
ECGg 
Xg 
 
Xg 
 
Xg 
 
 
Xg 
Xg 
Clinical Laboratory 
Testsh 
X 
X 
 
 
X 
X 
X 
X 
X 

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Activity/ 
Day 
Screening Baseline 
Inpatient (Treatment) 
Period 
Follow-up Period 
Unscheduled 
Visit 1 
Visit 2 
Visit 3 
Visit 4 Visit 5 
Visit 6 
Day -28 
to-2 
Day -1 
Day 1 
Days 2 
& 3 
Day 4 
Day 7 
(±1 day) 
Day 14 
(±1 day) 
Day 21/ 
End-of- 
Studys 
 (±2 days) 
Pregnancy Testi 
X 
X 
 
 
 
 
 
X 
 
FSHj 
X 
 
 
 
 
 
 
 
 
Drug Screenk 
X 
X 
 
 
 
 
 
 
 
Immunology Screenl 
X 
 
 
 
 
 
 
 
 
PK Blood Samplesm 
 
 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
PK Urine Samplesn 
 
 
Xn 
Xn 
Xn 
 
 
 
 
Future Use Specimen 
Collection 
 
 
X 
 
 
 
 
 
 
Prior/Concomitant 
Medications/Treatments 
X 
X 
Xo 
X 
X 
X 
X 
X 
X 
Review/confirm 
adherence to dietary 
restrictions/birth control 
methodsp 
X 
X 
 
 
X 
X 
X 
X 
 
Admit to CRU 
 
X 
 
 
 
 
 
 
 
Discharge from CRU 
 
 
 
 
X 
 
 
 
 
Receive study productq,r 
 
 
X 
 
 
 
 
 
 
Collect and Record AEs 
 
 
X 
X 
X 
X 
X 
X 
X 
 

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* Cohort 6 may enroll prior to the SMC meeting or prior to the start of Cohort 5 (but no less than 60 days after 
completion of Cohort 3).  
Abbreviations: AE: adverse event; BMI: body mass index; CBC: complete blood count; CRU: clinical research unit; 
ECG: electrocardiogram; EW: early withdrawal; FSH: follicle-stimulating hormone; HIV-1: Human 
Immunodeficiency Virus-1; HIV-2: Human Immunodeficiency Virus-2; HBsAg: Hepatitis B surface antigen; Anti-
HCV: anti-Hepatitis C virus; IMP: investigational medicinal product; PK: pharmacokinetics. 
Footnotes to Schedule of Assessments and Procedures: 
a Weight and BMI only. 
b Including alcohol and tobacco use history. 
c Update medical history as appropriate from previous visit. 
d Complete physical examination (general appearance; head, eyes, ears, nose, and throat; neck; chest and lungs; 
cardiovascular system, abdomen, musculoskeletal system, lymph nodes, extremities/skin, and neurological system). 
e Targeted physical examination (general appearance, heart, lungs, skin and abdomen). On Day 4, targeted PE will 
be performed at 72 hours (±30 min).  
f Vital signs (heart rate, blood pressure, temperature, and respiratory rate) at Screening, Day -1, pre-dose on Day 1 
and approximately 1, 2, 4, 8, 24 (Day 2), 48 (Day 3), 72 (Day 4), 144 (Day 7 outpatient visit), 312 (Day 14 
outpatient visit) and 480 (Day 21 outpatient visit) hours after dosing. The pre-dose Day 1 vital signs measurements 
should be taken within 60 minutes of dosing.  Day 1 post-dose vital signs measurements should be taken ±10 
minutes of the nominal timepoint.  All other vital signs measurements during the inpatient stay should be taken 
within ± 30 minutes of the nominal time point. For outpatient visits, vital signs measurements should be taken 
within the visit window. All vital signs are taken after subject is at rest for at least 5 minutes. 
g ECGs will be performed at Screening; pre-dose taken within 60 minutes of dosing and post-dose, taken 4 hours) 
after dosing on Day 1;  at 72 hour (± 30 minutes) prior to discharge from the CRU on Day 4 (±15 min), and on Day 
21. All ECG readings are triplicate recordings, at least 1 minute apart within a 15-minute period and are taken after 
at least 5 minutes in the supine position. For the Day 21 outpatient visit, the ECG should be taken within the visit 
window. 
h Clinical laboratory tests to include: clinical chemistry panel (albumin, glucose, blood urea nitrogen or urea, 
potassium, calcium, sodium, chloride, total protein, creatinine, triglycerides, total cholesterol, low-density 
lipoprotein cholesterol, high-density lipoprotein cholesterol, total carbon dioxide, creatine phosphokinase, 
phosphorus, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, total bilirubin, direct 
bilirubin, magnesium, gamma-glutamyl transferase (GGT) and serum cortisol), CBC (red blood cell count, total and 
differential white blood cell count, hemoglobin, hematocrit, and platelet count), coagulation parameters (activated 
partial thromboplastin time, prothrombin time, and international normalized ratio), and urinalysis (leukocyte 
esterase, blood, pH, and specific gravity [microscopic tests to be completed if dipstick urinalysis is abnormal]). 
Subjects must fast at least 8 hours before blood collection for the clinical chemistry panel.  Cortisol must be fasting 
and drawn before 10 a.m. 
i Serum pregnancy test for women of childbearing potential at Screening, Day -1 and Day 21 (Final Study Visit). 

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j Follicle-stimulating hormone on all post-menopausal women at Screening. 
k Urine drug test at Screening and on Day -1 to include cotinine, opiates, cocaine, cannabinoids, phencyclidine, 
benzodiazepines, barbiturates, amphetamines, and cotinine. Alcohol screen is performed by urine test. 
l Immunology screen to include tests for the detection of antibodies to HIV-1 and HIV-2, HBsAg, and antibodies to 
HCV. 
m PK blood samples will be collected on the following schedule following study product administration on Day 1: 
pre-dose, and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 24, 36, 48, 60, 72, 144 (Day 7 outpatient visit), 312 (Day 14 
outpatient visit) and 480 (Day 21 outpatient visit) hours post-dose. The pre-dose Day 1 PK blood sample should be 
taken within 60 minutes of before dosing for the fasted cohorts and within 30 minutes of the start of the pre-dose 
meal for the fed cohort; the Day 1 0.5-hour post dose blood sample should be taken within  ± 5 minutes of the 
nominal timepoint.  Remaining post-dose Day 1 PK blood samples should be taken within ± 10 minutes of the 
nominal time point. An additional 6 mL blood for future use is collected at 6 hours (±10 minutes) post dose. Day 2, 
3 and 4 PK blood samples should be taken within ± 30 minutes of the nominal time point.  For outpatient visits, PK 
blood samples should be taken within the visit window. PK blood samples take precedence; however, vital signs and 
ECGs should be completed before the blood draw, when possible. 
n PK urine samples will be collected in the following intervals following study product administration on Day 1: --
6to 0 hours before dose, and 0-6, 6-12, 12-24, 24-36, 36-48, 48-60, and 60-72 hours post-dose. 
.o A review for concomitant medication will be performed before and after dosing on Day 1. 
p Screening:  review birth control methods, permitted/non-permitted medications, non-medications, dietary and 
activity restrictions; Day -1: confirm that subject adhered to dietary restrictions (no food/beverages containing 
alcohol for previous 72 hours or caffeine for the previous 24 hours; no grapefruit, grapefruit juice, or juices 
containing grapefruit, or Seville oranges for previous 7 days); Days 7 and 14 - confirm that subject adhered to post-
discharge dietary restrictions (no consumption of grapefruit, or juices containing grapefruit or Seville oranges, no 
alcohol consumption) until after the visit to the CRU on Day 14;  Review post-discharge instructions (including 
birth control methods, permitted/non-permitted medications, non-medications, dietary and activity restrictions) 
qCohorts 1-5 will receive study product when fasted and subjects will remain fasted for at least 4 hours post-dose; 
Cohort 6 is administered study product following a high-fat, high-calorie meal, which is consumed within 30 
minutes and dosing is administered at 30 minutes after start of meal. 
r For the nominal dose escalations, the study product will be administered in a fasting state and the subjects will 
remain fasted for 4 hours post- dose.  Cohort 6 will be dosed with 160 mg of study product after ingestion of a high-
fat, high-calorie meal 
sFor unscheduled visits, Safety assessments including updated history and the following onsite evaluations: AE, PE, 
and any other study procedures deemed necessary by the PI will be obtained. Early termination assessments will be 
the same as the Day 21 procedures 
 
 

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VT-1598 TOXICITY GRADING CRITERIA FOR 
NORMAL HUMAN SUBJECTS 
Adverse Events* 
Mild 
Moderate    
(Grade 2) 
Severe 
(Grade 1) 
(Grade 3) 
Laboratory Adverse Events* (Blood, Serum or Plasma) 
Sodium (hyponatremia) – 
mEq/L 
131-132 
129-130 
<129 
Sodium (hypernatremia) – 
mEq/L 
144-145 
146-147 
>147 
Potassium (hyperkalemia) – 
mEq/L 
5.2 – 5.4 
5.5 – 5.6 
>5.6 
Potassium (hypokalemia) – 
mEq/L 
3.2-3.4 
3.0 – 3.1 
<3.0 
Phosphorus – mg/dL (Hypo) 
2.3 – 2.4 
2.1 – 2.2 
≤2.0 
Phosphorus – mg/dL (Hyper) 
N/A 
N/A 
N/A 
Magnesium – mg/dL   
1.3-1.5 
1.1-1.2 
<1.1 
Gamma- Glutamyl Transferase 
(GGT) – Male – U/L 
N/A 
N/A 
N/A 
Gamma- Glutamyl Transferase 
(GGT) – female – U/L 
N/A 
N/A 
N/A 
Glucose (hypoglycemia) – 
mg/dL 
65 – 69 
55 – 64 
<55 
Glucose (hyperglycemia) – 
mg/dL Fasting 
106 – 125 
126 – 200 
>200 
Blood Urea Nitrogen – mg/dL 
21-26 
27 – 31 
> 31 
Creatinine (Male) – mg/dL 
1.3 – 2.0 
2.1-2.3 
>2.3 
Creatinine (Female) – mg/dL 
1.0 – 1.7 
1.8 – 2.0 
>2.0 
Calcium (hypocalcemia) – 
mg/dL 
8.0 – <LLN 
7.5 – 7.9 
<7.5 

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Adverse Events* 
Mild 
Moderate    
(Grade 2) 
Severe 
(Grade 1) 
(Grade 3) 
Calcium (hypercalcemia) – 
mg/dL 
10.4-10.8 
10.9-11.4 
>11.4 
Chloride – mEq/L 
N/A 
N/A 
N/A 
CPKt-U/L (Male) 
1.1 - ≤ 1.5 x ULN 
>1.5 - ≤ 3.0 x ULN 
>3.0 ULN or higher 
CPKt – U/L(Female) 
1.1 - ≤ 1.5 x ULN 
>1.5 - ≤ 3.0 x ULN 
>3.0 ULN or higher 
A.M. Cortisol (serum, drawn 
prior to 10 a.m.) –  ug/dL 
1-10% below LLN 
10-25 % below LLN 
 >25% below LLN 
with or without 
symptoms 
Albumin (hypoalbuminemia) – 
g/dL 
2.8 – 3.4 
2.5 – 2.7 
< 2.5 
AST – U/L  
1.1 - ≤ 2.5 x ULN 
>2.5 - ≤ 5.0 x ULN 
>5.0 x ULN or higher 
ALT – U/L 
1.1 - ≤ 2.5 x ULN  
>2.5 - ≤ 5.0 x ULN 
>5.00 x ULN or higher 
Total Bilirubin (serum) – 
mg/dL 
  1.1 - ≤ 1.25 x ULN 
>1.25 - ≤ 1.50 x ULN 
>1.50 x ULN or higher 
Direct Bilirubin – mg/dL 
  1.1 - ≤ 1.25 x ULN 
>1.25 - ≤ 1.50 x ULN 
>1.50 x ULN or higher 
Indirect Bilirubin – mg/dL 
  1.1 - ≤ 1.25 x ULN 
>1.25 - ≤ 1.50 x ULN 
>1.50 x ULN or higher 
Amylase –  U/L 
1.1 - ≤ 1.5 x ULN 
>1.5 - ≤ 2.0 x ULN 
>2.0 x ULN or higher 
Lipase – U/L 
1.1 - ≤ 1.5 x ULN 
>1.5 - ≤ 2.0 x ULN 
>2.0 x ULN or higher 
Hemoglobin (Male) – g/dL 
11.2 - 12.2 
10.0 – 11.1 
<10.0 
Hemoglobin (Female) – g/dL 
9.8 - 10.8 
8.5 - 9.7 
<8.5 
WBC Increase – cell/mm3 
10,001– 15,000 
15,001 – 20,000 
> 20,000 
WBC Increase – cell/mm3 
(African America Males) 
9,001 – 14, 000 
14,001 – 19, 000 
>19,000 
WBC Increase – cell/mm3 
(African American Females) 
11,001 – 15,000 
15,001 – 20,000 
>20,000 

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Adverse Events* 
Mild 
Moderate    
(Grade 2) 
Severe 
(Grade 1) 
(Grade 3) 
WBC Decrease – cell/mm3 
2,500– 3,999 
1,500 – 2,499 
< 1,500 
WBC Decrease – cell/mm3 
(African American Males) 
2,200 – 2,499 
1,200 – 2,199 
<1,200 
WBC Decrease – cell/mm3 
(African American Females) 
2,200 – 2,499 
1,500 – 2,199 
<1,500 
Neutrophils Decrease –
cell/mm3 
1,300 – <1,699 
1,000 – 1,299 
< 1,000 
Neutrophils Decrease – 
cell/mm3 (African American 
Males) 
1,000 – 1,299 
800 - 999 
<800 
Neutrophils Decrease – 
cell/mm3 (African American 
Females) 
1,100 – 1,299 
1,000 – 1,099 
<1,000 
Platelets Decreased - cell/mm3 
120,000 – <150,000 
100,000 – 119,999 
<100,000 
PT (prothrombin time) – 
seconds 
 11.6 – 12.6  
 
12.7 – 13.7 
 >13.7 
PT INR (Prothrombin INR) 
1.2-1.4 
1.5-1.9 
2.0 or higher 
PTT (partial thromboplastin 
time) –seconds 
 30.1 – 36.8  
36.9 – 43.6  
>43.6 
Total Protein – g/dL 
5.5 - 5.9 
5.0 - 5.4 
<5.0 
Alkaline phosphatase – IU/L 
(Male) 
1.1 - ≤ 2.0 x ULN 
>2.0 - ≤ 3.0 x ULN 
>3.0 x ULN or higher 
Alkaline phosphatase – IU/L 
(Female) 
1.1 - ≤ 2.0 x ULN 
>2.0 - ≤ 3.0 x ULN 
>3.0 x ULN or higher 
Hematocrit (Male) - % 
33.0 -36.1 
29.8 - 32.9 
< 29.8 
Hematocrit (Female) - %  
29.5 - 32.6 
26.0 – 29.4 
< 26.0  
RBC (Male) – x 106/uL   
3.9 - 4.1 
3.4 - 3.8 
< 3.4 

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Adverse Events* 
Mild 
Moderate    
(Grade 2) 
Severe 
(Grade 1) 
(Grade 3) 
RBC (Female) – x 106/uL   
3.5 - 3.7 
3.0 - 3.4 
< 3.0 
Lymphocytes - cell/mm3 
decrease 
600- 799 
500 – 599 
< 500 
Monocytes – cell/mm3     
increase 
1001-2000 
2001-3000 
>3000 
Eosinophils - cell/mm3     
increase 
871 - 950 
951 - 1700 
>1700 
Basophils - cell/mm3       
increase 
101 - 300 
301 - 800 
> 800 
High Density Lipoproteins 
(HDL) Male – mg/dL 
N/A 
N/A 
N/A 
High Density Lipoproteins 
(HDL) Female – mg/dL 
N/A 
N/A 
N/A 
Total Carbon Dioxide – mEq/L 
N/A 
N/A 
N/A 
Total Cholesterol – mg/dL 
N/A 
N/A 
N/A 
Low Density Lipoprotein 
Cholesterol, Direct – mg/dL 
N/A 
N/A 
N/A 
Triglycerides – mg/dL 
N/A 
N/A 
N/A 
Laboratory Adverse Events* (Urine) 
Protein 
1+ 
2+ 
>2+ 
Glucose 
1+ 
2+ 
>2+ 
Blood (microscopic) - red 
blood cells per high power 
field (rbc/hpf)** 
3-10** 
11-50** 
>50 and/or gross 
blood** 
*Abnormal laboratory values, performed as part of hematology, chemistry panel, or urinalysis but not listed in 
Appendix B,  VT-1598 TOXICITY GRADING CRITERIA FOR NORMAL HUMAN SUBJECTS, will be 
evaluated by the study clinicians, recorded in the source document and, if clinically significant, considered AEs 
and graded according to the criterion described in Section 8.1. 

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Adverse Events* 
Mild 
Moderate    
(Grade 2) 
Severe 
(Grade 1) 
(Grade 3) 
** Hematuria during active menses is considered not clinically significant. 
 
Vital Sign Adverse Events 
Mild  
(Grade 1) 
Moderate 
 (Grade 2) 
Severe (Grade 3) 
Fever 
(°C) 
(°F) 
 
38.0 – 38.4 
100.4 – 101.1 
 
38.5 – 38.9 
101.2 – 102.0 
 
39.0 – 40 
102.1 – 104 
ECG – QTcF (ms) 
> 30 but ≤60 above 
baseline  
>60 above baseline to 
≤500  
>500  
Tachycardia – (beats per 
minute) 
101 – 115 
116 – 130 
>130 
Bradycardia – (beats per 
minute) 
50-54 if baseline >60 
45-49 if baseline >60 
<45 if baseline >60 
45-50 if baseline ≤ 60 
40-44 if baseline ≤ 60 
<40 if baseline ≤ 60 
Hypertension (systolic) – 
mmHg 
141 – 150 
151 – 155 
>155 
Hypertension (diastolic) 
– mmHg 
91 – 95 
96 – 100 
>100 
Hypotension (systolic)  
– mmHg 
85 – 89 
80 – 84 
<80 
Respiratory Rate – breaths 
per minute 
17-20 
21-25 
>25 
Nausea/vomiting 
No to mild interference 
with activity or 1 to 2 
episodes/24 hours 
Moderate interference 
with activity or >2 
episodes/24 hours 
Prevents daily activity, 
requires outpatient IV 
hydration 
Diarrhea 
2 - 4 loose stools or 
5-6 stools or 400 – 800 
7 or more watery stools or 
>800gms/24 hours or 

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Vital Sign Adverse Events 
Mild  
(Grade 1) 
Moderate 
 (Grade 2) 
Severe (Grade 3) 
< 400 gm/24 hours 
gm/24 hours 
requires outpatient IV 
hydration 
Headache 
No interference with 
activity 
Repeated use of non-
narcotic pain 
reliever > 24 hours or 
some interference with 
activity 
Significant; any use of 
narcotic pain reliever or 
prevents daily activity 
Fatigue 
No interference with 
activity 
Some interference with 
activity 
Significant; prevents daily 
activity 
Adverse Events – Other 
Illness or clinical AE (as 
defined according to 
applicable regulations 
No interference with 
activity 
Some interference with 
activity, not requiring 
medical intervention 
Prevents daily activity and 
requires medical 
intervention